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Sample records for cancer xenograft model

  1. Next-generation sequence analysis of cancer xenograft models.

    Directory of Open Access Journals (Sweden)

    Fernando J Rossello

    Full Text Available Next-generation sequencing (NGS studies in cancer are limited by the amount, quality and purity of tissue samples. In this situation, primary xenografts have proven useful preclinical models. However, the presence of mouse-derived stromal cells represents a technical challenge to their use in NGS studies. We examined this problem in an established primary xenograft model of small cell lung cancer (SCLC, a malignancy often diagnosed from small biopsy or needle aspirate samples. Using an in silico strategy that assign reads according to species-of-origin, we prospectively compared NGS data from primary xenograft models with matched cell lines and with published datasets. We show here that low-coverage whole-genome analysis demonstrated remarkable concordance between published genome data and internal controls, despite the presence of mouse genomic DNA. Exome capture sequencing revealed that this enrichment procedure was highly species-specific, with less than 4% of reads aligning to the mouse genome. Human-specific expression profiling with RNA-Seq replicated array-based gene expression experiments, whereas mouse-specific transcript profiles correlated with published datasets from human cancer stroma. We conclude that primary xenografts represent a useful platform for complex NGS analysis in cancer research for tumours with limited sample resources, or those with prominent stromal cell populations.

  2. Hypoxia and metastasis in an orthotopic cervix cancer xenograft model

    International Nuclear Information System (INIS)

    Background: Hypoxia can promote tumor metastasis by mechanisms that are believed to result from changes in gene expression. The current study examined the role of putative metastatic genes regulated by cyclic hypoxia in relation to metastasis formation in orthotopic models of cervix cancer. Methods: Orthotopic tumors derived from ME180 human cervix cancer cells or from early generation human cervix cancer xenografts were exposed to cyclic hypoxic conditions during growth in vivo and tumor growth and lymphnode metastases were monitored. Expression of the chemokine receptor CXCR4 and various genes in the Hedgehog (Hh) pathway were inhibited using genetic (inducible shRNA vs CXCR4) small molecule (AMD3100) or antibody (5E1) treatment (CXCR4 and Hh genes, respectively) during tumor growth. Results: As reported previously, exposure of tumor bearing mice to cyclic hypoxia caused a reduction of tumor growth but a large increase in metastasis. Inhibition of CXCR4 or Hh gene activity during tumor growth further reduced primary tumor size and reduced lymphatic metastasis to levels below those seen in control mice exposed to normoxic conditions. Conclusion: Blocking CXCR4 or Hh gene expression are potential therapeutic pathways for improving cervix cancer treatment

  3. Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model

    OpenAIRE

    Hung, Ming-Szu; Xu, Zhidong; Chen, Yu; Smith, Emmanuel; Mao, Jian-Hua; Hsieh, David; Lin, Yu-Ching; Yang, Cheng-Ta; Jablons, David M.; You, Liang

    2013-01-01

    Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer cell growth, Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway and increased apoptosis. In a murine xenograft model of lung cancer, hematein inhibited tumor growth without significant toxicity to the mice tested. Molecular docking showed t...

  4. The T61 human breast cancer xenograft: an experimental model of estrogen therapy of breast cancer

    DEFF Research Database (Denmark)

    Brunner, N; Spang-Thomsen, M; Cullen, K

    1996-01-01

    Endocrine therapy is one of the principal treatment modalities of breast cancer, both in an adjuvant setting and in advanced disease. The T61 breast cancer xenograft described here provides an experimental model of the effects of estrogen treatment at a molecular level. T61 is an estrogen receptor...... in the study of the molecular mechanism of estrogen therapy in breast cancer, and suggest that in this system, modulation of a specific growth factor (IGF-II) by endocrine therapy can have profound effects on tumor growth....... positive tumor which was originally derived from a T1N0M0 invasive ductal cancer and has been carried as a serially transplanted xenograft in nude mice. T61 is a hormone sensitive tumor whose growth is suppressed by both estrogen and tamoxifen, in contrast to other estrogen receptor positive tumors such as...

  5. Hematein, a casein kinase II inhibitor, inhibits lung cancer tumor growth in a murine xenograft model.

    Science.gov (United States)

    Hung, Ming-Szu; Xu, Zhidong; Chen, Yu; Smith, Emmanuel; Mao, Jian-Hua; Hsieh, David; Lin, Yu-Ching; Yang, Cheng-Ta; Jablons, David M; You, Liang

    2013-11-01

    Casein kinase II (CK2) inhibitors suppress cancer cell growth. In this study, we examined the inhibitory effects of a novel CK2 inhibitor, hematein, on tumor growth in a murine xenograft model. We found that in lung cancer cells, hematein inhibited cancer cell growth, Akt/PKB Ser129 phosphorylation, the Wnt/TCF pathway and increased apoptosis. In a murine xenograft model of lung cancer, hematein inhibited tumor growth without significant toxicity to the mice tested. Molecular docking showed that hematein binds to CK2α in durable binding sites. Collectively, our results suggest that hematein is an allosteric inhibitor of protein kinase CK2 and has antitumor activity to lung cancer. PMID:24008396

  6. Biodistribution of charged F(ab')2 photoimmunoconjugates in a xenograft model of ovarian cancer.

    OpenAIRE

    Duska, L. R.; Hamblin, M R; Bamberg, M. P.; Hasan, T.

    1997-01-01

    The effect of charge modification of photoimmunoconjugates (PICs) on their biodistribution in a xenograft model of ovarian cancer was investigated. Chlorin(e6)c(e6) was attached site specifically to the F(ab')2 fragment of the murine monoclonal antibody OC125, directed against human ovarian cancer cells, via poly-1-lysine linkers carrying cationic or anionic charges. Preservation of immunoreactivity was checked by enzyme-linked immunosorbent assay (ELISA). PICs were radiolabelled with 125I an...

  7. Strigolactone analogs act as new anti-cancer agents in inhibition of breast cancer in xenograft model.

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    Mayzlish-Gati, Einav; Laufer, Dana; Grivas, Christopher F; Shaknof, Julia; Sananes, Amiram; Bier, Ariel; Ben-Harosh, Shani; Belausov, Eduard; Johnson, Michael D; Artuso, Emma; Levi, Oshrat; Genin, Ola; Prandi, Cristina; Khalaila, Isam; Pines, Mark; Yarden, Ronit I; Kapulnik, Yoram; Koltai, Hinanit

    2015-01-01

    Strigolactones (SLs) are a novel class of plant hormones. Previously, we found that analogs of SLs induce growth arrest and apoptosis in breast cancer cell lines. These compounds also inhibited the growth of breast cancer stem cell enriched-mammospheres with increased potency. Furthermore, strigolactone analogs inhibited growth and survival of colon, lung, prostate, melanoma, osteosarcoma and leukemia cancer cell lines. To further examine the anti-cancer activity of SLs in vivo, we have examined their effects on growth and viability of MDA-MB-231 tumor xenografts model either alone or in combination with paclitaxel. We show that strigolactone act as new anti-cancer agents in inhibition of breast cancer in xenograft model. In addition we show that SLs affect the integrity of the microtubule network and therefore may inhibit the migratory phenotype of the highly invasive breast cancer cell lines that were examined. PMID:26192476

  8. Modeling of response to endocrine therapy in a panel of human luminal breast cancer xenografts.

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    Cottu, P; Marangoni, E; Assayag, F; de Cremoux, P; Vincent-Salomon, A; Guyader, Ch; de Plater, L; Elbaz, C; Karboul, N; Fontaine, J J; Chateau-Joubert, S; Boudou-Rouquette, P; Alran, S; Dangles-Marie, V; Gentien, D; Poupon, M-F; Decaudin, D

    2012-06-01

    Resistance to endocrine therapy is a major complication of luminal breast cancer and studies of the biological features of hormonal resistance are limited by the lack of adequate preclinical models. The aim of this study is to establish and characterize a panel of primary human luminal breast carcinoma xenografts, and to evaluate their response to endocrine therapies. Four hundred and twenty-three tumor fragments obtained directly from patients have been grafted in the interscapular fatpad of Swiss nude mice. After stable engraftment with estradiol supplementation, xenografted tumors have been validated by conventional pathology and immunohistochemistry examination, and additional molecular studies. In vivo tumor growth and response to different endocrine treatments were evaluated. We have engrafted 423 tumors including 314 ER+ tumors, and 8 new luminal breast cancer xenografts have been obtained (2.5%). Tumor take was much lower for luminal tumors than for non-luminal tumors (2.5 vs. 24.7%, P < 0.0001), and was associated with two independent criteria, i.e., ER status (P < 0.0001) and a high grade tumor (P = 0.05). Histological and immunohistochemical analyses performed on patient's tumors and xenografts showed striking similarities in the tumor morphology as well as in the expression level of ER, PR, and HER2. Response to hormone therapy, evaluated in 6 luminal models, showed different sensitivities, thus exhibiting heterogeneity similar to what is observed in the clinic. We have established a panel of primary human luminal breast cancer xenografts, recapitulating the biological and clinical behaviors of patient tumors, and therefore suitable for further preclinical experiments. PMID:22002565

  9. Hepatic vitamin A preloading reduces colorectal cancer metastatic multiplicity in a mouse xenograft model

    OpenAIRE

    Park, Eun Young; Pinali, Daniel; Lindley, Krista; Lane, Michelle A.

    2012-01-01

    Previous research in our laboratory showed that retinol inhibited all-trans retinoic acid (ATRA)-resistant human colon cancer cell invasion via a retinoic acid receptor (RAR)-independent mechanism in vitro. The objective of the current study was to determine if dietary vitamin A supplementation inhibited metastasis of ATRA-resistant colon cancer cells in a nude mouse xenograft model. Female nude mice (BALB/cAnNCr-nu/nu, n=14 per group) consumed a control diet (2400 IU retinyl palmitate/kg die...

  10. Inflammatory breast cancer: Vasculogenic mimicry and its hemodynamics of an inflammatory breast cancer xenograft model

    International Nuclear Information System (INIS)

    We recently established a new human inflammatory breast cancer (IBC) xenograft (WIBC-9) originating from a patient with IBC. The original tumor and WIBC-9 revealed invasive ductal carcinoma with a hypervascular structure of solid nests and marked lymphatic permeation in the overlying dermis. In the central part of the solid nests, vasculogenic mimicry, which showed an absence of endothelial cells, was observed. Comparison of WIBC-9 with an established non-IBC xenograft (MC-5), using time-course dynamic micro-magnetic resonance angiography analysis (with a newly developed intravascular macromolecular contrast agent for magnetic resonance imaging) demonstrated that the WIBC-9 tumor had blood flow and a vascular mimicry–angiogenesis junction

  11. A murine xenograft model for a transmissible cancer in Tasmanian devils.

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    Kreiss, A; Tovar, C; Obendorf, D L; Dun, K; Woods, G M

    2011-03-01

    The number of Tasmanian devils in the wild is rapidly declining owing to a transmissible cancer, devil facial tumor disease (DFTD). Although progress has been made to understand the spread of this disease, crucial research on the pathogenesis of DFTD has been limited because of the threatened status of the host species. Here, the authors describe the development of a NOD/SCID (nonobese diabetic / severe combined immunodeficiency) mouse model that reproduces DFTD and provides a much-needed model to undertake studies into this intriguing transmissible cancer. Histologically, the DFTD produced in NOD/SCID mice (xenografted DFTD) was indistinguishable from the DFTD identified in Tasmanian devils. At the protein level, all xenografted DFTD tumors expressed periaxin, a marker that confirmed the diagnosis of DFTD. The karyotype of DFTD in NOD/SCID mice reproduced similar chromosomal alterations as seen in diseased devils. Furthermore, each NOD/SCID mouse inoculated with cultured DFTD tumor cells developed tumors, whereas DFTD did not develop in any of the inoculated immune-competent BALB/c mice. PMID:20861503

  12. Establishment and characterisation of patient-derived xenografts as paraclinical models for gastric cancer

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    Choi, Yoon Young; Lee, Jae Eun; Kim, Hyunki; Sim, Moon Hee; Kim, Ka-Kyung; Lee, Gunho; Kim, Hyoung-Il; An, Ji Yeong; Hyung, Woo Jin; Kim, Choong-Bai; Noh, Sung Hoon; Kim, Sangwoo; Cheong, Jae-Ho

    2016-01-01

    The patient-derived xenograft (PDX) model is emerging as a promising translational platform to duplicate the characteristics of tumours. However, few studies have reported detailed histological and genomic analyses for model fidelity and for factors affecting successful model establishment of gastric cancer. Here, we generated PDX tumours surgically-derived from 62 gastric cancer patients. Fifteen PDX models were successfully established (24.2%, 15/62) and passaged to maintain tumours in immune-compromised mice. Diffuse type and low tumour cell percentage were negatively correlated with success rates (p = 0.005 and p = 0.025, respectively), while reducing ex vivo and overall procedure times were positively correlated with success rates (p = 0.003 and p = 0.01, respectively). The histology and genetic characteristics of PDX tumour models were stable over subsequent passages. Lymphoma transformation occurred in five cases (33.3%, 5/15), and all were in the NOG mouse, with none in the nude mouse. Together, the present study identified Lauren classification, tumour cell percentages, and ex vivo times along with overall procedure times, as key determinants for successful PDX engraftment. Furthermore, genetic and histological characteristics were highly consistent between primary and PDX tumours, which provide realistic paraclinical models, enabling personalised development of treatment options for gastric cancer. PMID:26926953

  13. Systematic repurposing screening in xenograft models identifies approved drugs with novel anti-cancer activity.

    Directory of Open Access Journals (Sweden)

    Jeffrey J Roix

    Full Text Available Approved drugs target approximately 400 different mechanisms of action, of which as few as 60 are currently used as anti-cancer therapies. Given that on average it takes 10-15 years for a new cancer therapeutic to be approved, and the recent success of drug repurposing for agents such as thalidomide, we hypothesized that effective, safe cancer treatments may be found by testing approved drugs in new therapeutic settings. Here, we report in-vivo testing of a broad compound collection in cancer xenograft models. Using 182 compounds that target 125 unique target mechanisms, we identified 3 drugs that displayed reproducible activity in combination with the chemotherapeutic temozolomide. Candidate drugs appear effective at dose equivalents that exceed current prescription levels, suggesting that additional pre-clinical efforts will be needed before these drugs can be tested for efficacy in clinical trials. In total, we suggest drug repurposing is a relatively resource-intensive method that can identify approved medicines with a narrow margin of anti-cancer activity.

  14. A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone

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    Laure Thibaudeau

    2014-02-01

    Full Text Available The skeleton is a preferred homing site for breast cancer metastasis. To date, treatment options for patients with bone metastases are mostly palliative and the disease is still incurable. Indeed, key mechanisms involved in breast cancer osteotropism are still only partially understood due to the lack of suitable animal models to mimic metastasis of human tumor cells to a human bone microenvironment. In the presented study, we investigate the use of a human tissue-engineered bone construct to develop a humanized xenograft model of breast cancer-induced bone metastasis in a murine host. Primary human osteoblastic cell-seeded melt electrospun scaffolds in combination with recombinant human bone morphogenetic protein 7 were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. The tissue-engineered constructs led to the formation of a morphologically intact ‘organ’ bone incorporating a high amount of mineralized tissue, live osteocytes and bone marrow spaces. The newly formed bone was largely humanized, as indicated by the incorporation of human bone cells and human-derived matrix proteins. After intracardiac injection, the dissemination of luciferase-expressing human breast cancer cell lines to the humanized bone ossicles was detected by bioluminescent imaging. Histological analysis revealed the presence of metastases with clear osteolysis in the newly formed bone. Thus, human tissue-engineered bone constructs can be applied efficiently as a target tissue for human breast cancer cells injected into the blood circulation and replicate the osteolytic phenotype associated with breast cancer-induced bone lesions. In conclusion, we have developed an appropriate model for investigation of species-specific mechanisms of human breast cancer-related bone metastasis in vivo.

  15. Assessment of the antitumor potential of Bithionol in vivo using a xenograft model of ovarian cancer.

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    Ayyagari, Vijayalakshmi N; Johnston, Nancy A; Brard, Laurent

    2016-07-01

    In terms of the concept of 'drug repurposing', we focused on pharmaceutical-grade Bithionol (BT) as a therapeutic agent against ovarian cancer. Our recent in-vitro study provides preclinical data suggesting a potential therapeutic role for BT against recurrent ovarian cancer. BT was shown to cause cell death by caspases-mediated apoptosis. The present preliminary study further explores the antitumor potential of pharmaceutical-grade BT in an in-vivo xenograft model of human ovarian cancer. Nude Foxn1 mice bearing SKOV-3 human ovarian tumor xenografts were treated with titrated doses of BT and the therapeutic efficacy of pharmaceutical BT was determined using bioluminescence imaging. BT-induced changes in cell proliferation and apoptosis were evaluated by Ki-67 immunochemical staining and TUNEL assay. The effect of BT on autotaxin levels in serum, ascitic fluid, and tumor tissue was assessed by colorimetric and western blot techniques. BT treatment did not show antitumor potential or enhanced survival time at any of the doses tested. No apparent signs of toxicity were observed with any of the doses tested. Immunohistological analysis of tumor sections did not indicate a significant decrease in cellular proliferation (Ki-67 assay). An increase in apoptosis (by TUNEL assay) was observed in all BT-treated mice compared with vehicle-treated mice. Although BT did not show significant antitumor activity in the present study, the ability of BT to induce apoptosis still makes it a promising therapeutic agent. Further confirmatory and optimization studies are essential to enhance the therapeutic effects of BT. PMID:27058706

  16. Development of Patient Derived Xenograft Models of Overt Spontaneous Breast Cancer Metastasis: A Cautionary Note

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    Paez-Ribes, Marta; Man, Shan; Xu, Ping; Kerbel, Robert S.

    2016-01-01

    Several approaches are being evaluated to improve the historically limited value of studying transplanted primary tumors derived by injection of cells from established cell lines for predicting subsequent cancer therapy outcomes in patients and clinical trials. These approaches include use of genetically engineered mouse models (GEMMs) of spontaneous tumors, or patient tumor tissue derived xenografts (PDXs). Almost all such therapy studies utilizing such models involve treatment of established primary tumors. An alternative approach we have developed involves transplanted human tumor xenografts derived from established cell lines to treat mice with overt visceral metastases after primary tumor resection. The rationale is to mimic the more challenging circumstance of treating patients with late stage metastatic disease. These metastatic models entail prior in vivo selection of heritable, phenotypically stable variants with increased aggressiveness for spontaneous metastasis; they were derived by orthotopic injection of tumor cells followed by primary tumor resection and serial selection of distant spontaneous metastases, from which variant cell lines having a more aggressive heritable metastatic phenotype were established. We attempted to adopt this strategy for breast cancer PDXs. We studied five breast cancer PDXs, with the emphasis on two, called HCI-001 and HCI-002, both derived from triple negative breast cancer patients. However significant technical obstacles were encountered. These include the inherent slow growth rates of PDXs, the rarity of overt spontaneous metastases (detected in only 3 of 144 mice), very high rates of tumor regrowths at the primary tumor resection site, the failure of the few human PDX metastases isolated to manifest a more aggressive metastatic phenotype upon re-transplantation into new hosts, and the formation of metastases which were derived from de novo mouse thymomas arising in aged SCID mice that we used for the experiments. We

  17. Growth hormone receptor antagonism suppresses tumour regrowth after radiotherapy in an endometrial cancer xenograft model.

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    Evans, Angharad; Jamieson, Stephen M F; Liu, Dong-Xu; Wilson, William R; Perry, Jo K

    2016-08-28

    Human GH expression is associated with poor survival outcomes for endometrial cancer patients, enhanced oncogenicity of endometrial cancer cells and reduced sensitivity to ionising radiation in vitro, suggesting that GH is a potential target for anticancer therapy. However, whether GH receptor inhibition sensitises to radiotherapy in vivo has not been tested. In the current study, we evaluated whether the GH receptor antagonist, pegvisomant (Pfizer), sensitises to radiotherapy in vivo in an endometrial tumour xenograft model. Subcutaneous administration of pegvisomant (20 or 100 mg/kg/day, s.c.) reduced serum IGF1 levels by 23% and 68%, respectively, compared to vehicle treated controls. RL95-2 xenografts grown in immunodeficient NIH-III mice were treated with vehicle or pegvisomant (100 mg/kg/day), with or without fractionated gamma radiation (10 × 2.5 Gy over 5 days). When combined with radiation, pegvisomant significantly increased the median time tumours took to reach 3× the pre-radiation treatment volume (49 days versus 72 days; p = 0.001). Immunohistochemistry studies demonstrated that 100 mg/kg pegvisomant every second day was sufficient to abrogate MAP Kinase signalling throughout the tumour. In addition, treatment with pegvisomant increased hypoxic regions in irradiated tumours, as determined by immunohistochemical detection of pimonidazole adducts, and decreased the area of CD31 labelling in unirradiated tumours, suggesting an anti-vascular effect. Pegvisomant did not affect intratumoral staining for HIF1α, VEGF-A, CD11b, or phospho-EGFR. Our results suggest that blockade of the human GH receptor may improve the response of GH and/or IGF1-responsive endometrial tumours to radiation. PMID:27241667

  18. Pentastatin-1, a collagen IV derived 20-mer peptide, suppresses tumor growth in a small cell lung cancer xenograft model

    International Nuclear Information System (INIS)

    Angiogenesis is the formation of neovasculature from a pre-existing vascular network. Progression of solid tumors including lung cancer is angiogenesis-dependent. We previously introduced a bioinformatics-based methodology to identify endogenous anti-angiogenic peptide sequences, and validated these predictions in vitro in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays. One family of peptides with high activity is derived from the α-fibrils of type IV collagen. Based on the results from the in vitro screening, we have evaluated the ability of a 20 amino acid peptide derived from the α5 fibril of type IV collagen, pentastatin-1, to suppress vessel growth in an angioreactor-based directed in vivo angiogenesis assay (DIVAA). In addition, pentastatin-1 suppressed tumor growth with intraperitoneal peptide administration in a small cell lung cancer (SCLC) xenograft model in nude mice using the NCI-H82 human cancer cell line. Pentastatin-1 decreased the invasion of vessels into angioreactors in vivo in a dose dependent manner. The peptide also decreased the rate of tumor growth and microvascular density in vivo in a small cell lung cancer xenograft model. The peptide treatment significantly decreased the invasion of microvessels in angioreactors and the rate of tumor growth in the xenograft model, indicating potential treatment for angiogenesis-dependent disease, and for translational development as a therapeutic agent for lung cancer

  19. Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model

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    Chen, Shanshan; Li, Xuechun; Chen, Rongming; Yin, Mingang; Zheng, Qiuhong

    2016-01-01

    Natural killer (NK) cells, discovered ~40 years ago, are believed to be the most effective cytotoxic lymphocytes to counteract cancer; however, adoptive NK cell therapy in vivo has encountered certain limitations, including a lack of specificity. The drug cetuximab can mediate antibody dependent cell mediated cytotoxicity (ADCC) activity through NK cells in vivo, and has been approved for the first-line treatment of epidermal growth factor receptor (EGFR)-positive metastatic colorectal cancer (CRC). However, the ADCC activity of adoptive NK cells, induced by cetuximab in a nude mouse CRC xenograft model, has not been previously reported. The aim of the present study was to explore the ADCC activity of cetuximab combined with adoptive NK cells in CRC xenograft models with various EGFR expressions. The nude mouse xenograft models were established by subcutaneously injecting LOVO or SW620 cells. The mice were then randomly divided into 6 groups: Phosphate-buffered saline, cetuximab, human immunoglobulin G (hIgG), NK cells, hIgG plus NK cells and cetuximab plus NK cells. The ADCC antitumor activity was evaluated in these CRC models. The results indicated that the cetuximab plus NK cells group showed the greatest tumor inhibition effect compared with the NK cells group in LOVO xenograft tumor models with positive EGFR expression. However, the combination of cetuximab and NK cells did not show a stronger tumor inhibitory effect against the SW620 xenograft tumor models compared with the efficiency of NK cells. In conclusion, cetuximab could intensify the ADCC antitumor activity of adoptive NK cells towards CRC with an increased EGFR expression. The combination of cetuximab and NK cells may be a potential immunotherapy for metastatic CRC patients with positive EGFR expression. PMID:27602116

  20. Biodistribution of charged F(ab')2 photoimmunoconjugates in a xenograft model of ovarian cancer.

    Science.gov (United States)

    Duska, L R; Hamblin, M R; Bamberg, M P; Hasan, T

    1997-01-01

    The effect of charge modification of photoimmunoconjugates (PICs) on their biodistribution in a xenograft model of ovarian cancer was investigated. Chlorin(e6)c(e6) was attached site specifically to the F(ab')2 fragment of the murine monoclonal antibody OC125, directed against human ovarian cancer cells, via poly-1-lysine linkers carrying cationic or anionic charges. Preservation of immunoreactivity was checked by enzyme-linked immunosorbent assay (ELISA). PICs were radiolabelled with 125I and compared with non-specific rabbit IgG PICs after intraperitoneal (i.p.) injection into nude mice. Samples were taken from normal organs and tumour at 3 h and 24 h. Tumour to normal 125I ratios showed that the cationic OC125F(ab')2 PIC had the highest tumour selectivity. Ratios for c(e6) were uniformly higher than for 125I, indicating that c(e6) became separated from 125I. OC125F(ab')2 gave highest tissue values of 125I, followed by cationic OC125F(ab')2 PIC; other species were much lower. The amounts of c(e6) delivered per gram of tumour were much higher for cationic OC125F(ab')2 PIC than for other species. The results indicate that cationic charge stimulates the endocytosis and lysosomal degradation of the OC125F(ab')2-pl-c(e6) that has bound to the i.p. tumour. Positively charged PICs may have applications in the i.p. photoimmunotherapy of minimal residual ovarian cancer. PMID:9062404

  1. Cellular characterization of ultrasound-stimulated microbubble radiation enhancement in a prostate cancer xenograft model

    Directory of Open Access Journals (Sweden)

    Azza A. Al-Mahrouki

    2014-03-01

    Full Text Available Tumor radiation resistance poses a major obstacle in achieving an optimal outcome in radiation therapy. In the current study, we characterize a novel therapeutic approach that combines ultrasound-driven microbubbles with radiation to increase treatment responses in a prostate cancer xenograft model in mice. Tumor response to ultrasound-driven microbubbles and radiation was assessed 24 hours after treatment, which consisted of radiation treatments alone (2 Gy or 8 Gy or ultrasound-stimulated microbubbles only, or a combination of radiation and ultrasound-stimulated microbubbles. Immunohistochemical analysis using in situ end labeling (ISEL and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL revealed increased cell death within tumors exposed to combined treatments compared with untreated tumors or tumors exposed to radiation alone. Several biomarkers were investigated to evaluate cell proliferation (Ki67, blood leakage (factor VIII, angiogenesis (cluster of differentiation molecule CD31, ceramide-formation, angiogenesis signaling [vascular endothelial growth factor (VEGF], oxygen limitation (prolyl hydroxylase PHD2 and DNA damage/repair (γH2AX. Results demonstrated reduced vascularity due to vascular disruption by ultrasound-stimulated microbubbles, increased ceramide production and increased DNA damage of tumor cells, despite decreased tumor oxygenation with significantly less proliferating cells in the combined treatments. This combined approach could be a feasible option as a novel enhancing approach in radiation therapy.

  2. Reversing Cancer Multidrug Resistance in Xenograft Models via Orchestrating Multiple Actions of Functional Mesoporous Silica Nanoparticles.

    Science.gov (United States)

    Yang, Debin; Wang, Tingfang; Su, Zhigui; Xue, Lingjing; Mo, Ran; Zhang, Can

    2016-08-31

    A multistimuli responsive drug delivery system (DDS) based on sulfhydryl and amino-cofunctionalized mesoporous silica nanoparticles (SH/NH2-MSNs) has been developed, in which the multifunctional hyaluronic acid (HA) derivatives were grafted onto the SH/NH2-MSNs by disulfide bonds for targeting delivery, controlling drug release and reversing multidrug resistance (MDR). The doxorubicin (Dox) loaded multifunctional HA derivatives modified mesoporous silica nanoparticles (Dox/HHS-MSNs) were enzyme and redox sensitive, which could respond to the intracellular stimuli of hyaluronidase (HAase) and glutathione (GSH) successively and prevent drug leakage before reaching the tumor tissues. The cellular uptake experiments showed that Dox/HHS-MSNs were vulnerable to be endocytosed into the Dox-resistant human breast adenocarcinoma (MCF-7/ADR) cells, efficiently realized the endolysosomal escape and remained in the cytoplasm. Because of orchestrating multiple actions above including active targeting, endolysosomal escape and efficient multilevel drug release, Dox/HHS-MSNs could induce the strongest apoptosis and cytotoxicity of MCF-7/ADR cells. Furthermore, a series of in vivo studies on MCF-7/ADR tumor-bearing xenograft mouse models demonstrated that Dox/HHS-MSNs possessed the enhanced tumor-targeting capacity and the best therapeutic efficacy to reverse cancer MDR. PMID:27420116

  3. Antitumor activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in mouse xenograft model of breast cancer

    OpenAIRE

    Muscella, A; Vetrugno, C.; Migoni, D.; Biagioni, F; Fanizzi, F P; Fornai, F; De Pascali, S A; Marsigliante, S

    2014-01-01

    The higher and selective cytotoxicity of [Pt(O,O′-acac)(γ-acac)(DMS)] toward cancer cell in both immortalized cell lines and in breast cancer cells in primary cultures, stimulated a pre-clinical study so as to evaluate its therapeutic potential in vivo. The efficacy of [Pt(O,O′-acac)(γ-acac)(DMS)] was assessed using a xenograft model of breast cancer developed by injection of MCF-7 cells in the flank of BALB/c nude mice. Treatment of solid tumor-bearing mice with [Pt(O,O′-acac)(γ-acac)(DMS)] ...

  4. Intratumoral Heterogeneity of Breast Cancer Xenograft Models: Texture Analysis of Diffusion-Weighted MR Imaging

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    Yun, Bo La; Cho, Nariya; Li, Mulun; Song, In Chan; Moon, Woo Kyung [Dept. of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul (Korea, Republic of); Jang, Min Hye; Park, So Yeon; Kim, Bo Young [Seoul National University Bundang Hospital, Seongnam (Korea, Republic of); Kang, Ho Chul [Dept. of Computer Science and Engineering, Seoul National University, Seoul (Korea, Republic of)

    2014-10-15

    .464), kurtosis (r = -0.581, r = -0.389), contrast (r = -0.473, r = -0.549) and COR (r = 0.588, r = 0.580) correlated with MVDmean and MVDdiff (p < 0.05 for all). The texture analysis of ADC maps may help to determine the intratumoral spatial heterogeneity of necrosis patterns, amount of cellular proliferation and the vascularity in MCF-7 and MDA-MB-231 xenograft breast cancer models.

  5. Aminomethylphosphonic acid inhibits growth and metastasis of human prostate cancer in an orthotopic xenograft mouse model

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    Parajuli, Keshab Raj; Zhang, Qiuyang; Liu, Sen; You, Zongbing

    2016-01-01

    Aminomethylphosphonic acid (AMPA) has been shown to inhibit prostate cancer cell growth in vitro. The purpose of the present study was to determine if AMPA could inhibit growth and metastasis of prostate cancer in vivo. Human prostate cancer PC-3-LacZ-luciferase cells were implanted into the ventral lateral lobes of the prostate in 39 athymic Nu/Nu nude male mice. Seven days later, mice were randomized into the control group (n = 14, treated intraperitoneally with phosphate buffered saline), low dose group (n = 10, treated intraperitoneally with AMPA at 400 mg/kg body weight/day), and high dose group (n = 15, treated intraperitoneally with AMPA at 800 mg/kg body weight/day). Tumor growth and metastasis were examined every 4-7 days by bioluminescence imaging of live mice. We found that AMPA treatment significantly inhibited growth and metastasis of orthotopic xenograft prostate tumors and prolonged the survival time of the mice. AMPA treatment decreased expression of BIRC2 and activated caspase 3, leading to increased apoptosis in the prostate tumors. AMPA treatment decreased expression of cyclin D1. AMPA treatment also reduced angiogenesis in the prostate tumors. Taken together, these results demonstrate that AMPA can inhibit prostate cancer growth and metastasis, suggesting that AMPA may be developed into a therapeutic agent for the treatment of prostate cancer. PMID:26840261

  6. Blood vessel hyperpermeability and pathophysiology in human tumour xenograft models of breast cancer: a comparison of ectopic and orthotopic tumours

    International Nuclear Information System (INIS)

    Human tumour xenografts in immune compromised mice are widely used as cancer models because they are easy to reproduce and simple to use in a variety of pre-clinical assessments. Developments in nanomedicine have led to the use of tumour xenografts in testing nanoscale delivery devices, such as nanoparticles and polymer-drug conjugates, for targeting and efficacy via the enhanced permeability and retention (EPR) effect. For these results to be meaningful, the hyperpermeable vasculature and reduced lymphatic drainage associated with tumour pathophysiology must be replicated in the model. In pre-clinical breast cancer xenograft models, cells are commonly introduced via injection either orthotopically (mammary fat pad, MFP) or ectopically (subcutaneous, SC), and the organ environment experienced by the tumour cells has been shown to influence their behaviour. To evaluate xenograft models of breast cancer in the context of EPR, both orthotopic MFP and ectopic SC injections of MDA-MB-231-H2N cells were given to NOD scid gamma (NSG) mice. Animals with matched tumours in two size categories were tested by injection of a high molecular weight dextran as a model nanocarrier. Tumours were collected and sectioned to assess dextran accumulation compared to liver tissue as a positive control. To understand the cellular basis of these observations, tumour sections were also immunostained for endothelial cells, basement membranes, pericytes, and lymphatic vessels. SC tumours required longer development times to become size matched to MFP tumours, and also presented wide size variability and ulcerated skin lesions 6 weeks after cell injection. The 3 week MFP tumour model demonstrated greater dextran accumulation than the size matched 5 week SC tumour model (for P < 0.10). Immunostaining revealed greater vascular density and thinner basement membranes in the MFP tumour model 3 weeks after cell injection. Both the MFP and SC tumours showed evidence of insufficient lymphatic drainage

  7. Blood vessel hyperpermeability and pathophysiology in human tumour xenograft models of breast cancer: a comparison of ectopic and orthotopic tumours

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    Ho Karyn S

    2012-12-01

    Full Text Available Abstract Background Human tumour xenografts in immune compromised mice are widely used as cancer models because they are easy to reproduce and simple to use in a variety of pre-clinical assessments. Developments in nanomedicine have led to the use of tumour xenografts in testing nanoscale delivery devices, such as nanoparticles and polymer-drug conjugates, for targeting and efficacy via the enhanced permeability and retention (EPR effect. For these results to be meaningful, the hyperpermeable vasculature and reduced lymphatic drainage associated with tumour pathophysiology must be replicated in the model. In pre-clinical breast cancer xenograft models, cells are commonly introduced via injection either orthotopically (mammary fat pad, MFP or ectopically (subcutaneous, SC, and the organ environment experienced by the tumour cells has been shown to influence their behaviour. Methods To evaluate xenograft models of breast cancer in the context of EPR, both orthotopic MFP and ectopic SC injections of MDA-MB-231-H2N cells were given to NOD scid gamma (NSG mice. Animals with matched tumours in two size categories were tested by injection of a high molecular weight dextran as a model nanocarrier. Tumours were collected and sectioned to assess dextran accumulation compared to liver tissue as a positive control. To understand the cellular basis of these observations, tumour sections were also immunostained for endothelial cells, basement membranes, pericytes, and lymphatic vessels. Results SC tumours required longer development times to become size matched to MFP tumours, and also presented wide size variability and ulcerated skin lesions 6 weeks after cell injection. The 3 week MFP tumour model demonstrated greater dextran accumulation than the size matched 5 week SC tumour model (for P  Conclusions Dextran accumulation and immunostaining results suggest that small MFP tumours best replicate the vascular permeability required to observe the EPR effect

  8. Quercetin inhibits angiogenesis by targeting calcineurin in the xenograft model of human breast cancer.

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    Zhao, Xin; Wang, Qiuting; Yang, Shijun; Chen, Chen; Li, Xiaoya; Liu, Jinyu; Zou, Zhongmei; Cai, Dayong

    2016-06-15

    Vascular endothelial growth factor receptor 2 (VEGFR2) mediated calcineurin/nuclear factor of activated T-cells (NFAT) pathway is crucial in the angiogenesis of human breast cancer. Quercetin (Qu), a flavonoid known to possess anti-angiogenesis and antitumor properties, inhibited calcineurin activity in vitro. Herein, we performed a study in vivo to evaluate the effects of Qu on the angiogenesis in breast cancer. Female BALB/c nude mice were injected with MCF-7 cells into the mammary fat and were randomly divided into four groups. The animals were treated with vehicle solution, tamoxifen (TAM, 5.6mg/kg), tacrolimus (FK506, 3mg/kg), or Qu (34mg/kg) for 21 days, respectively. The results showed that, similar to TAM and FK506, Qu decreased tumor growth, limited oncocyte proliferation and promoted tumor necrosis. Anti-angiogenic actions of Qu were demonstrated as decreased serum VEGF (P0.05). Effects of Qu on calcineurin/NFAT pathway were confirmed as decreased subcellular located levels of VEGF (Pangiogenesis of human breast cancer xenograft in nude mice, which was associated with suppressing calcineurin activity and its regulated pathway activation. PMID:27041643

  9. Therapeutic Effects of Microbubbles Added to Combined High-Intensity Focused Ultrasound and Chemotherapy in a Pancreatic Cancer Xenograft Model

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    Yu, Mi Hye; Kim, Hae Ri; Kim, Bo Ram; Park, Eun-Joo; Kim, Hoe Suk; Han, Joon Koo; Choi, Byung Ihn

    2016-01-01

    Objective To investigate whether high-intensity focused ultrasound (HIFU) combined with microbubbles enhances the therapeutic effects of chemotherapy. Materials and Methods A pancreatic cancer xenograft model was established using BALB/c nude mice and luciferase-expressing human pancreatic cancer cells. Mice were randomly assigned to five groups according to treatment: control (n = 10), gemcitabine alone (GEM; n = 12), HIFU with microbubbles (HIFU + MB, n = 11), combined HIFU and gemcitabine (HIGEM; n = 12), and HIGEM + MB (n = 13). After three weekly treatments, apoptosis rates were evaluated using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay in two mice per group. Tumor volume and bioluminescence were monitored using high-resolution 3D ultrasound imaging and in vivo bioluminescence imaging for eight weeks in the remaining mice. Results The HIGEM + MB group showed significantly higher apoptosis rates than the other groups (p < 0.05) and exhibited the slowest tumor growth. From week 5, the tumor-volume-ratio relative to the baseline tumor volume was significantly lower in the HIGEM + MB group than in the control, GEM, and HIFU + MB groups (p < 0.05). Despite visible distinction, the HIGEM and HIGEM + MB groups showed no significant differences. Conclusion High-intensity focused ultrasound combined with microbubbles enhances the therapeutic effects of gemcitabine chemotherapy in a pancreatic cancer xenograft model. PMID:27587968

  10. Treatment with kaempferol suppresses breast cancer cell growth caused by estrogen and triclosan in cellular and xenograft breast cancer models.

    Science.gov (United States)

    Kim, Seung-Hee; Hwang, Kyung-A; Choi, Kyung-Chul

    2016-02-01

    As a phytoestrogen, kaempferol (Kaem) is one of bioflavonoids, which are found in a variety of vegetables including broccoli, tea and tomato. In this study, the antiproliferative effects of Kaem in triclosn (TCS)-induced cell growth were examined in MCF-7 breast cancer cells. TCS promoted the cell viability of MCF-7 cells via estrogen receptor α (ERα) as did 17β-estradiol (E2), a positive control. On the other hand, Kaem significantly suppressed E2 or TCS-induced cell growth. To elucidate the molecular mechanisms of TCS and Kaem, alterations in the expressions of cell cycle, apoptosis and metastasis-related genes were identified using western blot assay. The treatment of the cells with TCS up-regulated the protein expressions of cyclin D1, cyclin E and cathepsin D, while down-regulated p21 and bax expressions. Kaem reversed TCS-induced gene expressions in an opposite manner. The phosphorylation of IRS-1, AKT, MEK1/2 and ERK was increased by TCS, indicating that TCS induced MCF-7 cell proliferation via nongenomic ER signaling pathway associated with IGF-1R. Kaem presented an antagonistic activity on this signaling by down-regulating the protein expression of pIRS-1, pAkt and pMEK1/2 promoted by E2 or TCS. In an in vivo xenografted mouse model, tumor growth was induced by treatment with E2 or TCS, which was identified in the measurement of tumor volume, hematoxylin and eosin staining, bromodeoxyuridine and immunohistochemistry assay. On the contrary, E2 or TCS-induced breast tumor growth was inhibited by co-treatment with Kaem, which is consistent with in vitro results. Taken together, these results revealed that Kaem has an anticancer effect against procancer activity of E2 or TCS, a xenoestrogen, in breast cancer and may be suggested as a prominent agent to neutralize breast cancer risk caused by TCS. PMID:26878784

  11. A novel patient-derived intra-femoral xenograft model of bone metastatic prostate cancer that recapitulates mixed osteolytic and osteoblastic lesions

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    Raheem Omer

    2011-10-01

    Full Text Available Abstract Prostate cancer metastasizes to bone in the majority of patients with advanced disease leading to painfully debilitating fractures, spinal compression and rapid decline. In addition, prostate cancer bone metastases often become resistant to standard therapies including androgen deprivation, radiation and chemotherapy. There are currently few models to elucidate mechanisms of interaction between the bone microenvironment and prostate cancer. It is, thus, essential to develop new patient-derived, orthotopic models. Here we report the development and characterization of PCSD1 (Prostate Cancer San Diego 1, a novel patient-derived intra-femoral xenograft model of prostate bone metastatic cancer that recapitulates mixed osteolytic and osteoblastic lesions. Methods A femoral bone metastasis of prostate cancer was removed during hemiarthroplasty and transplanted into Rag2-/-;γc-/- mice either intra-femorally or sub-cutaneously. Xenograft tumors that developed were analyzed for prostate cancer biomarker expression using RT-PCR and immunohistochemistry. Osteoblastic, osteolytic and mixed lesion formation was measured using micro-computed tomography (microCT. Results PCSD1 cells isolated directly from the patient formed tumors in all mice that were transplanted intra-femorally or sub-cutaneously into Rag2-/-;γc-/- mice. Xenograft tumors expressed human prostate specific antigen (PSA in RT-PCR and immunohistochemical analyses. PCSD1 tumors also expressed AR, NKX3.1, Keratins 8 and 18, and AMACR. Histologic and microCT analyses revealed that intra-femoral PCSD1 xenograft tumors formed mixed osteolytic and osteoblastic lesions. PCSD1 tumors have been serially passaged in mice as xenografts intra-femorally or sub-cutaneously as well as grown in culture. Conclusions PCSD1 xenografts tumors were characterized as advanced, luminal epithelial prostate cancer from a bone metastasis using RT-PCR and immunohistochemical biomarker analyses. PCSD1 intra

  12. Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model

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    de Boeck, Miriam; Cui, Chao; Mulder, Aat A; Jost, Carolina R; Ikeno, Souichi; ten Dijke, Peter

    2016-01-01

    The transforming growth factor-β (TGF-β) family is known to play critical roles in cancer progression. While the dual role of TGF-β is well described, the function of bone morphogenetic proteins (BMPs) is unclear. In this study, we established the involvement of Smad6, a BMP-specific inhibitory Smad, in breast cancer cell invasion. We show that stable overexpression of Smad6 in breast cancer MCF10A M2 cells inhibits BMP signalling, thereby mitigating BMP6-induced suppression of mesenchymal marker expression. Using a zebrafish xenograft model, we demonstrate that overexpression of Smad6 potentiates invasion of MCF10A M2 cells and enhances the aggressiveness of breast cancer MDA-MB-231 cells in vivo, whereas a reversed phenotype is observed after Smad6 knockdown. Interestingly, BMP6 pre-treatment of MDA-MB-231 cells induced cluster formation at the invasive site in the zebrafish. BMP6 also stimulated cluster formation of MDA-MB-231 cells co-cultured on Human Microvascular Endothelial Cells (HMEC)-1 in vitro. Electron microscopy illustrated an induction of cell-cell contact by BMP6. The clinical relevance of our findings is highlighted by a correlation of high Smad6 expression with poor distant metastasis free survival in ER-negative cancer patients. Collectively, our data strongly indicates the involvement of Smad6 and BMP signalling in breast cancer cell invasion in vivo. PMID:27113436

  13. Smad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft model.

    Science.gov (United States)

    de Boeck, Miriam; Cui, Chao; Mulder, Aat A; Jost, Carolina R; Ikeno, Souichi; Ten Dijke, Peter

    2016-01-01

    The transforming growth factor-β (TGF-β) family is known to play critical roles in cancer progression. While the dual role of TGF-β is well described, the function of bone morphogenetic proteins (BMPs) is unclear. In this study, we established the involvement of Smad6, a BMP-specific inhibitory Smad, in breast cancer cell invasion. We show that stable overexpression of Smad6 in breast cancer MCF10A M2 cells inhibits BMP signalling, thereby mitigating BMP6-induced suppression of mesenchymal marker expression. Using a zebrafish xenograft model, we demonstrate that overexpression of Smad6 potentiates invasion of MCF10A M2 cells and enhances the aggressiveness of breast cancer MDA-MB-231 cells in vivo, whereas a reversed phenotype is observed after Smad6 knockdown. Interestingly, BMP6 pre-treatment of MDA-MB-231 cells induced cluster formation at the invasive site in the zebrafish. BMP6 also stimulated cluster formation of MDA-MB-231 cells co-cultured on Human Microvascular Endothelial Cells (HMEC)-1 in vitro. Electron microscopy illustrated an induction of cell-cell contact by BMP6. The clinical relevance of our findings is highlighted by a correlation of high Smad6 expression with poor distant metastasis free survival in ER-negative cancer patients. Collectively, our data strongly indicates the involvement of Smad6 and BMP signalling in breast cancer cell invasion in vivo. PMID:27113436

  14. Appropriateness of using patient-derived xenograft models for pharmacologic evaluation of novel therapies for esophageal/gastro-esophageal junction cancers.

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    Lorin Dodbiba

    Full Text Available The high morbidity and mortality of patients with esophageal (E and gastro-esophageal junction (GEJ cancers, warrants new pre-clinical models for drug testing. The utility of primary tumor xenografts (PTXGs as pre-clinical models was assessed. Clinicopathological, immunohistochemical markers (p53, p16, Ki-67, Her-2/neu and EGFR, and global mRNA abundance profiles were evaluated to determine selection biases of samples implanted or engrafted, compared with the underlying population. Nine primary E/GEJ adenocarcinoma xenograft lines were further characterized for the spectrum and stability of gene/protein expression over passages. Seven primary esophageal adenocarcinoma xenograft lines were treated with individual or combination chemotherapy. Tumors that were implanted (n=55 in NOD/SCID mice had features suggestive of more aggressive biology than tumors that were never implanted (n=32. Of those implanted, 21/55 engrafted; engraftment was associated with poorly differentiated tumors (p=0.04 and older patients (p=0.01. Expression of immunohistochemical markers were similar between patient sample and corresponding xenograft. mRNA differences observed between patient tumors and first passage xenografts were largely due to loss of human stroma in xenografts. mRNA patterns of early vs late passage xenografts and of small vs large tumors of the same passage were similar. Complete resistance was present in 2/7 xenografts while the remaining tumors showed varying degrees of sensitivity, that remained constant across passages. Because of their ability to recapitulate primary tumor characteristics during engraftment and across serial passaging, PTXGs can be useful clinical systems for assessment of drug sensitivity of human E/GEJ cancers.

  15. Autophagy induction by leptin contributes to suppression of apoptosis in cancer cells and xenograft model: Involvement of p53/FoxO3A axis

    OpenAIRE

    Nepal, Saroj; Kim, Mi Jin; Hong, Jin Tae; Kim, Sang Hyun; Sohn, Dong-Hwan; Lee, Sung Hee; Song, Kyung; Choi, Dong Young; Lee, Eung Seok; Park, Pil-Hoon

    2015-01-01

    Leptin, a hormone mainly produced from adipose tissue, has been shown to induce proliferation of cancer cells. However, the molecular mechanisms underlying leptin-induced tumor progression have not been clearly elucidated. In the present study, we investigated the role of autophagy in leptin-induced cancer cell proliferation using human hepatoma (HepG2) and breast cancer cells (MCF-7), and tumor growth in a xenograft model. Herein, we showed that leptin treatment caused autophagy induction as...

  16. Distinct choline metabolic profiles are associated with differences in gene expression for basal-like and luminal-like breast cancer xenograft models

    International Nuclear Information System (INIS)

    Increased concentrations of choline-containing compounds are frequently observed in breast carcinomas, and may serve as biomarkers for both diagnostic and treatment monitoring purposes. However, underlying mechanisms for the abnormal choline metabolism are poorly understood. The concentrations of choline-derived metabolites were determined in xenografted primary human breast carcinomas, representing basal-like and luminal-like subtypes. Quantification of metabolites in fresh frozen tissue was performed using high-resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS). The expression of genes involved in phosphatidylcholine (PtdCho) metabolism was retrieved from whole genome expression microarray analyses. The metabolite profiles from xenografts were compared with profiles from human breast cancer, sampled from patients with estrogen/progesterone receptor positive (ER+/PgR+) or triple negative (ER-/PgR-/HER2-) breast cancer. In basal-like xenografts, glycerophosphocholine (GPC) concentrations were higher than phosphocholine (PCho) concentrations, whereas this pattern was reversed in luminal-like xenografts. These differences may be explained by lower choline kinase (CHKA, CHKB) expression as well as higher PtdCho degradation mediated by higher expression of phospholipase A2 group 4A (PLA2G4A) and phospholipase B1 (PLB1) in the basal-like model. The glycine concentration was higher in the basal-like model. Although glycine could be derived from energy metabolism pathways, the gene expression data suggested a metabolic shift from PtdCho synthesis to glycine formation in basal-like xenografts. In agreement with results from the xenograft models, tissue samples from triple negative breast carcinomas had higher GPC/PCho ratio than samples from ER+/PgR+ carcinomas, suggesting that the choline metabolism in the experimental models is representative for luminal-like and basal-like human breast cancer. The differences in choline metabolite

  17. Development of a Patient-Derived Xenograft (PDX of Breast Cancer Bone Metastasis in a Zebrafish Model

    Directory of Open Access Journals (Sweden)

    Laura Mercatali

    2016-08-01

    Full Text Available Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary culture of bone metastasis derived from a 67-year-old patient with breast cancer was cultured and then injected into zebrafish (ZF embryos to study its metastatic potential. In vivo behavior and results of gene expression analyses of the primary culture were compared with those of cancer cell lines with different metastatic potential (MCF7 and MDA-MB-231. The MCF7 cell line, which has the same hormonal receptor status as the bone metastasis primary culture, did not survive in the in vivo model. Conversely, MDA-MB-231 disseminated and colonized different parts of the ZF, including caudal hematopoietic tissues (CHT, revealing a migratory phenotype. Primary culture cells disseminated and in later stages extravasated from the vessels, engrafting into ZF tissues and reaching the CHT. Primary cell behavior reflected the clinical course of the patient’s medical history. Our results underline the potential for using PDX models in bone metastasis research and outline new methods for the clinical application of this in vivo model.

  18. Development of a Patient-Derived Xenograft (PDX) of Breast Cancer Bone Metastasis in a Zebrafish Model

    Science.gov (United States)

    Mercatali, Laura; La Manna, Federico; Groenewoud, Arwin; Casadei, Roberto; Recine, Federica; Miserocchi, Giacomo; Pieri, Federica; Liverani, Chiara; Bongiovanni, Alberto; Spadazzi, Chiara; de Vita, Alessandro; van der Pluijm, Gabri; Giorgini, Andrea; Biagini, Roberto; Amadori, Dino; Ibrahim, Toni; Snaar-Jagalska, Ewa

    2016-01-01

    Bone metastasis is a complex process that needs to be better understood in order to help clinicians prevent and treat it. Xenografts using patient-derived material (PDX) rather than cancer cell lines are a novel approach that guarantees more clinically realistic results. A primary culture of bone metastasis derived from a 67-year-old patient with breast cancer was cultured and then injected into zebrafish (ZF) embryos to study its metastatic potential. In vivo behavior and results of gene expression analyses of the primary culture were compared with those of cancer cell lines with different metastatic potential (MCF7 and MDA-MB-231). The MCF7 cell line, which has the same hormonal receptor status as the bone metastasis primary culture, did not survive in the in vivo model. Conversely, MDA-MB-231 disseminated and colonized different parts of the ZF, including caudal hematopoietic tissues (CHT), revealing a migratory phenotype. Primary culture cells disseminated and in later stages extravasated from the vessels, engrafting into ZF tissues and reaching the CHT. Primary cell behavior reflected the clinical course of the patient’s medical history. Our results underline the potential for using PDX models in bone metastasis research and outline new methods for the clinical application of this in vivo model. PMID:27556456

  19. The impact of bone morphogenetic protein 4 (BMP4) on breast cancer metastasis in a mouse xenograft model.

    Science.gov (United States)

    Ampuja, M; Alarmo, E L; Owens, P; Havunen, R; Gorska, A E; Moses, H L; Kallioniemi, A

    2016-06-01

    Bone morphogenetic protein 4 (BMP4) is a key regulator of cell proliferation and differentiation. In breast cancer cells, BMP4 has been shown to reduce proliferation in vitro and interestingly, in some cases, also to induce migration and invasion. Here we investigated whether BMP4 influences breast cancer metastasis formation by using a xenograft mouse model. MDA-MB-231 breast cancer cells were injected intracardially into mice and metastasis formation was monitored using bioluminescence imaging. Mice treated with BMP4 developed metastases slightly earlier as compared to control animals but the overall number of metastases was similar in both groups (13 in the BMP4 group vs. 12 in controls). In BMP4-treated mice, bone metastases were more common (10 vs. 7) but adrenal gland metastases were less frequent (1 vs. 5) than in controls. Immunostaining revealed no differences in signaling activation, proliferation rate, blood vessel formation, EMT markers or the number of cancer-associated fibroblasts between the treatment groups. In conclusion, BMP4 caused a trend towards accelerated metastasis formation, especially in bone. More work is needed to uncover the long-term effects of BMP4 and the clinical relevance of these findings. PMID:26970275

  20. Prolonged sulforaphane treatment does not enhance tumorigenesis in oncogenic K-ras and xenograft mouse models of lung cancer

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    Ponvijay Kombairaju

    2012-01-01

    Full Text Available Background: Sulforaphane (SFN, an activator of nuclear factor erythroid-2 related factor 2 (Nrf2, is a promising chemopreventive agent which is undergoing clinical trial for several diseases. Studies have indicated that there is gain of Nrf2 function in lung cancer and other solid tumors because of mutations in the inhibitor Kelch-like ECH-associated protein 1 (Keap1. More recently, several oncogenes have been shown to activate Nrf2 signaling as the main prosurvival pathway mediating ROS detoxification, senescence evasion, and neoplastic transformation. Thus, it is important to determine if there is any risk of enhanced lung tumorigenesis associated with prolonged administration of SFN using mouse models of cancer. Materials and Methods: We evaluated the effect of prolonged SFN treatment on oncogenic K-ras (K-ras LSL-G12D -driven lung tumorigenesis. One week post mutant-K-ras expression, mice were treated with SFN (0.5 mg, 5 d/wk for 3 months by means of a nebulizer. Fourteen weeks after mutant K-ras expression (K-ras LSL-G12D , mice were sacrificed, and lung sections were screened for neoplastic foci. Expression of Nrf2-dependent genes was measured using real time RT-PCR. We also determined the effect of prolonged SFN treatment on the growth of preclinical xenograft models using human A549 (with mutant K-ras and Keap1 allele and H1975 [with mutant epidermal growth factor receptor (EGFR allele] nonsmall cell lung cancer cells. Results: Systemic SFN administration did not promote the growth of K-ras LSL-G12D -induced lung tumors and had no significant effect on the growth of A549 and H1975 established tumor xenografts in nude mice. Interestingly, localized delivery of SFN significantly attenuated the growth of A549 tumors in nude mice, suggesting an Nrf2-independent antitumorigenic activity of SFN. Conclusions: Our results demonstrate that prolonged SFN treatment does not promote lung tumorigenesis in various mouse models of lung cancer.

  1. Antitumor activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in mouse xenograft model of breast cancer.

    Science.gov (United States)

    Muscella, A; Vetrugno, C; Migoni, D; Biagioni, F; Fanizzi, F P; Fornai, F; De Pascali, S A; Marsigliante, S

    2014-01-01

    The higher and selective cytotoxicity of [Pt(O,O'-acac)(γ-acac)(DMS)] toward cancer cell in both immortalized cell lines and in breast cancer cells in primary cultures, stimulated a pre-clinical study so as to evaluate its therapeutic potential in vivo. The efficacy of [Pt(O,O'-acac)(γ-acac)(DMS)] was assessed using a xenograft model of breast cancer developed by injection of MCF-7 cells in the flank of BALB/c nude mice. Treatment of solid tumor-bearing mice with [Pt(O,O'-acac)(γ-acac)(DMS)] induced up to 50% reduction of tumor mass compared with an average 10% inhibition recorded in cisplatin-treated animals. Thus, chemotherapy with [Pt(O,O'-acac)(γ-acac)(DMS)] was much more effective than cisplatin. We also demonstrated enhanced in vivo pharmacokinetics, biodistribution and tolerability of [Pt(O,O'-acac)(γ-acac)(DMS)] when compared with cisplatin administered in Wistar rats. Pharmacokinetics studies with [Pt(O,O'-acac)(γ-acac)(DMS)] revealed prolonged Pt persistence in systemic blood circulation and decreased nefrotoxicity and hepatotoxicity, major target sites of cisplatin toxicity. Overall, [Pt(O,O'-acac)(γ-acac)(DMS)] turned out to be extremely promising in terms of greater in vivo anticancer activity, reduced nephrotoxicity and acute toxicity compared with cisplatin. PMID:24457958

  2. The HDACi Panobinostat Shows Growth Inhibition Both In Vitro and in a Bioluminescent Orthotopic Surgical Xenograft Model of Ovarian Cancer

    Science.gov (United States)

    Helland, Øystein; Popa, Mihaela; Bischof, Katharina; Gjertsen, Bjørn Tore; McCormack, Emmet; Bjørge, Line

    2016-01-01

    Background In most epithelial ovarian carcinomas (EOC), epigenetic changes are evident, and overexpression of histone deacetylases (HDACs) represents an important manifestation. In this study, we wanted to evaluate the effects of the novel HDAC inhibitor (HDACi) panobinostat, both alone and in combination with carboplatin, on ovarian cancer cell lines and in a murine bioluminescent orthotopic surgical xenograft model for EOC. Methods The effects of panobinostat, both alone and in combination with carboplatin, on proliferation and apoptosis in ovarian cancer cell lines, were evaluated using colony and WST-1 assays, Hoechst staining and flow cytometry analysis. In addition, mechanisms were characterised by western blotting and phosphoflow analysis. Immuno-deficient mice were engrafted orthotopically with SKOV-3luc+ cells and serial bioluminescence imaging monitored the effects of treatment with panobinostat and/or carboplatin and/or surgery. Survival parameters were also measured. Results Panobinostat treatment reduced cell growth and diminished cell viability, as shown by the induced cell cycle arrest and apoptosis in vitro. We observed increased levels of cleaved PARP and caspase-3, downregulation of cdc2 protein kinase, acetylation of H2B and higher pH2AX expression. The combined administration of carboplatin and panobinostat synergistically increased the anti-tumour effects compared to panobinostat or carboplatin treatment alone. In our novel ovarian cancer model, the mice showed significantly higher rates of survival when treated with panobinostat, carboplatin or a combination of both, compared to the controls. Panobinostat was as efficient as carboplatin regarding prolongation of survival. No significant additional effect on survival was observed when surgery was combined with carboplatin/panobinostat treatment. Conclusions Panobinostat demonstrates effective in vitro growth inhibition in ovarian cancer cells. The efficacy of panobinostat and carboplatin was

  3. A novel technique, using radioluminography, for the measurement of uniformity of radiolabelled antibody distribution in a colorectal cancer xenograft model

    International Nuclear Information System (INIS)

    Purpose: Radioimmunotherapy of cancer employs an antitumour antibody to carry a radionuclide selectively to deposits of cancer. Conventional dose estimates, based on the Medical Internal Radiation Dose (MIRD) formulation, assume uniform distribution of radiolabelled antitumour antibody within tissue source regions. This assumption has been tested by using a statistical model to predict the pixel value distribution obtained from the digitised radioluminographs of a known radioactive source. The model uses the statistical nature of the detection of radiation where any uniform source distribution can be expected to have a detected histogram of pixel counts that is normal or Gaussian. Therefore, any test for the degree of normality in the detected distribution is also a measure of the degree of uniformity in the source. Methods and Materials: Three statistical techniques have been used to test the normality of the histogram of pixel values produced from the antibody distribution in a tissue section. Kurtosis, skew, and Lilliefor's are tests for normality and have statistically defined critical values for a normal distribution. After administration of 125I-labelled F(ab)2 antibody to nude mice bearing the LS174T colorectal cancer xenograft, the uniformity of antibody distribution in tumour and healthy tissues is measured using the radioluminographs of formalin-fixed paraffin sections. The test statistic for kurtosis, skew, and Lilliefor's is calculated for each tissue and is compared to critical values from statistical tables. Results: The radiolabelled antibody is distributed uniformly in liver, spleen, muscle, lung, and colon and, therefore, conforms to conventional use of the MIRD formulation. The study showed that the kidney cortex and medulla should be considered separately in macroscopic absorbed-dose calculations, as should bone marrow and hard bone. Antibody heterogeneity in the tumour necessitates the incorporation of a microdosimetric tumour model into a

  4. Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer

    International Nuclear Information System (INIS)

    The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERα. Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps. In vitro study demonstrated that the ERα in BJMC3879luc2 cells was smaller (between 50 and 64 kDa) than the normal-sized ERα (66 kDa) and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERα mRNA levels were significantly higher in females than in males. In vitro studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ERα mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups. These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERα may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development

  5. Raloxifene inhibits tumor growth and lymph node metastasis in a xenograft model of metastatic mammary cancer

    Directory of Open Access Journals (Sweden)

    Li Zhong-Lian

    2010-10-01

    Full Text Available Abstract Background The effects of raloxifene, a novel selective estrogen receptor modulator, were studied in a mouse metastatic mammary cancer model expressing cytoplasmic ERα. Methods Mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879luc2 cells, were subsequently treated with raloxifene at 0, 18 and 27 mg/kg/day using mini-osmotic pumps. Results In vitro study demonstrated that the ERα in BJMC3879luc2 cells was smaller (between 50 and 64 kDa than the normal-sized ERα (66 kDa and showed cytoplasmic localization. A statistically significant but weak estradiol response was observed in this cell line. When BJMC3879luc2 tumors were implanted into mice, the ERα mRNA levels were significantly higher in females than in males. In vitro studies showed that raloxifene induced mitochondria-mediated apoptosis and cell-cycle arrest in the G1-phase and a decrease in the cell population in the S-phase. In animal experiments, tumor volumes were significantly suppressed in the raloxifene-treated groups. The multiplicity of lymph node metastasis was significantly decreased in the 27 mg/kg group. Levels of apoptosis were significantly increased in the raloxifene-treated groups, whereas the levels of DNA synthesis were significantly decreased in these groups. No differences in microvessel density in tumors were observed between the control and raloxifene-treated groups. The numbers of dilated lymphatic vessels containing intraluminal tumor cells were significantly reduced in mammary tumors in the raloxifene-treated groups. The levels of ERα mRNA in mammary tumors tended to be decreased in the raloxifene-treated groups. Conclusion These results suggest that the antimetastatic activity of raloxifene in mammary cancer expressing cytoplasmic ERα may be a crucial finding with clinical applications and that raloxifene may be useful as an adjuvant therapy and for the chemoprevention of breast cancer development.

  6. Mouse Models in Prostate Cancer Translational Research: From Xenograft to PDX.

    Science.gov (United States)

    Rea, Domenica; Del Vecchio, Vitale; Palma, Giuseppe; Barbieri, Antonio; Falco, Michela; Luciano, Antonio; De Biase, Davide; Perdonà, Sisto; Facchini, Gaetano; Arra, Claudio

    2016-01-01

    Despite the advancement of clinical and preclinical research on PCa, which resulted in the last five years in a decrement of disease incidence by 3-4%, it remains the most frequent cancer in men and the second for mortality rate. Based on this evidence we present a brief dissertation on numerous preclinical models, comparing their advantages and disadvantages; among this we report the PDX mouse models that show greater fidelity to the disease, in terms of histopathologic features of implanted tumor, gene and miRNA expression, and metastatic pattern, well describing all tumor progression stages; this characteristic encourages the translation of preclinical results. These models become particularly useful in meeting the need of new treatments identification that eradicate PCa bone metastases growing, clarifying pathway of angiogenesis, identifying castration-resistant stem-like cells, and studying the antiandrogen therapies. Also of considerable interest are the studies of 3D cell cultures derived from PDX, which have the ability to maintain PDX cell viability with continued native androgen receptor expression, also showing a differential sensitivity to drugs. 3D PDX PCa may represent a diagnostic platform for the rapid assessment of drugs and push personalized medicine. Today the development of preclinical models in vitro and in vivo is necessary in order to obtain increasingly reliable answers before reaching phase III of the drug discovery. PMID:27294148

  7. Mouse Models in Prostate Cancer Translational Research: From Xenograft to PDX

    Directory of Open Access Journals (Sweden)

    Domenica Rea

    2016-01-01

    Full Text Available Despite the advancement of clinical and preclinical research on PCa, which resulted in the last five years in a decrement of disease incidence by 3-4%, it remains the most frequent cancer in men and the second for mortality rate. Based on this evidence we present a brief dissertation on numerous preclinical models, comparing their advantages and disadvantages; among this we report the PDX mouse models that show greater fidelity to the disease, in terms of histopathologic features of implanted tumor, gene and miRNA expression, and metastatic pattern, well describing all tumor progression stages; this characteristic encourages the translation of preclinical results. These models become particularly useful in meeting the need of new treatments identification that eradicate PCa bone metastases growing, clarifying pathway of angiogenesis, identifying castration-resistant stem-like cells, and studying the antiandrogen therapies. Also of considerable interest are the studies of 3D cell cultures derived from PDX, which have the ability to maintain PDX cell viability with continued native androgen receptor expression, also showing a differential sensitivity to drugs. 3D PDX PCa may represent a diagnostic platform for the rapid assessment of drugs and push personalized medicine. Today the development of preclinical models in vitro and in vivo is necessary in order to obtain increasingly reliable answers before reaching phase III of the drug discovery.

  8. Mouse Models in Prostate Cancer Translational Research: From Xenograft to PDX

    Science.gov (United States)

    del Vecchio, Vitale; Palma, Giuseppe; Barbieri, Antonio; Falco, Michela; Luciano, Antonio; De Biase, Davide; Perdonà, Sisto; Facchini, Gaetano; Arra, Claudio

    2016-01-01

    Despite the advancement of clinical and preclinical research on PCa, which resulted in the last five years in a decrement of disease incidence by 3-4%, it remains the most frequent cancer in men and the second for mortality rate. Based on this evidence we present a brief dissertation on numerous preclinical models, comparing their advantages and disadvantages; among this we report the PDX mouse models that show greater fidelity to the disease, in terms of histopathologic features of implanted tumor, gene and miRNA expression, and metastatic pattern, well describing all tumor progression stages; this characteristic encourages the translation of preclinical results. These models become particularly useful in meeting the need of new treatments identification that eradicate PCa bone metastases growing, clarifying pathway of angiogenesis, identifying castration-resistant stem-like cells, and studying the antiandrogen therapies. Also of considerable interest are the studies of 3D cell cultures derived from PDX, which have the ability to maintain PDX cell viability with continued native androgen receptor expression, also showing a differential sensitivity to drugs. 3D PDX PCa may represent a diagnostic platform for the rapid assessment of drugs and push personalized medicine. Today the development of preclinical models in vitro and in vivo is necessary in order to obtain increasingly reliable answers before reaching phase III of the drug discovery. PMID:27294148

  9. The role of alpha 6 integrin in prostate cancer migration and bone pain in a novel xenograft model.

    Directory of Open Access Journals (Sweden)

    Tamara E King

    Full Text Available Of the estimated 565,650 people in the U.S. who will die of cancer in 2008, almost all will have metastasis. Breast, prostate, kidney, thyroid and lung cancers metastasize to the bone. Tumor cells reside within the bone using integrin type cell adhesion receptors and elicit incapacitating bone pain and fractures. In particular, metastatic human prostate tumors express and cleave the integrin A6, a receptor for extracellular matrix components of the bone, i.e., laminin 332 and laminin 511. More than 50% of all prostate cancer patients develop severe bone pain during their remaining lifetime. One major goal is to prevent or delay cancer induced bone pain. We used a novel xenograft mouse model to directly determine if bone pain could be prevented by blocking the known cleavage of the A6 integrin adhesion receptor. Human tumor cells expressing either the wildtype or mutated A6 integrin were placed within the living bone matrix and 21 days later, integrin expression was confirmed by RT-PCR, radiographs were collected and behavioral measurements of spontaneous and evoked pain performed. All animals independent of integrin status had indistinguishable tumor burden and developed bone loss 21 days after surgery. A comparison of animals containing the wild type or mutated integrin revealed that tumor cells expressing the mutated integrin resulted in a dramatic decrease in bone loss, unicortical or bicortical fractures and a decrease in the ability of tumor cells to reach the epiphyseal plate of the bone. Further, tumor cells within the bone expressing the integrin mutation prevented cancer induced spontaneous flinching, tactile allodynia, and movement evoked pain. Preventing A6 integrin cleavage on the prostate tumor cell surface decreased the migration of tumor cells within the bone and the onset and degree of bone pain and fractures. These results suggest that strategies for blocking the cleavage of the adhesion receptors on the tumor cell surface can

  10. Imaging-Guided Curative Surgical Resection of Pancreatic Cancer in a Xenograft Mouse Model

    OpenAIRE

    Ni, Xiaoling; Yang, Jingxuan; Min LI

    2012-01-01

    Pancreatic cancer is the fourth leading cause of cancer related deaths in North America. The poor survival statistics are due to the fact that there are no reliable tests for early diagnosis and no effective therapies once metastasis has occurred. Surgical resection is the only curative treatment for pancreatic cancer; however, only less than 15% of the patients are eligible for surgery at diagnosis. New therapies are urgently needed for this malignant disease. And combinational therapy inclu...

  11. Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model

    Science.gov (United States)

    A previous study indicated that lycopene could significantly inhibit the proliferation of human colon cancer cells in vitro. However, the in vivo anticancer effects of lycopene against colon cancer have not been demonstrated yet. Therefore, this study investigated whether consumption of lycopene cou...

  12. Porphyrin lipid nanoparticles for enhanced photothermal therapy in a patient-derived orthotopic pancreas xenograft cancer model

    Science.gov (United States)

    MacLaughlin, Christina M.; Ding, Lili; Jin, Cheng; Cao, Pingjiang; Siddiqui, Iram; Hwang, David M.; Chen, Juan; Wilson, Brian C.; Zheng, Gang; Hedley, David W.

    2016-03-01

    Local disease control is a major problem in the treatment of pancreatic cancer, because curative-intent surgery is only possible in a minority of patients, and radiotherapy cannot be delivered in curative doses. Despite the promise of photothermal therapy (PTT) for ablation of pancreatic tumors, this approach remains under investigated. Using photothermal sensitizers in combination with laser light for PTT can result in more efficient conversion of light energy to heat, and confinement of thermal destruction to the tumor, thus sparing adjacent organs and vasculature. Porphyrins have been previously employed as photosensitizers for PDT and PTT, however their incorporation in to "porphysomes", lipid-based nanoparticles each containing ~80,000 porphyrins through conjugation of pyropheophorbide to phospholipids, carries two distinct advantages: 1) high-density porphyrin packing imparts the nanoparticles with enhanced photonic properties for imaging and phototherapy; 2) the enhanced permeability and retention effect may be exploited for optimal delivery of porphysomes to the tumor region thus high payload porphyrin delivery. The feasibility of porphysome-enhanced PTT for pancreatic cancer treatment was investigated using a patient-derived orthotopic pancreas xenograft tumor model. Uptake of porphysomes at the orthotopic tumor site was validated using ex vivo fluorescence imaging of intact organs of interest. The accumulation of porphysomes in orthotopic tumor microstructure was also confirmed by fluorescence imaging of excised tissue slices. PTT progress was monitored as changes in tumor surface temperature using IR optical imaging. Histological analyses were conducted to examine microstructure changes in tissue morphology, and the viability of remaining tumor tissues following exposure to heat. These studies may also provide insight as to the contribution of heat sink in application of thermal therapies to highly vascularized pancreatic tumors.

  13. Critical role of c-Jun overexpression in liver metastasis of human breast cancer xenograft model

    International Nuclear Information System (INIS)

    c-Jun/AP-1 has been linked to invasive properties of aggressive breast cancer. Recently, it has been reported that overexpression of c-Jun in breast cancer cell line MCF-7 resulted in increased AP-1 activity, motility and invasiveness of the cells in vitro and tumor formation in nude mice. However, the role of c-Jun in metastasis of human breast cancer in vivo is currently unknown. To further investigate the direct involvement of c-Jun in tumorigenesis and metastasis, in the present study, the effects of c-Jun overexpression were studied in both in vitro and in nude mice. Ectopic overexpression of c-Jun promoted the growth of MCF-7 cells and resulted in a significant increase in the percentage of cells in S phase and increased motility and invasiveness. Introduction of c-Jun gene alone into weakly invasive MCF-7 cells resulted in the transfected cells capable of metastasizing to the nude mouse liver following tail vein injection. The present study confirms that overexpression of c-Jun contributes to a more invasive phenotype in MCF-7 cells. It indicates an interesting relationship between c-Jun expression and increased property of adhesion, migration and in vivo liver metastasis of MCF-7/c-Jun cells. The results provide further evidence that c-Jun is involved in the metastasis of breast cancer. The finding also opens an opportunity for development of anti-c-Jun strategies in breast cancer therapy

  14. A HLA-A2-restricted CTL epitope induces anti-tumor effects against human lung cancer in mouse xenograft model.

    Science.gov (United States)

    Sher, Yuh-Pyng; Lin, Su-I; Chen, I-Hua; Liu, Hsin-Yu; Lin, Chen-Yuan; Chiang, I-Ping; Roffler, Steve; Chen, Hsin-Wei; Liu, Shih-Jen

    2016-01-01

    Cancer immunotherapy is attractive for antigen-specific T cell-mediated anti-tumor therapy, especially in induction of cytotoxic T lymphocytes. In this report, we evaluated human CTL epitope-induced anti-tumor effects in human lung cancer xenograft models. The tumor associated antigen L6 (TAL6) is highly expressed in human lung cancer cell lines and tumor specimens as compared to normal lung tissues. TAL6 derived peptides strongly inhibited tumor growth, cancer metastasis and prolonged survival time in HLA-A2 transgenic mice immunized with a formulation of T-helper (Th) peptide, synthetic CpG ODN, and adjuvant Montanide ISA-51 (ISA-51). Adoptive transfer of peptide-induced CTL cells from HLA-A2 transgenic mice into human tumor xenograft SCID mice significantly inhibited tumor growth. Furthermore, combination of CTL-peptide immunotherapy and gemcitabine additively improved the therapeutic effects. This pre-clinical evaluation model provides a useful platform to develop efficient immunotherapeutic drugs to treat lung cancer and demonstrates a promising strategy with benefit of antitumor immune responses worthy of further development in clinical trials. PMID:26621839

  15. [18F]-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography of LAPC4-CR Castration-Resistant Prostate Cancer Xenograft Model in Soft Tissue Compartments

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    Keisha C. McCall

    2015-06-01

    Full Text Available Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [18F]-fluorodeoxyglucose (FDG positron emission tomography (PET/computed tomography (CT designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [18F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [18F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively. [18F]-FDG metabolism of the LAPC4-CR tumors was 2.1 ± 0.8 ID/cm3*wt, with tumor to muscle ratio of 7.4 ± 4.7 and tumor to liver background ratio of 6.7 ± 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [18F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models.

  16. Intratracheally Administered 5-Azacytidine Is Effective Against Orthotopic Human Lung Cancer Xenograft Models and Devoid of Important Systemic Toxicity

    Science.gov (United States)

    Mahesh, Sameer; Saxena, Ashish; Qiu, Xuan; Perez-Soler, Roman; Zou, Yiyu

    2014-01-01

    Introduction Hypermethylation of key tumor suppressor genes plays an important role in lung carcinogenesis. The purpose of this study is to explore the therapeutic potential of regional administration (via the airways) of the demethylating agent 5-azacytidine (5-Aza) for the treatment of early lung cancer. Patients and Methods We administered 5-Aza solution directly into the trachea in imprinting control region (ICR) mice (to study its toxicity) and in nude mice bearing orthotopic human lung cancer xenografts (to assess its antitumor activity). Results In vitro, 5-Aza inhibited the growth of human lung cancer cell lines H226, H358, and H460 in a dose-dependent manner. The concentrations to inhibit cell growth by 50% (IC50) were about 0.6-4.9 μg/mL. 5-Azacytidine reversed hypermethylation in the promoter of tumor suppressor gene RASSF1a in the H226 cells at a 6000-fold lower concentration than its IC50. In animal studies, intratracheal (I.T.) administration of 90 mg/kg 5-Aza (the maximum tolerated dose of 5-Aza intravenous injection [I.V.]) resulted in moderate pulmonary toxicity and 5-fold reduced myelosuppression compared with the same dose of I.V. 5-Aza. Using an optimized multiple dose schedule, I.T. 5-Aza was about 3-fold more effective than I.V. 5-Aza in prolonging the survival of mice bearing orthotopic H460 and H358 xenografts, and did not cause any detectable toxicity. Conclusion 5-Azacytidine can reverse the hypermethylation in the human lung cancer cell lines at a nontoxic dose. Regional administration to the airways enhances the therapeutic index of 5-Aza by 75-fold. The potential of regional administration of 5-Aza (including by aerosolization) for the treatment of advanced bronchial premalignancy deserves further investigation. PMID:21062731

  17. Pharmacologic inhibition of MLK3 kinase activity blocks the in vitro migratory capacity of breast cancer cells but has no effect on breast cancer brain metastasis in a mouse xenograft model.

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    Kun Hyoe Rhoo

    Full Text Available Brain metastasis of breast cancer is an important clinical problem, with few therapeutic options and a poor prognosis. Recent data have implicated mixed lineage kinase 3 (MLK3 in controlling the in vitro migratory capacity of breast cancer cells, as well as the metastasis of MDA-MB-231 breast cancer cells from the mammary fat pad to distant lymph nodes in a mouse xenograft model. We therefore set out to test whether MLK3 plays a role in brain metastasis of breast cancer cells. To address this question, we used a novel, brain penetrant, MLK3 inhibitor, URMC099. URMC099 efficiently inhibited the migration of breast cancer cells in an in vitro cell monolayer wounding assay, and an in vitro transwell migration assay, but had no effect on in vitro cell growth. We also tested the effect of URMC099 on tumor formation in a mouse xenograft model of breast cancer brain metastasis. This analysis showed that URMC099 had no effect on the either the frequency or size of breast cancer brain metastases. We conclude that pharmacologic inhibition of MLK3 by URMC099 can reduce the in vitro migratory capacity of breast cancer cells, but that it has no effect on either the frequency or size of breast cancer brain metastases, in a mouse xenograft model.

  18. Human Tumor Xenograft Models for Preclinical Assessment of Anticancer Drug Development

    OpenAIRE

    Jung, Joohee

    2014-01-01

    Xenograft models of human cancer play an important role in the screening and evaluation of candidates for new anticancer agents. The models, which are derived from human tumor cell lines and are classified according to the transplant site, such as ectopic xenograft and orthotopic xenograft, are still utilized to evaluate therapeutic efficacy and toxicity. The metastasis model is modified for the evaluation and prediction of cancer progression. Recently, animal models are made from patient-der...

  19. Establishment and Its Biological Characteristics of Patient-derived Lung Cancer Xenograft Modelse

    OpenAIRE

    Zhuo, Ying; Yilong WU; Guo, Ailin; Chen, Siyuan; Su, Jian

    2010-01-01

    Background and objective With the ongoing need to improve therapy for lung cancer, there has been an increasing interest in the development of reliable preclinical models to test novel therapeutics. The aim of this study is to establish a patient-derived lung cancer xenograft model in mice and to observe the biological characteristics of xenografts. Methods Surgically resectected tumor specimens from patients with lung cancer were implanted in the subcutaneous layer of the NOD/SCID mice. Canc...

  20. Establishment and Its Biological Characteristics of Patient-derived Lung Cancer Xenograft Modelse

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    Ying ZHUO

    2010-06-01

    Full Text Available Background and objective With the ongoing need to improve therapy for lung cancer, there has been an increasing interest in the development of reliable preclinical models to test novel therapeutics. The aim of this study is to establish a patient-derived lung cancer xenograft model in mice and to observe the biological characteristics of xenografts. Methods Surgically resectected tumor specimens from patients with lung cancer were implanted in the subcutaneous layer of the NOD/SCID mice. Cancer specimens of percutaneous lung biopsy by CT fluoroscopy were implanted into the subrenal capsule of nude mouse. The subcutaneous carcinoma was surgically removed when it grew to approximately 1.0 cm in diameter, and then re-transplanted into new nude mice. The growth process of transplanted tumor was observed. Expression of CEA, cytokeratin, and Ki67 were detected by immunohistochemistry. Mutations in the exons 18-21 of EGFR and exons 12,59 of K-ras of primary and xenograft tumors were examined. The cell cycle of xenograft tumor cells was analyzed by flow cytometry. Results Eleven cases were conducted for NOD/SCID mice and nude mice modelling. The patient-derived lung cancer xenografts have been established successfully, and the tumor could be passed to new nude mice, including No 2 model (adenocasinoma, No. 3 model (small cell lung cancer, and No. 5 model (squamous cell cancer. High homogeneity was found between xenograft tumors and human lung cancer in histopathology, immunohistochemical phenotype, and EGFR, K-ras mutation status . The S-phase fraction of xenograft cell cycle was prolonged, which indicated that the xenografts remains highly proliferated. Conclusion The xenotransplantation models established for patient-derived lung cancer in immune deficient mice. The success rate is 27%. This model system displayed the biological characteristics of human lung cancer, suggesting that it may provide a stable, reliable, and useful animal model in human

  1. Effects of exogenous human leptin on heat shock protein 70 expression in MCF-7 breast cancer cells and breast carcinoma of nude mice xenograft model

    Institute of Scientific and Technical Information of China (English)

    XUE Rong-quan; GU Jun-chao; YU Wei; WANG Yu; ZHANG Zhong-tao; MA Xue-mei

    2012-01-01

    Background It is important to identify the multiple sites of leptin activity in obese women with breast cancer.In this study,we examined the effect of exogenous human leptin on heat shock protein 70 (HSP70) expression in MCF-7 human breast cancer cells and in a breast carcinoma xenograft model of nude mice.Methods We cultured MCF-7 human breast cancer cells and established nude mice bearing xenograffs of these cells,and randomly divided them into experimental and control groups.The experimental group was treated with human leptin,while the control group was treated with the same volume of normal saline.A real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay was developed to quantify the mRNA expression of HSP70 in the MCF-7 human breast cancer cells and in tumor tissues.Western blotting analysis was applied to quantify the protein expression of HSP70 in the MCF-7 cells.Immunohistochemical staining was done to assess the positive rate of HSP70 expression in the tumor tissues.Results Leptin activated HSP70 in a dose-dependent manner in vitro:leptin upregulated significantly the expression of HSP70 at mRNA and protein levels in MCF-7 human breast cancer cells (P <0.001).There was no significant difference in expression of HSP70 mRNA in the implanted tumors between the leptin-treated group and the control group (P>0.05).Immunohistochemical staining revealed no significant difference in tumor HSP70 expression between the leptin-treated group and the control group (P>0.05).Conclusions A nude mouse xenograft model can be safely and efficiently treated with human leptin by subcutaneous injections around the tumor.HSP70 may be target of leptin in breast cancer.Leptin can significantly upregulate the expression of HSP70 in a dose-dependent manner in vitro.

  2. Metabonomic studies of pancreatic cancer response to radiotherapy in a mouse xenograft model using magnetic resonance spectroscopy and principal components analysis

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    Xin-Hong He

    2013-01-01

    Full Text Available AIM: To investigate the metabolic profiles of xenograft pancreatic cancer before and after radiotherapy by high-resolution magic angle spinning proton magnetic resonance spectroscopy (HRMAS 1H NMR combined with principal components analysis (PCA and evaluate the radiotherapeutic effect. METHODS: The nude mouse xenograft model of human pancreatic cancer was established by injecting human pancreatic cancer cell SW1990 subcutaneously into the nude mice. When the tumors volume reached 800 mm3, the mice received various radiation doses. Two weeks later, tumor tissue sections were prepared for running the NMR measurements. 1H NMR and PCA were used to determine the changes in the metabolic profiles of tumor tissues after radiotherapy. Metabolic profiles of normal pancreas, pancreatic tumor tissues, and radiation- treated pancreatic tumor tissues were compared. RESULTS: Compared with 1H NMR spectra of the normal nude mouse pancreas, the levels of choline, taurine, alanine, isoleucine, leucine, valine, lactate, and glutamic acid of the pancreatic cancer group were increased, whereas an opposite trend for phosphocholine, glycerophosphocholine, and betaine was observed. The ratio of phosphocholine to creatine, and glycerophosphocholine to creatine showed noticeable decrease in the pancreatic cancer group. After further evaluation of the tissue metabolic profile after treatment with three different radiation doses, no significant change in metabolites was observed in the 1H NMR spectra, while the inhibition of tumor growth was in proportion to the radiation doses. However, PCA results showed that the levels of choline and betaine were decreased with the increased radiation dose, and conversely, the level of acetic acid was dramatically increased. CONCLUSION: The combined methods were demonstrated to have the potential for allowing early diagnosis and assessment of pancreatic cancer response to radiotherapy.

  3. Pharmacologic Inhibition of MLK3 Kinase Activity Blocks the In Vitro Migratory Capacity of Breast Cancer Cells but Has No Effect on Breast Cancer Brain Metastasis in a Mouse Xenograft Model

    OpenAIRE

    Rhoo, Kun Hyoe; Granger, Megan; Sur, Joynita; Feng, Changyong; Gelbard, Harris A.; Dewhurst, Stephen; Polesskaya, Oksana

    2014-01-01

    Brain metastasis of breast cancer is an important clinical problem, with few therapeutic options and a poor prognosis. Recent data have implicated mixed lineage kinase 3 (MLK3) in controlling the in vitro migratory capacity of breast cancer cells, as well as the metastasis of MDA-MB-231 breast cancer cells from the mammary fat pad to distant lymph nodes in a mouse xenograft model. We therefore set out to test whether MLK3 plays a role in brain metastasis of breast cancer cells. To address thi...

  4. Anti-Tumoral Effects of Anti-Progestins in a Patient-Derived Breast Cancer Xenograft Model.

    Science.gov (United States)

    Esber, Nathalie; Cherbonnier, Clément; Resche-Rigon, Michèle; Hamze, Abdallah; Alami, Mouad; Fagart, Jérôme; Loosfelt, Hugues; Lombès, Marc; Chabbert-Buffet, Nathalie

    2016-04-01

    Breast cancer is a hormone-dependent disease in which estrogen signaling targeting drugs fail in about 10 % due to resistance. Strong evidences highlighted the mitogen role of progesterone, its ligands, and the corresponding progesterone receptor (PR) isoforms in mammary carcinoma. Several PR antagonists have been synthesized; however, some of them are non-selective and led to side or toxic effects. Herein, we evaluated the anti-tumor activity of a commercially available PR modulator, ulipristal acetate (UPA), and a new selective and passive PR antagonist "APR19" in a novel preclinical approach based on patient-derived breast tumor (HBCx-34) xenografted in nude mice. As opposed to P4 that slightly reduces tumor volume, UPA and APR19 treatment for 42 days led to a significant 30 % reduction in tumor weight, accompanied by a significant 40 % retardation in tumor growth upon UPA exposure while a 1.5-fold increase in necrotic areas was observed in APR19-treated tumors. Interestingly, PR expression was upregulated by a 2.5-fold factor in UPA-treated tumors while APR19 significantly reduced expression of both PR and estrogen receptor α, indicating a potential distinct molecular mechanism among PR antagonists. Cell proliferation was clearly reduced in UPA group compared to vehicle conditions, as revealed by the significant reduction in Ki-67, Cyclin D1, and proliferating cell nuclear antigen (PCNA) expression. Likewise, an increase in activated, cleaved poly(ADP-ribose) polymerase (PARP) expression was also demonstrated upon UPA exposure. Collectively, our findings provide direct in vivo evidence for anti-progestin-mediated control of human breast cancer growth, given their anti-proliferative and pro-apoptotic activities, supporting a potential role in breast cancer therapy. PMID:26941094

  5. Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice

    Science.gov (United States)

    Ji, Xi-wei; Ji, Shuang-min; Li, Run-tao; Wu, Ke-hua; Zhu, Xiao; Lu, Wei; Zhou, Tian-yan

    2016-01-01

    Aim: The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor (EGFR-TKI). Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition. Methods: Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 (50 or 150 mg·kg−1·d−1, ig) or vehicle for 18 d. The pharmacokinetics (PK) and pharmacodynamics (PD) of TM208 were evaluated. Results: The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC50 (55.9 μg/L), as well as three parameters ('a' of 27.2%, 'b' of 2730%, 'c' of 0.58 h−1) denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/transit compartment model with estimated parameters associated with tumor growth characteristics kng (0.282 day−1), drug potency kTM208 (0.0499 cm3/day) and the kinetics of tumor cell death k1 (0.141 day−1), which provided insight into drug mechanisms and behaviors. Conclusion: The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance. PMID:27133303

  6. 184AA3: a xenograft model of ER+ breast adenocarcinoma.

    Science.gov (United States)

    Hines, William C; Kuhn, Irene; Thi, Kate; Chu, Berbie; Stanford-Moore, Gaelen; Sampayo, Rocío; Garbe, James C; Stampfer, Martha; Borowsky, Alexander D; Bissell, Mina J

    2016-01-01

    Despite the prevalence and significant morbidity resulting from estrogen receptor positive (ER(+)) breast adenocarcinomas, there are only a few models of this cancer subtype available for drug development and arguably none for studying etiology. Those models that do exist have questionable clinical relevance. Given our goal of developing luminal models, we focused on six cell lines derived by minimal mutagenesis from normal human breast cells, and asked if any could generate clinically relevant xenografts, which we then extensively characterized. Xenografts of one cell line, 184AA3, consistently formed ER(+) adenocarcinomas that had a high proliferative rate and other features consistent with "luminal B" intrinsic subtype. Squamous and spindle cell/mesenchymal differentiation was absent, in stark contrast to other cell lines that we examined or others have reported. We explored intratumoral heterogeneity produced by 184AA3 by immunophenotyping xenograft tumors and cultured cells, and characterized marker expression by immunofluorescence and flow cytometry. A CD44(High) subpopulation was discovered, yet their tumor forming ability was far less than CD44(Low) cells. Single cell cloning revealed the phenotypic plasticity of 184AA3, consistent with the intratumoral heterogeneity observed in xenografts. Characterization of ER expression in cultures revealed ER protein and signaling is intact, yet when estrogen was depleted in culture, and in vivo, it did not impact cell or tumor growth, analogous to therapeutically resistant ER(+) cancers. This model is appropriate for studies of the etiology of ovarian hormone independent adenocarcinomas, for identification of therapeutic targets, predictive testing, and drug development. PMID:26661596

  7. Comparison of intratumoral FDG and Cu-ATSM distributions in cancer tissue originated spheroid (CTOS) xenografts, a tumor model retaining the original tumor properties

    International Nuclear Information System (INIS)

    Introduction: The intratumoral distributions of [18F]FDG and [64Cu]Cu-ATSM have been reported to be similar in adenocarcinomas but different in squamous cell carcinoma (SCC) in clinical studies. In the present study, we compared the intratumoral distributions of these two tracers in cancer tissue originated spheroid (CTOS) xenografts derived from adenocarcinoma and SCC, which retain the histological characteristics of the original tumors, and in cancer cell line xenografts of corresponding origin, to investigate the underlying mechanism of the distinct FDG and Cu-ATSM distribution patterns in adenocarcinoma and SCC. Methods: CTOSs derived from colon adenocarcinoma and lung SCC and cell lines established from colon adenocarcinoma and lung SCC, which were used for comparison, were subcutaneously transplanted into immunodeficient mice. One hour after administering [14C]FDG and [64Cu]Cu-ATSM, the intratumoral distributions were compared in the xenografts by using dual-tracer autoradiography. Adjacent sections were evaluated for necrosis, vasculature anatomy, Ki-67 antigen, and pimonidazole adducts using hematoxylin and eosin and immunohistochemical staining. Results: There was a higher regional overlap of high FDG and Cu-ATSM accumulations in the adenocarcinoma CTOS xenografts than in the SCC CTOS xenografts, while the overlap in the adenocarcinoma cell line xenograft was lower than that observed in the SCC cell line. High FDG accumulation occurred primarily in proximity to necrotic or pimonidazole adduct positive regions, while high Cu-ATSM accumulation occurred primarily in live cell regions separate from the necrotic regions. The adenocarcinoma CTOS xenograft had the stereotypical glandular structure, resulting in more intricately mixed regions of live and necrotic cells compared to those observed in the SCC CTOS or the cell line xenografts. Conclusion: Tumor morphological characteristics, specifically the spatial distribution of live and necrotic cell regions

  8. Frankincense essential oil prepared from hydrodistillation of Boswellia sacra gum resins induces human pancreatic cancer cell death in cultures and in a xenograft murine model

    Directory of Open Access Journals (Sweden)

    Ni Xiao

    2012-12-01

    Full Text Available Abstract Background Regardless of the availability of therapeutic options, the overall 5-year survival for patients diagnosed with pancreatic cancer remains less than 5%. Gum resins from Boswellia species, also known as frankincense, have been used as a major ingredient in Ayurvedic and Chinese medicine to treat a variety of health-related conditions. Both frankincense chemical extracts and essential oil prepared from Boswellia species gum resins exhibit anti-neoplastic activity, and have been investigated as potential anti-cancer agents. The goals of this study are to identify optimal condition for preparing frankincense essential oil that possesses potent anti-tumor activity, and to evaluate the activity in both cultured human pancreatic cancer cells and a xenograft mouse cancer model. Methods Boswellia sacra gum resins were hydrodistilled at 78°C; and essential oil distillate fractions were collected at different durations (Fraction I at 0–2 h, Fraction II at 8–10 h, and Fraction III at 11–12 h. Hydrodistillation of the second half of gum resins was performed at 100°C; and distillate was collected at 11–12 h (Fraction IV. Chemical compositions were identified by gas chromatography–mass spectrometry (GC-MS; and total boswellic acids contents were quantified by high-performance liquid chromatography (HPLC. Frankincense essential oil-modulated pancreatic tumor cell viability and cytotoxicity were determined by colorimetric assays. Levels of apoptotic markers, signaling molecules, and cell cycle regulators expression were characterized by Western blot analysis. A heterotopic (subcutaneous human pancreatic cancer xenograft nude mouse model was used to evaluate anti-tumor capability of Fraction IV frankincense essential oil in vivo. Frankincense essential oil-induced tumor cytostatic and cytotoxic activities in animals were assessed by immunohistochemistry. Results Longer duration and higher temperature hydrodistillation produced more

  9. NGAL Expression Is Elevated in Both Colorectal Adenoma–Carcinoma Sequence and Cancer Progression and Enhances Tumorigenesis in Xenograft Mouse Models

    Science.gov (United States)

    Sun, Yan; Yokoi, Kenji; Li, Hui; Gao, Jun; Hu, Limei; Liu, Ben; Chen, Kexin; Hamilton, Stanley R.; Fan, Dominic; Sun, Baocun; Zhang, Wei

    2013-01-01

    Purpose There is growing evidence implicating that neutrophil gelatinase–associated lipocalin (NGAL) plays a role in the development and progression of cancers. However, the effect of NGAL in colorectal carcinoma (CRC) has not been clearly elucidated. In this study, we investigated the role of NGAL in the tumorigenesis and progression of CRC and evaluated the clinical value of NGAL expression. Experimental Design We examined NGAL expression in 526 colorectal tissue samples, including 53 sets of matched specimens (histologically normal mucosa, adenomas, and carcinomas) using immunohistochemical analysis. In CRCs, correlations between NGAL expression and clinicopathologic parameters were analyzed, and survival analysis was conducted. The role of NGAL was further tested using mouse xenograft models. Results NGAL expression was elevated during the colorectal adenoma–carcinoma sequence both among the 526 cases (rs = 0.66, P < 0.001) and in the 53 sets of matched specimens (rs = 0.60, P < 0.001). In CRCs, NGAL expression was associated with cancer stage (P = 0.041) and tumor recurrence in stage II patients (P = 0.037). Survival analysis revealed that NGAL expression was an independent prognostic factor for overall survival (HR = 1.84, P = 0.004) and for disease-free survival of stage II patients (HR = 5.88, P = 0.021). In mouse models, the xenografts in cecum and spleen were heavier and more numerous in the group injected with NGAL-overexpressing CRC cells (P < 0.05). Conclusions NGAL overexpression may promote the tumorigenesis and progression of CRC. Detecting NGAL expression in tumor tissues may be useful for evaluating prognosis of patients with CRC. PMID:21622717

  10. Biodistribution of 131I-Herceptin in breast cancer xenograft

    International Nuclear Information System (INIS)

    Objective: to establish Her-2 positive SK-BR-3 human breast cancer xenografts in athymic mice. To explore the biologic distribution of 131I-herceptin in human breast cancer xenografts. Methods: Implant SK-BR-3 cells subcutaneously to BALB/c-neu athymic mice to establish animal model. To measure the radiocounting per minute (cpm) of every organ on a γ arithmometer at 4, 12, 24, 48 h postinjection of 131I-Herceptin or 131I-mIgG, then to gain the T/NT ratios and the uptakes percentage per gram of the injection dose (% ID/g). Results: After subcutaneously planted, a 96% of tumor forming rate was achieved. Compared with the control group, bigger T/NT and % ID/g was obtained in the experimental group (P<0.05 and <0.01). Conclusion: A high tumor forming rate can be get by implanting SK-BR-3 cells subcutaneously to athymic mouse, 131I-Herceptin is obviously concentrated in tumor tissues. (authors)

  11. Efficacy of a non-hypercalcemic vitamin-D2 derived anti-cancer agent (MT19c and inhibition of fatty acid synthesis in an ovarian cancer xenograft model.

    Directory of Open Access Journals (Sweden)

    Richard G Moore

    Full Text Available BACKGROUND: Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models. METHODOLOGY/PRINCIPAL FINDING: Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3 xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c-VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K activity independently of PPAR-gamma protein. SIGNIFICANCE: Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis.

  12. The IGR-CaP1 Xenograft Model Recapitulates Mixed Osteolytic/Blastic Bone Lesions Observed in Metastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Nader Al Nakouzi

    2012-05-01

    Full Text Available Bone metastases have a devastating impact on quality of life and bone pain in patients with prostate cancer and decrease survival. Animal models are important tools in investigating the pathogenesis of the disease and in developing treatment strategies for bone metastases, but few animal models recapitulate spontaneous clinical bone metastatic spread. In the present study, IGR-CaP1, a new cell line derived from primary prostate cancer, was stably transduced with a luciferase-expressing viral vector to monitor tumor growth in mice using bioluminescence imaging. The IGR-CaP1 tumors grew when subcutaneously injected or when orthotopically implanted, reconstituted the prostate adenocarcinoma with glandular acini-like structures, and could disseminate to the liver and lung. Bone lesions were detected using bioluminescence imaging after direct intratibial or intracardiac injections. Anatomic bone structure assessed using high-resolution computed tomographic scans showed both lytic and osteoblastic lesions. Technetium Tc 99m methylene diphosphonate micro single-photon emission computed tomography confirmed the mixed nature of the lesions and the intensive bone remodeling. We also identified an expression signature for responsiveness of IGR-CaP1 cells to the bone microenvironment, namely expression of CXCR4, MMP-9, Runx2, osteopontin, osteoprotegerin, ADAMTS14, FGFBP2, and HBB. The IGR-CaP1 cell line is a unique model derived from a primary tumor, which can reconstitute human prostate adenocarcinoma in animals and generate experimental bone metastases, providing a novel means for understanding the mechanisms of bone metastasis progression and allowing preclinical testing of new therapies.

  13. Exosomal secretion of cytoplasmic prostate cancer xenograft-derived proteins

    NARCIS (Netherlands)

    F.H. Jansen (Flip); J. Krijgsveld (Jeroen); A.L. Rijswijk (Angelique); G.J.C.M. van den Bemd (Gert-Jan); M.S. van den Berg (Mirella); W.M. van Weerden (Wytske); R. Willemsen (Rob); L.J.M. Dekker (Lennard); T.M. Luider (Theo); G.W. Jenster (Guido)

    2009-01-01

    textabstractNovel markers for prostate cancer (PCa) are needed because current established markers such as prostate-specific antigen lack diagnostic specificity and prognostic value. Proteomics analysis of serum from mice grafted with human PCa xenografts resulted in the identification of 44 tumor-d

  14. In vivo sampling of Verteporfin uptake in pancreas cancer xenograft models: comparison of surface, oral, and interstitial measurements

    Science.gov (United States)

    Isabelle, Martin; O'Hara, Julia A.; Samkoe, Kimberley S.; Hoopes, P. Jack; Mosse, Sandy; Pereira, Stephen; Hasan, Tayyaba; Pogue, Brian W.

    2010-02-01

    Photodynamic therapy (PDT) mediated with Verteporfin is being investigated as a pancreatic cancer treatment in the cases for non-surgical candidates. Tissue response to PDT is based on a number of parameters including photosensitizer (PS) dose, light dose and time interval between light application and PS injection. In this study, PS uptake and distribution in animal leg muscle, oral cavity tissues, pancreas and tumor was measured in vivo using light-induced fluorescence spectroscopy (LIFS) via an Aurora Optics Inc. PDT fluorescence dosimeter. An orthotopic pancreatic cancer model (AsPC-1) was implanted in SCID mice and treated with the PS. Probe measurements were made using a surface probe and an interstitial needle probe before and up to one hour after intravenous tail vein injection of the PS. The study demonstrated that it is possible to correlate in-vivo LIFS measurements of the PS uptake in the pancreas with measurements taken from the oral cavity indicating that light dosimetry of PDT of the pancreas can be ascertained from the LIFS measurements in the oral cavity. These results emphasize the importance of light dosimetry in improving the therapeutic outcome of PDT through light dose adaptation to the relative in situ tissue PS concentration.

  15. Impact of bevacizumab in combination with erlotinib on EGFR-mutated non-small cell lung cancer xenograft models with T790M mutation or MET amplification.

    Science.gov (United States)

    Furugaki, Koh; Fukumura, Junko; Iwai, Toshiki; Yorozu, Keigo; Kurasawa, Mitsue; Yanagisawa, Mieko; Moriya, Yoichiro; Yamamoto, Kaname; Suda, Kenichi; Mizuuchi, Hiroshi; Mitsudomi, Tetsuya; Harada, Naoki

    2016-02-15

    Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, shows notable efficacy against non-small cell lung cancer (NSCLC) harboring EGFR mutations. Bevacizumab (BEV), a humanized monoclonal antibody to vascular endothelial cell growth factor (VEGF), in combination with ERL (BEV+ERL) significantly extended progression-free survival in patients with EGFR-mutated NSCLC compared with ERL alone. However, the efficacy of BEV+ERL against EGFR-mutated NSCLC harboring T790M mutation or MET amplification, is unclear. Here, we examined the antitumor activity of BEV+ERL in four xenograft models of EGFR-mutated NSCLC (three harboring ERL resistance mutations). In the HCC827 models (exon 19 deletion: DEL), ERL significantly inhibited tumor growth by blocking EGFR signal transduction. Although there was no difference between ERL and BEV+ERL in maximum tumor growth inhibition, BEV+ERL significantly suppressed tumor regrowth during a drug-cessation period. In the HCC827-EPR model (DEL+T790M) and HCC827-vTR model (DEL+MET amplification), ERL reduced EGFR signal transduction and showed less pronounced but still significant tumor growth inhibition than in the HCC827 model. In these models, tumor growth inhibition was significantly stronger with BEV+ERL than with each single agent. In the NCI-H1975 model (L858R+T790M), ERL did not inhibit growth or EGFR signal transduction, and BEV+ERL did not inhibit growth more than BEV. BEV alone significantly decreased microvessel density in each tumor. In conclusion, addition of BEV to ERL did not enhance antitumor activity in primarily ERL-resistant tumors with T790M mutation; however, BEV+ERL enhanced antitumor activity in T790M mutation- or MET amplification-positive tumors as long as their growth remained significantly suppressed by ERL. PMID:26370161

  16. Induction of premature senescence by single and fractionated irradiation in human cancer cell line and xenografted mice model

    International Nuclear Information System (INIS)

    Radiation therapy (RT) is one of the best therapeutic strategies for cancer treatment. The cellular responses to ionizing radiation (IR) are varied ranging from cellular senescence to apoptotic cell death. To increase the efficacy of IR treatment is a major issue of radiation biology. From the point of view, the induction of premature senescence using the therapeutic dose of IR could be a promising treatment for tumors. The aim of this study is whether the premature senescence could contribute to cancer treatment by irradiation

  17. Host-derived RANKL is responsible for osteolysis in a C4-2 human prostate cancer xenograft model of experimental bone metastases

    International Nuclear Information System (INIS)

    C4-2 prostate cancer (CaP) cells grown in mouse tibiae cause a mixed osteoblastic/osteolytic response with increases in osteoclast numbers and bone resorption. Administration of osteoprotegerin (OPG) blocks these increases, indicating the critical role of RANKL in osteolysis in this model. The objective of our study was to investigate whether RANKL expressed by tumor cells (human origin) directly stimulates osteolysis associated with the growth of these cells in bone or whether the increased osteolysis is caused by RANKL expressed by the host environment cells (murine origin). The relative contribution of tumor-vs. host-derived RANKL has been difficult to establish, even with human xenografts, because murine and human RANKL are both capable of stimulating osteolysis in mice, and the RANKL inhibitors used to date (OPG and RANK-Fc) inhibit human and murine RANKL. To address this question we used a neutralizing, antibody (huRANKL MAb), which specifically neutralizes the biological activities of human RANKL and thereby the contribution of C4-2 derived RANKL in this tibial injection model of experimental bone metastases. Administration of huRANKL MAb did not inhibit the osteolytic response of the bone to these cells, or affect the establishment and growth of the C4-2 tumors in this environment. In conclusion, our results suggest that in this model, murine RANKL and not the tumor-derived human RANKL is the mediator of the osteolytic reaction associated with C4-2 growth in bone. We hypothesize that C4-2 cells express other factor/s inducing host production of RANKL, thereby driving tumor-associated osteolysis

  18. lacZ transduced human breast cancer xenografts as an in vivo model for the study of invasion and metastasis

    DEFF Research Database (Denmark)

    Brünner, N; Thompson, E W; Spang-Thomsen, M; Rygaard, J; Danø, K; Zwiebel, J A

    A number of human cancer cell lines have been described as being invasive and metastatic in immune incompetent animals. However, it is difficult to assess metastatic spread of a subcutaneously injected or inoculated cell line, since an exact detection of all microfoci of human tumour cells in the...

  19. Concomitant consumption of lycopene and fish oil inhibits tumor growth and progression in a mouse xenograft model of colon cancer

    Science.gov (United States)

    Our previous report showed that concomitant supplementation of lycopene and eicosa-pentaenoic acid synergistically inhibited the proliferation of human colon cancer HT-29 cells in vitro. To validate our findings, the present study investigated whether consumption of lycopene and fish oil would help ...

  20. Inhibition of Cell Proliferation and Growth of Pancreatic Cancer by Silencing of Carbohydrate Sulfotransferase 15 In Vitro and in a Xenograft Model

    Science.gov (United States)

    Shibazaki, Yuichiro; Yoneyama, Hiroyuki; Fujii, Masato; Hashiguchi, Taishi; Ito, Zensho; Kajihara, Mikio; Misawa, Takeyuki; Homma, Sadamu; Ohkusa, Toshifumi

    2015-01-01

    Chondroitin sulfate E (CS-E), a highly sulfated glycosaminoglycan, is known to promote tumor invasion and metastasis. Because the presence of CS-E is detected in both tumor and stromal cells in pancreatic ductal adenocarcinoma (PDAC), multistage involvement of CS-E in the development of PDAC has been considered. However, its involvement in the early stage of PDAC progression is still not fully understood. In this study, to clarify the direct role of CS-E in tumor, but not stromal, cells of PDAC, we focused on carbohydrate sulfotransferase 15 (CHST15), a specific enzyme that biosynthesizes CS-E, and investigated the effects of the CHST15 siRNA on tumor cell proliferation in vitro and growth in vivo. CHST15 mRNA is highly expressed in the human pancreatic cancer cell lines PANC-1, MIA PaCa-2, Capan-1 and Capan-2. CHST15 siRNA significantly inhibited the expression of CHST15 mRNA in these four cells in vitro. Silencing of the CHST15 gene in the cells was associated with significant reduction of proliferation and up-regulation of the cell cycle inhibitor-related gene p21CIP1/WAF1. In a subcutaneous xenograft tumor model of PANC-1 in nude mice, a single intratumoral injection of CHST15 siRNA almost completely suppressed tumor growth. Reduced CHST15 protein signals associated with tumor necrosis were observed with the treatment with CHST15 siRNA. These results provide evidence of the direct action of CHST15 on the proliferation of pancreatic tumor cells partly through the p21CIP1/WAF1 pathway. Thus, CHST15-CS-E axis-mediated tumor cell proliferation could be a novel therapeutic target in the early stage of PDAC progression. PMID:26642349

  1. Evaluation of {sup 99m}Tc-glucarate as a breast cancer imaging agent in a xenograft animal model

    Energy Technology Data Exchange (ETDEWEB)

    Gambini, Juan Pablo [Nuclear Medicine Center, Clinical Hospital, University of Uruguay, Montevideo, 11600 (Uruguay); Cabral, Pablo [Nuclear Investigations Center, School of Science, University of Uruguay, Montevideo, 11400 (Uruguay); Alonso, Omar [Nuclear Medicine Center, Clinical Hospital, University of Uruguay, Montevideo, 11600 (Uruguay); Savio, Eduardo [Department of Radiochemistry, School of Chemistry, University of Uruguay, Montevideo, 11800 (Uruguay); Daibes Figueroa, Said [Research Service, Harry S. Truman Veterans Memorial Hospital, Columbia, MO 65201 (United States); Zhang Xiuli [Research Service, Harry S. Truman Veterans Memorial Hospital, Columbia, MO 65201 (United States); Department of Biochemistry, University of Missouri, Columbia, MO 65211 (United States); Ma Lixin [Research Service, Harry S. Truman Veterans Memorial Hospital, Columbia, MO 65201 (United States); Department of Radiology, University of Missouri, Columbia, MO 65212 (United States); Deutscher, Susan L. [Research Service, Harry S. Truman Veterans Memorial Hospital, Columbia, MO 65201 (United States); Department of Biochemistry, University of Missouri, Columbia, MO 65211 (United States); Quinn, Thomas P., E-mail: quinnt@missouri.ed [Research Service, Harry S. Truman Veterans Memorial Hospital, Columbia, MO 65201 (United States); Department of Biochemistry, University of Missouri, Columbia, MO 65211 (United States); Department of Radiology, University of Missouri, Columbia, MO 65212 (United States)

    2011-02-15

    Introduction: The use of [{sup 99m}Tc]glucarate has been reported as an infarct-avid agent with the potential for very early detection of myocardial infarction. [{sup 99m}Tc]Glucarate has also been postulated as an agent for non-invasive detection of tumors. The aim of our study was to develop a Glucarate kit and evaluate [{sup 99m}Tc]glucarate as a potential cancer imaging agent in female SCID mice bearing human MDA-MB-435 breast tumors. Methods: Glucarate in a kit formulation was labeled with {sup 99m}Tc and evaluated for radiolabelling efficiency and radiochemical purity. The Glucarate kit stability was assessed by monthly quality controls. The pharmacokinetics of [{sup 99m}Tc]glucarate were determined in female SCID mice bearing MDA-MB-435 human breast carcinoma tumors at 0.5, 1, 2, 4 and 24 h. Nuclear imaging studies were performed with a micro-single photon emission tomography (SPECT)/computed tomography (CT) system at 2 h post injection, while magnetic resonance imaging (MRI) was employed for tumor morphology analysis and metastatic deposit localization. Results: The Glucarate kits exhibited a stable shelf life of 6 months. [{sup 99m}Tc]Glucarate was obtained with radiochemical purity greater than 95%. Biodistribution studies demonstrated moderate tumor uptake coupled with high renal clearance. Tumor-to-muscle ratios were 4.85 and 5.14 at 1 and 4 h post injection. MRI analysis showed tumors with dense cellular growth and moderate central necrosis. [{sup 99m}Tc]Glucarate uptake in the primary MDA-MB-435 shoulder tumors and metastatic lesions were clearly visualized with micro-SPECT/CT imaging. Conclusions: Selective tumor uptake and rapid clearance from nontarget organs makes [{sup 99m}Tc]glucarate a potential agent for breast cancer imaging that awaits validation in a clinical trial.

  2. Lentivirus-mediated RNA interference targeting the ObR gene in human breast cancer MCF-7 cells in a nude mouse xenograft model

    Institute of Scientific and Technical Information of China (English)

    XUE Rong-quan; GU Jun-chao; DU Song-tao; YU Wei; WANG Yu; ZHANG Zhong-tao; BAI Zhi-gang; MA Xue-mei

    2012-01-01

    Background There is a significant association between obesity and breast cancer,which is possibly due to the expression of leptin.Therefore,it is important to clarify the role of leptin/ObR (leptin receptor) signaling during the progression of human breast cancer.Methods Nude mice with xenografts of MCF-7 human breast cancer cells were administered recombinant human leptin subcutaneous via injection around the tumor site.Mice in the experimental group were intratumorally injected with ObR-RNAi-lentivirus,while negative control group mice were injected with the same dose of negative-lentivirus.Tumor size was blindly measured every other day,and mRNA and protein expression levels of ObR,estrogen receptor α(ERα),and vascular endothelial growth factor (VEGF) for each group were determined.Results Knockdown of ObR-treated xenografted nude mice with a high leptin microenvironment was successfully established.Local injection of ObR-RNAi-lentivirus significantly suppressed the established tumor growth in nude mice.ObR level was significantly lower in the experimental group than in the negative control group,while the amounts of ERα and VEGF expression were significantly lower in the leptin group than in the control group (P <0.01 for all).Conclusions Inhibition of leptin/ObR signaling is essential to breast cancer proliferation and possible crosstalk between ObR and ERα,and VEGF,and may lead to novel therapeutic treatments aiming at targeting ObR in breast cancers.

  3. Improvement of Radiation-Mediated Immunosuppression of Human NSCLC Tumour Xenografts in a Nude Rat Model

    Directory of Open Access Journals (Sweden)

    Sergey V. Tokalov

    2010-01-01

    Full Text Available Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC xenografts in a nude rat model irradiation (2 + 2 Gy from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

  4. Effects of Per2 overexpression on growth inhibition and metastasis, and on MTA1, nm23-H1 and the autophagy-associated PI3K/PKB signaling pathway in nude mice xenograft models of ovarian cancer

    Science.gov (United States)

    WANG, ZHAOXIA; LI, LI; WANG, YANG

    2016-01-01

    The aim of the present study was to evaluate the association between Period2 (Per2) and the occurrence and development of ovarian cancer, in addition to evaluating the effect of this gene on the growth and metastasis of ovarian cancer in nude mice xenograft models. The detection of Per2 by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting methods at various stages of ovarian cancer in tumor tissue samples was conducted. Nude mice xenograft models of ovarian cancer were constructed using an ovarian cancer cell line and, using a gene transfection technique, exogenous infusion of the recombinant gene, Per2, was performed. To assess for the successful and stable expression of Per2 in the tumor tissue, levels of Per2 expression in the nude mice xenograft models were detected by RT-qPCR. During the experimental period, the tumor volumes were measured every three days. Two weeks following treatment cessation, the nude mice were sacrificed and the tumor weight and volume were measured. Furthermore, detection of the changes in expression levels of metastasis-associated gene 1 (MTA-1) and tumor metastasis suppressor gene, non-metastasis protein 23-H1 (nm23-H1), and the expression change of autophagy-associated signal transduction pathway, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB) kinase were analyzed. The findings demonstrated that with ovarian cancer stage development, the expression of Per2 gradually reduced or ceased. In addition, exogenous Per2 was successfully and stably expressed in nude mice tumor tissue samples. Furthermore, in the Per2 overexpression group, MTA-1 protein expression was significantly reduced when compared with the phosphate-buffered saline (PBS) control and empty plasmid groups, while nm23-H1 protein expression was significantly higher when compared with those two groups. The expression levels of PI3K and PKB kinase, which are marker proteins of the autophagy associated signaling pathway PI3

  5. Plumbagin, a medicinal plant (Plumbago zeylanica) - derived 1,4-naphthoquinone, inhibits growth and metastasis of human prostate cancer PC-3M-luciferase cells in an orthotopic xenograft mouse model

    OpenAIRE

    Hafeez, Bilal Bin; Zhong, Weixiong; Fischer, Joseph W.; Mustafa, Ala; Shi, Xudong Daniel; Meske, Louise; Hong, Hao; Cai, Weibo; Havighurst, Thomas; Kim, KyungMann; Verma, Ajit K.

    2012-01-01

    We present here first time that Plumbagin (PL), a medicinal plant-derived 1,4-naphthoquinone, inhibits the growth and metastasis of prostate cancer (PCa) in an orthotopic xenograft mouse model. In this study, human PCa PC-3M-luciferase cells (2X106) were injected into the prostate of athymic nude mice. Three days post cell implantation, mice were treated with PL (2 mg/kg body wt. i.p five days in a week) for 8 weeks. Growth and metastasis of PC-3M-luciferase cells was examined weekly by biolu...

  6. Patient-derived bladder cancer xenografts in the preclinical development of novel targeted therapies

    OpenAIRE

    Jäger, Wolfgang; Xue, Hui; Hayashi, Tetsutaro; Janssen, Claudia; Awrey, Shannon; Wyatt, Alexander W.; Anderson, Shawn; Moskalev, Igor; Haegert, Anne; Alshalalfa, Mohammed; Erho, Nicholas; Davicioni, Elai; Fazli, Ladan; Li, Estelle; Collins, Colin

    2015-01-01

    Optimal animal models of muscle invasive bladder cancer (MIBC) are necessary to overcome the current lack of novel targeted therapies for this malignancy. Here we report on the establishment and characterization of patient-derived primary xenografts (PDX). Patient tumors were grafted under the renal capsule of mice and subsequently transplanted over multiple generations. Patient tumor and PDX were processed for analysis of copy number variations by aCGH, gene expression by microarray, and exp...

  7. Selective antitumor effect of neural stem cells expressing cytosine deaminase and interferon-beta against ductal breast cancer cells in cellular and xenograft models

    Directory of Open Access Journals (Sweden)

    Bo-Rim Yi

    2014-01-01

    Full Text Available Due to their inherent tumor-tropic properties, genetically engineered stem cells may be advantageous for gene therapy treatment of various human cancers, including brain, liver, ovarian, and prostate malignancies. In this study, we employed human neural stem cells (HB1.F3; hNSCs transduced with genes expressing Escherichia coli cytosine deaminase (HB1.F3.CD and human interferon-beta (HB1.F3.CD.IFN-β as a treatment strategy for ductal breast cancer. CD can convert the prodrug 5-fluorocytosine (5-FC to its active chemotherapeutic form, 5-fluorouracil (5-FU, which induces a tumor-killing effect through DNA synthesis inhibition. IFN-β also strongly inhibits tumor growth by the apoptotic process. RT-PCR confirmed that HB1.F3.CD cells expressed CD and HB1.F3.CD.IFN-β cells expressed both CD and IFN-β. A modified transwell migration assay showed that HB1.F3.CD and HB1.F3.CD.IFN-β cells selectively migrated toward MCF-7 and MDA-MB-231 human breast cancer cells. In hNSC-breast cancer co-cultures the viability of breast cancer cells which were significantly reduced by HB1.F3.CD or HB1.F3.CD.IFN-β cells in the presence of 5-FC. The tumor inhibitory effect was greater with the HB1.F3.CD.IFN-β cells, indicating an additional effect of IFN-β to 5-FU. In addition, the tumor-tropic properties of these hNSCs were found to be attributed to chemoattractant molecules secreted by breast cancer cells, including stem cell factor (SCF, c-kit, vascular endothelial growth factor (VEGF, and VEGF receptor 2. An in vivo assay performed using MDA-MB-231/luc breast cancer mammary fat pad xenografts in immunodeficient mice resulted in 50% reduced tumor growth and increased long-term survival in HB1.F3.CD and HB1.F3.CD.IFN-β plus 5-FC treated mice relative to controls. Our results suggest that hNSCs genetically modified to express CD and/or IFN-β genes can be used as a novel targeted cancer gene therapy.

  8. 4-tert-Octylphenol stimulates the expression of cathepsins in human breast cancer cells and xenografted breast tumors of a mouse model via an estrogen receptor-mediated signaling pathway

    International Nuclear Information System (INIS)

    Highlights: ► Cathepsins B and D were markedly enhanced by octylphenol (OP) in MCF-7 cells. ► OP may accelerate breast cancer cell growth and cathepsins via ER-mediated signaling. ► Breast cancer cells exposed with OP to mouse model were more aggressive. ► OP can promote metastasis through the amplification of cathepsins B and D via ER-mediated signaling pathway. -- Abstract: Endocrine disrupting chemicals (EDCs) are defined as environmental compounds that modulate steroid hormone receptor-dependent responses an abnormal manner, resulting in adverse health problems for humans such as cancer growth and metastasis. Cathepsins are proteases that have been implicated in cancer progression. However, there have been few studies about the association between cathepsins and estrogenic chemicals during the cancer progression. In this study, we examined the effect(s) of 4-tert-octylphenol (OP), a potent EDC, on the expression of cathepsins B and D in human MCF-7 breast cancer cells and a xenograft mouse model. Treatment with OP significantly induced the proliferation MCF-7 cells in an MTT assay. In addition, the expression of cathepsins B and D was markedly enhanced in MCF-7 cells at both the transcriptional and the translational levels following treatment with E2 or OP up to 48 h. These results demonstrated the ability of OP to disrupt normal transcriptional regulation of cathepsins B and D in human breast cancer cells. However, the effects of OP on cell growth or overexpression of cathepsins by inhibiting ER-mediated signaling were abolished by an ER antagonist and siRNA specific for ERα. In conclusion, our findings suggest that OP at 10−6 M, like E2, may accelerate breast cancer cell proliferation and the expression of cathepsins through an ER-mediated signaling pathway. In addition, the breast cancer cells exposed with OP to a xenograft mouse model were more aggressive according to our histological analysis and showed markedly increased expression of cathepsin

  9. Imaging Axl expression in pancreatic and prostate cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Nimmagadda, Sridhar, E-mail: snimmag1@jhmi.edu [Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287 (United States); Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287 (United States); Pullambhatla, Mrudula; Lisok, Ala [Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287 (United States); Hu, Chaoxin [Department of Pathology, Johns Hopkins University, Baltimore, MD 21287 (United States); Maitra, Anirban [Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287 (United States); Department of Pathology, Johns Hopkins University, Baltimore, MD 21287 (United States); Pomper, Martin G, E-mail: mpomper@jhmi.edu [Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD 21287 (United States); Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287 (United States)

    2014-01-10

    Highlights: •Axl is overexpressed in a variety of cancers. •Axl overexpression confers invasive phenotype. •Axl imaging would be useful for therapeutic guidance and monitoring. •Axl expression imaging is demonstrated in pancreatic and prostate cancer xenografts. •Graded levels of Axl expression imaging is feasible. -- Abstract: The receptor tyrosine kinase Axl is overexpressed in and leads to patient morbidity and mortality in a variety of cancers. Axl–Gas6 interactions are critical for tumor growth, angiogenesis and metastasis. The goal of this study was to investigate the feasibility of imaging graded levels of Axl expression in tumors using a radiolabeled antibody. We radiolabeled anti-human Axl (Axl mAb) and control IgG1 antibodies with {sup 125}I with high specific radioactivity and radiochemical purity, resulting in an immunoreactive fraction suitable for in vivo studies. Radiolabeled antibodies were investigated in severe combined immunodeficient mice harboring subcutaneous CFPAC (Axl{sup high}) and Panc1 (Axl{sup low}) pancreatic cancer xenografts by ex vivo biodistribution and imaging. Based on these results, the specificity of [{sup 125}I]Axl mAb was also validated in mice harboring orthotopic Panc1 or CFPAC tumors and in mice harboring subcutaneous 22Rv1 (Axl{sup low}) or DU145 (Axl{sup high}) prostate tumors by ex vivo biodistribution and imaging studies at 72 h post-injection of the antibody. Both imaging and biodistribution studies demonstrated specific and persistent accumulation of [{sup 125}I]Axl mAb in Axl{sup high} (CFPAC and DU145) expression tumors compared to the Axl{sup low} (Panc1 and 22Rv1) expression tumors. Axl expression in these tumors was further confirmed by immunohistochemical studies. No difference in the uptake of radioactivity was observed between the control [{sup 125}I]IgG1 antibody in the Axl{sup high} and Axl{sup low} expression tumors. These data demonstrate the feasibility of imaging Axl expression in pancreatic

  10. Ovarian and cervical cancer patient derived xenografts: The past, present, and future.

    Science.gov (United States)

    Boone, Jonathan D; Dobbin, Zachary C; Straughn, J Michael; Buchsbaum, Donald J

    2015-08-01

    Preclinical research in gynecologic malignancies has largely relied upon cloned cancer-derived cell lines and tumor xenografts derived from these cell lines. Unfortunately, the use of cell lines for translational research has disadvantages because genetic and phenotypic alterations from serial passaging have resulted in expression profiles that are different from the original patient tumors. The patient-derived xenograft (PDX) model derived from human tumor not previously cultured has shown better representation of the heterogeneity of gynecologic malignancies and the human tumor microenvironment with preservation of cytogenetics, cellular complexity, and vascular and stromal tumor architecture. Studies have shown promise with these models to analyze tumor development and adaptation, test drug efficacy, and predict clinical outcomes. Their ultimate value may be seen with preclinical drug screening including novel targeted therapies, biomarker identification, and the development of individualized treatment plans. This article reviews PDX model development, current studies testing chemotherapeutics and targeted therapies, and limitations of the PDX model in gynecologic malignancies. PMID:26026736

  11. Effects of Per2 overexpression on growth inhibition and metastasis, and on MTA1, nm23-H1 and the autophagy-associated PI3K/PKB signaling pathway in nude mice xenograft models of ovarian cancer.

    Science.gov (United States)

    Wang, Zhaoxia; Li, Li; Wang, Yang

    2016-06-01

    The aim of the present study was to evaluate the association between Period2 (Per2) and the occurrence and development of ovarian cancer, in addition to evaluating the effect of this gene on the growth and metastasis of ovarian cancer in nude mice xenograft models. The detection of Per2 by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting methods at various stages of ovarian cancer in tumor tissue samples was conducted. Nude mice xenograft models of ovarian cancer were constructed using an ovarian cancer cell line and, using a gene transfection technique, exogenous infusion of the recombinant gene, Per2, was performed. To assess for the successful and stable expression of Per2 in the tumor tissue, levels of Per2 expression in the nude mice xenograft models were detected by RT‑qPCR. During the experimental period, the tumor volumes were measured every three days. Two weeks following treatment cessation, the nude mice were sacrificed and the tumor weight and volume were measured. Furthermore, detection of the changes in expression levels of metastasis‑associated gene 1 (MTA‑1) and tumor metastasis suppressor gene, non‑metastasis protein 23‑H1 (nm23‑H1), and the expression change of autophagy‑associated signal transduction pathway, phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (PKB) kinase were analyzed. The findings demonstrated that with ovarian cancer stage development, the expression of Per2 gradually reduced or ceased. In addition, exogenous Per2 was successfully and stably expressed in nude mice tumor tissue samples. Furthermore, in the Per2 overexpression group, MTA‑1 protein expression was significantly reduced when compared with the phosphate‑buffered saline (PBS) control and empty plasmid groups, while nm23‑H1 protein expression was significantly higher when compared with those two groups. The expression levels of PI3K and PKB kinase, which are marker proteins of the autophagy

  12. Preliminary Research in Establishment, Characterization, and Application of Human Primary Esophageal Cancer Xenograft Models%人源性食管癌移植瘤模型的建立、评价及其应用的初步研究

    Institute of Scientific and Technical Information of China (English)

    欧阳可栋; 刘继斌; 王科; 胡刚; 顾莹; 谢付波; 赵强; 张亚华; 杨伟敏

    2013-01-01

    瘤模型具有很好的应用价值,可用于抗肿瘤药物的筛选及转化医学研究.%Objective To establish and characterize human primary esophageal xenografts by subcutaneous implantation of fresh resected esophageal cancer (EC) specimens in immunodeficient mice with unchanged tumor histological features and validate their application value. Methods Thirty-six fresh resected human esophageal cancer specimens were subcutaneously implanted into SCID mice. After tumor developed, they were serially passaged with nude mice using the same methods. For each case, when the xenograft tumors reached size 500-1000mm3, tumors were excised and devided into four parts: the first part was implanted into nude mice for the growth of next generation; the second part of tumor was viably saved in liquid nitrogen for future model recovery; the third part of tumor was snap frozen for DNA/RNA extraction; and the last part of tumor was fixed in formalin and embedded into paraffin (FFPE) for H&E staining and pathology analysis. Using four cases of human primary EC xenografts passaged in nude mice, chemosensitivity study in vitro and efficacy study in vivo were performed to evaluate the application value of these models. Results Twenty-three in 36 cases by fresh EC specimens implantation were successfully developed into tumor in immunodeficient mice, the implantation success rate was 63.89%. These xenografts were grown up stably and could be continuous passaged to next generation. Histopathology examination of transplanted tumors showed that these xenografts were stable with similar histological features compared with the original donors. Twenty-one in 23 models were successfully established in SCID mice when implanted with recovering cryopreserved xenograft tissues, the recovery success rate was 91.30%. In in vitro chemo-sensitivity assay, the selected four cases were sensitive to Sorafenib, 5-FU, Doxorubicin, Tarceva and Irinotecan; however, there were individual differences in

  13. Human Xenografts Are Not Rejected in a Naturally Occurring Immunodeficient Porcine Line: A Human Tumor Model in Pigs

    OpenAIRE

    Basel, Matthew T; Balivada, Sivasai; Beck, Amanda P; Kerrigan, Maureen A.; Pyle, Marla M; Dekkers, Jack C.M.; Wyatt, Carol R.; Rowland, Robert R. R.; Anderson, David E.; Bossmann, Stefan H; Troyer, Deryl L.

    2012-01-01

    Abstract Animal models for cancer therapy are invaluable for preclinical testing of potential cancer treatments; however, therapies tested in such models often fail to translate into clinical settings. Therefore, a better preclinical model for cancer treatment testing is needed. Here we demonstrate that an immunodeficient line of pigs can host and support the growth of xenografted human tumors and has the potential to be an effective animal model for cancer therapy. Wild-type and immunodefici...

  14. Src controls castration recurrence of CWR22 prostate cancer xenografts

    International Nuclear Information System (INIS)

    Recurrence of prostate cancer (CaP) after androgen-deprivation therapy continues to have the greatest impact on patient survival. Castration-recurrent (CR)-CaP is likely driven by the activation of androgen receptor (AR) through multiple mechanisms including induction of AR coregulators, AR mutants or splice variants, and AR posttranslational modification such as phosphorylation by Src-family and Ack1 tyrosine kinases. Here, we address whether Src is required for the CR growth of human CWR22 CaP xenografts. The shRNA-mediated Src knockdown or treatment with the Src inhibitors, dasatinib or KXO1, reduced CaP recurrence over controls and increased time-to-recurrence following castration. Moreover, CR-CaP [Src-shRNA] tumors that recurred had similar Src protein and activation levels as those of parental cells, strengthening the notion that Src activity is required for progression to CR-CaP. In contrast, the ability of dasatinib or KXO1 to inhibit Src kinase activity in vitro did not correlate with their ability to inhibit serum-driven in vitro proliferation of CR and androgen-dependent stable cell lines derived from CWR22 tumors (CWR22Rv1 and CWR22PC, respectively), suggesting that the in vitro proliferation of these CaP lines is Src independent. Taken together, these findings strongly suggest that Src is a potent and specific therapeutic target for CR-CaP progression

  15. Inhibition of Human Breast Cancer Xenograft Growth by Cruciferous Vegetable Constituent Benzyl Isothiocyanate

    OpenAIRE

    Warin, Renaud; Xiao, Dong; Arlotti, Julie A.; Bommareddy, Ajay; Singh, Shivendra V

    2010-01-01

    Benzyl isothiocyanate (BITC), a constituent of cruciferous vegetables such as gardencress, inhibits growth of human breast cancer cell lines in culture. The present study was undertaken to determine in vivo efficacy of BITC against MDA-MB-231 human breast cancer xenografts. The BITC administration retarded growth of MDA-MB-231 cells subcutaneously implanted in female nude mice without causing weight loss or any other side effects. The BITC-mediated suppression of MDA-MB-231 xenograft growth c...

  16. Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model.

    Science.gov (United States)

    Handratta, Venkatesh D; Vasaitis, Tadas S; Njar, Vincent C O; Gediya, Lalji K; Kataria, Ritesh; Chopra, Pankaj; Newman, Donnell; Farquhar, Rena; Guo, Zhiyong; Qiu, Yun; Brodie, Angela M H

    2005-04-21

    tentatively identified as 17-(1H-benzimidazol-1-yl)androsta-3-one. When tested in vivo, 5 proved to be very effective at inhibiting the growth of androgen-dependent LAPC4 human prostate tumor xenograft, while 6 was ineffective. Compound 5 (50 mg/kg/twice daily) resulted in a 93.8% reduction (P = 0.00065) in the mean final tumor volume compared with controls, and it was also significantly more effective than castration. To our knowledge, this is the first example of an antihormonal agent (an inhibitor of androgen synthesis (CYP17 inhibitor)/antiandrogen) that is significantly more effective than castration in suppression of androgen-dependent prostate tumor growth. In view of these impressive anticancer properties, compound 5 is a strong candidate for development for the treatment of human prostate cancer. PMID:15828836

  17. Radiation biology of human tumour xenografts

    International Nuclear Information System (INIS)

    The radiation response of human tumour xenografts can be measured with sufficient accuracy using cell survival in vitro and tumour growth delay in vivo as endpoints. There is evidence that radiation response of xenografts mirrors clinical radioresponsiveness of corresponding tumours in patients. Thus xenografts may have a significant potential in experimental radiotherapeutic research, e.g. in development of in vitro and in vivo predictive assays of clinical radioresponsiveness. There are at least three main disadvantages with xenografts as models for human cancer. Firstly, volume doubling time is usually shorter for xenografts than for tumours in patients. Secondly, the haematological system and vascular network of xenografts originate from the host. Thirdly, host defence mechanisms may be active against xenografts. These disadvantages may limit the usefulness of xenografts as models for human cancer in some types of radiobiological studies. (author)

  18. Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model

    Directory of Open Access Journals (Sweden)

    Claudia Tulotta

    2016-02-01

    Full Text Available Triple-negative breast cancer (TNBC is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC.

  19. Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

    Directory of Open Access Journals (Sweden)

    Francis Richard W

    2010-04-01

    Full Text Available Abstract Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL. However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo.

  20. Benzophenone-1 stimulated the growth of BG-1 ovarian cancer cells by cell cycle regulation via an estrogen receptor alpha-mediated signaling pathway in cellular and xenograft mouse models

    International Nuclear Information System (INIS)

    Highlights: ► BP-1 induced cell growth was reversed by an ER antagonist in BG-1 cells. ► BP-1 up-regulated the mRNA expression of cyclin D1. ► Up-regulation of cyclin D1 by BP-1 was reversed by an ER antagonist. ► BP-1 is a potential endocrine disruptor that exerts estrogenic effects. - Abstract: 2,4-Dihydroxybenzophenone (benzophenone-1; BP-1) is an UV stabilizer primarily used to prevent polymer degradation and deterioration in quality due to UV irradiation. Recently, BP-1 has been reported to bioaccumulate in human bodies by absorption through the skin and has the potential to induce health problems including endocrine disruption. In the present study, we examined the xenoestrogenic effect of BP-1 on BG-1 human ovarian cancer cells expressing estrogen receptors (ERs) and relevant xenografted animal models in comparison with 17-β estradiol (E2). In in vitro cell viability assay, BP-1 (10−8–10−5 M) significantly increased BG-1 cell growth the way E2 did. The mechanism underlying the BG-1 cell proliferation was proved to be related with the up-regulation of cyclin D1, a cell cycle progressor, by E2 or BP-1. Both BP-1 and E2 induced cell growth and up-regulation of cyclin D1 were reversed by co-treatment with ICI 182,780, an ER antagonist, suggesting that BP-1 may mediate the cancer cell proliferation via an ER-dependent pathway like E2. On the other hand, the expression of p21, a regulator of cell cycle progression at G1 phase, was not altered by BP-1 though it was down-regulated by E2. In xenograft mouse models transplanted with BG-1 cells, BP-1 or E2 treatment significantly increased the tumor mass formation compared to a vehicle (corn oil) within 8 weeks. In histopathological analysis, the tumor sections of E2 or BP-1 group displayed extensive cell formations with high density and disordered arrangement, which were supported by the increased number of BrdUrd positive nuclei and the over-expression of cyclin D1 protein. Taken together, these

  1. Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer-derived cell lines and in a NTera2 xenograft model

    DEFF Research Database (Denmark)

    Jørgensen, Anne; Blomberg Jensen, Martin; Nielsen, John Erik;

    2013-01-01

    of pluripotency genes and simultaneous upregulation of the cell cycle regulators p21, p27, p53, p73 and FOXO1, while no significant effects were found in TCam-2 and 2102Ep cell lines (derived from seminoma and embryonal carcinoma, respectively). Anti-tumor effects of cholecalciferol, 1,25(OH)(2)D(3...... alone. Also, cholecalciferol supplemented diet (1100IU daily) after tumor formation did not increase cisplatin sensitivity in vivo. In conclusion, addition of 1,25(OH)(2)D(3) augmented the antitumor effect of cisplatin monotherapy in vitro, but not in this in vivo testicular germ cell cancer model...

  2. Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts

    Directory of Open Access Journals (Sweden)

    Zhu Y

    2014-12-01

    Full Text Available Yin Zhu,1,* Ming Cheng,2,* Zhen Yang,3 Chun-Yan Zeng,3 Jiang Chen,3 Yong Xie,3 Shi-Wen Luo,3 Kun-He Zhang,3 Shu-Feng Zhou,4 Nong-Hua Lu1,31Department of Gastroenterology, 2Department of Orthopedics, 3Institute of Digestive Disease, The First Affiliated Hospital of Nanchang University, Jiangxi, People’s Republic of China; 4Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA*These authors contributed equally to this workAbstract: Mesenchymal stem cells (MSCs have been recognized as promising delivery vehicles for gene therapy of tumors. Gastric cancer is the third leading cause of worldwide cancer mortality, and novel treatment modalities are urgently needed. NK4 is an antagonist of hepatocyte growth factor receptors (Met which are often aberrantly activated in gastric cancer and thus represent a useful candidate for targeted therapies. This study investigated MSC-delivered NK4 gene therapy in nude mice bearing gastric cancer xenografts. MSCs were transduced with lentiviral vectors carrying NK4 complementary DNA or enhanced green fluorescent protein (GFP. Such transduction did not change the phenotype of MSCs. Gastric cancer xenografts were established in BALB/C nude mice, and the mice were treated with phosphate-buffered saline (PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4. The tropism of MSCs toward gastric cancer cells was determined by an in vitro migration assay using MKN45 cells, GES-1 cells and human fibroblasts and their presence in tumor xenografts. Tumor growth, tumor cell apoptosis and intratumoral microvessel density of tumor tissue were measured in nude mice bearing gastric cancer xenografts treated with PBS, MSCs-GFP, Lenti-NK4, or MSCs-NK4 via tail vein injection. The results showed that MSCs migrated preferably to gastric cancer cells in vitro. Systemic MSCs-NK4 injection significantly suppressed the growth of gastric cancer xenografts. MSCs-NK4 migrated and accumulated in tumor

  3. Patient-derived xenograft models of squamous cell carcinoma of the uterine cervix.

    Science.gov (United States)

    Rofstad, Einar K; Simonsen, Trude G; Huang, Ruixia; Andersen, Lise Mari K; Galappathi, Kanthi; Ellingsen, Christine; Wegner, Catherine S; Hauge, Anette; Gaustad, Jon-Vidar

    2016-04-10

    Patient-derived xenograft (PDX) models of cancer are considered to reflect the biology and treatment response of human tumors to a larger extent than xenograft models initiated from established cell lines. The characterization of a panel of four novel PDX models of cervical carcinoma of the uterine cervix is described in this communication. The outcome of treatment differed substantially among the donor patients, and the PDX models were found to mirror the histology, aggressiveness, and metastatic propensity of the donor patients' tumors. Two of the models (BK-12 and LA-19) were highly metastatic, one model (ED-15) was poorly metastatic, and one model (HL-16) was non-metastatic. The primary tumors of the two highly metastatic models showed high density of intratumoral lymphatics, whereas the other two models did not develop intratumoral lymphatics. The potential of the models to metastasize to lymph nodes was associated with high expression of both angiogenesis-related genes and cancer stem cell-related genes. The models may be highly valuable for studying mechanisms linking lymph node metastasis to lymphangiogenesis, hemangiogenesis, and the presence of cancer stem cells. PMID:26828134

  4. Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts

    International Nuclear Information System (INIS)

    Extracellular human sulfatases modulate growth factor signaling by alteration of the heparin/heparan sulfate proteoglycan (HSPG) 6-O-sulfation state. HSPGs bind to numerous growth factor ligands including fibroblast growth factors (FGF), epidermal growth factors (EGF), and vascular endothelial growth factors (VEGF), and are critically important in the context of cancer cell growth, invasion, and metastasis. We hypothesized that sulfatase activity in the tumor microenvironment would regulate tumor growth in vivo. We established a model of stable expression of sulfatases in the human breast cancer cell line MDA-MB-231 and purified recombinant human Sulfatase 2 (rhSulf2) for exogenous administration. In vitro studies were performed to measure effects on breast cancer cell invasion and proliferation, and groups were statistically compared using Student's t-test. The effects of hSulf2 on tumor progression were tested using in vivo xenografts with two methods. First, MDA-MB-231 cells stably expressing hSulf1, hSulf2, or both hSulf1/hSulf2 were grown as xenografts and the resulting tumor growth and vascularization was compared to controls. Secondly, wild type MDA-MB-231 xenografts were treated by short-term intratumoral injection with rhSulf2 or vehicle during tumor growth. Ultrasound analysis was also used to complement caliper measurement to monitor tumor growth. In vivo studies were statistically analyzed using Student's t test. In vitro, stable expression of hSulf2 or administration of rhSulf2 in breast cancer cells decreased cell proliferation and invasion, corresponding to an inhibition of ERK activation. Stable expression of the sulfatases in xenografts significantly suppressed tumor growth, with complete regression of tumors expressing both hSulf1 and hSulf2 and significantly smaller tumor volumes in groups expressing hSulf1 or hSulf2 compared to control xenografts. Despite significant suppression of tumor volume, sulfatases did not affect vascular

  5. Liposomal doxorubicin improves radiotherapy response in hypoxic prostate cancer xenografts

    International Nuclear Information System (INIS)

    Tumor vasculature frequently fails to supply sufficient levels of oxygen to tumor tissue resulting in radioresistant hypoxic tumors. To improve therapeutic outcome radiotherapy (RT) may be combined with cytotoxic agents. In this study we have investigated the combination of RT with the cytotoxic agent doxorubicin (DXR) encapsulated in pegylated liposomes (PL-DXR). The PL-DXR formulation Caelyx® was administered to male mice bearing human, androgen-sensitive CWR22 prostate carcinoma xenografts in a dose of 3.5 mg DXR/kg, in combination with RT (2 Gy/day × 5 days) performed under normoxic and hypoxic conditions. Hypoxic RT was achieved by experimentally inducing tumor hypoxia by clamping the tumor-bearing leg five minutes prior to and during RT. Treatment response evaluation consisted of tumor volume measurements and dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) with subsequent pharmacokinetic analysis using the Brix model. Imaging was performed pre-treatment (baseline) and 8 days later. Further, hypoxic fractions were determined by pimonidazole immunohistochemistry of excised tumor tissue. As expected, the therapeutic effect of RT was significantly less effective under hypoxic than normoxic conditions. However, concomitant administration of PL-DXR significantly improved the therapeutic outcome following RT in hypoxic tumors. Further, the pharmacokinetic DCE MRI parameters and hypoxic fractions suggest PL-DXR to induce growth-inhibitory effects without interfering with tumor vascular functions. We found that DXR encapsulated in liposomes improved the therapeutic effect of RT under hypoxic conditions without affecting vascular functions. Thus, we propose that for cytotoxic agents affecting tumor vascular functions liposomes may be a promising drug delivery technology for use in chemoradiotherapy

  6. 3′-hydroxy-3,4,5,4′-tetramethoxystilbene, the metabolite of resveratrol analogue DMU-212, inhibits ovarian cancer cell growth in vitro and in a mice xenograft model

    Science.gov (United States)

    Piotrowska-Kempisty, Hanna; Ruciński, Marcin; Borys, Sylwia; Kucińska, Małgorzata; Kaczmarek, Mariusz; Zawierucha, Piotr; Wierzchowski, Marcin; Łażewski, Dawid; Murias, Marek; Jodynis-Liebert, Jadwiga

    2016-01-01

    In screening studies, the cytotoxic activity of four metabolites of resveratrol analogue 3,4,5,4′-tetramethoxystilbene (DMU-212) against A-2780 and SKOV-3 ovarian cancer cells was investigated. The most active metabolite, 3′-hydroxy-3,4,5,4′-tetramethoxystilbene (DMU-214), was chosen for further studies. The cytotoxicity of DMU-214 was shown to be higher than that of the parent compound, DMU-212, in both cell lines tested. Since DMU-212 was supposed to undergo metabolic activation through its conversion to DMU-214, an attempt was made to elucidate the mechanism of its anti-proliferative activity. We found that in SKOV-3 cells lacking p53, DMU-214 induced receptor-mediated apoptosis. In A-2780 cell line with expression of wild-type p53, DMU-214 modulated the expression pattern of p53-target genes driving intrinsic and extrinsic apoptosis pathways, as well as DNA repair and damage prevention. Regardless of the up-regulation of p48, p53R2, sestrins and Gaad45 genes involved in cancer cell DNA repair, we demonstrated the stronger anti-proliferative and pro-apoptotic effects of DMU-214 in A-2780 cells when compared to those in SKOV-3. Hence we verified DMU-214 activity in the xenograft model using SCID mice injected with A-2780 cells. The strong anti-proliferative activity of DMU-214 in the in vivo model allowed to suggest the tested compound as a potential therapeutic in ovarian cancer treatment. PMID:27585955

  7. Effects of darbufelone on the growth of tumor xenograft with SGC-7901 gastric cancer cells in nude mouse

    Directory of Open Access Journals (Sweden)

    Xiao-meng XU

    2011-02-01

    Full Text Available Objective To evaluate the effect of darbufelone,a 5-lipoxygenase/cyclooxygenase-2(5-LOX/COX-2 dual inhibitor,on the growth of subcutaneous tumor xenograft of SGC-7901 gastric cancer cells and its mechanism.Methods The xenograft model of human gastric carcinoma with SGC-7901 gastric cancer cells was reproduced in nude mice.Fourteen nude mice were randomly divided into the darbufelone group and the control group(7 each.The mice were consecutively given intragastric administration with 45mg/(kg d darbufelone in darbufelone group,or NS in control group for 4 weeks.The tumor volume in each group was measured regularly,and the tumor growth inhibition was calculated.The xenograft,liver,kidneys,spleen and lungs of nude mice were observed pathologically after HE staining.The expressions of mRNA and protein of 5-LOX,COX-2,PCNA,Bcl-2 and caspase-3 in transplanted tumor were detected by RT-PCR and immunohistochemistry.Results Darbufelone showed significant inhibitory effects,with an inhibition ratio of 58.42%,on the growth of tumor xenograft in vivo.The volume and weight of tumor in darbufelone group decreased significantly compared with that in control group(P < 0.05.Darbufelone inhibited the growth of tumor xenograft with no adverse effect.Immunohistochemistry and RT-PCR analyses showed that darbufelone effectively inhibited the expression of mRNA and protein of 5-LOX,COX-2,PCNA,Bcl-2,while increased the expression of caspase-3 compared with that in the control group(P < 0.05.Conclusions Darbufelone can inhibit the growth of gastric carcinoma in vivo,the mechanism may be related to inhibition of growth of cancer cells and the induction of apoptosis.

  8. Growth of LAPC4 prostate cancer xenograft tumor is insensitive to 5α-reductase inhibitor dutasteride

    OpenAIRE

    Garcia, Raquel Ramos; Masoodi, Khalid Z.; Pascal, Laura E.; Nelson, Joel B.; Wang, Zhou

    2014-01-01

    Intermittent androgen deprivation therapy (IADT) allows prostate cancer patients a break from the side-effects of continuous androgen deprivation therapy (ADT). Although clinical studies suggest that IADT can significantly improve patient quality of life over ADT, it has not been demonstrated to improve patient survival. Recently, increased survival has been demonstrated when 5α-reductase inhibitors have been used during the off-cycle of IADT in animal xenograft tumor models LNCaP and LuCaP35...

  9. 2'-(2-bromohexadecanoyl-paclitaxel conjugate nanoparticles for the treatment of non-small cell lung cancer in an orthotopic xenograft mouse model

    Directory of Open Access Journals (Sweden)

    Peng L

    2014-07-01

    Full Text Available Lei Peng,1 Allison N Schorzman,2 Ping Ma,1 Andrew J Madden,2 William C Zamboni,2–4 Soumya Rahima Benhabbour,1 Russell J Mumper1,4 1Center for Nanotechnology in Drug Delivery, Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 2Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 3Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, 4UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, North Carolina, NC, USA Abstract: A nanoparticle (NP formulation with 2'-(2-bromohexadecanoyl-paclitaxel (Br-16-PX conjugate was developed in these studies for the treatment of non-small cell lung cancer (NSCLC. The lipophilic paclitaxel conjugate Br-C16-PX was synthesized and incorporated into lipid NPs where the 16-carbon chain enhanced drug entrapment in the drug delivery system and improved in vivo pharmacokinetics. The electron-withdrawing bromine group was used to facilitate the conversion of Br-C16-PX to paclitaxel at the tumor site. The developed system was evaluated in luciferase-expressing A549 cells in vitro and in an orthotopic NSCLC mouse model. The results demonstrated that the Br-C16-PX NPs had a higher maximum tolerated dose (75 mg/kg than Taxol® (19 mg/kg and provided significantly longer median survival (88 days versus 70 days, P<0.05 in the orthotopic NSCLC model. An improved pharmacokinetic profile was observed for the Br-C16-PX NPs at 75 mg/kg compared to Taxol at 19 mg/kg. The area under the concentration versus time curve (AUC0–96 h of Br-C16-PX from the NPs was 91.7-fold and 49.6-fold greater than Taxol in plasma and tumor-bearing lungs, respectively, which provided sustained drug exposure and higher antitumor efficacy in the NP-treated group. Keywords: tubulin polymerization, pharmacokinetic, maximum

  10. Inhibition of Stromal PlGF Suppresses the Growth of Prostate Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Dietmar Abraham

    2013-09-01

    Full Text Available The growth and vascularization of prostate cancer is dependent on interactions between cancer cells and supporting stromal cells. The primary stromal cell type found in prostate tumors is the carcinoma-associated fibroblast, which produces placental growth factor (PlGF. PlGF is a member of the vascular endothelial growth factor (VEGF family of angiogenic molecules and PlGF mRNA levels increase after androgen deprivation therapy in prostate cancer. In this study, we show that PlGF has a direct dose-dependent proliferative effect on human PC-3 prostate cancer cells in vitro and fibroblast-derived PlGF increases PC-3 proliferation in co-culture. In xenograft tumor models, intratumoral administration of murine PlGF siRNA reduced stromal-derived PlGF expression, reduced tumor burden and decreased the number of Ki-67 positive proliferating cells associated with reduced vascular density. These data show that targeting stromal PlGF expression may represent a therapeutic target for the treatment of prostate cancer.

  11. Growth of LAPC4 prostate cancer xenograft tumor is insensitive to 5α-reductase inhibitor dutasteride.

    Science.gov (United States)

    Garcia, Raquel Ramos; Masoodi, Khalid Z; Pascal, Laura E; Nelson, Joel B; Wang, Zhou

    2014-01-01

    Intermittent androgen deprivation therapy (IADT) allows prostate cancer patients a break from the side-effects of continuous androgen deprivation therapy (ADT). Although clinical studies suggest that IADT can significantly improve patient quality of life over ADT, it has not been demonstrated to improve patient survival. Recently, increased survival has been demonstrated when 5α-reductase inhibitors have been used during the off-cycle of IADT in animal xenograft tumor models LNCaP and LuCaP35. In the current study, the sensitivity of LAPC4 xenograft tumor regrowth to the 5ARI dutasteride was determined. Tumor regrowth and gene expression changes in LAPC4 tumors were compared to the previously determined response of LNCaP and LuCaP35 xenograft tumors to 5ARI treatment during the off-cycle of IADT, LAPC4, LNCaP and LuCaP35 tumors were sensitive to androgen manipulation. However, in contrast to LNCaP and LuCaP35, dutasteride treatment during testosterone-stimulated prostate regrowth did not affect tumor regrowth or the expression of androgen responsive genes. Tumor response to dutasteride during the off-cycle of IADT is variable in xenograft prostate tumor models. Future studies will be required to elucidate the mechanisms contributing to the dutasteride resistance observed in the LAPC4 model during the off-cycle. PMID:25374909

  12. Pre-osteoblastic MC3T3-E1 cells promote breast cancer growth in bone in a murine xenograft model

    Institute of Scientific and Technical Information of China (English)

    Thomas M. Bodenstine; Benjamin H. Beck; Xuemei Cao; Leah M. Cook; Aimen Ismai; J. Kent Powers; Andrea M. Mastro; Danny R. Welch

    2011-01-01

    The bones are the most common sites of breast cancer metastasis. Upon arrival within the bone microenvironment, breast cancer cells coordinate the activities of stromal cells, resulting in an increase in osteoclast activity and bone matrix degradation. In late stages of bone metastasis, breast cancer cells induce apoptosis in osteoblasts, which further exacerbates bone loss. However, in early stages, breast cancer cells induce osteoblasts to secrete inflammatory cytokines purported to drive tumor progression. To more thoroughly evaluate the role of osteoblasts in early stages of breast cancer metastasis to the bones, we used green fluorescent protein-labeled human breast cancer cell lines MDA-MB-231 and MDA-MB-435, which both induce osteolysis after intra-femoral injection in athymic mice, and the murine pre-osteoblastic cell line MC3T3-E1 to modulate osteoblast populations at the sites of breast cancer metastasis. Breast cancer cells were injected directly into the femur with or without equal numbers of MC3T3-E1 cells. Tumors grew significantly larger when co-injected with breast cancer cells and MC3T3-E1 cells than injected with breast cancer cells alone. Osteolysis was induced in both groups, indicating that MC3T3-E1 cells did not block the ability of breast cancer cells to cause bone destruction. MC3T3-E1 cells promoted tumor growth out of the bone into the extraosseous stroma. These data suggest that breast cancer cells and osteoblasts communicate during early stages of bone metastasis and promote tumor growth.

  13. α-Mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p53 mutation

    Directory of Open Access Journals (Sweden)

    Okuno Yasushi

    2011-06-01

    Full Text Available Abstract Background The mangosteen fruit has a long history of medicinal use in Chinese and Ayurvedic medicine. Recently, the compound α-mangostin, which is isolated from the pericarp of the fruit, was shown to induce cell death in various types of cancer cells in in vitro studies. This led us to investigate the antitumor growth and antimetastatic activities of α-mangostin in an immunocompetent xenograft model of mouse metastatic mammary cancer having a p53 mutation that induces a metastatic spectrum similar to that seen in human breast cancers. Methods Mammary tumors, induced by inoculation of BALB/c mice syngeneic with metastatic BJMC3879luc2 cells, were subsequently treated with α-mangostin at 0, 10 and 20 mg/kg/day using mini-osmotic pumps and histopathologically examined. To investigate the mechanisms of antitumor ability by α-mangostin, in vitro studies were also conducted. Results Not only were in vivo survival rates significantly higher in the 20 mg/kg/day α-mangostin group versus controls, but both tumor volume and the multiplicity of lymph node metastases were significantly suppressed. Apoptotic levels were significantly increased in the mammary tumors of mice receiving 20 mg/kg/day and were associated with increased expression of active caspase-3 and -9. Other significant effects noted at this dose level were decreased microvessel density and lower numbers of dilated lymphatic vessels containing intraluminal tumor cells in mammary carcinoma tissues. In vitro, α-mangostin induced mitochondria-mediated apoptosis and G1-phase arrest and S-phase suppression in the cell cycle. Since activation by Akt phosphorylation plays a central role in a variety of oncogenic processes, including cell proliferation, anti-apoptotic cell death, angiogenesis and metastasis, we also investigated alterations in Akt phosphorylation induced by α-mangostin treatment both in vitro and in vivo. Quantitative analysis and immunohistochemistry showed that

  14. Pre-osteoblastic MC3T3-E1 promote breast cancer cell growth in bone in a murine xenograft model

    Science.gov (United States)

    The bones are the most common sites of breast cancer metastasis. Upon arrival within the bone microenvironment, breast cancer cells coordinate the activities of stromal cells, resulting in an increase in osteoclast activity and bone matrix degradation. In late stages of bone metastasis, breast cance...

  15. Effect of ghrelin and anamorelin (ONO-7643), a selective ghrelin receptor agonist, on tumor growth in a lung cancer mouse xenograft model

    OpenAIRE

    Northrup, R.; K. Kuroda; Duus, E. Manning; Barnes, S. Routt; Cheatham, L; Wiley, T.; Pietra, C.

    2013-01-01

    Purpose Anamorelin (ONO-7643) is an orally active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related anorexia/cachexia. It displays both orexigenic and anabolic properties via ghrelin mimetic activity and transient increases in growth hormone (GH). However, increasing GH and insulin-like growth factor-1 in cancer patients raises concerns of potentially stimulating tumor growth. Therefore, we investigated the effect of ghrelin and anamorelin on tumor growth ...

  16. Anti-tumor efficacy of paclitaxel against human lung cancer xenografts.

    Science.gov (United States)

    Yamori, T; Sato, S; Chikazawa, H; Kadota, T

    1997-12-01

    We examined paclitaxel for anti-tumor activity against human lung cancer xenografts in nude mice and compared its efficacy with that of cisplatin, currently a key drug for lung cancer chemotherapy. Five non-small cell lung cancers (A549, NCI-H23, NCI-H226, NCI-H460 and NCI-H522) and 2 small cell lung cancers (DMS114 and DMS273) were chosen for this study, since these cell lines have been well characterized as regards in vitro and in vivo drug sensitivity. These cells were exposed to graded concentrations of paclitaxel (0.1 to 1000 nM) for 48 h. The 50% growth-inhibitory concentrations (GI50) for the cell lines ranged from 4 to 24 nM, which are much lower than the achievable peak plasma concentration of paclitaxel. In the in vivo study, 4 cell lines (A549, NCI-H23, NCI-H460, DMS-273) were grown as subcutaneous tumors xenografts in nude mice. Paclitaxel was given intravenously as consecutive daily injections for 5 days at the doses of 24 and 12 mg/kg/day. Against every xenograft, paclitaxel produced a statistically significant tumor growth inhibition compared to the saline control. Paclitaxel at 24 mg/kg/day was more effective than cisplatin at 3 mg/kg/day with the same dosing schedule as above, although the toxicity of paclitaxel was similar to or rather lower than that of cisplatin, in terms of body weight loss. In addition, paclitaxel showed potent activity against 2 other lung cancer xenografts (NCI-H226 and DMS114). Therefore, paclitaxel showed more effective, wider-spectrum anti-tumor activity than cisplatin in this panel of 6 lung cancer xenografts. These findings support the potential utility of paclitaxel in the treatment of human lung cancer. PMID:9473739

  17. Effect of a low-fat diet combined with IGF-1 receptor blockade on 22Rv1 prostate cancer xenografts

    OpenAIRE

    Konijeti, Ramdev; Koyama, Satomi; Gray, Ashley; Barnard, R. James; Said, Jonathan W; Castor, Brandon; Elashoff, David; Wan, Junxiang; Beltran, Pedro J.; Calzone, Frank J; Cohen, Pinchas; Galet, Colette; Aronson, William J.

    2012-01-01

    In pre-clinical models, both dietary fat reduction and IGF-I receptor (IGF-1R) blockade individually inhibit prostate cancer xenograft growth. We hypothesized that a low-fat diet combined with IGF-1R blockade would cause additive inhibition of prostate cancer growth and offset possible untoward metabolic effects of IGF-1R blockade antibody therapy. Fifty SCID mice were injected with 22Rv1 cells subcutaneously. Ten days post-injection, the animals were randomized to four groups: 1) high fat di...

  18. Establishment and characterization of intraperitoneal xenograft models by co-injection of human tumor cells and extracellular matrix gel

    OpenAIRE

    Yao, Yuqin; Zhou, Yongjun; SU, XIAOLAN; Dai, Lei; Yu, Lin; Deng, Hongxin; Gou, Lantu; YANG, JINLIANG

    2015-01-01

    Establishing a feasible intraperitoneal (i.p.) xenograft model in nude mice is a good strategy to evaluate the antitumor effect of drugs in vivo. However, the manipulation of human cancer cells in establishing a stable peritoneal carcinomatosis model in nude mice is problematic. In the present study, the ovarian and colorectal peritoneal tumor models were successfully established in nude mice by co-injection of human tumor cells and extracellular matrix gel. In ovarian tumor models, the mean ...

  19. Peloruside A Inhibits Growth of Human Lung and Breast Tumor Xenografts in an Athymic nu/nu Mouse Model.

    Science.gov (United States)

    Meyer, Colin J; Krauth, Melissa; Wick, Michael J; Shay, Jerry W; Gellert, Ginelle; De Brabander, Jef K; Northcote, Peter T; Miller, John H

    2015-08-01

    Peloruside A is a microtubule-stabilizing agent isolated from a New Zealand marine sponge. Peloruside prevents growth of a panel of cancer cell lines at low nanomolar concentrations, including cell lines that are resistant to paclitaxel. Three xenograft studies in athymic nu/nu mice were performed to assess the efficacy of peloruside compared with standard anticancer agents such as paclitaxel, docetaxel, and doxorubicin. The first study examined the effect of 5 and 10 mg/kg peloruside (QD×5) on the growth of H460 non-small cell lung cancer xenografts. Peloruside caused tumor growth inhibition (%TGI) of 84% and 95%, respectively, whereas standard treatments with paclitaxel (8 mg/kg, QD×5) and docetaxel (6.3 mg/kg, Q2D×3) were much less effective (%TGI of 50% and 18%, respectively). In a second xenograft study using A549 lung cancer cells and varied schedules of dosing, activity of peloruside was again superior compared with the taxanes with inhibitions ranging from 51% to 74%, compared with 44% and 50% for the two taxanes. A third xenograft study in a P-glycoprotein-overexpressing NCI/ADR-RES breast tumor model showed that peloruside was better tolerated than either doxorubicin or paclitaxel. We conclude that peloruside is highly effective in preventing the growth of lung and P-glycoprotein-overexpressing breast tumors in vivo and that further therapeutic development is warranted. Mol Cancer Ther; 14(8); 1816-23. ©2015 AACR. PMID:26056149

  20. Frankincense essential oil prepared from hydrodistillation of Boswellia sacra gum resins induces human pancreatic cancer cell death in cultures and in a xenograft murine model

    OpenAIRE

    Ni Xiao; Suhail Mahmoud M; Yang Qing; Cao Amy; Fung Kar-Ming; Postier Russell G; Woolley Cole; Young Gary; Zhang Jingzhe; Lin Hsueh-Kung

    2012-01-01

    Abstract Background Regardless of the availability of therapeutic options, the overall 5-year survival for patients diagnosed with pancreatic cancer remains less than 5%. Gum resins from Boswellia species, also known as frankincense, have been used as a major ingredient in Ayurvedic and Chinese medicine to treat a variety of health-related conditions. Both frankincense chemical extracts and essential oil prepared from Boswellia species gum resins exhibit anti-neoplastic activity, and have bee...

  1. Re-engineered p53 Activates Apoptosis In Vivo and Causes Primary Tumor Regression in A Dominant Negative Breast Cancer Xenograft Model

    OpenAIRE

    Okal, Abood; Matissek, Karina J.; Matissek, Stephan J.; Price, Robert; Salama, Mohamed E.; Janát-Amsbury, Margit Maria; Lim, Carol S

    2014-01-01

    Inactivation of p53 pathway is reported in more than half of all human tumors and can be correlated to malignant development. Missense mutation in the DNA binding region (DBD) of p53 is the most common mechanism of p53 inactivation in cancer cells. The resulting tumor-derived p53 variants, similar to wild-type (wt) p53, retain their ability to oligomerize via the tetramerization domain (TD). Upon hetero-oligomerization, mutant p53 enforces a dominant negative effect over active wt-p53 in canc...

  2. NOSH–aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model

    International Nuclear Information System (INIS)

    Highlights: ► NOSH–aspirin is the first dual acting NO and H2S releasing hybrid. ► Its IC50 for cell growth inhibition is in the low nano-molar range. ► Structure–activity studies show that the sum of the parts does not equal the whole. ► NOSH–aspirin reduced tumor growth by 85% in mice bearing a colon cancer xenograft. -- Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H2S) can increase mucosal defense mechanisms has led to the development of NO- and H2S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH–aspirin, which is an NO- and H2S-releasing agent. NOSH–aspirin inhibited HT-29 colon cancer growth with IC50s of 45.5 ± 2.5, 19.7 ± 3.3, and 7.7 ± 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH–aspirin inhibited cell proliferation, induced apoptosis, and caused G0/G1 cell cycle block. Reconstitution and structure–activity studies representing a fairly close approximation to the intact molecule showed that NOSH–aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH–aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH–ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH–aspirin has strong anti-cancer potential and merits further evaluation.

  3. Doxorubicin-Loaded PEG-PCL-PEG Micelle Using Xenograft Model of Nude Mice: Effect of Multiple Administration of Micelle on the Suppression of Human Breast Cancer

    International Nuclear Information System (INIS)

    The triblock copolymer is composed of two identical hydrophilic segments Monomethoxy poly(ethylene glycol) (mPEG) and one hydrophobic segment poly(ε-caprolactone) (PCL); which is synthesized by coupling of mPEG-PCL-OH and mPEG-COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer can self-assemble into nanoscopic micelles to accommodate doxorubixin (DOX) in the hydrophobic core. The physicochemical properties and in vitro tests, including cytotoxicity of the micelles, have been characterized in our previous study. In this study, DOX was encapsulated into micelles with a drug loading content of 8.5%. Confocal microscopy indicated that DOX was internalized into the cytoplasm via endocystosis. A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice. Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats. A biodistribution study displayed that plasma extravasation of DOX in liver and spleen occurred in the first four hours. Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX

  4. Doxorubicin-Loaded PEG-PCL-PEG Micelle Using Xenograft Model of Nude Mice: Effect of Multiple Administration of Micelle on the Suppression of Human Breast Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Cuong, Nguyen-Van [Department of Biomedical Engineering, Chung Yuan Christian University, 200, Chung Pei Rd., Chung Li, Taiwan (China); Department of Chemical Engineering, Ho Chi Minh City University of Industry, 12 Nguyen Van Bao St, Ho Chi Minh (Viet Nam); Jiang, Jian-Lin; Li, Yu-Lun [Department of Biomedical Engineering, Chung Yuan Christian University, 200, Chung Pei Rd., Chung Li, Taiwan (China); Chen, Jim-Ray [Department of Pathology, Chang Gung Memorial Hospital at Keelung, Taiwan and Chang Gung University, College of Medicine, Taoyuan, Taiwan (China); Jwo, Shyh-Chuan [Division of General Surgery, Chang Gung Memorial Hospital at Keelung, Taiwan and Chang Gung University, College of Medicine, Taoyuan, Taiwan (China); Hsieh, Ming-Fa, E-mail: mfhsieh@cycu.edu.tw [Department of Biomedical Engineering, Chung Yuan Christian University, 200, Chung Pei Rd., Chung Li, Taiwan (China)

    2010-12-28

    The triblock copolymer is composed of two identical hydrophilic segments Monomethoxy poly(ethylene glycol) (mPEG) and one hydrophobic segment poly(ε-caprolactone) (PCL); which is synthesized by coupling of mPEG-PCL-OH and mPEG-COOH in a mild condition using dicyclohexylcarbodiimide and 4-dimethylamino pyridine. The amphiphilic block copolymer can self-assemble into nanoscopic micelles to accommodate doxorubixin (DOX) in the hydrophobic core. The physicochemical properties and in vitro tests, including cytotoxicity of the micelles, have been characterized in our previous study. In this study, DOX was encapsulated into micelles with a drug loading content of 8.5%. Confocal microscopy indicated that DOX was internalized into the cytoplasm via endocystosis. A dose-finding scheme of the polymeric micelle (placebo) showed a safe dose of PEG-PCL-PEG micelles was 71.4 mg/kg in mice. Importantly, the circulation time of DOX-loaded micelles in the plasma significantly increased compared to that of free DOX in rats. A biodistribution study displayed that plasma extravasation of DOX in liver and spleen occurred in the first four hours. Lastly, the tumor growth of human breast cancer cells in nude mice was suppressed by multiple injections (5 mg/kg, three times daily on day 0, 7 and 14) of DOX-loaded micelles as compared to multiple administrations of free DOX.

  5. Andrographolide radiosensitizes human ovarian cancer SKOV3 xenografts due to an enhanced apoptosis and autophagy.

    Science.gov (United States)

    Zhang, Chao; Qiu, Xingsheng

    2015-11-01

    Andrographolide (AND), a diterpenoid lactone isolated from Andrographis paniculata, has been shown to have radiosensitivity in several types of cancer. Whether AND can radiosensitize ovarian cancer remains unknown. The present study investigated the radiosensitizing effects of AND in human ovarian SKOV3 xenografts and examined the molecular mechanisms of AND-mediated radiosensitization. Nude mice bearing human ovarian SKOV3 were treated with AND to investigate the effects of drug administration on tumor growth, radiosensitivity, apoptosis, and autophagy. Subsequent Western blot analysis and monodansylcadaverine (MDC) staining (autophagy analysis) were used to determine the role of AND. Finally, the pathway of apoptosis was characterized by caspase-3 activity assay as well as TUNEL analysis. AND potently sensitized SKOV3 xenografts to radiation. Moreover, apoptosis and autophagy in radiation combined with drug-treated xenografts increased significantly compared with the simple drug or single radiation treatment. This result was associated with an increase in the Bax/Bcl-2 protein ratio and p-p53 expression after exposure to combination treatment. Meanwhile, the level of Beclin 1 and Atg5 and the conversion from LC3-I to LC3-II, three important proteins involved in autophagy, were increased. AND acts as a strong radiosensitizer in human ovarian SKOV3 xenografts in vivo by increasing the Bax/Bcl-2 protein ratio and promoting the activation of caspase-3, leading to enhanced apoptosis as well as autophagy. PMID:26014516

  6. Patient-Derived Xenografts as a Model System for Radiation Research.

    Science.gov (United States)

    Willey, Christopher D; Gilbert, Ashley N; Anderson, Joshua C; Gillespie, George Yancey

    2015-10-01

    The cancer literature is filled with promising preclinical studies demonstrating impressive efficacy for new therapeutics, yet translation of these approaches into clinical successes has been rare, indicating that current methods used to predict efficacy are suboptimal. The most likely reason for the limitation of these studies is the disconnect between preclinical models and cancers treated in the clinic. Specifically, most preclinical models are poor representations of human disease. Immortalized cancer cell lines that dominate the cancer literature may be, in a sense, "paper tigers" that have been selected by decades of culture to be artificially driven by highly targetable proteins. Thus, although effective in treating these cell lines either in vitro or as artificial tumors transplanted from culture into experimental animals as xenografts, the identified therapies would likely underperform in a clinical setting. This inherent limitation applies not only to drug testing but also to experiments with radiation therapy. Indeed, traditional radiobiology methods rely on monolayer culture systems, with emphasis on colony formation and DNA damage assessment that may have limited clinical translation. As such, there has been keen interest in developing tumor explant systems in which patient tumors are directly transplanted into and solely maintained in vivo, using immunocompromised mice. These so-called patient-derived xenografts (PDXs) represent a robust model system that has been garnering support in academia and industry as a superior preclinical approach to drug testing. Likewise, PDX models have the potential to improve radiation research. In this review, we describe how PDX models are currently being used for both drug and radiation testing and how they can be incorporated into a translational research program. PMID:26384275

  7. Raman spectroscopy identifies radiation response in human non-small cell lung cancer xenografts

    Science.gov (United States)

    Harder, Samantha J.; Isabelle, Martin; Devorkin, Lindsay; Smazynski, Julian; Beckham, Wayne; Brolo, Alexandre G.; Lum, Julian J.; Jirasek, Andrew

    2016-02-01

    External beam radiation therapy is a standard form of treatment for numerous cancers. Despite this, there are no approved methods to account for patient specific radiation sensitivity. In this report, Raman spectroscopy (RS) was used to identify radiation-induced biochemical changes in human non-small cell lung cancer xenografts. Chemometric analysis revealed unique radiation-related Raman signatures that were specific to nucleic acid, lipid, protein and carbohydrate spectral features. Among these changes was a dramatic shift in the accumulation of glycogen spectral bands for doses of 5 or 15 Gy when compared to unirradiated tumours. When spatial mapping was applied in this analysis there was considerable variability as we found substantial intra- and inter-tumour heterogeneity in the distribution of glycogen and other RS spectral features. Collectively, these data provide unique insight into the biochemical response of tumours, irradiated in vivo, and demonstrate the utility of RS for detecting distinct radiobiological responses in human tumour xenografts.

  8. Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model.

    Science.gov (United States)

    Bruno, Robert D; Vasaitis, Tadas S; Gediya, Lalji K; Purushottamachar, Puranik; Godbole, Abhijit M; Ates-Alagoz, Zeynep; Brodie, Angela M H; Njar, Vincent C O

    2011-11-01

    In a continuing study of our clinical candidate 5 VN/124-1 (TOK-001) and analogs as potential agents for prostate cancer therapy, putative metabolites (10, 15 and 18) of compound 5 were rationally designed and synthesized. However, none of these agents were as efficacious as 5 in several in vitro studies. Using western blot analysis, we have generated a preliminary structure-activity relationship (SAR) of 5 and related analogs as androgen receptor ablative agents (ARAAs). In vivo using the androgen-dependent LAPC-4 prostate cancer xenograft model, we demonstrated for the first time that 5 is more efficacious than the 17-lyase inhibitor 3 (abiraterone)/4 (abiraterone acetate) that is currently in phase III clinical trials. In our desire to optimize the potency of 5, compounds 6 (3ξ-fluoro-) and 9 (3β-sulfamate-) designed to increase the stability and oral bioavailability of 5, respectively were evaluated in vivo. We showed, that on equimolar basis, compound 6 was ∼2-fold more efficacious versus LAPC-4 xenografts than 5, but the toxicity observed with 6 is of concern. These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer. PMID:21729712

  9. Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001) analogs: Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model

    Science.gov (United States)

    Bruno, Robert D.; Vasaitis, Tadas S.; Gediya, Lalji K.; Purushottamachar, Puranik; Godbole, Abhijit M.; Ates-Alagoz, Zeynep; Brodie, Angela M. H.; Njar, Vincent C. O.

    2011-01-01

    In a continuing study of our clinical candidate 5 (VN/124-1 or TOK-001) and analogs as potential agents for prostate cancer therapy, putative metabolites (10, 15 and 18) of compound 5 were rationally designed and synthesized. However, none of these agents were as efficacious as 5 in several in vitro studies. Using western blot analysis, we have generated a preliminary structure-activity relationship (SAR) of 5 and related analogs as androgen receptor ablative agents (ARAAs). In vivo using the androgen-dependent LAPC-4 prostate cancer xenograft model, we demonstrated for the first time that 5 is more efficacious than the 17-lyase inhibitor 3 (abiraterone)/4 (abiraterone acetate) that is currently in phase III clinical trials. In our desire to optimize the potency of 5, compounds 6 (3ξ-fluoro-) and 9 (3β-sulfamate-) designed to increase the stability and oral bioavailability of 5, respectively were evaluated in vivo. We showed, that on equimolar basis, compound 6 was ~2-fold more efficacious versus LAPC-4 xenografts than 5, but the toxicity observed with 6 is of concern. These studies further demonstrate the efficacy of 5 in a clinically relevant prostate cancer model and justify its current clinical development as a potential treatment of prostate cancer. PMID:21729712

  10. Antitumor Activity of Garcinol in Human Prostate Cancer Cells and Xenograft Mice.

    Science.gov (United States)

    Wang, Yu; Tsai, Mei-Ling; Chiou, Li-Yu; Ho, Chi-Tang; Pan, Min-Hsiung

    2015-10-21

    Garcinol, which is isolated from fruit rinds of Garcinia indica, is a polyisoprenylated benzophenone. It has been studied for its antitumor activity by inducing apoptosis and inhibiting autophagy in human prostate cancer cells. The Bax/Bcl-2 ratio increased when garcinol was applied to PC-3 cells indicating a presence of apoptosis. Meanwhile, procaspases-9 and -3 were suppressed with attenuating PARP and DFF-45. Autophagy was inhibited through activating p-mTOR and p-PI3 Kinase/AKT by garcinol, which as a result induced the cells to apoptosis directly. In addition, the apoptosis effect of garcinol in a xenograft mouse model was also tested, suggesting a consistent result with PC-3 cell model. The tumor size was reduced more than 80 percent after the mouse accepted the garcinol treatment. Garcinol was demonstrated to have a strong antitumor activity through inhibiting autophagy and inducing apoptosis, which was discovered for the first time. Based on these findings, our data suggests that garcinol deserves further investigation as a potent chemopreventive agent. PMID:26442822

  11. NOSH-aspirin (NBS-1120), a novel nitric oxide- and hydrogen sulfide-releasing hybrid is a potent inhibitor of colon cancer cell growth in vitro and in a xenograft mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Chattopadhyay, Mitali; Kodela, Ravinder [Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031 (United States); Olson, Kenneth R. [Department of Physiology, Indiana University School of Medicine, South Bend, IN 46617 (United States); Kashfi, Khosrow, E-mail: kashfi@med.cuny.edu [Department of Physiology, Pharmacology, and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031 (United States)

    2012-03-16

    Highlights: Black-Right-Pointing-Pointer NOSH-aspirin is the first dual acting NO and H{sub 2}S releasing hybrid. Black-Right-Pointing-Pointer Its IC{sub 50} for cell growth inhibition is in the low nano-molar range. Black-Right-Pointing-Pointer Structure-activity studies show that the sum of the parts does not equal the whole. Black-Right-Pointing-Pointer NOSH-aspirin reduced tumor growth by 85% in mice bearing a colon cancer xenograft. -- Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are prototypical anti-cancer agents. However, their long-term use is associated with adverse gastrointestinal effects. Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H{sub 2}S) can increase mucosal defense mechanisms has led to the development of NO- and H{sub 2}S-releasing NSAIDs with increased safety profiles. Here we report on a new hybrid, NOSH-aspirin, which is an NO- and H{sub 2}S-releasing agent. NOSH-aspirin inhibited HT-29 colon cancer growth with IC{sub 50}s of 45.5 {+-} 2.5, 19.7 {+-} 3.3, and 7.7 {+-} 2.2 nM at 24, 48, and 72 h, respectively. This is the first NSAID based agent with such high degree of potency. NOSH-aspirin inhibited cell proliferation, induced apoptosis, and caused G{sub 0}/G{sub 1} cell cycle block. Reconstitution and structure-activity studies representing a fairly close approximation to the intact molecule showed that NOSH-aspirin was 9000-fold more potent than the sum of its parts towards growth inhibition. NOSH-aspirin inhibited ovine COX-1 more than ovine COX-2. NOSH-ASA treatment of mice bearing a human colon cancer xenograft caused a reduction in volume of 85%. Taken together, these results demonstrate that NOSH-aspirin has strong anti-cancer potential and merits further evaluation.

  12. Xenograft assessment of predictive biomarkers for standard head and neck cancer therapies

    International Nuclear Information System (INIS)

    Head and neck squamous cell carcinoma (HNSCC) remains a challenging cancer to treat with overall 5-year survival on the order of 50–60%. Therefore, predictive biomarkers for this disease would be valuable to provide more effective and individualized therapeutic approaches for these patients. While prognostic biomarkers such as p16 expression correlate with outcome; to date, no predictive biomarkers have been clinically validated for HNSCC. We generated xenografts in immunocompromised mice from six established HNSCC cell lines and evaluated response to cisplatin, cetuximab, and radiation. Tissue microarrays were constructed from pre- and posttreatment tumor samples derived from each xenograft experiment. Quantitative immunohistochemistry was performed using a semiautomated imaging and analysis platform to determine the relative expression of five potential predictive biomarkers: epidermal growth factor receptor (EGFR), phospho-EGFR, phospho-Akt, phospho-ERK, and excision repair cross-complementation group 1 (ERCC1). Biomarker levels were compared between xenografts that were sensitive versus resistant to a specific therapy utilizing a two-sample t-test with equal standard deviations. Indeed the xenografts displayed heterogeneous responses to each treatment, and we linked a number of baseline biomarker levels to response. This included low ERCC1 being associated with cisplatin sensitivity, low phospho-Akt correlated with cetuximab sensitivity, and high total EGFR was related to radiation resistance. Overall, we developed a systematic approach to identifying predictive biomarkers and demonstrated several connections between biomarker levels and treatment response. Despite these promising initial results, this work requires additional preclinical validation, likely involving the use of patient-derived xenografts, prior to moving into the clinical realm for confirmation among patients with HNSCC

  13. Dietary omega-3 fatty acids and ionizing irradiation on human breast cancer xenograft growth and angiogenesis

    OpenAIRE

    Cameron Ivan L; Short Nicholas; Sun LuZhe; Hardman W Elaine

    2005-01-01

    Abstract Background The effects of an omega-3 (n-3) fatty acid enriched diet alone and in combination with gamma irradiation (IR) therapy in nude mice bearing a human MDA-MB231 breast cancer xenograft were tested. The cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into two diet groups: 1) mice with 10% corn oil (rich in omega 6 fatty acids) in their food, 2) mice consuming a 10% fat diet that was enriched in n-3 fatty acid...

  14. Mouse Xenograft Model for Mesothelioma | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The National Cancer Institute is seeking parties interested in collaborative research to co-develop, evaluate, or commercialize a new mouse model for monoclonal antibodies and immunoconjugates that target malignant mesotheliomas. Applications of the technology include models for screening compounds as potential therapeutics for mesothelioma and for studying the pathology of mesothelioma.

  15. Development and Characterization of Bladder Cancer Patient-Derived Xenografts for Molecularly Guided Targeted Therapy.

    Directory of Open Access Journals (Sweden)

    Chong-Xian Pan

    Full Text Available The overarching goal of this project is to establish a patient-derived bladder cancer xenograft (PDX platform, annotated with deep sequencing and patient clinical information, to accelerate the development of new treatment options for bladder cancer patients. Herein, we describe the creation, initial characterization and use of the platform for this purpose.Twenty-two PDXs with annotated clinical information were established from uncultured unselected clinical bladder cancer specimens in immunodeficient NSG mice. The morphological fidelity was maintained in PDXs. Whole exome sequencing revealed that PDXs and parental patient cancers shared 92-97% of genetic aberrations, including multiple druggable targets. For drug repurposing, an EGFR/HER2 dual inhibitor lapatinib was effective in PDX BL0440 (progression-free survival or PFS of 25.4 days versus 18.4 days in the control, p = 0.007, but not in PDX BL0269 (12 days versus 13 days in the control, p = 0.16 although both expressed HER2. To screen for the most effective MTT, we evaluated three drugs (lapatinib, ponatinib, and BEZ235 matched with aberrations in PDX BL0269; but only a PIK3CA inhibitor BEZ235 was effective (p<0.0001. To study the mechanisms of secondary resistance, a fibroblast growth factor receptor 3 inhibitor BGJ398 prolonged PFS of PDX BL0293 from 9.5 days of the control to 18.5 days (p<0.0001, and serial biopsies revealed that the MAPK/ERK and PIK3CA-AKT pathways were activated upon resistance. Inhibition of these pathways significantly prolonged PFS from 12 day of the control to 22 days (p = 0.001. To screen for effective chemotherapeutic drugs, four of the first six PDXs were sensitive to the cisplatin/gemcitabine combination, and chemoresistance to one drug could be overcome by the other drug.The PDX models described here show good correlation with the patient at the genomic level and known patient response to treatment. This supports further evaluation of the PDXs for their

  16. The use of matrigel has no influence on tumor development or PET imaging in FaDu human head and neck cancer xenografts

    DEFF Research Database (Denmark)

    Fliedner, Frederikke P.; Hansen, Anders Elias; Jorgensen, Jesper T.;

    2016-01-01

    . In sub study II ten mice from each group (+MG, n = 10; -MG, n = 10) were included and tumors collected for immunohistochemistry (IHC) analysis of tumor microenvironment including; proliferation ratio, micro vessel density, average vessel area, hypoxia, nuclear density, and necrosis. Tumors for IHC......Background: In preclinical research MatrixgelTM Basement Membrane Matrix (MG) is used frequently for the establishment of syngeneic and xenograft cancer models. Limited information on its influence on parameters including; tumor growth, vascularization, hypoxia and imaging characteristics is...... currently available. This study evaluates the potential effect of matrigel use in a human head and neck cancer xenograft model (FaDu; hypopharyngeal carcinoma) in NMRI nude mice. The FaDu cell line was chosen based on its frequent use in studies of cancer imaging and tumor microenvironment. Methods: NMRI...

  17. Regulation of estrogen receptors α and β in human breast carcinoma by exogenous leptin in nude mouse xenograft model

    Institute of Scientific and Technical Information of China (English)

    YU Wei; GU Jun-chao; LIU Jian-zhong; WANG Shao-hong; WANG Yu; ZHANG Zhong-tao; MA Xue-mei; SONG Mao-min

    2010-01-01

    Background It is essential to clarify the interactions of hormones during the progression of human breast cancer. This study examined the effects of exogenous human leptin on estrogen receptor (ER) α and β in human breast tumor tissue in a nude mouse xenograft model.Methods We created nude mice xenografts of MCF-7 human breast cancer cells, and randomly divided them into an experimental group and a control group. The mice in experimental group were injected subcutaneously around tumors with human leptin, while the control group were injected with the same dose of normal saline. A real-time RT-PCR assay was developed to quantify the mRNA of Erα,β in the tumor tissues. Western blotting analyses were used to assess the relative quantities of the Erα,β proteins.Results Leptin-treated xenografted nude mice were successfully established. The amount of Era mRNA was significantly higher in the leptin group than in the control group (P<0.01), while the amount of Erβ mRNA was significantly lower in the leptin group than in the control group (P<0.01). Western blotting analyses revealed that the Erα protein level was significantly higher in the leptin group than in the control group (P<0.01), while the Erβ protein level was significantly lower in the leptin group than in the control group (P <0.01).Conclusions Nude mouse xenograft model can be safely and serviceably treated with human leptin by subcutaneous injections around tumor. Erα,β were both targets of leptin in breast cancer. Leptin can up-regulate the expression of Erα and down-regulate the expression of the Erβ in human breast tumor.

  18. VEGF-D-induced draining lymphatic enlargement and tumor lymphangiogenesis promote lymph node metastasis in a xenograft model of ovarian carcinoma

    OpenAIRE

    Du, Li-Cheng; Chen, Xian-Cheng; Wang, Dong; Wen, Yan-Jun; Wang, Chun-Ting; Wang, Xue-mei; Kan, Bing; WEI, YU-QUAN; Zhao, Xia

    2014-01-01

    Background Vascular endothelial growth factor (VEGF)-D has been shown to promote lymph node metastasis in several cancers. Although generally overexpressed in ovarian carcinoma, its role in nodal dissemination of this cancer is unclear. To clarify the role of VEGF-D and the underlying molecular mechanisms, we investigated the function of VEGF-D using a mouse xenograft model of ovarian cancer. Methods Human ovarian serous adenocarcinoma SKOV3 cells were transfected with VEGF-D recombinant plas...

  19. Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth

    International Nuclear Information System (INIS)

    Angiogenesis plays a key role in tumor growth. Vascular endothelial growth factor (VEGF) is a pro-angiogenic that is involved in tumor angiogenesis. When VEGF binds to membrane-bound vascular endothelial growth factor receptor 2 (mVEGFR2), it promotes angiogenesis. Through alternative polyadenylation, VEGFR2 is also expressed in a soluble form (sVEGFR2). sVEGFR2 sequesters VEGF and is therefore anti-angiogenic. The aim of this study was to show that treatment with a previously developed and reported antisense morpholino oligomer that shifts expression from mVEGFR2 to sVEGFR2 would lead to reduced tumor vascularization and growth in a murine colon cancer xenograft model. Xenografts were generated by implanting human HCT-116 colon cancer cells into the flanks of NMRI nu/nu mice. Treatment with the therapeutic morpholino reduced both tumor growth and tumor vascularization. Because the HCT-116 cells used for the experiments did not express VEGFR2 and because the treatment morpholino targeted mouse rather than human VEGFR2, it is likely that treatment morpholino was acting on the mouse endothelial cells rather than directly on the tumor cells

  20. Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth

    Energy Technology Data Exchange (ETDEWEB)

    Stagg, Brian C., E-mail: briancstagg@gmail.com; Uehara, Hironori; Lambert, Nathan; Rai, Ruju; Gupta, Isha; Radmall, Bryce; Bates, Taylor; Ambati, Balamurali K. [John A Moran Eye Center, University of Utah, Salt Lake City, UT, 65 Mario Capecchi Drive, Salt Lake City, UT 84132 (United States)

    2014-11-26

    Angiogenesis plays a key role in tumor growth. Vascular endothelial growth factor (VEGF) is a pro-angiogenic that is involved in tumor angiogenesis. When VEGF binds to membrane-bound vascular endothelial growth factor receptor 2 (mVEGFR2), it promotes angiogenesis. Through alternative polyadenylation, VEGFR2 is also expressed in a soluble form (sVEGFR2). sVEGFR2 sequesters VEGF and is therefore anti-angiogenic. The aim of this study was to show that treatment with a previously developed and reported antisense morpholino oligomer that shifts expression from mVEGFR2 to sVEGFR2 would lead to reduced tumor vascularization and growth in a murine colon cancer xenograft model. Xenografts were generated by implanting human HCT-116 colon cancer cells into the flanks of NMRI nu/nu mice. Treatment with the therapeutic morpholino reduced both tumor growth and tumor vascularization. Because the HCT-116 cells used for the experiments did not express VEGFR2 and because the treatment morpholino targeted mouse rather than human VEGFR2, it is likely that treatment morpholino was acting on the mouse endothelial cells rather than directly on the tumor cells.

  1. Targeting cancer stem cells with an 131I-labeled anti-AC133 monoclonal antibody in human colorectal cancer xenografts

    International Nuclear Information System (INIS)

    Introduction: Cancer stem cells (CSCs) are a subpopulation within a tumor, which possesses the characteristics of self-renewal, differentiation, tumorigenicity, and drug resistance. The aim of this study was to target the colorectal CSC marker CD133 with an131I-labeled specific monoclonal antibody (AC133 mAb) in a nude mouse xenograft model. Methods: Colorectal adenocarcinoma cells (LoVo cell line) were separated into CD133(+) and CD133(−) cells by magnetic activated cell sorting. CD133(+), CD133(−), and unsorted LoVo cells were cultured and then implanted subcutaneously into the lower limbs of nude mice (n = 5). AC133 mAb was labeled with 131I by the iodogen method. Results: The radiolabeled compound, 131I-AC133 mAb, showed high stability, specificity, and immunoactivity in vitro. Obvious accumulation of 131I-AC133 mAb was seen in nude mice bearing xenografts of CD133(+) and unsorted LoVo cells, but no uptake was found in mice bearing CD133(−) xenografts or specifically blocked xenografts. Biodistribution analysis showed that the tumor uptake of 131I-AC133 mAb was 6.97 ± 1.40, 1.35 ± 0.48, 6.12 ± 1.91, and 1.61 ± 0.44% ID/g (n = 4) at day 7 after injection of 131I-AC133 mAb in CD133(+), CD133(−), unsorted LoVo cell and specifically blocked xenografts, respectively. The results of immunofluorescence, autoradiography, and western blotting further verified the specific binding of 131I-AC133 mAb to CD133(+) tumors. Conclusions: This study demonstrates the possibility of targeting CSCs with a radiolabeled AC133 mAb in colorectal cancer xenografts based on in vitro, ex vivo, and in vivo experiments. Our findings suggest a new method for imaging CSCs non-invasively

  2. Emerging and Evolving Ovarian Cancer Animal Models

    OpenAIRE

    Bobbs, Alexander S; Jennifer M. Cole; Cowden Dahl, Karen D.

    2015-01-01

    Ovarian cancer (OC) is the leading cause of death from a gynecological malignancy in the United States. By the time a woman is diagnosed with OC, the tumor has usually metastasized. Mouse models that are used to recapitulate different aspects of human OC have been evolving for nearly 40 years. Xenograft studies in immunocompromised and immunocompetent mice have enhanced our knowledge of metastasis and immune cell involvement in cancer. Patient-derived xenografts (PDXs) can accurately reflect ...

  3. Early effects of radiotherapy in small cell lung cancer xenografts monitored by 31P magnetic resonance spectroscopy and biochemical analysis

    DEFF Research Database (Denmark)

    Kristjansen, P E; Pedersen, E J; Quistorff, B;

    1990-01-01

    31P magnetic resonance spectroscopy (31P MRS) and biochemical analysis of extracts were applied to study the metabolic response to X-irradiation of small cell lung cancer in nude mice. Two small cell lung cancer xenografts, CPH SCCL 54A and 54B, with different radiosensitivity, although derived...

  4. Tumor-specific accumulation of 125I-labeled mouse-human chimeric anti-CEA antibody in a xenografted human cancer model demonstrated by whole-body autoradiography and immunostaining

    International Nuclear Information System (INIS)

    Whole-body autoradiography (WBAR) was used to study the biodistribution of 125I-labeled mouse-human chimeric antibody (Ch F11-39) to carcinoembryonic antigen (CEA) in athymic nude mice bearing the CEA-producing MKN-45 human gastric carcinoma xenografts. Significantly high uptake of 125I-Ch F11-39 in the tumors obtained by tissue-counting technique was confirmed by WBAR of mice of 12, 24, 48, and 96 h postinjection of 125I-Ch F11-39. When compared with histochemical or immunohistochemical staining results of the tumor tissue sections, imaging profiles of 125I-Ch F11-39 obtained by WBARs were topographically correlated with histopathological findings of tissues and immunohistochemical localization of CEA in the tumor tissues, indicating that the accumulation of 125I-Ch F11-39 at the tumor site is based on its specificity for CEA. These results demonstrate that this chimeric antibody may serve as a potential useful diagnostic and/or therapeutic reagent for human CEA-producing cancers

  5. Tumour bed irradiation of human tumour xenografts in a nude rat model using a common X-ray tube

    International Nuclear Information System (INIS)

    Studies that investigate the radiation of human tumour xenografts require an appropriate radiation source and highly standardized conditions during radiation. This work reports on the design of standardized irradiation device using a commercially available X-ray tube with a custom constructed lead collimator with two circular apertures and an animal bed plate, permitting synchronous irradiation of two animals. Dosimetry and the corresponding methodology for radiotherapy of human non-small cell lung cancer xenograft tumours transplanted to and growing subcutaneously on the right lower limb in a nude rat model were investigated. Procedures and results described herein prove the feasibility of use of the device, which is applicable for any investigation involving irradiation of non-tumorous and tumorous lesions in small animals. (author)

  6. Tumour bed irradiation of human tumour xenografts in a nude rat model using a common X-ray tube

    Indian Academy of Sciences (India)

    S V Tokalov; W Enghardt; N Abolmaali

    2010-06-01

    Studies that investigate the radiation of human tumour xenografts require an appropriate radiation source and highly standardized conditions during radiation. This work reports on the design of a standardized irradiation device using a commercially available X-ray tube with a custom constructed lead collimator with two circular apertures and an animal bed plate, permitting synchronous irradiation of two animals. Dosimetry and the corresponding methodology for radiotherapy of human non-small cell lung cancer xenograft tumours transplanted to and growing subcutaneously on the right lower limb in a nude rat model were investigated. Procedures and results described herein prove the feasibility of use of the device, which is applicable for any investigation involving irradiation of non-tumorous and tumorous lesions in small animals.

  7. Establishment of human patient-derived endometrial cancer xenografts in NOD scid gamma mice for the study of invasion and metastasis.

    Directory of Open Access Journals (Sweden)

    Kenji Unno

    Full Text Available Most endometrial cancers are detected early and have a good prognosis, while some endometrial cancers are highly invasive, metastasize early, and respond suboptimally to therapy. Currently, appropriate model systems to study the aggressive nature of these tumors are lacking. The objective of this study was to establish a mouse xenograft model of endometrial tumors derived from patients in order to study the biological aggressive characteristics that underlie invasion and metastasis.Endometrial tumor tissue fragments (1.5 mm × 1.5 mm from patients undergoing surgery, were transplanted under the renal capsule of NOD scid gamma mice. After 6-8 weeks, tumors were excised and serially transplanted into additional mice for propagation. Immunohistochemical analysis of the tumors was done for various tumor markers.Four cases of different subtypes of endometrial cancer were grown and propagated in mice. Three of the four tumor cases invaded into the kidneys and to adjacent organs. While all tumors exhibited minimal to no staining for estrogen receptor α, progesterone receptor staining was observed for tumor grafts. In addition, levels and localization of E-cadherin, cytokeratin and vimentin varied depending on subtype. Finally, all tumor xenografts stained positively for urokinase plasminogen activator while 3 tumor xenografts, which showed invasive characteristics, stained positively for urokinase plasminogen activator receptor.Endometrial tumors transplanted under the renal capsule exhibit growth, invasion and local spread. These tumors can be propagated and used to study aggressive endometrial cancer.

  8. beta 1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Park, Catherine C.; Park, Catherine C.; Zhang, Hui J.; Yao, Evelyn S.; Park, Chong J.; Bissell, Mina J.

    2008-06-02

    {beta}1 integrin signaling has been shown to mediate cellular resistance to apoptosis after exposure to ionizing radiation (IR). Other signaling molecules that increase resistance include Akt, which promotes cell survival downstream of {beta}1 integrin signaling. We showed previously that {beta}1 integrin inhibitory antibodies, AIIB2, enhance apoptosis and decrease growth in human breast cancer cells in 3 dimensional laminin-rich extracellular matrix (3D lrECM) cultures and in vivo. Here we asked whether AIIB2 could synergize with IR to modify Akt-mediated IR resistance. We used 3D lrECM cultures to test the optimal combination of AIIB2 with IR treatment of two breast cancer cell lines, MCF-7 and HMT3522-T4-2, as well as T4-2 myr-Akt breast cancer colonies or HMT3522-S-1, which form normal organotypic structures in 3D lrECM. Colonies were assayed for apoptosis and {beta}1 integrin/Akt signaling pathways were evaluated using western blot. In addition, mice bearing MCF-7 xenografts were used to validate the findings in 3D lrECM. We report that AIIB2 increased apoptosis optimally post-IR by down regulating Akt in breast cancer colonies in 3D lrECM. In vivo, addition of AIIB2 after IR significantly enhanced tumor growth inhibition and apoptosis compared to either treatment alone. Remarkably, the degree of tumor growth inhibition using AIIB2 plus 2 Gy radiation was similar to that of 8 Gy alone. We showed previously that AIIB2 had no discernible toxicity in mice; here, its addition allowed for a significant reduction in the IR dose that was necessary to achieve comparable growth inhibition and apoptosis in breast cancer xenografts in vivo.

  9. Tumor-specific targeting by Bavituximab, a phosphatidylserine-targeting monoclonal antibody with vascular targeting and immune modulating properties, in lung cancer xenografts

    OpenAIRE

    Gerber, David E.; Hao, Guiyang; Watkins, Linda; Jason H. Stafford; Anderson, Jon; Holbein, Blair; Öz, Orhan K.; Mathews, Dana; Thorpe, Philip E; Hassan, Gedaa; Kumar, Amit; Brekken, Rolf A.; Sun, Xiankai

    2015-01-01

    Bavituximab is a chimeric monoclonal antibody with immune modulating and tumor-associated vascular disrupting properties demonstrated in models of non-small cell lung cancer (NSCLC). The molecular target of Bavituximab, phosphatidylserine (PS), is exposed on the outer leaflet of the membrane bi-layer of malignant vascular endothelial cells and tumor cells to a greater extent than on normal tissues. We evaluated the tumor-targeting properties of Bavituximab for imaging of NSCLC xenografts when...

  10. Orthotopic human melanoma xenograft model systems for studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern.

    OpenAIRE

    Rofstad, E. K.

    1994-01-01

    Adequate tumour models are a prerequisite in experimental cancer research. The purpose of the present work was to establish and assess the validity of four new orthotopic human melanoma xenograft model systems (A-07, D-12, R-18, U-25). Permanent cell lines were established in monolayer culture from subcutaneous metastases of four different melanoma patients by using an in vivo-in vitro procedure, and cells from these lines were inoculated intradermally in Balb/c nu/nu mice to form tumours. In...

  11. Effects of heavy ion radiation on cancer stem cells of xenograft tumor in nude mice

    International Nuclear Information System (INIS)

    Experiments were design to determine the effects of Carbon ion radiation on cancer stem cells within xenograft tumors, and to assess the impact of high LET radiation on radiocurability. HCT116 human colon cancer cells were inoculated into nude mice and animals were irradiated when tumors reached a certain size. When irradiated with 15 Gy Carbon ions, the xenograft tumors re-grew after 60 days. However, when irradiated with 30 Gy all tumors were eradicated without relapse within the 90 day follow-up period. In comparison, with X-ray radiation, the tumors were suppressed for 31 days with a dose of 30 Gy and eradicated following a 60 Gy dose. The relative biological effectiveness (RBE) value of Carbon ion relative to X-rays was calculated at 3.82. At an isodose of 30 Gy, Carbon ion radiation predominantly induced tumor cell cavitation and fibrosis, whereas X-ray radiation only partially destroyed the tumor cell mass. Tumor-supplying blood vessels were markedly reduced in mice following Carbon ion irradiation compared to mice irradiated with X-rays. The expression of cancer stem cell related markers or proteins, such as CD133, EpCAM, HIF-1α and B-catenin was predominantly suppressed following Carbon ion radiation. In contrast, X-rays actually increased the expression of these factors. In conclusion, heavy ion radiation can disrupt cancer stem cell populations more effectively than conventional X-ray treatment. These findings emphasize the importance of utilising heavy ion radiation as a tool to achieve high tumor radiocurability. (author)

  12. Systematic analysis of a xenograft mice model for KSHV+ primary effusion lymphoma (PEL.

    Directory of Open Access Journals (Sweden)

    Lu Dai

    Full Text Available Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL, which arises preferentially in the setting of infection with human immunodeficiency virus (HIV. Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV(+ PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV(+ PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.

  13. Combined therapeutic effect and molecular mechanisms of metformin and cisplatin in human lung cancer xenografts in nude mice

    Directory of Open Access Journals (Sweden)

    Yu-Qin Chen

    2015-01-01

    Full Text Available Objective: This work was aimed at studying the inhibitory activity of metformin combined with the commonly used chemotherapy drug cisplatin in human lung cancer xenografts in nude mice. We also examined the combined effects of these drugs on the molecular expression of survivin, matrix metalloproteinase-2 (MMP-2, vascular endothelial growth factor-C (VEGF-C, and vascular endothelial growth factorreceptor-3 (VEGFR-3 to determine the mechanism of action and to explore the potential applications of the new effective drug therapy in lung cancer. Materials and Methods: The nude mice model of lung cancer xenografts was established, and mice were randomly divided into the metformin group, the cisplatin group, the metformin + cisplatin group, and the control group. The animals were killed 42 days after drug administration, and the tumor tissues were then sampled to detect the messenger ribonucleic acid (mRNA and protein expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR. Results: The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the cisplatin group and the combined treatment group were lower than that in the control group (P < 0.05. In the metformin group, the expression of MMP-2 protein and mRNA was lower than that in the control group (P < 0.05. The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the combined treatment group were lower than that in the cisplatin group and the metformin group (P < 0.05. Conclusions: Metformin inhibited the expression of MMP-2, cisplatin and the combined treatment inhibited the expression of survivin, MMP-2, VEGF-C, and VEGFR-3, and the combined treatment of metformin with cisplatin resulted in enhanced anti-tumor efficacy.

  14. Inhibition of human prostate cancer xenograft growth by 125I labeled triple-helin forming oligonucleotide directed against androgen receptor

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yong; MA Yi; LU Han-ping; GAO Jin-hui; LIANG Chang-sheng; LIU Chang-zheng; ZOU Jun-tao; WANG Hua-qiao

    2008-01-01

    Background The failure of hormone treatment for advanced prostate cancer might be related to aberrant activation of the androgen receptor.We have shown that 125I labeled triple-helix forming oligonucleotide (TFO) against the androgen receptor gene inhibits androgen receptor expression and cell proliferation of LNCaP prostate cancer cells in vitro.This study aimed at exploring the effects of the 125I-TFO on prostate tumor growth in vivo using a nude mouse xenograft model.Methods TFO was labeled with 125I by the iodogen method.Thirty-two nude mice bearing LNCaP xenograft tumors were randomized into 4 groups and were intratumorally injected with 125I-TFO,unlabeled TFO,Na125I and normal saline.Tumor size was measured weekly.The tumor growth inhibition rate (RI) was calculated by measurement of tumor weight.The expression of the androgen receptor gene was performed by RT-PCR and immunohistochemical study.The prostate specific antigen (PSA) serum levels were measured by enzyme linked immunosorbent assay.The tumor cell apoptosis index (Al) was detected by TUNEL assay.Results Tumor measurements showed that tumor development was significantly inhibited by either 125I-TFO or TFO,with tumor RIs of 50.79% and 32.80% respectively.125I-TFO caused greater inhibition of androgen receptor expression and higher Als in tumor tissue than TFO.Both the tumor weight and the PSA serum levels in 125I-TFO treated mice ((0.93±0.15) g and (17.43±1.85) ng/ml,respectively) were significantly lower than those ((1.27±0.21) g and (28.25±3.41)ng/ml,respectively) in TFO treated mice (all P<0.05).Na125I did not significantly affect tumor growth and androgen receptor expression in tumor tissue.Conclusions The 125I-TFO can effectively inhibit androgen receptor expression and tumor growth of human prostate cancer xenografts in vivo.The inhibitory efficacy of 125I-TFO is more potent than that of TFO,providing a reference for future studies of antigen radiotherapy.

  15. Chronic modulation of AMP-Kinase, Akt and mTOR pathways by ionizing radiation in human lung cancer xenografts

    International Nuclear Information System (INIS)

    Earlier, we showed that in cancer cells, AMP-activated kinase (AMPK) participates in a signal transduction pathway involving ATM-AMPK-p53/p21cip1 which is activated by ionizing radiation (IR) to mediate G2-M arrest and enhanced cytotoxicity. We also observed that AMPK modulates ATM expression and activity and the IR response of the Akt-mTOR pathway. Since the ATM, AMPK and Akt pathways are key targets of novel radio-sensitizing therapeutics, we examined the chronic modultion of expression and activity of those pathways by IR alone in xenograft models of lung cancer. Immuno-compromised mice were grafted with human lung A549 and H1299 cells, were treated with a single fraction of 0 or 10 Gy, and left to grow for 8 weeks. Extracted tumors were subjected to lysis and immunoblotting or fixation and immunohistochemical analysis. IR inhibited significantly xenograft growth and was associated with increased expression of Ataxia Telengiectasia Mutated (ATM) and enhanced phosphorylation of two ATM targets, H2Ax and checkpoint kinase Chk2. Irradiated tumours showed increased total AMPK levels and phosphorylation of AMPK and its substrate Acetyl-CoA Carboxylase (ACC). IR led to enhanced expression and phosphorylation of p53 and cyclin dependent kinase inhibitors p21cip1 and p27kip1. However, irradiated tumours had reduced phosphorylation of Akt, mTOR and it‘s target translation initiation inhibitor 4EBP1. Irradiated xenografts showed reduced microvessel density, reduced expression of CD31 but increased expression of hypoxia-induced factor 1A (HIF1a) compared to controls. IR inhibits epithelial cancer tumour growth and results in sustained expression and activation of ATM-Chk2, and AMPK-p53/p21cip1/p27kip1 but partial inhibition of the Akt-mTOR signaling pathways. Future studies should examine causality between those events and explore whether further modulation of the AMPK and Akt-mTOR pathways by novel therapeutics can sensitize lung tumours to radiation

  16. Radiation Response Modulation of GW572016 (EGFR/HER2 Dual Tyrosine Kinase Inhibitor) in Human Breast Cancer Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Yeon Sil; Roh, Kwang Won; Chae, Soo Min; Yoon, Sei Chul; Jang, Hong Seok; Chung, Su Mi [The Catholic University of Korea, College of Medicine, Seoul (Korea, Republic of); Mun, Seong Kwon [Eulji University Hospital, Daejeon (Korea, Republic of)

    2007-12-15

    Purpose: We examined the effect of the dual EGFR/HER2 tyrosine kinase inhibitor, GW572016, on EGFR/HER2 receptor phosphorylation, inhibition of downstream signaling and radiosensitization in either an EGFR or HER2 overexpressing human breast cancer xenograft. Materials and Methods: We established SCID mice xenografts from 4 human breast cancer cell line that overexpressed EGFR or HER 2 (SUM 102, SUM 149, SUM 185, SUM 225). Two series of xenografts were established. One series was established for determining inhibition of the EGFR/HER2 receptor and downstream signaling activities by GW572016. The other series was established for determining the radiosensitization effect of GW572016. Inhibition of the receptor and downstream signaling proteins were measured by the use of immunoprecipitation and Western blotting. For determining the in vivo radiosensitization effect of GW572016, we compared tumor growth delay curves in the following four treatment arms: a) control; b) GW572016 alone; c) radiotherapy (RT) alone; d) GW572016 and RT. Results: GW572016 inhibited EGFR, HER2 receptor phosphorylation in SUM 149 and SUM 185 xenografts. In addition, the p44/42 MAPK (ERK 1/2) downstream signaling pathway was inactivated by GW572016 in the SUM 185 xenograft. In the SUM 225 xenograft, we could not observe inhibition of HER2 receptor phosphorylation by GW572016; both p44/42 MAPK (Erk1/2) and Akt downstream signal protein phosphorylation were inhibited by GW572016. GW572016 inhibited growth of the tumor xenograft of SUM 149 and SUM 185. The combination of GW572016 and RT enhanced growth inhibition greater than that with GW572016 alone or with RT alone in the SUM 149 xenograft. GW572016 appears to act as an in vivo radiosensitizer. Conclusion: GW572016 inhibited EGFR/HER2 receptor phosphorylation and downstream signaling pathway proteins. GW572016 modestly inhibited the growth of tumor in the SUM 185 xenograft and showed radiosensitization in the SUM 149 xenograft. Our results

  17. Setting up a wide panel of patient-derived tumor xenografts of non–small cell lung cancer by improving the preanalytical steps

    International Nuclear Information System (INIS)

    With the ongoing need to improve therapy for non–small cell lung cancer (NSCLC) there has been increasing interest in developing reliable preclinical models to test novel therapeutics. Patient-derived tumor xenografts (PDX) are considered to be interesting candidates. However, the establishment of such model systems requires highly specialized research facilities and introduces logistic challenges. We aimed to establish an extensive well-characterized panel of NSCLC xenograft models in the context of a long-distance research network after careful control of the preanalytical steps. One hundred fresh surgically resected NSCLC specimens were shipped in survival medium at room temperature from a hospital-integrated biobank to animal facilities. Within 24 h post-surgery, tumor fragments were subcutaneously xenografted into immunodeficient mice. PDX characterization was performed by histopathological, immunohistochemical, aCGH and next-generation sequencing approaches. For this model system, the tumor take rate was 35%, with higher rates for squamous carcinoma (60%) than for adenocarcinoma (13%). Patients for whom PDX tumors were obtained had a significantly shorter disease-free survival (DFS) compared to patients for whom no PDX tumors (P = 0.039) were obtained. We established a large panel of PDX NSCLC models with a high frequency of mutations (29%) in EGFR, KRAS, NRAS, MEK1, BRAF, PTEN, and PI3KCA genes and with gene amplification (20%) of c-MET and FGFR1. This new patient-derived NSCLC xenograft collection, established regardless of the considerable time required and the distance between the clinic and the animal facilities, recapitulated the histopathology and molecular diversity of NSCLC and provides stable and reliable preclinical models for human lung cancer research

  18. Androgen Receptor Expression and Cellular Proliferation During Transition from Androgen-Dependent to Recurrent Growth after Castration in the CWR22 Prostate Cancer Xenograft

    OpenAIRE

    Kim, Desok; Gregory, Christopher W.; French, Frank S.; Smith, Gary J.; Mohler, James L.

    2002-01-01

    Androgen receptor expression was analyzed in the CWR22 human prostate cancer xenograft model to better understand its role in prostate cancer recurrence after castration. In androgen-dependent tumors, 98.5% of tumor cell nuclei expressed androgen receptor with a mean optical density of 0.26 ± 0.01. On day 2 after castration androgen deprivation decreased immunostained cells to 2% that stained weakly (mean optical density, 0.16 ± 0.08). Cellular proliferation measured using Ki-67 revealed

  19. Intratumoral radioimmunotherapy of a human colon cancer xenograft using a sustained-release gel

    International Nuclear Information System (INIS)

    Low tumor uptake and normal tissue toxicity limit the efficacy of RIT for the treatment of solid tumors. In this study, an intratumoral injectable gel drug delivery system for local administration of RIT was evaluated using the LS174T human colon cancer xenograft model in SCID mice. The injectable gel is a collagen-based drug delivery system designed for intratumoral (i.t.) administration, which has previously been shown to enhance drug retention at the injection site and reduce systemic drug exposure. We compared the local (tumor) retention and biodistribution of 111In-labeled NR-LU-10 monoclonal antibody given i.t. in the injectable gel versus simple aqueous solution. 111In gel given i.t. and 111In-NR-LU-10 given intraperitoneally (i.p.) were used as controls. The results showed that tumors treated with 111In-NR-LU-10 gel maintained the highest levels of radioactivity for up to 96 h. At 48 h after the administration of 111In-NR-LU-10 gel i.t., 111In-NR-LU-10 solution i.t., 111In gel i.t., or111 In-NR-LU-10 i.p., the level of radioactivity remaining in each gram of tumor was 98, 49, 45, and 16% of the injected dose, respectively. It was estimated that if 100 μCi of 90Y-NR-LU-10 were administered similarly, tumor treated with 90Y-NR-LU-10 gel i.t. would receive a dose of 90.0 Gy, whereas normal tissues in the same animal would receive a dose of approximately 2.43 Gy. In contrast, if 90Y-NR-LU-10 were delivered i.p., a comparable tumor would receive a dose of 16.8 Gy and corresponding normal tissues would receive 3.36 Gy. Consistent with these estimates, enhanced antitumor efficacy was observed when 90Y-NR-LU-10 gel was administered i.t. Tumor growth delay time was 6.9-fold (P 90Y-NR-LU-10 i.p. (2.1 days). Systemic toxicity was also significantly reduced in gel-treated animals as monitored by loss of body weight. This study demonstrated that intratumoral delivery of 90Y-NR-LU-10 gel markedly increased the retention of the radioisotope in tumors, enhanced the

  20. Gene expression changes during repopulation in a head and neck cancer xenograft

    International Nuclear Information System (INIS)

    Background/purpose: To investigate temporal changes in global gene expression and pathways involved in the response to irradiation during phases of growth inhibition, recovery and repopulation in a human head and neck squamous cell cancer (HNSCC) xenograft. Methods and materials: Low passage head and neck squamous cancer cells (UT-14-SCC) were injected into the flanks of female nu/nu mice to generate xenografts. After tumors reached a size of 500 mm3, they were treated with either sham RT or 15 Gy in one fraction. At different time points, days 0, 3, and 10 for controls and days 4, 7, 12, and 21 after irradiation, the tumors were harvested for global gene expression analysis and pathway analysis. Results: The tumors showed growth inhibition through days 4–7 and began the transition to regrowth around the day 12 time point. When comparing the pooled controls to each day of treatment, there were 22, 119, 125, and 25 differentially expressed genes on days 4, 7, 12, and 21 respectively using a p ⩽ 0.01 and a 2-fold cut-off. Gene Ontology (GO), gene set enrichment analysis (GSEA) and sub-network enrichment analysis (SNEA) identified different biological processes, cell process pathways and expression targets to be active on each time point after irradiation. An important observation was that the molecular events on day 12 which represented the transition from growth inhibition to regrowth identified interferon and cytokine related genes and signaling pathways as the most prominent. Conclusion: The findings in this study compliment research which has identified components of interferon-related signaling pathways to be involved in radioresistance. Further work will be required to understand the significance of these genes in both radioresistance and treatment response leading to new therapeutic strategies and prognostic tools

  1. Stereotactic Orthotopic Xenograft Injections into the Mouse Brain

    OpenAIRE

    sprotocols

    2015-01-01

    Authors: Michelle Lee, Florian Muller, Elisa Aquilanti, Baoli Hu & Ronald DePinho ### Abstract Xenografting of human cancer cell lines injected subcutanously in nude mice has become the standard testing platform for dissecting mechanistic aspects of tumorigenesis and for pre-clinical drug development. However, subcutanous xenografts do not model tumors in their tissue of origin and thus may have some clinically relevant limitations. Xenografted human tumor cells directly injected ...

  2. A Walnut-Enriched Diet Reduces the Growth of LNCaP Human Prostate Cancer Xenografts in Nude Mice

    OpenAIRE

    Reiter, Russel J.; Tan, Dun-Xian; Manchester, Lucien C.; Korkmaz, Ahmet; Fuentes-Broto, Lorena; Hardman, W. Elaine; Rosales-Corral, Sergio A; Qi, Wenbo

    2013-01-01

    It was investigated whether a standard mouse diet (AIN-76A) supplemented with walnuts reduced the establishment and growth of LNCaP human prostate cancer cells in nude (nu/nu) mice. The walnut-enriched diet reduced the number of tumors and the growth of the LNCaP xenografts; 3 of 16 (18.7%) of the walnut-fed mice developed tumors; conversely, 14 of 32 mice (44.0%) of the control diet-fed animals developed tumors. Similarly, the xenografts in the walnut-fed animals grew more slowly than those ...

  3. Imaging the microenvironment of pancreatic cancer patient-derived orthotopic xenografts (PDOX) growing in transgenic nude mice expressing GFP, RFP, or CFP.

    Science.gov (United States)

    Hoffman, Robert M; Bouvet, Michael

    2016-09-28

    We have developed a multi-color, imageable, orthotopic mouse model for individual patients with pancreatic cancer. The tumors are labeled by first passaging them orthotopically through transgenic nude mice expressing green fluorescent protein (GFP), red fluorescent protein (RFP), or cyan fluorescent protein (CFP). Passage of the tumors in these colored transgenic mice labels the stromal cells of the tumor. The cancer cells in the PDOX are labeled in situ with GFP by telomerase-dependent adenovirus OBP-401. The models are termed imageable patient-derived orthotopic xenografts (iPDOX). The tumors acquired brightly-fluorescent stromal cells from the transgenic host mice, which were stably associated with the tumors through multiple passages. The colored fluorescent protein-expressing stromal cells included cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). This model enables powerful color-coded imaging of the interaction of cancer and stromal cells during tumor progression and treatment. PMID:26742463

  4. Interleukin-12 Inhibits Tumor Growth in a Novel Angiogenesis Canine Hemangiosarcoma Xenograft Model

    Directory of Open Access Journals (Sweden)

    Nasim Akhtar

    2004-03-01

    Full Text Available We established a canine hemangiosarcoma cell line derived from malignant endothelial cells comprising a spontaneous tumor in a dog to provide a renewable source of endothelial cells for studies of angiogenesis in malignancy. Pieces of the hemangiosarcoma biopsy were engrafted subcutaneously in a bg/nu/XID mouse allowing the tumor cells to expand in vivo. A cell line, SB-HSA, was derived from the xenograft. SB-HSA cells expressed vascular endothelial growth factor (VEGF receptors 1 and 2, CD31, CD146, and αvβ3 integrin, and produced several growth factors and cytokines, including VEGF, basic fibroblast growth factor, and interleukin (IL-8 that are stimulatory to endothelial cell growth. These results indicated that the cells recapitulated features of mitotically activated endothelia. In vivo, SB-HSA cells stimulated robust angiogenic responses in mice and formed tumor masses composed of aberrant vascular channels in immunocompromised mice providing novel opportunities for investigating the effectiveness of antiangiogenic agents. Using this model, we determined that IL-12, a cytokine with both immunostimulatory and antiangiogenic effects, suppressed angiogenesis induced by, and tumor growth of, SB-HSA cells. The endothelial cell model we have described offers unique opportunities to pursue further investigations with IL-12, as well as other antiangiogenic approaches in cancer therapy.

  5. Cyclophosphamide Enhances Human Tumor Growth in Nude Rat Xenografted Tumor Models

    Directory of Open Access Journals (Sweden)

    Yingjen Jeffrey Wu

    2009-02-01

    Full Text Available The effect of the immunomodulatory chemotherapeutic agent cyclophosphamide (CTX on tumor growth was investigated in primary and metastatic intracerebral and subcutaneous rat xenograft models. Nude rats were treated with CTX (100 mg/kg, intraperitoneally 24 hours before human ovarian carcinoma (SKOV3, small cell lung carcinoma (LX-1 SCLC, and glioma (UW28, U87MG, and U251 tumor cells were inoculated subcutaneously, intraperitoneally, or in the right cerebral hemisphere or were infused into the right internal carotid artery. Tumor development was monitored and recorded. Potential mechanisms were further investigated. Only animals that received both CTX and Matrigel showed consistent growth of subcutaneous tumors. Cyclophosphamide pretreatment increased the percentage (83.3% vs 0% of animals showing intraperitoneal tumors. In intracerebral implantation tumor models, CTX pretreatment increased the tumor volume and the percentage of animals showing tumors. Cyclophosphamide increased lung carcinoma bone and facial metastases after intra-arterial injection, and 20% of animals showed brain metastases. Cyclophosphamide transiently decreased nude rat white blood cell counts and glutathione concentration, whereas serum vascular endothelial growth factor was significantly elevated. Cyclophosphamide also increased CD31 reactivity, a marker of vascular endothelium, and macrophage (CD68-positive infiltration into glioma cell-inoculated rat brains. Cyclophosphamide may enhance primary and metastatic tumor growth through multiple mechanisms, including immune modulation, decreased response to oxidative stress, increased tumor vascularization, and increased macrophage infiltration. These findings may be clinically relevant because chemotherapy may predispose human cancer subjects to tumor growth in the brain or other tissues.

  6. Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo

    Directory of Open Access Journals (Sweden)

    He Y

    2016-05-01

    Full Text Available Yan He,1,* Zhiyun Du,1,* Shijing Ma,1 Yue Liu,2 Dongli Li,1 Huarong Huang,1 Sen Jiang,1 Shupeng Cheng,1 Wenjing Wu,1 Kun Zhang,1 Xi Zheng1,2 1Allan H Conney Laboratory for Anticancer Drug Research, School of Chemical Engineering and Light Industry, Guandong University of Technology, Guangzhou, People’s Republic of China; 2Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, USA *These authors contributed equally to this work Abstract: Silver nanoparticles (AgNPs have now been recognized as promising therapeutic molecules and are extending their use in cancer diagnosis and therapy. This study demonstrates for the first time the antitumor activity of green-synthesized AgNPs against lung cancer in vitro and in vivo. Cytotoxicity effect was explored on human lung cancer H1299 cells in vitro by MTT and trypan blue assays. Apoptosis was measured by morphological assessment, and nuclear factor-κB (NF-κB transcriptional activity was determined by a luciferase reporter gene assay. The expressions of phosphorylated stat3, bcl-2, survivin, and caspase-3 were examined by Western blot analysis. AgNPs showed dose-dependent cytotoxicity and stimulation of apoptosis in H1299 cells. The effects on H1299 cells correlated well with the inhibition of NF-κB activity, a decrease in bcl-2, and an increase in caspase-3 and survivin expression. AgNPs significantly suppressed the H1299 tumor growth in a xenograft severe combined immunodeficient (SCID mouse model. The results demonstrate the anticancer activities of AgNPs, suggesting that they may act as potential beneficial molecules in lung cancer chemoprevention and chemotherapy, especially for early-stage intervention. Keywords: silver nanoparticles, antitumor, lung cancer, cytotoxicity, H1299

  7. Potent anti-cancer effect of 3'-hydroxypterostilbene in human colon xenograft tumors.

    Directory of Open Access Journals (Sweden)

    Tzu-Chun Cheng

    Full Text Available Here we report that 3'-hydroxypterostilbene (HPSB, a natural pterostilbene analogue, was more potent than pterostilbene against the growth of human cancer cells (COLO 205, HCT-116, and HT-29 with measured IC50 values of 9.0, 40.2, and 70.9 µM, respectively. We found that HPSB effectively inhibited the growth of human colon cancer cells by inducing apoptosis and autophagy. Autophagy occurred at an early stage and was observed through the formation of acidic vesicular organelles and microtubule-associated protein 1 light chain 3-II production. At the molecular levels, the results from western blot analysis showed that HPSB significantly down-regulated phosphatidylinositol 3-kinase (PI3K/Akt and mitogen-activated protein kinases (MAPKs signalings including decreased the phosphorylation of mammalian target of rapamycin (mTOR. Significant therapeutic effects were demonstrated in vivo by treating nude mice bearing COLO 205 tumor xenografts with HPSB (10 mg/kg i.p.. These inhibitory effects were accompanied by mechanistic down-regulation of the protein levels of cyclooxygenase-2 (COX-2, matrix metallopeptidase-9 (MMP-9, vascular endothelial growth factor (VEGF, and cyclin D1, as well as by the induction of apoptosis in colon tumors. Our findings suggest that HPSB could serve as a novel promising agent for colon cancer treatment.

  8. AML cells are differentially sensitive to chemotherapy treatment in a human xenograft model

    OpenAIRE

    Wunderlich, Mark; Mizukawa, Benjamin; Chou, Fu-Sheng; Sexton, Christina; Shrestha, Mahesh; Saunthararajah, Yogen; Mulloy, James C.

    2013-01-01

    A relevant xenograft chemotherapy model was developed by using standard AML induction therapy drugs and primary human AML patient samples.Human AML cells show significantly increased sensitivity to in vivo chemotherapy treatment compared with murine LSK and total bone marrow cells.

  9. Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity.

    Science.gov (United States)

    Cantor, Joshua P; Iliopoulos, Dimitrios; Rao, Atul S; Druck, Teresa; Semba, Shuho; Han, Shuang-Yin; McCorkell, Kelly A; Lakshman, Thiru V; Collins, Joshua E; Wachsberger, Phyllis; Friedberg, Joseph S; Huebner, Kay

    2007-01-01

    Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16(INK4a) and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5-aza-2-deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm(3)); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16(INKa), Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re-expressed tumor suppressors as markers and effectors of the responses. PMID:17019711

  10. Interstitial chemotherapy with ricin-loaded thermosensitive hydrogel in pancreatic cancer xenograft

    Institute of Scientific and Technical Information of China (English)

    Zhi-Kui Chen; Li-Wu Lin; Xiu-Hua Weng; En-Sheng Xue; Yong-Hua Lin

    2009-01-01

    BACKGROUND:Pancreatic cancer is one of the most aggressive malignancies, and has a poor prognosis. Despite efforts made in multiple ifelds, there has been little success in improving the disease-free survival rate of patients. This study was undertaken to investigate the effectiveness and feasibility of using intra-tumoral injection of ricin-loaded thermosensitive hydrogel for treatment of pancreatic cancer xenografts, attempting to develop a new treatment for human pancreatic cancer. METHODS:BALB/c-(nu/nu) nude mice were inoculated subcutaneously in the right lfank with the human pancreatic cancer cells, SW1990. Fourteen days after inoculation, 32 mice, bearing tumors of volume 1.5-2.0 cm3, were randomly assigned to one of four groups, and given an intra-tumoral injection of: (1) saline; (2) 23%w/w thermosensitive hydrogel alone; (3) ricin, 10 μg/kg; or (4) 10 μg/kg ricin loaded in thermosensitive hydrogel. On day 14 after administration, the tumors were excised to calculate the inhibition rate of tumor growth and perform histopathological examination. Tumor cell apoptosis was detected by lfow cytometry, and RT-PCR was performed to evaluate the mRNA expression levels of Bcl2 and Bax. RESULTS:Intra-tumoral injection of ricin-loaded thermo-sensitive hydrogel resulted in remarkable control of tumor growth. The tumor became necrotic by day 14 after administration. The histological results clearly conifrmed that the tumor cells were lysed. The percentage of apoptotic cells detected by lfow cytometry was higher in the ricin hydrogel group than in the other groups. Semi-quantitative RT-PCR revealed that the mRNA expression level of Bcl2 was down-regulated whereas Bax was upregulated.CONCLUSIONS:Intra-tumoral injection of ricin-loaded thermosensitive hydrogel may provide an effective approach for interstitial chemotherapy in pancreatic cancer. Inducing apoptosis by downregulating Bcl2 expression and upregulating Bax expression may be a key molecular mechanism.

  11. Pancratistatin selectively targets cancer cell mitochondria and reduces growth of human colon tumor xenografts.

    Science.gov (United States)

    Griffin, Carly; Karnik, Aditya; McNulty, James; Pandey, Siyaram

    2011-01-01

    The naturally occurring Amaryllidaceae alkaloid pancratistatin exhibits potent apoptotic activity against a large panel of cancer cells lines and has an insignificant effect on noncancerous cell lines, although with an elusive cellular target. Many current chemotherapeutics induce apoptosis via genotoxic mechanisms and thus have low selectivity. The observed selectivity of pancratistatin for cancer cells promoted us to consider the hypothesis that this alkaloid targets cancer cell mitochondria rather than DNA or its replicative machinery. In this study, we report that pancratistatin decreased mitochondrial membrane potential and induced apoptotic nuclear morphology in p53-mutant (HT-29) and wild-type p53 (HCT116) colorectal carcinoma cell lines, but not in noncancerous colon fibroblast (CCD-18Co) cells. Interestingly, pancratistatin was found to be ineffective against mtDNA-depleted (ρ(0)) cancer cells. Moreover, pancratistatin induced cell death in a manner independent of Bax and caspase activation, and did not alter β-tubulin polymerization rate nor cause double-stranded DNA breaks. For the first time we report the efficacy of pancratistatin in vivo against human colorectal adenocarcinoma xenografts. Intratumor administration of pancratistatin (3 mg/kg) caused significant reduction in the growth of subcutaneous HT-29 tumors in Nu/Nu mice (n = 6), with no apparent toxicity to the liver or kidneys as indicated by histopathologic analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Altogether, this work suggests that pancratistatin may be a novel mitochondria-targeting compound that selectively induces apoptosis in cancer cells and significantly reduces tumor growth. PMID:21220492

  12. The study of irradiation combined with targeted suicide gene therapy for prostate cancer xenografts

    International Nuclear Information System (INIS)

    Objective: To study whether RGD-4C AAVP HSV-TK/GCV, one of suicide gene therapy targeting to Integrin αv, can enhance radiotherapeutic effect for DU145 prostate cancer xenografts or not. Methods: When the diameter of tumor in 48 nude mice bearing DU145 prostate cancer in the right leg attained 6.0 mm (5.8-6.3 mm), the mice were entered into the experiment. There were 6 experimental groups (8 mice per group), including the control, radiotherapy only (RT), RGD-4C AAVP HSV-TK/GCV only (Targeted, RGD-4C), AAVP HSV-TK/GCV (Non-targeted, non RGD-4C ), radiotherapy plus RGD- 4C AAVP HSV-TK/GCV(XRT + RGD-4C) and radiotherapy plus AAVP HSV-TK/GCV group (XRT + Non RGD-4C). The effect of treatment was assessed by tumor growth delay ( the time required when tumor grew from 6.0 mm to 12.0 mm) and tumor cure. Results: Five mice died during the treatment course. There were 6 mice without tumor after treatment, including 1 in RT group, 1 in RGD-4C group, 1 in non RGD-4C group and 3 in XRT + RGD-4C group, respectively. For tumor growth delay analysis in 37 mice, the absolute growth delay (AGD) for RGD-4C, non RGD-4C and RT group was 24.4 ± 9.0, 22.6±11.3 and 28.3 ±5.5 days, respectively. When RGD-4C AAVP HSV-TK/GCV or AAVP HSV-TK/GCV combined with radiotherapy, their AGD was 64.7±23.8 and 35.4±9.6 days, and nominal growth delay (NGD) was 40.3 ± 23.8 and 12.8 ± 9.6 days, respectively. The enhancement factor of RGD-4C AAVP HSV-TK/GCV and AAVP HSV-TK/GCV for radiotherapy were 1.42 and 0.45. Conclusion: RGD-4C AAVP HSV-TK/GCV can enhance radiotherapeutic effect for DU145 prostate cancer xenografts. Further study is needed. (authors)

  13. Vascular Differences Detected by MRI for Metastatic Versus Nonmetastatic Breast and Prostate Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Zaver M. Bhujwalla

    2001-01-01

    Full Text Available Several studies have linked vascular density, identified in histologic sections, to “metastatic risk.” Functional information of the vasculature, not readily available from histologic sections, can be obtained with contrast-enhanced MRI to exploit for therapy or metastasis prevention. Our aims were to determine if human breast and prostate cancer xenograffs preselected for differences in invasive and metastatic characteristics established correspondingly different vascular volume and permeability, quantified here with noninvasive MRI of the intravascular contrast agent albumin-GdDTPA. Tumor vascular volume and permeability of human breast and prostate cancer xenografts were characterized using MRI. Parallel studies confirmed the invasive behavior of these cell lines. Vascular endothelial growth factor (VEGF expression in the cell lines was measured using ELISA and Western blots. Metastasis to the lungs was evaluated with spontaneous as well as experimental assay. Metastatic tumors formed vasculature with significantly higher permeability or vascular volume (P < .05, two-sided unpaired t test. The permeability profile matched VEGF expression. Within tumors, regions of high vascular volume usually exhibited low permeability whereas regions of low vascular volume exhibited high permeability. We observed that although invasion was necessary, without adequate vascularization it was not sufficient for metastasis to occur.

  14. High hRFI expression correlates with resistance to Fluoro pyrimidines in human colon cancer cell lines and in xenografts

    International Nuclear Information System (INIS)

    We previously reported that the over-expression of hRFI, a protein preferentially expressed in the digestive tract regions of several cancers, exhibited a tendency to inhibit TNF-α induced apoptosis. In this study, we sought to determine the potential effect of hRFI expression on the sensitivity to 5-fluorouracil (5-FU) and/or other fluoro pyrimidines. For the whole lysates of 8 colon cancer cell lines, we performed Western blotting with anti-hRFI antibody and analyzed the correlations between the expression level of hRFI and the cell lines' sensitivity to 5-FU induced apoptosis. Furthermore, for a tissue micro array consisting of 32 xenograft derived human cancer cell lines, we examined the expression levels of hRFI and survivin by immunohistochemical staining, and analyzed the correlations between the expression of each protein and the sensitivity to several chemotherapeutic agents in the xenografts examined. Both in colon cancer cell lines and in xenografts, the expression level of hRFI was correlated with resistance to 5-FU and its derivatives. This evidence suggests that hRFI may be a marker predicting the response to fluorouracil derived chemotherapeutic agents and that the reduction of the expression level of hRFI might improve the outcome of chemotherapy

  15. The use of thermographic imaging to evaluate therapeutic response in human tumour xenograft models.

    Science.gov (United States)

    Hussain, Nosheen; Connah, David; Ugail, Hassan; Cooper, Patricia A; Falconer, Robert A; Patterson, Laurence H; Shnyder, Steven D

    2016-01-01

    Non-invasive methods to monitor tumour growth are an important goal in cancer drug development. Thermographic imaging systems offer potential in this area, since a change in temperature is known to be induced due to changes within the tumour microenvironment. This study demonstrates that this imaging modality can be applied to a broad range of tumour xenografts and also, for the first time, the methodology's suitability to assess anti-cancer agent efficacy. Mice bearing subcutaneously implanted H460 lung cancer xenografts were treated with a novel vascular disrupting agent, ICT-2552, and the cytotoxin doxorubicin. The effects on tumour temperature were assessed using thermographic imaging over the first 6 hours post-administration and subsequently a further 7 days. For ICT-2552 a significant initial temperature drop was observed, whilst for both agents a significant temperature drop was seen compared to controls over the longer time period. Thus thermographic imaging can detect functional differences (manifesting as temperature reductions) in the tumour response to these anti-cancer agents compared to controls. Importantly, these effects can be detected in the first few hours following treatment and therefore the tumour is observable non-invasively. As discussed, this technique will have considerable 3Rs benefits in terms of reduction and refinement of animal use. PMID:27491535

  16. Biological Analysis of Human CML Stem Cells; Xenograft Model of Chronic Phase Human Chronic Myeloid Leukemia.

    Science.gov (United States)

    Abraham, Sheela A

    2016-01-01

    Xenograft mouse models have been instrumental in expanding our knowledge of hematopoiesis and can provide a functional description of stem cells that possess engrafting potential. Here we describe methodology outlining one way of analyzing human malignant cells that are able to engraft immune compromised mice. Using models such as these will allow researchers to gain valuable insight into the primitive leukemic subtypes that evade current therapy regimes and are critical to understand, in order to eradicate malignancy. PMID:27581148

  17. New peptide receptor radionuclide therapy of invasive cancer cells: in vivo studies using 177Lu-DOTA-AE105 targeting uPAR in human colorectal cancer xenografts

    International Nuclear Information System (INIS)

    The proposition of uPAR as a potential target in cancer therapy is advanced by its predominant expression at the invasive front of colorectal cancer (CRC) and its value as prognostic biomarker for poor survival in this disease. In this study, we provide the first in vivo proof-of-concept for a theranostic approach as treatment modality in a human xenograft colorectal cancer model. Methods: A DOTA-conjugated 9-mer high affinity uPAR binding peptide (DOTA-AE105) was radiolabeled with 64Cu and 177Lu, for PET imaging and targeted radionuclide therapy study, respectively. Human uPAR-positive CRC HT-29 cells were inoculated in Nude mice and treated with 177Lu-DOTA-AE105 once a visible tumor had formed. To evaluate the true effect of the targeted radiotherapy, two controls groups were included in this study, one receiving a 177Lu-labeled non-binding control peptide and one receiving vehicle. All animals were treated day 0 and 7. A parallel 18F-FLT PET/CT study was performed on day 0, 1, 3 and 6. Dosimetry calculations were based on a biodistribution study, where organs and tissue of interest were collected 0.5, 1.0, 2.0, 4.0 and 24 h post injection of 177Lu-DOTA-AE105. Toxicity was assessed by recording mouse weight and by H and E staining of kidneys in each treatment group. Results: uPAR-positive HT-29 xenograft was clearly visualized by PET/CT imaging using 64Cu-DOTA-AE105. Subsequently, these xenograft transplants were locally irradiated using 177Lu-DOTA-AE105, where a significant effect on tumor size and the number of uPAR-positive cells in the tumor was found (p 18F-FLT PET/CT imaging study revealed a significant correlation between 18F-FLT tumor uptake and efficacy of the radionuclide therapy. A histological examination of the kidneys from one animal in each treatment group did not reveal any gross abnormalities and the general performance of all treated animals also showed no indications of radioactivity-induced toxicity. Conclusion: These findings document for the

  18. Biological studies of samarium-153 bleomycin complex in human breast cancer murine xenografts for therapeutic applications

    International Nuclear Information System (INIS)

    In this work, a potential therapeutic DNA targeting agent, 153Sm-bleomycin complex (153Sm-BLM), was developed and the tumor accumulation studies were performed using single photon emission computed tomography (SPECT) and scarification studies. 153Sm-BLM was prepared at optimized conditions (room temperature, 4-8 h, 0.1 mg bleomycin for 740-3700 MBq 153SmCl3, radiochemical purity over 98%, HPLC, specific activity = 55 TBq/mmol). 153Sm-BLM was administered into human breast cancer murine xenografts and the biodistribution and imaging studies were performed up to 48 h. 153Sm-BLM demonstrated superior tumor accumulation properties in contrast with the other radiolabeled bleomycins with tumor:blood ratios of 41, 72 and 182 at 4, 24 and 48 h, respectively, and tumor:muscle ratios of 23, 33 and > 1490 at 4, 24 and 48 h, respectively, while administered intravenously. The SPECT images also demonstrated the obvious tumor uptake at the chest region of the breast-tumor bearing mice. These initial experiments demonstrate significant accumulation of 153Sm-BLM in tumor tissues. (orig.)

  19. Expression of myc family oncoproteins in small-cell lung-cancer cell lines and xenografts

    DEFF Research Database (Denmark)

    Rygaard, K; Vindeløv, L L; Spang-Thomsen, M

    1993-01-01

    A number of genes have altered activity in small-cell lung cancer (SCLC), but especially genes of the myc family (c-myc, L-myc and N-myc) are expressed at high levels in SCLC. Most studies have explored expression at the mRNA level, whereas studies of myc family oncoprotein expression are sparse....... WE examined the expression of myc proto-oncogenes at the mRNA and protein level in 23 cell lines or xenografts. In the cell lines, the doubling time and the cell-cycle distribution, as determined by flow-cytometric DNA analysis, were examined to establish whether the level of myc...... general, the level of expression of c-myc and N-myc was similar at the mRNA and the protein level. Expression of c-myc was positively correlated with the proliferative index (sum of S and G2+M phases) of cell lines, but not with the population doubling time. In general, L-myc-expressing cell lines had a...

  20. Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models

    Directory of Open Access Journals (Sweden)

    Wu Xianhua

    2012-08-01

    Full Text Available Abstract Background Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models. Methods PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC tissues into immunodeficient (SCID/nude mice. HER-2 gene copy number (GCN and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group. Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient’s ESCC tissues. Similarity between the PDECX models and their corresponding patient’s ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation. Results None of the PDECX models (or their corresponding patient’s ESCC tissues harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+ in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+. A second HER-2 positive (IHC 2+ model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model. Conclusions

  1. Effects of recombinant human growth hormone on growth of human gastric carcinoma xenograft model in nude mice

    Institute of Scientific and Technical Information of China (English)

    Dao-Ming Liang; Jia-Yong Chen; Yi Zhang; Ping Gan; Jie Lin; An-Bao Chen

    2006-01-01

    AIM: To study effects of recombinant human growth hormone (rhGH) on growth of a human gastric carcinoma cell in vivo.METHODS: Experimental mice were divided into control group, rhGH group, oxaliplatin (L-OHP) group and rhGH+L-OHP group. Cultured human gastric carcinoma cells BGC823 were inoculated into right axilla of nude mice and carcinoma xenograft model wasestablished successfully. Inhibitory rate of xenograft tumor growth was estimated by measuring tumor volume; expression of proliferating cell nuclear antigen (PCNA), Bax and Bcl-2 proteins of xenograft tumor was detected using immunohistochemical S-P method.RESULTS: Tumor growth inhibitory rate, the positive expression rate of PCNA, Bax and Bcl-2 were 49.3%,58.2%, 65.2% and 59.2% in rhGH+L-OHP group respectively; 46.6%, 62.5%, 59.7% and 64.7% in L-OHP group; 5.0%, 82.7%, 23.2% and 82.2% in rhGH group and 0, 77.8%, 23.5% and 80.3% in control group. There was significant difference between rhGH+L-OHP group (or L-OHP group ) and control group or rhGH group (P <0.05), whereas there were no significant differences (P >0.05) between L-OHP group and rhGH+L-OHP group and between rhGH group and control group.CONCLUSION: rhGH does not accelerate the proliferation of human gastric cancer cell in vivo.

  2. Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers.

    Science.gov (United States)

    Bradford, James R; Wappett, Mark; Beran, Garry; Logie, Armelle; Delpuech, Oona; Brown, Henry; Boros, Joanna; Camp, Nicola J; McEwen, Robert; Mazzola, Anne Marie; D'Cruz, Celina; Barry, Simon T

    2016-04-12

    The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment.In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery. PMID:26980748

  3. Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers

    Science.gov (United States)

    Bradford, James R.; Wappett, Mark; Beran, Garry; Logie, Armelle; Delpuech, Oona; Brown, Henry; Boros, Joanna; Camp, Nicola J.; McEwen, Robert; Mazzola, Anne Marie; D'Cruz, Celina; Barry, Simon T.

    2016-01-01

    The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX). Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment. In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery. PMID:26980748

  4. Monitoring longitudinal changes in irradiated head and neck cancer xenografts using diffuse reflectance spectroscopy

    Science.gov (United States)

    Vishwanath, Karthik; Jiang, Shudong; Gunn, Jason R.; Marra, Kayla; Andreozzi, Jacqueline M.; Pogue, Brian W.

    2016-02-01

    Radiation therapy is often used as the preferred clinical treatment for control of localized head and neck cancer. However, during the course of treatment (6-8 weeks), feedback about functional and/or physiological changes within impacted tissue are not obtained, given the onerous financial and/or logistical burdens of scheduling MRI, PET or CT scans. Diffuse optical sensing is well suited to address this problem since the instrumentation can be made low-cost and portable while still being able to non-invasively provide information about vascular oxygenation in vivo. Here we report results from studies that employed an optical fiber-based portable diffuse reflectance spectroscopy (DRS) system to longitudinally monitor changes in tumor vasculature within two head and neck cancer cell lines (SCC-15 and FaDu) xenografted in the flanks of nude mice, in two separate experiments. Once the tumor volumes were 100mm3, 67% of animals received localized (electron beam) radiation therapy in five fractions (8Gy/day, for 5 days) while 33% of the animals served as controls. DRS measurements were obtained from each animal on each day of treatment and then for two weeks post-treatment. Reflectance spectra were parametrized to extract total hemoglobin concentration and blood oxygen-saturation and the resulting time-trends of optical parameters appear to be dissimilar for the two cell-lines. These findings are also compared to previous animal experiments (using the FaDu line) that were irradiated using a photon beam radiotherapy protocol. These results and implications for the use of fiber-based DRS measurements made at local (irradiated) tumor site as a basis for identifying early radiotherapy-response are presented and discussed.

  5. Therapeutic Electromagnetic Field (TEMF and gamma irradiation on human breast cancer xenograft growth, angiogenesis and metastasis

    Directory of Open Access Journals (Sweden)

    Hardman W Elaine

    2005-07-01

    Full Text Available Abstract Background The effects of a rectified semi-sinewave signal (15 mT amplitude, 120 pulses per second, EMF Therapeutics, Inc. (TEMF alone and in combination with gamma irradiation (IR therapy in nude mice bearing a human MDA MB231 breast cancer xenograft were tested. Green fluorescence protein transfected cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into four treatment groups: untreated controls; 10 minute daily TEMF; 200 cGy of IR every other day (total 800 cGy; IR plus daily TEMF. Some mice in each group were euthanized 24 hours after the end of IR. TEMF treatment continued for 3 additional weeks. Tumor sections were stained for: endothelial cells with CD31 and PAS or hypoxia inducible factor 1α (HIF. Results Most tumors 3 were white but tumors >35 mm3 were pink and had a vascularized capsule. The cortex within 100 microns of the capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at >100 microns from the capsule (subcortex. Tumors >35 mm3 treated with IR 24 hours previously or with TEMF had decreased blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic, HIF positive areas than tumors from the control group. Mice that received either IR or TEMF had significantly fewer lung metastatic sites and slower tumor growth than did untreated mice. No harmful side effects were attributed to TEMF. Conclusion TEMF therapy provided a safe means for retarding tumor vascularization, growth and metastasis.

  6. Dietary omega-3 fatty acids and ionizing irradiation on human breast cancer xenograft growth and angiogenesis

    Directory of Open Access Journals (Sweden)

    Cameron Ivan L

    2005-04-01

    Full Text Available Abstract Background The effects of an omega-3 (n-3 fatty acid enriched diet alone and in combination with gamma irradiation (IR therapy in nude mice bearing a human MDA-MB231 breast cancer xenograft were tested. The cancer cells were injected into the mammary fat pad of young female mice. Six weeks later, mice were randomly divided into two diet groups: 1 mice with 10% corn oil (rich in omega 6 fatty acids in their food, 2 mice consuming a 10% fat diet that was enriched in n-3 fatty acids. After two weeks on the diet, treatment with 200 cGy of IR every second day for four treatments (total 800 cGy was initiated on half of the mice from each diet group. Some mice in each of the 4 groups were euthanized 24 hours after the end of IR while the remaining mice were followed for 3 additional weeks. Tumor sections were stained for endothelial cells with CD31 and PAS and for hypoxia inducible factor 1α (HIF-α. Results The tumor cortex within 100 microns of the well-vascularized capsule had little vascularization. Blood vessels, capillaries, and endothelial pseudopods were found at areas greater than 100 microns from the capsule (subcortex. Mice on the corn oil diet and treated with IR 24 hours previously or non-irradiated mice fed the n-3 diet had tumors with fewer blood vessels in the subcortex and more endothelial pseudopods projecting into hypoxic (HIF- α positive areas than did mice from the non-irradiated corn oil fed group. The tumor growth rate of mice that received IR or that were fed the n-3 fatty acid enriched diet was significantly slower than in the mice fed the 10% corn oil diet. Harmful side effects were found only in the IR treated mice. Conclusion The omega-3 fatty acid enriched diet proved to be a safe means for retarding tumor growth and vascularization.

  7. Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma

    OpenAIRE

    Guastella, Anthony R.; Michelhaugh, Sharon K; Klinger, Neil V.; Kupsky, William J.; Polin, Lisa A.; Muzik, Otto; Juhász, Csaba; Mittal, Sandeep

    2016-01-01

    Increasing evidence demonstrates the immunosuppressive kynurenine pathway’s (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[11C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 p...

  8. Inflammation precedes the development of human malignant mesotheliomas in a SCID mouse xenograft model

    OpenAIRE

    Hillegass, Jedd M; Shukla, Arti; Lathrop, Sherrill A.; MacPherson, Maximilian B; Beuschel, Stacie L; Butnor, Kelly J.; Testa, Joseph R.; Harvey I Pass; Carbone, Michele; Steele, Chad; Mossman, Brooke T.

    2010-01-01

    Asbestos fibers cause chronic inflammation that may be critical to the development of malignant mesothelioma (MM). Two human MM cell lines (Hmeso, PPM Mill) were used in a SCID mouse xenograft model to assess time-dependent patterns of inflammation and tumor formation. After intraperitoneal (IP) injection of MM cells, mice were euthanized at 7, 14, and 30 days, and peritoneal lavage fluid (PLF) was examined for immune cell profiles and human and mouse cytokines. Increases in human MM-derived ...

  9. Antiangiogenic effects of pazopanib in xenograft hepatocellular carcinoma models: evaluation by quantitative contrast-enhanced ultrasonography

    International Nuclear Information System (INIS)

    Antiangiogenesis is a promising therapy for advanced hepatocellular carcinoma (HCC), but the effects are difficult to be evaluated. Pazopanib (GW786034B) is a pan-vascular endothelial growth factor receptor inhibitor, the antitumor effects or antiangiogenic effects haven't been investigated in HCC. In vitro direct effects of pazopanib on human HCC cell lines and endothelial cells were evaluated. In vivo antitumor effects were evaluated in three xenograft nude mice models. In the subcutaneous HCCLM3 model, intratumoral blood perfusion was detected by contrast-enhanced ultrasonography (CEUS), and serial quantitative parameters were profiled from the time-intensity curves of ultrasonograms. In vitro proliferation of various HCC cell lines were not inhibited by pazopanib. Pazopanib inhibited migration and invasion and induced apoptosis significantly in two HCC cell lines, HCCLM3 and PLC/PRF/5. Proliferation, migration, and tubule formation of human umbilical vein endothelial cells were inhibited by pazopanib in a dose-dependent manner. In vivo tumor growth was significantly inhibited by pazopanib in HCCLM3, HepG2, and PLC/PRF/5 xenograft models. Various intratumoral perfusion parameters changed over time, and the signal intensity was significantly impaired in the treated tumors before the treatment efficacy on tumor size could be observed. Mean transit time of the contrast media in hotspot areas of the tumors was reversely correlated with intratumoral microvessel density. Antitumor effects of pazopanib in HCC xenografts may owe to its antiangiogenic effects, and the in vivo antiangiogenic effects could be evaluated by quantitative CEUS

  10. The chick chorioallantoic membrane as an in vivo xenograft model for Burkitt lymphoma

    International Nuclear Information System (INIS)

    Burkitt lymphoma (BL) is an aggressive malignancy that arises from B-cells and belongs to the group of Non-Hodgkin lymphomas (NHL). Due to the lack of appropriate in vivo models NHL research is mainly performed in vitro. Here, we studied the use of the chick chorioallantoic membrane (CAM) for the generation of human BL xenograft tumors, which we compared with known characteristics of the human disease. In order to generate experimental BL tumors, we inoculated human BL2B95 and BL2-GFP cells on the CAM. BL2B95 xenograft-tumors were grown for seven days and subsequently analyzed with transmission electron and immunofluorescence microscopy, as well as histological staining approaches. BL2-GFP cells were studied at regular intervals up to seven days, and their metastatic behavior was visualized with intravital immunofluorescence techniques. Xenografted BL2B95 cells formed solid tumors in the CAM model with a Ki67-index greater than 90%, preservation of typical tumor markers (CD10, CD19, CD20), a ‘starry sky’ morphology, production of agyrophilic fibers in the stroma, formation of blood and lymphatic vessels and lymphogenic dissemination of BL2B95 to distant sites. We identified macrophages, lymphocytes and heterophilic granulocytes (chick homolog of neutrophils) as the most abundant immune cells in the experimental tumors. BL2-GFP cells could be traced in real-time during their distribution in the CAM, and the first signs for their dissemination were visible after 2-3 days. We show that xenografted BL2B95 cells generate tumors in the CAM with a high degree of cellular, molecular and proliferative concord with the human disease, supporting the application of the CAM model for NHL research with a focus on tumor-stroma interactions. Additionally we report that BL2-GFP cells, grafted on the CAM of ex ovo cultured chick embryos, provide a powerful tool to study lymphogenic dissemination in real-time

  11. Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Berthou Christian

    2010-12-01

    Full Text Available Abstract Background We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from Guttiferae trees, display in vitro antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL and leukemia B cell lines. Results Here, we investigated the in vivo therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (p = 0.0006 and p = 0.0141, respectively. The same treatment of mice which were not xenografted induced no mortality. Conclusion These data show for the first time the in vivo antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.

  12. Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model

    DEFF Research Database (Denmark)

    van den Driesche, Sander; Macdonald, Joni; Anderson, Richard A; Johnston, Zoe C; Chetty, Tarini; Smith, Lee B; McKinnell, Chris; Dean, Afshan; Homer, Natalie Z; Jorgensen, Anne; Camacho-Moll, Maria E; Sharpe, Richard M; Mitchell, Rod T

    2015-01-01

    Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons......, but effects on fetal testosterone production have not been demonstrated. We used a validated xenograft model to expose human fetal testes to clinically relevant doses and regimens of acetaminophen. Exposure to a therapeutic dose of acetaminophen for 7 days significantly reduced plasma testosterone (45......% reduction; P = 0.025) and seminal vesicle weight (a biomarker of androgen exposure; 18% reduction; P = 0.005) in castrate host mice bearing human fetal testis xenografts, whereas acetaminophen exposure for just 1 day did not alter either parameter. Plasma acetaminophen concentrations (at 1 hour after the...

  13. Evaluation of the Metabolic Response to Cyclopamine Therapy in Pancreatic Cancer Xenografts Using a Clinical PET-CT System1

    OpenAIRE

    Kayed, Hany; MEYER, Patrick; He, Yong; Kraenzlin, Bettina; Fink, Christian; Gretz, Norbert; Schoenberg, Stefan O; Sadick, Maliha

    2012-01-01

    OBJECTIVES: We analyzed the effects of anti-hedgehog signaling on the 18F-FDG uptake of pancreatic cancer xenografts (PCXs) using a clinically implemented positron emission tomography (PET)-computer tomography (CT) scanner with high-resolution reconstruction. METHODS: PCXs from two pancreatic cancer cell lines were developed subcutaneously in nude mice and injected intraperitoneally with a low dose of cyclopamine for 1 week. 18F-FDG PET-CT was performed using a new-generation clinical PET-CT ...

  14. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    International Nuclear Information System (INIS)

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice

  15. A novel rabbit anti-hepatocyte growth factor monoclonal neutralizing antibody inhibits tumor growth in prostate cancer cells and mouse xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yanlan; Chen, Yicheng; Ding, Guoqing; Wang, Mingchao; Wu, Haiyang; Xu, Liwei; Rui, Xuefang; Zhang, Zhigen, E-mail: srrshurology@163.com

    2015-08-14

    The hepatocyte growth factor and its receptor c-Met are correlated with castration-resistance in prostate cancer. Although HGF has been considered as an attractive target for therapeutic antibodies, the lack of cross-reactivity of monoclonal antibodies with human/mouse HGFs is a major obstacle in preclinical developments. We generated a panel of anti-HGF RabMAbs either blocking HGF/c-Met interaction or inhibiting c-Met phosphorylation. We selected one RabMAb with mouse cross-reactivity and demonstrated that it blocked HGF-stimulated downstream activation in PC-3 and DU145 cells. Anti-HGF RabMAb inhibited not only the growth of PC-3 cells but also HGF-dependent proliferation in HUVECs. We further demonstrated the efficacy and potency of the anti-HGF RabMAb in tumor xenograft mice models. Through these in vitro and in vivo experiments, we explored a novel therapeutic antibody for advanced prostate cancer. - Highlights: • HGF is an attractive target for castration-refractory prostate cancer. • We generated and characterized a panel of anti-HGF rabbit monoclonal antibodies. • More than half of these anti-HGF RabMAbs was cross-reactive with mouse HGF. • Anti-HGF RabMAb blocks HGF-stimulated phosphorylation and cell growth in vitro. • Anti-HGF RabMAb inhibits tumor growth and angiogenesis in xenograft mice.

  16. Endocrine-Therapy-Resistant ESR1 Variants Revealed by Genomic Characterization of Breast-Cancer-Derived Xenografts

    Directory of Open Access Journals (Sweden)

    Shunqiang Li

    2013-09-01

    Full Text Available To characterize patient-derived xenografts (PDXs for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation.

  17. Improved response of colon cancer xenografts to radioimmunotherapy with pentoxifylline treatment

    International Nuclear Information System (INIS)

    A methylxanthine, pentoxifylline (PTX), has the potential to improve tumour microcirculation and oxygenation in vivo. We aimed to determine whether this agent would enhance the response of tumours to experimental radioimmunotherapy (RIT). Balb/c nu/nu mice with xenografts of LS180 human colon cancer were treated with 4.63 MBq of 131I-A7 anti-colorectal monoclonal antibody. A dose of 50 mg/kg of PTX was administered i.p. immediately after the 131I-A7 injection and daily thereafter for 7 days. The effect of PTX administration on 131I-A7 targeting in tumours was assessed with biodistribution and radioluminography on day 2. Intratumoural pO2 was measured with microelectrodes. The administration of PTX alone did not suppress tumour growth, but the efficacy of RIT with 131I-A7 was significantly improved by PTX: tumour volumes on day 15, relative to the initial volume, were 16.8±3.60 in the non-treated controls, 13.9±2.17 with PTX, 3.43±0.44 with RIT, and 1.86±0.59 with RIT+PTX (P131I-A7. However, intratumoural pO2 was significantly improved by PTX administration: 16.9±9.75 mmHg in control tumours versus 25.6±11.3 mmHg in PTX-treated tumours (P<0.01). These results indicate that PTX-induced radiosensitisation of tumour cells due to better oxygenation is responsible for the better RIT outcomes, because the net radiation absorbed dose to the tumours did not appear to be changed. (orig.)

  18. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Dolores Hernán Pérez de la Ossa

    Full Text Available Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9-Tetrahydrocannabinol (THC and Cannabidiol (CBD - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

  19. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

    Science.gov (United States)

    Hernán Pérez de la Ossa, Dolores; Lorente, Mar; Gil-Alegre, Maria Esther; Torres, Sofía; García-Taboada, Elena; Aberturas, María Del Rosario; Molpeceres, Jesús; Velasco, Guillermo; Torres-Suárez, Ana Isabel

    2013-01-01

    Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w) of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies. PMID:23349970

  20. Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products.

    Science.gov (United States)

    Manu, Kanjoormana A; Shanmugam, Muthu K; Li, Feng; Chen, Luxi; Siveen, Kodappully Sivaraman; Ahn, Kwang Seok; Kumar, Alan Prem; Sethi, Gautam

    2014-03-01

    Chemoresistance remains a major problem in the treatment of gastric cancer patients. Hence, novel pharmacological agents that can overcome drug resistance are urgently required. Whether simvastatin can sensitize the gastric cancer to the antitumor effects of capecitabine in vitro and in vivo was investigated. The effect of simvastatin on the proliferation of gastric cancer cells was examined by mitochondrial dye-uptake 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, apoptosis by esterase staining, NF-κB activation by DNA binding assay, and protein expression by western blot analysis. The effect of simvastatin on the tumor growth in xenograft mouse model of human gastric cancer was also examined. Simvastatin suppressed the proliferation of gastric cancer cells, enhanced the apoptotic effects of capecitabine, suppressed the constitutive activation of NF-κB, and abrogated the expression of cyclooxygenase-2 (COX-2), cyclin D1, Bcl-2, survivin, CXC motif receptor 4, and MMP-9 proteins. In a xenograft mouse model, we observed that the administration of simvastatin alone (5 mg/kg body weight, intraperitoneal thrice/week) significantly suppressed the growth of the tumor and this effect was further potentiated by capecitabine treatment. As compared to the vehicle control, simvastatin also suppressed the expression of NF-κB-regulated gene products such as cyclin D1, COX-2, ICAM-1, MMP-9, survivin, Bcl-xL, and XIAP in tumor tissues. Overall, our results demonstrate that simvastatin can enhance the effects of capecitabine through suppression of NF-κB-regulated markers of proliferation, invasion, angiogenesis, and metastasis. PMID:24233024

  1. Effects and possible anti-tumor immunity of electrochemotherapy with bleomycin on human colon cancer xenografts in nude mice

    Institute of Scientific and Technical Information of China (English)

    Min-Hua Zheng; Bao-Ming Yu; Bo Feng; Jian-Wen Li; Ai-Guo Lu; Ming-Liang Wang; Wei-Guo Hu; Ji-Yuan Sun; Yan-Yan Hu; Jun-Jun Ma

    2005-01-01

    AIM: To evaluate the anti-tumor effects and possible involvement of anti-tumor immunity of electrochemotherapy (ECT) employing electroporation and bleomycin in human colon cancer xenografts in nude mice, and to establish the experimental basis for clinical application of ECT.METHODS: Forty nude mice, inoculated subcutaneously human colon cancer cell line LoVo for 3 wk, were allocated randomly into four groups: B+E+ (ECT), B+E- (administration of bleomycin alone), B-E+ (administration of electric pulses alone), and B-E- (no treatment). Tumor volumes were measured daily. The animals were killed on the 7th d, the weights of xenografts were measured, and histologies of tumors were evaluated. Cytotoxicity of spleen natural killer (NK) and lymphokine-activated killer (LAK) cells was then assessed by lactic dehydrogenase release assay.RESULTS: The mean tumor volume of group B+E+ was statistically different from the other three groups after the treatment (F= 36.80, P<0.01). There was one case of complete response, seven cases of partial response (PR) in group B+E+, one case of PR in group B+E- and group B-E+ respectively, and no response was observed in group B-E-. The difference of response between group B+E+ and the other three groups was statistically significant (χ2 = 25.67, P<0.01). Histologically, extensive necrosis of tumor cells with considerable vascular damage and inflammatory cells infiltration were observed in group B+E+. There was no statistical difference between the cytotoxicity of NK and LAK cells in the four treatment groups.CONCLUSION: ECT significantly enhances the chemosensitivity and effects of chemotherapy in human colon cancer xenografts in nude mice, and could be a kind of novel treatment modality for human colon cancer.The generation of T-cell-dependent, tumor-specific immunity might be involved in the process of ECT.

  2. Remission of invasive, cancer stem-like glioblastoma xenografts using lentiviral vector-mediated suicide gene therapy.

    Directory of Open Access Journals (Sweden)

    Peter C Huszthy

    Full Text Available BACKGROUND: Glioblastoma is the most frequent and most malignant primary brain tumor with a poor prognosis. The translation of therapeutic strategies for glioblastoma from the experimental phase into the clinic has been limited by insufficient animal models, which lack important features of human tumors. Lentiviral gene therapy is an attractive therapeutic option for human glioblastoma, which we validated in a clinically relevant animal model. METHODOLOGY/PRINCIPAL FINDINGS: We used a rodent xenograft model that recapitulates the invasive and angiogenic features of human glioblastoma to analyze the transduction pattern and therapeutic efficacy of lentiviral pseudotyped vectors. Both, lymphocytic choriomeningitis virus glycoprotein (LCMV-GP and vesicular stomatitis virus glycoprotein (VSV-G pseudotyped lentiviral vectors very efficiently transduced human glioblastoma cells in vitro and in vivo. In contrast, pseudotyped gammaretroviral vectors, similar to those evaluated for clinical therapy of glioblastoma, showed inefficient gene transfer in vitro and in vivo. Both pseudotyped lentiviral vectors transduced cancer stem-like cells characterized by their CD133-, nestin- and SOX2-expression, the ability to form spheroids in neural stem cell medium and to express astrocytic and neuronal differentiation markers under serum conditions. In a therapeutic approach using the suicide gene herpes simplex virus thymidine kinase (HSV-1-tk fused to eGFP, both lentiviral vectors mediated a complete remission of solid tumors as seen on MRI resulting in a highly significant survival benefit (p<0.001 compared to control groups. In all recurrent tumors, surviving eGFP-positive tumor cells were found, advocating prodrug application for several cycles to even enhance and prolong the therapeutic effect. CONCLUSIONS/SIGNIFICANCE: In conclusion, lentiviral pseudotyped vectors are promising candidates for gene therapy of glioma in patients. The inefficient gene delivery

  3. Identification of multipotent mesenchymal stromal cells in the reactive stroma of a prostate cancer xenograft by side population analysis

    International Nuclear Information System (INIS)

    Cancer stem cells are a distinct cellular population that is believed to be responsible for tumor initiation and maintenance. Recent data suggest that solid tumors also contain another type of stem cells, the mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs), which contribute to the formation of tumor-associated stroma. The Hoechst 33342 efflux assay has proved useful to identify a rare cellular fraction, named Side Population (SP), enriched in cells with stem-like properties. Using this assay, we identified SP cells in a prostate cancer xenograft containing human prostate cancer cells and mouse stromal cells. The SP isolation, subculture and sequential sorting allowed the generation of single-cell-derived clones of murine origin that were recognized as MSC by their morphology, plastic adherence, proliferative potential, adipogenic and osteogenic differentiation ability and immunophenotype (CD45-, CD81+ and Sca-1+). We also demonstrated that SP clonal cells secrete transforming growth factor β1 (TGF-β1) and that their inhibition reduces proliferation and accelerates differentiation. These results reveal the existence of SP cells in the stroma of a cancer xenograft, and provide evidence supporting their MSC nature and the role of TGF-β1 in maintaining their proliferation and undifferentiated status. Our data also reveal the usefulness of the SP assay to identify and isolate MSC cells from carcinomas.

  4. Radionuclide imaging and therapy mediated by hNIS gene transfection in nasopharyngeal carcinoma xenograft model

    International Nuclear Information System (INIS)

    Objective: To explore the feasibility of 131I radiotherapy mediated by hNIS gene transfection in nasopharyngeal carcinoma (NPC). Methods: NPC xenograft models were established with CNE-2-hNIS cells (experimental group) and CNE-2 cells (control group). Radioactivity of different organs of nude mice was counted at 0.5,1,2,6 and 24 h after intraperitoneal injection of 125I using a gamma counter. 99TcmO4- imaging was also performed in nude mice. Changes in the xenograft tumor volume were observed after 131I treatment in the experimental group and control group. Cell apoptosis was detected after 131I treatment by the terminal oxynucleotidyl transferase mediated dUTP biotin nick end labeling (TUNEL) method and caspase 3 and Ki67 expressions measured with immunohistochemistry of the tumor tissue. Statistical analysis was performed using SPSS 13.0 software, and the mean values between groups were compared using t test. Results: CNE-2-hNIS and CNE-2 NPC xenografts were established successfully in nude mice. Biodistribution of 125I in tumor-bearing nude mice showed enhanced tumor uptake of 125I in the experimental group, with peak uptake at 1 h ((20.28 ± 0.15)%). The biological half-life of 125I in the tumors transfected with hNIS was about 1.56 h. Imaging studies showed that the tumors in the experimental group accumulated 99TcmO4- with a peak at 1.5-2 h, whereas the control tumors were not visualized. The mean volume of the experimental xenograft tumors was (0.44 ±0.04) cm3 before 131I treatment and increased to (0.97 ±0.08) cm3 after 131I treatment. However, the volume of the control xenografts was (0.45 ± 0.06) cm3 before 131I treatment and (2.98 ±0.16) cm3 after 131I treatment. The tumor volume of the experimental group was significantly smaller compared with that of the control group after 131I treatment (t=19.46, P<0.01). A higher apoptotic index and caspase 3 positive rate as well as lower Ki67 proliferation index were observed in the experimental group after

  5. Expression of cadherin and NCAM in human small cell lung cancer cell lines and xenografts

    DEFF Research Database (Denmark)

    Rygaard, K; Møller, C; Bock, E;

    1992-01-01

    embryonic development, which may play a role in connection with tumour invasion and metastasis, was found in 14/18 NCAM expressing SCLC tumours. Individual tumours grown as cell lines and as nude mouse xenografts showed no qualitative differences in cadherin or NCAM expression....

  6. Imaging of dihydrofolate reductase fusion gene expression in xenografts of human liver metastases of colorectal cancer in living rats

    International Nuclear Information System (INIS)

    Radionuclide imaging has been demonstrated to be feasible to monitor transgene expression in vivo. We hypothesized that a potential application of this technique is to non-invasively detect in deep tissue, such as cancer cells metastatic to the liver, a specific molecular response following systemic drug treatment. Utilizing human colon adenocarcinoma cells derived from a patient's liver lesion we first developed a nude rat xenograft model for colorectal cancer metastatic to the liver. Expression of a dihydrofolate reductase-herpes simplex virus 1 thymidine kinase fusion (DHFR-HSV1 TK) transgene in the hepatic tumors was monitored in individual animals using the tracer [124I]2'-fluoro-2'-deoxy-5-iodouracil-β-d-arabinofuranoside (FIAU) and a small animal micro positron emission tomograph (microPET), while groups of rats were imaged using the tracer [131I]FIAU and a clinical gamma camera. Growth of the human metastatic colorectal cancer cells in the rat liver was detected using magnetic resonance imaging and confirmed by surgical inspection. Single as well as multiple lesions of different sizes and sites were observed in the liver of the animals. Next, using a subset of rats bearing hepatic tumors, which were retrovirally bulk transduced to express the DHFR-HSV1 TK transgene, we imaged the fusion protein expression in the hepatic tumor of living rats using the tracer [124I]FIAU and a microPET. The observed deep tissue signals were highly specific for the tumors expressing the DHFR-HSV1 TK fusion protein compared with parental untransduced tumors and other tissues as determined by gamma counting of tissue samples. A subsequent study used the tracer [131I]FIAU and a gamma camera to monitor two groups of transduced hepatic tumor-bearing rats. Prior to imaging, one group was treated with trimetrexate to exploit DHFR-mediated upregulation of the fusion gene product. Imaging in the living animal as well as subsequent gamma counting of tissue samples showed increased

  7. Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway.

    Science.gov (United States)

    Wang, Yongwei; Wu, Xiangsong; Zhou, Yinan; Jiang, Hongchi; Pan, Shangha; Sun, Bei

    2016-03-01

    Pancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigate whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-κB, and suppressed the NF-κB-regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor properties of gemcitabine. These results were consistent with the downregulation of NF-κB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-κB- and NF-κB-regulated gene products. PMID:26667450

  8. Hwanggeumchal sorghum induces cell cycle arrest, and suppresses tumor growth and metastasis through Jak2/STAT pathways in breast cancer xenografts.

    Directory of Open Access Journals (Sweden)

    Jin Hee Park

    Full Text Available BACKGROUND: Cancer is one of the highly virulent diseases known to humankind with a high mortality rate. Breast cancer is the most common cancer in women worldwide. Sorghum is a principal cereal food in many parts of the world, and is critical in folk medicine of Asia and Africa. In the present study, we analyzed the effects of HSE in metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS: Preliminary studies conducted on MDA-MB 231 and MCF-7 xenograft models showed tumor growth suppression by HSE. Western blotting studies conducted both in vivo and in vitro to check the effect of HSE in Jak/STAT pathways. Anti-metastatic effects of HSE were confirmed using both MDA-MB 231 and MCF-7 metastatic animal models. These studies showed that HSE can modulate Jak/STAT pathways, and it hindered the STAT5b/IGF-1R and STAT3/VEGF pathways not only by down-regulating the expression of these signal molecules and but also by preventing their phosphorylation. The expression of angiogenic factors like VEGF, VEGF-R2 and cell cycle regulators like cyclin D, cyclin E, and pRb were found down-regulated by HSE. In addition, it also targets Brk, p53, and HIF-1α for anti-cancer effects. HSE induced G1 phase arrest and migration inhibition in MDA-MB 231 cells. The metastasis of breast cancer to the lungs also found blocked by HSE in the metastatic animal model. CONCLUSIONS/SIGNIFICANCE: Usage of HS as a dietary supplement is an inexpensive natural cancer therapy, without any side effects. We strongly recommend the use of HS as an edible therapeutic agent as it possesses tumor suppression, migration inhibition, and anti-metastatic effects on breast cancer.

  9. AML cells are differentially sensitive to chemotherapy treatment in a human xenograft model.

    Science.gov (United States)

    Wunderlich, Mark; Mizukawa, Benjamin; Chou, Fu-Sheng; Sexton, Christina; Shrestha, Mahesh; Saunthararajah, Yogen; Mulloy, James C

    2013-03-21

    As acute myeloid leukemia (AML) xenograft models improve, the potential for using them to evaluate novel therapeutic strategies becomes more appealing. Currently, there is little information on using standard chemotherapy regimens in AML xenografts. Here we have characterized the immunodeficient mouse response to combined Ara-C (cytarabine) and doxorubicin treatment. We observed significant toxicity associated with doxorubicin that required optimization of the route of injection as well as the maximum-tolerated dose for immunodeficient strains. Mice treated with an optimized 5-day induction protocol showed transient weight loss, short-term reduction of peripheral blood cell and platelet counts, and slight anemia. Considerable cytotoxicity was observed in the bone marrow (BM), with primitive LSK cells having a significant survival advantage relative to more mature cells, consistent with the idea of chemotherapy targeting actively growing cells. Treated leukemic mice demonstrated reduced disease burden and increased survival, demonstrating efficacy. AML cells showed significantly increased sensitivity to doxorubicin-containing therapy compared with murine BM cells. Although early treatment could result in some cures, mice with significant leukemia grafts were not cured by using induction therapy alone. Overall, the data show that this model system is useful for the evaluation of novel chemotherapies in combination with standard induction therapy. PMID:23349390

  10. Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes

    International Nuclear Information System (INIS)

    Human hemangiosarcoma (HSA) tends to have a poor prognosis; its tumorigenesis has not been elucidated, as there is a dearth of HSA clinical specimens and no experimental model for HSA. However, the incidence of spontaneous HSA is relatively high in canines; therefore, canine HSA has been useful in the study of human HSA. Recently, the production of angiogenic growth factors and their receptors in human and canine HSA has been reported. Moreover, the growth-factor environment of HSA is very similar to that of pathophysiological angiogenesis, which some homeobox genes regulate in the transcription of angiogenic molecules. In the present study, we established 6 xenograft canine HSA tumors and detected the expression of growth factors, their receptors, and angiogenic homeobox genes. Six primary canine HSAs were xenografted to nude mice subcutaneously and serially transplanted. Subsequently, the expressions of vascular endothelial growth factor (VEGF)-A, basic fibroblast growth factors (bFGF), flt-1 and flk-1 (receptors of VEGF-A), FGFR-1, and angiogenic homeobox genes HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 were investigated in original and xenograft tumors by histopathology, immunostaining, and reverse transcription polymerase chain reaction (RT-PCR), using canine-specific primer sets. Histopathologically, xenograft tumors comprised a proliferation of neoplastic cells that were varied in shape, from spindle-shaped and polygonal to ovoid; some vascular-like structures and vascular clefts of channels were observed, similar to those in the original tumors. The expression of endothelial markers (CD31 and vWF) was detected in xenograft tumors by immunohistochemistry and RT-PCR. Moreover, the expression of VEGF-A, bFGF, flt-1, flk-1, FGFR-1, HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 was detected in xenograft tumors. Interestingly, expressions of bFGF tended to be higher in 3 of the xenograft HSA tumors than in the other tumors. We established 6 xenograft canine HSA

  11. High-resolution Magnetic Resonance Imaging analysis of breast cancer xenograft on the chick chorioallantoic membrane

    OpenAIRE

    ZUO, ZHI

    2015-01-01

    In this thesis an age-adapted cooling regime for immobilization of the chick embryo is proposed. Reliable immobilization completely avoided motion artifacts, enabling high resolution magnetic resonance imaging (MRI) of the chicken embryo and also tumor xenograft on the chorioallantoic membrane (CAM). Tumor growth monitoring was firstly evaluated after xenotransplantation of MDA-MB-231 cells on the CAM. Tumor volumes were monitored from day 4 to day 9 after grafting applying a T2-weighted R...

  12. Ovarian tumor attachment, invasion and vascularization reflect unique microenvironments in the peritoneum:Insights from xenograft and mathematical models

    Directory of Open Access Journals (Sweden)

    Mara P. Steinkamp

    2013-05-01

    Full Text Available Ovarian cancer relapse is often characterized by metastatic spread throughout the peritoneal cavity with tumors attached to multiple organs. In this study, interaction of ovarian tumor cells with the peritoneal tumor microenvironment was evaluated in a xenograft model based on intraperitoneal injection of fluorescent SKOV3.ip1 ovarian cancer cells. Intra-vital microscopy of mixed GFP-RFP cell populations injected into the peritoneum demonstrated that tumor cells aggregate and attach as mixed spheroids, emphasizing the importance of homotypic adhesion in tumor formation. Electron microscopy provided high resolution structural information about local attachment sites. Experimental measurements from the mouse model were used to build a three-dimensional cellular Potts ovarian tumor model (OvTM that examines ovarian tumor cell attachment, chemotaxis, growth and vascularization. OvTM simulations provide insight into the relative influence of tumor cell-cell adhesion, oxygen availability, and local architecture on tumor growth and morphology. Notably, tumors on the mesentery, omentum or spleen readily invade the open architecture, while tumors attached to the gut encounter barriers that restrict invasion and instead rapidly expand into the peritoneal space. Simulations suggest that rapid neovascularization of SKOV3.ip1 tumors is triggered by constitutive release of angiogenic factors in the absence of hypoxia. This research highlights the importance of cellular adhesion and tumor microenvironment in the seeding of secondary ovarian tumors on diverse organs within the peritoneal cavity. Results of the OvTM simulations indicate that invasion is strongly influenced by features underlying the mesothelial lining at different sites, but is also affected by local production of chemotactic factors. The integrated in vivo mouse model and computer simulations provide a unique platform for evaluating targeted therapies for ovarian cancer relapse.

  13. ANTITUMOR EFFECT OF SARCNU IN A 06-METHYLGUANINE-DNA METHYLTRANSFERASE POSITIVE HUMAN GLIOMA XENOGRAFT MODEL

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    To assess whether novel analogue of nitrosoureas, 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU), has antitumor effect to 06-methylguanine-DNA methyltransferase (MGMT) positive tumors in vivo. Methods: MGMT positive human glioma cell line SF-767 xenografts in nude mice were treated with SarCNU. The antitumor efficacy of SarCNU was compared with the results of 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) treatment with or without 06-benzylguanine (06-BG) preadministration. Results: Since the SF-767 is MGMT strongly positive, BCNU treatment alone did not result in a satisfactory anticancer effect. As expected, 06-BG by depleting MGMT activity, significantly enhanced BCNU antitumor efficacy (p<0.001). More interestingly, SarCNU treatment alone had a better antitumor effect than 06-BG plus BCNU treatment (F=51.7, p=0.00036). Conclusion: Since SarCNU enters cells via extraneuronal monoamine transporter (EMT), the enhanced antitumor activity of SarCNU in this MGMT positive human tumor xenograft model may be due to the presence of EMT in SF-767.SarCNU may be used as an alternative treatment for MGMT positive tumors, specifically for tumors expressing EMT.

  14. Efficacy of Tumor-Targeting Salmonella A1-R on a Melanoma Patient-Derived Orthotopic Xenograft (PDOX) Nude-Mouse Model

    Science.gov (United States)

    Yamamoto, Mako; Zhao, Ming; Hiroshima, Yukihiko; Zhang, Yong; Shurell, Elizabeth; Eilber, Fritz C.; Bouvet, Michael; Noda, Makoto; Hoffman, Robert M.

    2016-01-01

    Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0.021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0.001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer. PMID:27500926

  15. Yiqi Formula Enhances the Antitumor Effects of Erlotinib for Treatment of Triple-Negative Breast Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Ming-juan Liao

    2014-01-01

    Full Text Available Yiqi formula (YF, a traditional herbal prescription, has long been used to treat triple-negative breast cancer (TNBC patients. The present study aims to investigate the effects and the related mechanism of YF for treatment of TNBC xenografts. MDA-MB-231 (human TNBC cells were subcutaneously injected into the second mammary fat pad of 40 female nude mice, which were divided into four groups: control, erlotinib (an epidermal growth factor receptor (EGFR tyrosine kinase inhibitor, YF, and combination (YF plus erlotinib. All treatments were administered orally for 30 days. Inhibition rate of tumor weight by erlotinib, YF, and the combination was 26.47%, 17.24%, and 39.15%, respectively. Western blotting showed that YF, erlotinib, and the combination downregulated p-EGFR (P<0.01 and p-Akt1 (pT308 (P<0.05 and upregulated PTEN compared with control, and the combination was more efficacious than erlotinib alone (P<0.05. Similar results were detected by immunohistochemistry. Real-time quantitative PCR showed that YF, erlotinib, and the combination increased PTEN mRNA (P<0.05, P<0.01 compared with control, and the combination was more efficacious than erlotinib alone (P<0.05. In conclusion, YF can regulate the main components of the PI3K/Akt pathway in TNBC xenografts. When YF was used in combination with erlotinib, it enhanced the antitumor effects of erlotinib on TNBC xenografts. These findings suggest that YF is suitable to use for the treatment of TNBC patients.

  16. Amelioration of psoriasis by anti-TNF-alpha RNAi in the xenograft transplantation model

    DEFF Research Database (Denmark)

    Jakobsen, Maria; Stenderup, Karin; Rosada, Cecilia; Moldt, Brian; Kamp, Søren; Dam, Tomas N; Jensen, Thomas G; Mikkelsen, Jacob Giehm

    2009-01-01

    Tumor necrosis factor-alpha (TNF-alpha) is upregulated in psoriatic skin and represents a prominent target in psoriasis treatment. The level of TNF-alpha-encoding mRNA, however, is not increased in psoriatic skin, and it remains unclear whether intervention strategies based on RNA interference...... skin in the psoriasis xenograft transplantation model by the use of lentiviral vectors. TNF-alpha shRNA treatment leads to amelioration of the psoriasis phentotype in the model, as documented by reduced epidermal thickness, normalization of the skin morphology, and reduced levels of TNF-alpha mRNA as...... detected in skin biopsies 3 weeks after a single vector injection of lentiviral vectors encoding TNF-alpha shRNA. Our data show efficient lentiviral gene delivery to psoriatic skin and therapeutic applicability of anti-TNF-alpha shRNAs in human skin. These findings validate TNF-alpha mRNA as a target...

  17. Early therapy monitoring of 125I seed interstitial implant in a pancreatic cancer xenograft by 18F-FDG Micro-PET/CT

    International Nuclear Information System (INIS)

    Objective: To investigate the application value of early evaluation and monitoring of 125I interstitial implantation in a pancreatic cancer xenograft. Methods: Xenograft models were created by subcutaneous injection of Sw 1990 human pancreatic cancer cell suspensions into the right hind limbs of the immunodeficient BABL/c nude mice. The tumors size were about 8-10 mm after two weeks. The mice were randomly divided into 3 groups,including control group (n=4), empty seed implantation group (n=4) and 125I implantation group (n=4). Before treatment and one week after treatment, 18F-FDG Micro-PET/CT scan was performed and then maximum standardized uptake values (SUVmax), mean standardized uptake values (SUVmean), tumor size and necrosis rate were measured. HE staining and TK1 immunohistochemistry examination were carried out in the paraffin-embedded sample. Results: Before treatment the SUVmax and SUVmean values of three groups did not reach statistical significance. One week after treatment the SUVmax and SUVmean values of three groups were 3.53±1.20 and 0.57±0.26 vs. 3.83±2.13 and 0.59 ±0.24 vs. 0.29±0.23 and 0.016±0.001, respectively, with a significant difference (F=7.62, P=0.01; F=10.34, P=0.005). The SUVmax and SUVmean values of 125I implant group were significantly lower than empty seed implant group and control group and were significantly lower than before treatment. Before treatment, tumor necrosis rate of three groups were not significantly different. Immunohistochemical staining found the TK1 positive staining index of three groups were respectively (64.25±1.71)%, (62.25±2.22)% and (38.25±1.71)% with statistically significant difference (F=233.67, P<0.001). The TK1 positive staining index of 125I implant group was significantly lower than empty seed implant group and control group. The SUVmax values had some positive correlation with TK1 positive staining index (r=0.85, P=0.001). Conclusions: 18F-FDG Micro-PET/CT may be useful as a noninvasive

  18. Modifications in Dynamic Contrast-Enhanced Magnetic Resonance Imaging Parameters After α-Particle-Emitting {sup 227}Th-trastuzumab Therapy of HER2-Expressing Ovarian Cancer Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Heyerdahl, Helen, E-mail: Helen.Heyerdahl@rr-research.no [Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, Oslo (Norway); Røe, Kathrine [Department of Oncology, Division of Medicine, Akershus University Hospital, Lørenskog (Norway); Brevik, Ellen Mengshoel [Department of Research and Development, Algeta ASA, Oslo (Norway); Dahle, Jostein [Nordic Nanovector AS, Oslo (Norway)

    2013-09-01

    Purpose: The purpose of this study was to investigate the effect of α-particle-emitting {sup 227}Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of {sup 227}Th-trastuzumab. Methods and Materials: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm{sup 3} (mean ± SEM) were treated with a single injection of either {sup 227}Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of {sup 227}Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors. Results: Significant increases of k{sub ep}, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and k{sub el,} the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of k{sub ep} and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01). Conclusions: Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after {sup 227}Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts.

  19. Frondoside A inhibits human breast cancer cell survival, migration, invasion and the growth of breast tumor xenografts.

    Science.gov (United States)

    Al Marzouqi, Nadia; Iratni, Rabah; Nemmar, Abderrahim; Arafat, Kholoud; Ahmed Al Sultan, Mahmood; Yasin, Javed; Collin, Peter; Mester, Jan; Adrian, Thomas E; Attoub, Samir

    2011-10-01

    Breast cancer is a major challenge for pharmacologists to develop new drugs to improve the survival of cancer patients. Frondoside A is a triterpenoid glycoside isolated from the sea cucumber, Cucumaria frondosa. It has been demonstrated that Frondoside A inhibited the growth of pancreatic cancer cells in vitro and in vivo. We investigated the impact of Frondoside A on human breast cancer cell survival, migration and invasion in vitro, and on tumor growth in nude mice, using the human estrogen receptor-negative breast cancer cell line MDA-MB-231. The non-tumorigenic MCF10-A cell line derived from normal human mammary epithelium was used as control. Frondoside A (0.01-5 μM) decreased the viability of breast cancer cells in a concentration- and time-dependent manner, with 50%-effective concentration (EC50) of 2.5 μM at 24h. MCF10-A cells were more resistant to the cytotoxic effect of Frondoside A (EC50 superior to 5 μM at 24 h). In the MDA-MB-231 cells, Frondoside A effectively increased the sub-G1 (apoptotic) cell fraction through the activation of p53, and subsequently the caspases 9 and 3/7 cell death pathways. In addition, Frondoside A induced a concentration-dependent inhibition of MDA-MB-231 cell migration and invasion. In vivo, Frondoside A (100 μg/kg/dayi.p. for 24 days) strongly decreased the growth of MDA-MB-231 tumor xenografts in athymic mice, without manifest toxic side-effects. Moreover, we found that Frondoside A could enhance the killing of breast cancer cells induced by the chemotherapeutic agent paclitaxel. These findings identify Frondoside A as a promising novel therapeutic agent for breast cancer. PMID:21741966

  20. Alphastatin downregulates vascular endothelial cells sphingosine kinase activity and suppresses tumor growth in nude mice bearing human gastric cancer xenografts

    Institute of Scientific and Technical Information of China (English)

    Lin Chen; Tao Li; Rong Li; Bo Wei; Zheng Peng

    2006-01-01

    AIM: To investigate whether alphastatin could inhibit human gastric cancer growth and furthermore whether sphingosine kinase (SPK) activity is involved in this process.METHODS: Using migration assay, MTT assay and Matrigel assay, the effect of alphastatin on vascular endothelial cells (ECs) was evaluated in vitro. SPK and endothelial differentiation gene (EDG)-1, -3, -5 mRNAs were detected by reverse transcription-polymerase chain reaction (RT-PCR). SPK activity assay was used to evaluate the effect of alphastatin on ECs. Matrigel plug assay in nude mice was used to investigate the effect of alphastatin on angiogenesis in vivo. Female nude mice were subcutaneously implanted with human gastric cancer cells (BGC823) for the tumor xenografts studies.Micro vessel density was analyzed in Factor Ⅷ-stained tumor sections by the immunohistochemical SP method.RESULTS: In vitro, alphastatin inhibited the migration and tube formation of ECs, but had no effect on proliferation of ECs. RT-PCR analysis demonstrated that ECs expressed SPK and EDG-1, -3, -5 mRNAs. In vivo,alphastatin sufficiently suppressed neovascularization of the tumor in the nude mice. Daily administration of alphastatin produced significant tumor growth suppression. Immunohistochemical studies of tumor tissues revealed decreased micro vessel density in alphastatin-treated animals as compared with controls.CONCLUSION: Downregulating ECs SPK activity may be one of the mechanisms that alphastatin inhibits gastric cancer angiogenesis. Alphastatin might be a useful and relatively nontoxic adjuvant therapy in the treatment of gastric cancer.

  1. Utility of a human-mouse xenograft model and in vivo near-infrared fluorescent imaging for studying wound healing.

    Science.gov (United States)

    Shanmugam, Victoria K; Tassi, Elena; Schmidt, Marcel O; McNish, Sean; Baker, Stephen; Attinger, Christopher; Wang, Hong; Shara, Nawar; Wellstein, Anton

    2015-12-01

    To study the complex cellular interactions involved in wound healing, it is essential to have an animal model that adequately mimics the human wound microenvironment. Currently available murine models are limited because wound contraction introduces bias into wound surface area measurements. The purpose of this study was to demonstrate utility of a human-mouse xenograft model for studying human wound healing. Normal human skin was harvested from elective abdominoplasty surgery, xenografted onto athymic nude (nu/nu) mice, and allowed to engraft for 3 months. The graft was then wounded using a 2-mm punch biopsy. Wounds were harvested on sequential days to allow tissue-based markers of wound healing to be followed sequentially. On the day of wound harvest, mice were injected with XenoLight RediJect cyclooxygenase-2 (COX-2) probe and imaged according to package instructions. Immunohistochemistry confirms that this human-mouse xenograft model is effective for studying human wound healing in vivo. Additionally, in vivo fluorescent imaging for inducible COX-2 demonstrated upregulation from baseline to day 4 (P = 0·03) with return to baseline levels by day 10, paralleling the reepithelialisation of the wound. This human-mouse xenograft model, combined with in vivo fluorescent imaging provides a useful mechanism for studying molecular pathways of human wound healing. PMID:24373153

  2. Early evaluation of the effects of chemotherapy with longitudinal FDG small-animal PET in human testicular cancer xenografts: early flare response does not reflect refractory disease

    International Nuclear Information System (INIS)

    We aimed to evaluate the usefulness of FDG PET in the early prediction of the effects of chemotherapy on human testicular cancer xenografts. Nude rats bearing subcutaneous human embryonal carcinoma xenografts received either cisplatin (5 mg/kg) or saline serum. Small-animal PET studies were performed on days 0, 2, 4 and 7 and compared to immunochemistry studies, flow cytometry studies and hexokinase assays. Cisplatin treatment resulted in biphasic FDG uptake evolution: a peak was observed on day 2, followed by a marked decrease on day 7 despite an insignificant change in tumour volume. Similarly, a peak in cyclin A immunostaining was observed on days 2 and 4, followed by a significant decrease on day 7. Flow cytometry showed that the cyclin A peak was not related to increased cell proliferation but was due to a transient S and G2/M cell cycle arrest. A marked increase in cell apoptosis was observed from day 2 to day 7. GLUT-1 showed a significant decrease on day 7. Macrophagic infiltrate remained stable except for an increase observed on day 7. In control tumours, continuous growth was observed, all immunostaining markers remaining stable over time. Hexokinase activity was significantly lower on day 7 in treated tumours than in controls. FDG PET may be useful in the early evaluation of treatment in patients with testicular cancer. In our model, a very early increased [18F]-FDG uptake was related to a transient cell cycle arrest and early stage apoptosis but did not reveal refractory disease. (orig.)

  3. Early evaluation of the effects of chemotherapy with longitudinal FDG small-animal PET in human testicular cancer xenografts: early flare response does not reflect refractory disease

    Energy Technology Data Exchange (ETDEWEB)

    Aide, Nicolas [GRECAN, EA 1772, IFR 146 ICORE, Caen University, Bioticla Unit, Caen (France); Francois Baclesse Comprehensive Cancer Centre, Nuclear Medicine Department, Caen (France); Centre Francois Baclesse, Service de Medecine Nucleaire, Caen Cedex 5 (France); Poulain, Laurent; Briand, Melanie; Dutoit, Soizic; Labiche, Alexandre; Gauduchon, Pascal [GRECAN, EA 1772, IFR 146 ICORE, Caen University, Bioticla Unit, Caen (France); Allouche, Stephane [University Hospital, Biochemistry Department, Caen (France); Ngo-Van Do, Aurelie; Nataf, Valerie; Talbot, Jean-Noel; Montravers, Francoise [Tenon Hospital and University Pierre et Marie Curie (Paris 6), LIMP, Paris (France); Batalla, Alain [Francois Baclesse Comprehensive Cancer Centre, Medical Physics Unit, Caen (France)

    2009-03-15

    We aimed to evaluate the usefulness of FDG PET in the early prediction of the effects of chemotherapy on human testicular cancer xenografts. Nude rats bearing subcutaneous human embryonal carcinoma xenografts received either cisplatin (5 mg/kg) or saline serum. Small-animal PET studies were performed on days 0, 2, 4 and 7 and compared to immunochemistry studies, flow cytometry studies and hexokinase assays. Cisplatin treatment resulted in biphasic FDG uptake evolution: a peak was observed on day 2, followed by a marked decrease on day 7 despite an insignificant change in tumour volume. Similarly, a peak in cyclin A immunostaining was observed on days 2 and 4, followed by a significant decrease on day 7. Flow cytometry showed that the cyclin A peak was not related to increased cell proliferation but was due to a transient S and G{sub 2}/M cell cycle arrest. A marked increase in cell apoptosis was observed from day 2 to day 7. GLUT-1 showed a significant decrease on day 7. Macrophagic infiltrate remained stable except for an increase observed on day 7. In control tumours, continuous growth was observed, all immunostaining markers remaining stable over time. Hexokinase activity was significantly lower on day 7 in treated tumours than in controls. FDG PET may be useful in the early evaluation of treatment in patients with testicular cancer. In our model, a very early increased [{sup 18}F]-FDG uptake was related to a transient cell cycle arrest and early stage apoptosis but did not reveal refractory disease. (orig.)

  4. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models.

    Science.gov (United States)

    Garcia, P L; Miller, A L; Kreitzburg, K M; Council, L N; Gamblin, T L; Christein, J D; Heslin, M J; Arnoletti, J P; Richardson, J H; Chen, D; Hanna, C A; Cramer, S L; Yang, E S; Qi, J; Bradner, J E; Yoon, K J

    2016-02-18

    The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (Pcycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1. PMID:25961927

  5. Treatment of pancreatic cancer xenografts with Erbitux (IMC-C225) anti-EGFR antibody, gemcitabine, and radiation

    International Nuclear Information System (INIS)

    Purpose: To investigate treatment of human pancreatic cancer cell lines and xenografts with combinations of Erbitux (IMC-C225) anti-epidermal growth factor receptor (EGFR) antibody, gemcitabine, and radiation. Methods and Materials: BxPC-3 and MiaPaCa-2 human pancreatic carcinoma cells were treated in vitro for 24 h with IMC-C225 (5 μg/mL), then exposed to epidermal growth factor (EGF) (10 mM) for 5 min. Immunoblots were screened for EGFR expression and the ability of IMC-C225 to block EGF-induced tyrosine phosphorylation of EGFR. Cells were treated with IMC-C225 (5 μg/mL) on Day 0, the IC50 dose of gemcitabine on Day 1 for 24 h, followed by 3 Gy 60Co irradiation on Day 2, or the combination of each agent. For cell proliferation, cells were counted on Day 4, and for apoptosis, cells were stained with annexin V-FITC and propidium iodide, then analyzed by FACS. Cells were treated with the same single or multiple treatments and analyzed in a clonogenic cell survival assay. The effect of IMC-C225, gemcitabine, and radiation on the growth of BxPC-3 and MiaPaCa-2 tumor xenografts was determined. Athymic nude mice bearing established s.c. tumor xenografts of 6-8 mm diameter received 6 weeks of treatment with IMC-C225 (1 mg every 3 days x 6) alone or in combination with gemcitabine (120 mg/kg i.v. every 6 days x 6), and 6 weekly fractions of 3 Gy radiation on the days after gemcitabine administration. Tumor growth was measured with Vernier calipers. Results: BxPC-3 and MiaPaCa-2 cell lines expressed low levels of EGFR. IMC-C225 inhibited EGF-induced tyrosine phosphorylation of the EGF receptor on both cell lines. Treatment of cells with a combination of IMC-C225 + gemcitabine + radiation produced the highest induction of apoptosis and inhibition of proliferation in vitro. Combination treatment with IMC-C225, gemcitabine, and radiation produced 100% complete regression of MiaPaCa-2 tumors for more than 250 days, and the greatest growth inhibition of BxPC-3 tumors compared

  6. Antisense imaging targeting mouse double minute 2 oncogene in prostate cancer xenografts

    International Nuclear Information System (INIS)

    Objective: To explore the value of antisense imaging of 99Tcm-labeled ASON targeting mouse double minute 2(MDM2) mRNA for the diagnosis of human prostate cancer. Methods: The ASON targeting MDM2 mRNA and the mismatched oligonucleotide (ASONM) were synthesized and radiolabeled with 99Tcm using the bifunctional chelator HYNIC. The labeling efficiency and radiochemical purity were investigated. Animal models of nude mice bearing human prostate cancer LNCaP were established and divided into 3 groups with 10 mice in each group. 99Tcm-HYNIC-ASON, 99Tcm-HYNIC-ASONM (study groups) and 99TcmO4- (control group) were injected at the dose of 7.4 MBq through the tail vein, respectively. Tumor imaging was acquired with SPECT and the tumor-to-muscle (T/M) ratio was measured. The data was compared by one-way analysis of variance. Results: The labeling efficiencies of ASON and ASONM were (65.15± 2.05) % and (64.93±2.18) %, respectively. Their radiochemical purity was greater than 90%. At 1, 4 and 10 h post injection, the T/M ratios of 99Tcm-HYNIC-ASON group were 3.217±0.125, 3.749± 0.201 and 4.028±0.186, and those of 99Tcm-HYNIC-ASONM group were 1.579±0.128, 1.715±1.140 and 1.683±0.139, and control group 2.146±0.132, 1.847±0.124, 1.528±0.152, respectively. The T/M ratios in control group and 99Tcm-HYNIC-ASONM group were significantly lower than those in 99Tcm-HYNIC-ASON group at 1, 4 and 10 h, respectively (F=213.37-235.41, t=3.527-4.738; all P<0.01). The T/M ratios of 99Tcm-HYNIC-ASONM group and control group were not significantly different at 1, 4 and 10 h (t=2.154, 2.287 and 2.236, all P>0.05). Conclusion: The antisense probe of MDM2 can accumulate specifically in prostate cancer tissue in animal models, which might be useful as a non-invasive genetic tool for the early diagnosis of prostate cancer. (authors)

  7. In vitro and in vivo MMP gene expression localisation by In Situ-RT-PCR in cell culture and paraffin embedded human breast cancer cell line xenografts

    International Nuclear Information System (INIS)

    Members of the matrix metalloproteinase (MMP) family of proteases are required for the degradation of the basement membrane and extracellular matrix in both normal and pathological conditions. In vitro, MT1-MMP (MMP-14, membrane type-1-MMP) expression is higher in more invasive human breast cancer (HBC) cell lines, whilst in vivo its expression has been associated with the stroma surrounding breast tumours. MMP-1 (interstitial collagenase) has been associated with MDA-MB-231 invasion in vitro, while MMP-3 (stromelysin-1) has been localised around invasive cells of breast tumours in vivo. As MMPs are not stored intracellularly, the ability to localise their expression to their cells of origin is difficult. We utilised the unique in situ-reverse transcription-polymerase chain reaction (IS-RT-PCR) methodology to localise the in vitro and in vivo gene expression of MT1-MMP, MMP-1 and MMP-3 in human breast cancer. In vitro, MMP induction was examined in the MDA-MB-231 and MCF-7 HBC cell lines following exposure to Concanavalin A (Con A). In vivo, we examined their expression in archival paraffin embedded xenografts derived from a range of HBC cell lines of varied invasive and metastatic potential. Mouse xenografts are heterogenous, containing neoplastic human parenchyma with mouse stroma and vasculature and provide a reproducible in vivo model system correlated to the human disease state. In vitro, exposure to Con A increased MT1-MMP gene expression in MDA-MB-231 cells and decreased MT1-MMP gene expression in MCF-7 cells. MMP-1 and MMP-3 gene expression remained unchanged in both cell lines. In vivo, stromal cells recruited into each xenograft demonstrated differences in localised levels of MMP gene expression. Specifically, MDA-MB-231, MDA-MB-435 and Hs578T HBC cell lines are able to influence MMP gene expression in the surrounding stroma. We have demonstrated the applicability and sensitivity of IS-RT-PCR for the examination of MMP gene expression both in vitro and in

  8. Therapeutic Efficacy Assessment of CK6, a Monoclonal KIT Antibody, in a Panel of Gastrointestinal Stromal Tumor Xenograft Models

    Directory of Open Access Journals (Sweden)

    Thomas Van Looy

    2015-04-01

    Full Text Available We evaluated the efficacy of CK6, a KIT monoclonal antibody, in a panel of human gastrointestinal stromal tumor (GIST xenograft models. Nude mice were bilaterally transplanted with human GIST xenografts (four patient derived and two cell line derived, treated for 3 weeks, and grouped as follows: control (untreated; CK6 (40 mg/kg, 3× weekly; imatinib (50 mg/kg, twice daily; sunitinib (40 mg/kg, once daily; imatinib + CK6; sunitinib + CK6 (same doses and schedules as in the single-agent treatments. Tumor volume assessment, Western blot analysis, and histopathology were used for evaluation of efficacy. Statistical analysis was performed using Mann-Whitney U (MWU and Wilcoxon matched-pairs tests. CK6 as a single agent only reduced tumor growth rate in the UZLX-GIST3 model (P = .053, MWU compared to control, while in none of the other GIST models an effect on tumor growth rate was observed. CK6 did not result in significant anti-proliferative or pro-apoptotic effects in any of the GIST models, and moreover, CK6 did not induce a remarkable inhibition of KIT activation. Furthermore, no synergistic effect of combining CK6 with tyrosine kinase inhibitors (TKIs was observed. Conversely, in certain GIST xenografts, anti-tumor effects seemed to be inferior under combination treatment compared to single-agent TKI treatment. In the GIST xenografts tested, the anti-tumor efficacy of CK6 was limited. No synergy was observed on combination of CK6 with TKIs in these GIST models. Our findings highlight the importance of using relevant in vivo human tumor xenograft models in the preclinical assessment of drug combination strategies.

  9. The Influence of Tissue Ischemia Time on RNA Integrity and Patient-Derived Xenografts (PDX) Engraftment Rate in a Non-Small Cell Lung Cancer (NSCLC) Biobank

    OpenAIRE

    Guerrera, Francesco; Tabbò, Fabrizio; Bessone, Luca; Maletta, Francesca; Gaudiano, Marcello; Ercole, Elisabetta; Annaratone, Laura; Todaro, Maria; Boita, Monica; Filosso, Pier Luigi; Solidoro, Paolo; Delsedime, Luisa; Oliaro, Alberto; Sapino, Anna; Ruffini, Enrico

    2016-01-01

    Introduction Bio-repositories are invaluable resources to implement translational cancer research and clinical programs. They represent one of the most powerful tools for biomolecular studies of clinically annotated cohorts, but high quality samples are required to generate reliable molecular readouts and functional studies. The objective of our study was to define the impact of cancer tissue ischemia time on RNA and DNA quality, and for the generation of Patient-Derived Xenografts (PDXs). Me...

  10. Biodistribution and γ imaging of 125I-labeled goat anti-human IgG polyclonal antibody in nude mice bearing human colon cancer xenografts

    International Nuclear Information System (INIS)

    The possibility of IgG secreted from tumor cells as a target for radioimmunoimaging and targeted therapy of cancers were investigated. Goat anti-human IgG polyclonal anti- body (GAHG) was radioiodinated using Iodogen method, and the in vitro stability and pharmacokinetics were evaluated. The biodistribution and γ imaging of 125I-GAHG were performed in nude mice bearing HT-29 human colon cancer xenografts. 125I-GAHG showed good in vitro stability, and its blood clearance was defined as a two-compartment model, with T1/2α and T1/2β were 1.19 h and 43.99 h, respectively. The tumor uptake of 125I-GAHG was higher than that of 125I-labeled normal goat IgG control (125I-GIgG). 125I-GAHG showed good tumor retention when injecting via intra-tumor. In the biodistribution study, the highest tumor uptake of 125I-GAHG was 6.71±2.19%ID/g at 72 h postinjection and the T/NT increased along with the postinjection time. The results show that 125I-GAHG have good tumor-specific uptake which may provide a novel idea for radioimmunoimaging and targeted therapy of cancers. (authors)

  11. Relaxin reduces xenograft tumour growth of human MDA-MB-231 breast cancer cells

    OpenAIRE

    Radestock, Yvonne; Hoang-Vu, Cuong; Hombach-Klonisch, Sabine

    2008-01-01

    Introduction Relaxin levels are increased in cases of human breast cancer and has been shown to promote cancer cell migration in carcinoma cells of the breast, prostate gland and thyroid gland. In oestrogen receptor alpha-negative MDA-MB-231 human breast cancer cells, relaxin was shown to down-regulate the metastasis-promoting protein S100A4 (metastasin), a highly significant prognostic factor for poor survival in breast cancer patients. The cellular mechanisms of relaxin exposure in breast c...

  12. Histone modifications patterns in tissues and tumours from acute promyelocytic leukemia xenograft model in response to combined epigenetic therapy.

    Science.gov (United States)

    Valiulienė, Giedrė; Treigytė, Gražina; Savickienė, Jūratė; Matuzevičius, Dalius; Alksnė, Milda; Jarašienė-Burinskaja, Rasa; Bukelskienė, Virginija; Navakauskas, Dalius; Navakauskienė, Rūta

    2016-04-01

    Xenograft models are suitable for in vivo study of leukemia's pathogenesis and the preclinical development of anti-leukemia agents but understanding of epigenetic regulatory mechanisms linking to adult cell functions in pathological conditions during different in vivo treatments is yet unknown. In this study, for the first time epigenetic chromatin modifications were characterized in tissues and tumours from murine xenograft model generated using the human acute promyelocytic leukemia (APL) NB4 cells engrafted in immunodeficient NOG mice. Xenografts were subjected to combined epigenetic treatment by histone deacetylase inhibitor Belinostat, histone methyltransferase inhibitor 3-DZNeaplanocin A and all-trans-retinoic acid based on in vitro model, where such combination inhibited NB4 cell growth and enhanced retinoic acid-induced differentiation to granulocytes. Xenotransplantation was assessed by peripheral blood cells counts, the analysis of cell surface markers (CD15, CD33, CD45) and the expression of certain genes (PML-RAR alpha, CSF3, G-CSFR, WT1). The combined treatment prolonged APL xenograft mice survival and prevented tumour formation. The analysis of the expression of histone marks such as acetylation of H4, trimethylation of H3K4, H3K9 and H3K27 in APL xenograft mice tumours and tissues demonstrated tissue-specific changes in the level of histone modifications and the APL prognostic mark, WT1 protein. In summary, the effects of epigenetic agents used in this study were positive for leukemia prevention and linked to a modulation of the chromatin epigenetic environment in adult tissues of malignant organism. PMID:27044813

  13. Pharmacokinetic modeling of an induction regimen for in vivo combined testing of novel drugs against pediatric acute lymphoblastic leukemia xenografts.

    Directory of Open Access Journals (Sweden)

    Barbara Szymanska

    Full Text Available Current regimens for induction therapy of pediatric acute lymphoblastic leukemia (ALL, or for re-induction post relapse, use a combination of vincristine (VCR, a glucocorticoid, and L-asparaginase (ASP with or without an anthracycline. With cure rates now approximately 80%, robust pre-clinical models are necessary to prioritize active new drugs for clinical trials in relapsed/refractory patients, and the ability of these models to predict synergy/antagonism with established therapy is an essential attribute. In this study, we report optimization of an induction-type regimen by combining VCR, dexamethasone (DEX and ASP (VXL against ALL xenograft models established from patient biopsies in immune-deficient mice. We demonstrate that the VXL combination was synergistic in vitro against leukemia cell lines as well as in vivo against ALL xenografts. In vivo, VXL treatment caused delays in progression of individual xenografts ranging from 22 to >146 days. The median progression delay of xenografts derived from long-term surviving patients was 2-fold greater than that of xenografts derived from patients who died of their disease. Pharmacokinetic analysis revealed that systemic DEX exposure in mice increased 2-fold when administered in combination with VCR and ASP, consistent with clinical findings, which may contribute to the observed synergy between the 3 drugs. Finally, as proof-of-principle we tested the in vivo efficacy of combining VXL with either the Bcl-2/Bcl-xL/Bcl-w inhibitor, ABT-737, or arsenic trioxide to provide evidence of a robust in vivo platform to prioritize new drugs for clinical trials in children with relapsed/refractory ALL.

  14. Molecular imaging of human breast cancer xenografts in nude mice by epidermal growth factor labelled by near infrared fluorescent dye

    International Nuclear Information System (INIS)

    Objective: This work was to determine the feasibility of using epidermal growth factor (EGF) labeled with a near-infrared fluorescent (NIRF) dye (Cy5.5) to selectively localize and image epidermal growth factor receptor (EGFR)of the human breast cancer. Methods: MDA-MB-231 of human mammary adenocarcinoma and MDA-MB-435S of human mammary ductal carcinoma were detected using a flow cytometry. Laser confocal microscopy was used to examine the intake of EGF-Cy5.5 by MDA-MB-231 and MDA-MB-435S cells. MDA-MB-231 and MDA-MB435S human breast cancer orthotopic xenograft nude mice models were established. In vivo NIRF imaging was acquired after intravenous injection of EGF-Cy5.5 (1 nmol/0.2 ml)immediately and different time intervals. The up-take of EGF-Cy5.5 in MDA-MB-231 and MDA-MB-435S was detected using ROI technique. The blockage of the monocolonal antibody C225 to the EGF-Cy5.5 uptake were observed in viovo and ex vivo. Ex vivo tumor tissue fluorescent imaging was executed and the histological sections were stained by HE method for pathobiology assay. Student t test was used for statistical analysis with SPSS for Windows. Results: Flow cytometry indicated the EGFR expression percentage of MDA-MB-231 was 41.96% and the percentage of MDA-MB-435S was 0.12%. The fluorescence showed that the uptake of EGF-Cy5.5 by MDA-MB-231 cells could be observed by the laser confocal microscopy. There was no specific uptake of EGF-Cy5.5 by MDA-MB-435S. In vivo NIRF images showed mean fluorescence intensity in MDA-MB-231 tumors was (38 220±3 144)au, which was significantly higher than MDA-MB435S's ( 11 885 + 1 144 ) au (t = 17. 600, P < 0.01) or normal region' s (11 980 ±1 496) au(t=17. 491, P<0.01) at 24 h postinjection of EGF-Cy5.5. The mean fluorescence intensity was significantly reduced in MDA-MB-231 group with preadministration of C225, whose mean intensity was (10 472±842) au (t=16.772, P<0.01), while the mean intensity was not apparently decreased in MDA-MB-435S block group

  15. Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma.

    Science.gov (United States)

    Guastella, Anthony R; Michelhaugh, Sharon K; Klinger, Neil V; Kupsky, William J; Polin, Lisa A; Muzik, Otto; Juhász, Csaba; Mittal, Sandeep

    2016-01-01

    Increasing evidence demonstrates the immunosuppressive kynurenine pathway's (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[(11)C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM. PMID:27151136

  16. Tryptophan PET Imaging of the Kynurenine Pathway in Patient-Derived Xenograft Models of Glioblastoma

    Science.gov (United States)

    Guastella, Anthony R.; Michelhaugh, Sharon K.; Klinger, Neil V.; Kupsky, William J.; Polin, Lisa A.; Muzik, Otto; Juhász, Csaba; Mittal, Sandeep

    2016-01-01

    Increasing evidence demonstrates the immunosuppressive kynurenine pathway’s (KP) role in the pathophysiology of human gliomas. To study the KP in vivo, we used the noninvasive molecular imaging tracer α-[11C]-methyl-l-tryptophan (AMT). The AMT-positron emission tomography (PET) has shown high uptake in high-grade gliomas and predicted survival in patients with recurrent glioblastoma (GBM). We generated patient-derived xenograft (PDX) models from dissociated cells, or tumor fragments, from 5 patients with GBM. Mice bearing subcutaneous tumors were imaged with AMT-PET, and tumors were analyzed to detect the KP enzymes indoleamine 2,3-dioxygenase (IDO) 1, IDO2, tryptophan 2,3-dioxygenase, kynureninase, and kynurenine 3-monooxygenase. Overall, PET imaging showed robust tumoral AMT uptake in PDX mice with prolonged tracer accumulation over 60 minutes, consistent with AMT trapping seen in humans. Immunostained tumor tissues demonstrated positive detection of multiple KP enzymes. Furthermore, intracranial implantation of GBM cells was performed with imaging at both 9 and 14 days postimplant, with a marked increase in AMT uptake at 14 days and a corresponding high level of tissue immunostaining for KP enzymes. These results indicate that our PDX mouse models recapitulate human GBM, including aberrant tryptophan metabolism, and offer an in vivo system for development of targeted therapeutics for patients with GBM. PMID:27151136

  17. Antitumor effects of inductive hyperthermia using magnetic ferucarbotran nanoparticles on human lung cancer xenografts in nude mice

    Directory of Open Access Journals (Sweden)

    Araya T

    2013-03-01

    Full Text Available Tomoyuki Araya,1 Kazuo Kasahara,1 Shingo Nishikawa,1 Hideharu Kimura,1 Takashi Sone,1 Hideo Nagae,2 Yoshio Ikehata,3 Isamu Nagano,3 Masaki Fujimura11Department of Respiratory Medicine, Cellular Transplantation Biology, Kanazawa University Graduate School of Medical Science, 2Cooperative Research Center for Kanazawa University, 3Department of Information and Systems Engineering, Kanazawa University, Kanazawa, JapanBackground: The effects of inductive hyperthermia on lung cancer have yet to be fully investigated. Magnetic nanoparticles used in inductive hyperthermia are made-to-order and expensive. This study was performed to investigate the use of ferucarbotran in inductive hyperthermia and to clarify whether inductive hyperthermia using ferucarbotran promotes antitumor effects in vivo using a lung cancer cell line.Methods: We injected A549 cells subcutaneously into the right thighs of BALB/c nu/nu nude mice. Forty mice with A549 xenografts were then classified into three groups. Group 1 was the control group. All mice in groups 2 and 3 had ferucarbotran injected into their tumors, and mice in group 3 were then subjected to alternating magnetic field irradiation. We evaluated tumor temperature during the hyperthermic procedure, the time course of tumor growth, histologic findings in tumors after hyperthermic treatment, and adverse events.Results: Intratumor temperature rose rapidly and was maintained at 43°C–45°C for 20 minutes in an alternating magnetic field. Tumor volumes in groups 1 and 2 increased exponentially, but tumor growth in group 3 was significantly suppressed. No severe adverse events were observed. Histologic findings for the tumors in group 3 revealed mainly necrosis.Conclusion: Inductive hyperthermia using ferucarbotran is a beneficial and promising approach in the treatment of lung cancer. Ferucarbotran is a novel tool for further development of inductive hyperthermia.Keywords: inductive hyperthermia, ferucarbotran, magnetic

  18. Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel.

    Science.gov (United States)

    Lee, Jong Hyun; Kim, Chulwon; Sethi, Gautam; Ahn, Kwang Seok

    2015-03-20

    Persistent phosphorylation of signal transducers and activators of transcription 3 (STAT3) is frequently observed in tumor cells. We found that brassinin (BSN) suppressed both constitutive and IL-6-inducible STAT3 activation in lung cancer cells. Moreover, BSN induced PIAS-3 protein and mRNA, whereas the expression of SOCS-3 was reduced. Knockdown of PIAS-3 by small interfering RNA prevented inhibition of STAT3 and cytotoxicity by BSN. Overexpression of SOCS-3 in BSN-treated cells increased STAT3 phosphorylation and cell viability. BSN down-regulated STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced apoptosis. Most importantly, when administered intraperitoneally, combination of BSN and paclitaxel significantly decreased the tumor development in a xenograft lung cancer mouse model associated with down-modulation of phospho-STAT3, Ki-67 and CD31. We suggest that BSN inhibits STAT3 signaling through modulation of PIAS-3 and SOCS-3, thereby attenuating tumor growth and increasing sensitivity to paclitaxel. PMID:25788267

  19. Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model.

    Science.gov (United States)

    Lamming, Dudley W; Cummings, Nicole E; Rastelli, Antonella L; Gao, Feng; Cava, Edda; Bertozzi, Beatrice; Spelta, Francesco; Pili, Roberto; Fontana, Luigi

    2015-10-13

    Reduced dietary protein intake and intermittent fasting (IF) are both linked to healthy longevity in rodents, and are effective in inhibiting cancer growth. The molecular mechanisms underlying the beneficial effects of chronic protein restriction (PR) and IF are unclear, but may be mediated in part by a down-regulation of the IGF/mTOR pathway. In this study we compared the effects of PR and IF on tumor growth in a xenograft mouse model of breast cancer. We also investigated the effects of PR and IF on the mechanistic Target Of Rapamycin (mTOR) pathway, inhibition of which extends lifespan in model organisms including mice. The mTOR protein kinase is found in two distinct complexes, of which mTOR complex 1 (mTORC1) is responsive to acute treatment with amino acids in cell culture and in vivo. We found that both PR and IF inhibit tumor growth and mTORC1 phosphorylation in tumor xenografts. In somatic tissues, we found that PR, but not IF, selectively inhibits the activity of the amino acid sensitive mTORC1, while the activity of the second mTOR complex, mTORC2, was relatively unaffected by PR. In contrast, IF resulted in increased S6 phosphorylation in multiple metabolic tissues. Our work represents the first finding that PR may reduce mTORC1 activity in tumors and multiple somatic tissues, and suggest that PR may represent a highly translatable option for the treatment not only of cancer, but also other age-related diseases. PMID:26378060

  20. Embelin suppresses growth of human pancreatic cancer xenografts, and pancreatic cancer cells isolated from KrasG12D mice by inhibiting Akt and Sonic hedgehog pathways.

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    Minzhao Huang

    Full Text Available Pancreatic cancer is a deadly disease, and therefore effective treatment and/or prevention strategies are urgently needed. The objectives of this study were to examine the molecular mechanisms by which embelin inhibited human pancreatic cancer cell growth in vitro, and xenografts in Balb C nude mice, and pancreatic cancer cell growth isolated from KrasG12D transgenic mice. XTT assays were performed to measure cell viability. AsPC-1 cells were injected subcutaneously into Balb c nude mice and treated with embelin. Cell proliferation and apoptosis were measured by Ki67 and TUNEL staining, respectively. The expression of Akt, and Sonic Hedgehog (Shh and their target gene products were measured by the immunohistochemistry, and Western blot analysis. The effects of embelin on pancreatic cancer cells isolated from 10-months old KrasG12D mice were also examined. Embelin inhibited cell viability in pancreatic cancer AsPC-1, PANC-1, MIA PaCa-2 and Hs 766T cell lines, and these inhibitory effects were blocked either by constitutively active Akt or Shh protein. Embelin-treated mice showed significant inhibition in tumor growth which was associated with reduced expression of markers of cell proliferation (Ki67, PCNA and Bcl-2 and cell cycle (cyclin D1, CDK2, and CDK6, and induction of apoptosis (activation of caspase-3 and cleavage of PARP, and increased expression of Bax. In addition, embelin inhibited the expression of markers of angiogenesis (COX-2, VEGF, VEGFR, and IL-8, and metastasis (MMP-2 and MMP-9 in tumor tissues. Antitumor activity of embelin was associated with inhibition of Akt and Shh pathways in xenografts, and pancreatic cancer cells isolated from KrasG12D mice. Furthermore, embelin also inhibited epithelial-to-mesenchymal transition (EMT by up-regulating E-cadherin and inhibiting the expression of Snail, Slug, and ZEB1. These data suggest that embelin can inhibit pancreatic cancer growth, angiogenesis and metastasis by suppressing Akt and

  1. Gamma Knife Surgery as Monotherapy with Clinically Relevant Doses Prolongs Survival in a Human GBM Xenograft Model

    OpenAIRE

    Bente Sandvei Skeie; Jian Wang; Ernest Dodoo; Jan Ingeman Heggdal; Janne Grønli; Linda Sleire; Sidsel Bragstad; Ganz, Jeremy C.; Martha Chekenya; Sverre Mørk; Paal-Henning Pedersen; Per Øyvind Enger

    2013-01-01

    Object. Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. Methods. GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS...

  2. Response of Patient-Derived Non-Small Cell Lung Cancer Xenografts to Classical and Targeted Therapies Is Not Related to Multidrug Resistance Markers

    OpenAIRE

    Jana Rolff; Iduna Fichtner; Johannes Merk; Cornelia Dorn

    2009-01-01

    Tumor cells that are nonsensitive to anticancer drugs frequently have a multidrug resistant (MDR) phenotype. Many studies with cell lines and patient material have been done to investigate the impact of different resistance markers at protein and mRNA level in drug resistance but with contradictory outcome. In the present study, 26 well-characterised patient-derived non-small cell lung cancer xenografts were used. The known chemosensitivity to etoposide, carboplatin, gemcitabine, paclitaxel a...

  3. MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts.

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    Xiaomeng Zhang

    Full Text Available TH-302 is a hypoxia-activated prodrug known to activate selectively under the hypoxic conditions commonly found in solid tumors. It is currently being evaluated in clinical trials, including two trials in Pancreatic Ductal Adenocarcinomas (PDAC. The current study was undertaken to evaluate imaging biomarkers for prediction and response monitoring of TH-302 efficacy in xenograft models of PDAC. Dynamic contrast-enhanced (DCE and diffusion weighted (DW magnetic resonance imaging (MRI were used to monitor acute effects on tumor vasculature and cellularity, respectively. Three human PDAC xenografts with known differential responses to TH-302 were imaged prior to, and at 24 h and 48 hours following a single dose of TH-302 or vehicle to determine if imaging changes presaged changes in tumor volumes. DW-MRI was performed at five b-values to generate apparent diffusion coefficient of water (ADC maps. For DCE-MRI, a standard clinically available contrast reagent, Gd-DTPA, was used to determine blood flow into the tumor region of interest. TH-302 induced a dramatic decrease in the DCE transfer constant (Ktrans within 48 hours after treatment in the sensitive tumors, Hs766t and Mia PaCa-2, whereas TH-302 had no effect on the perfusion behavior of resistant SU.86.86 tumors. Tumor cellularity, estimated from ADC, was significantly increased 24 and 48 hours after treatment in Hs766t, but was not observed in the Mia PaCa-2 and SU.86.86 groups. Notably, growth inhibition of Hs766t was observed immediately (day 3 following initiation of treatment, but was not observed in MiaPaCa-2 tumors until 8 days after initiation of treatment. Based on these preclinical findings, DCE-MRI measures of vascular perfusion dynamics and ADC measures of cell density are suggested as potential TH-302 response biomarkers in clinical trials.

  4. Early detection of antiangiogenic treatment responses in a mouse xenograft tumor model using quantitative perfusion MRI

    International Nuclear Information System (INIS)

    Angiogenesis plays a major role in tumor growth and metastasis, with tumor perfusion regarded as a marker for angiogenesis. To evaluate antiangiogenic treatment response in vivo, we investigated arterial spin labeling (ASL) magnetic resonance imaging (MRI) to measure tumor perfusion quantitatively. Chronic and 24-h acute treatment responses to bevacizumab were assessed by ASL and dynamic-contrast-enhanced (DCE) MRI in the A498 xenograft mouse model. After the MRI, tumor vasculature was assessed by CD34 staining. After 39 days of chronic treatment, tumor perfusion decreased to 44.8 ± 16.1 mL/100 g/min (P < 0.05), compared to 92.6 ± 42.9 mL/100 g/min in the control group. In the acute treatment study, tumor perfusion in the treated group decreased from 107.2 ± 32.7 to 73.7 ± 27.8 mL/100 g/min (P < 0.01; two-way analysis of variance), as well as compared with control group post dosing. A significant reduction in vessel density and vessel size was observed after the chronic treatment, while only vessel size was reduced 24 h after acute treatment. The tumor perfusion correlated with vessel size (r = 0.66; P < 0.005) after chronic, but not after acute treatment. The results from DCE-MRI also detected a significant change between treated and control groups in both chronic and acute treatment studies, but not between 0 and 24 h in the acute treatment group. These results indicate that tumor perfusion measured by MRI can detect early vascular responses to antiangiogenic treatment. With its noninvasive and quantitative nature, ASL MRI would be valuable for longitudinal assessment of tumor perfusion and in translation from animal models to human

  5. Increased Plasma Colloid Osmotic Pressure Facilitates the Uptake of Therapeutic Macromolecules in a Xenograft Tumor Model

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    Matthias Hofmann

    2009-08-01

    Full Text Available Elevated tumor interstitial fluid pressure (TIFP is a characteristic of most solid tumors. Clinically, TIFP may hamper the uptake of chemotherapeutic drugs into the tumor tissue reducing their therapeutic efficacy. In this study, a means of modulating TIFP to increase the flux of macromolecules into tumor tissue is presented, which is based on the rationale that elevated plasma colloid osmotic pressure (COP pulls water from tumor interstitium lowering the TIFP. Concentrated human serum albumin: (20% HSA, used as an agent to enhance COP, reduced the TIFP time-dependently from 8 to 2 mm Hg in human tumor xenograft models bearing A431 epidermoid vulva carcinomas. To evaluate whether this reduction facilitates the uptake of macromolecules, the intratumoral distribution of fluorescently conjugated dextrans (2.5 mg/ml and cetuximab (2.0 mg/ml was probed using novel time domain nearinfrared fluorescence imaging. This method permitted discrimination and semiquantification of tumor-accumulated conjugate from background and unspecific probe fluorescence. The coadministration of 20% HSA together with either dextrans or cetuximab was found to lower the TIFP significantly and increase the concentration of the substances within the tumor tissue in comparison to control tumors. Furthermore, combined administration of 20%HSA plus cetuximab reduced the tumor growth significantly in comparison to standard cetuximab treatment. These data demonstrate that increased COP lowers the TIFP within hours and increases the uptake of therapeutic macromolecules into the tumor interstitium leading to reduced tumor growth. This model represents a novel approach to facilitate the delivery of therapeutics into tumor tissue, particularly monoclonal antibodies.

  6. Antitumor activity of celastrol nanoparticles in a xenograft retinoblastoma tumor model

    Directory of Open Access Journals (Sweden)

    Li ZR

    2012-05-01

    Full Text Available Zhanrong Li,1,* Xianghua Wu,1,* Jingguo Li,2 Lin Yao,1 Limei Sun,1 Yingying Shi,1 Wenxin Zhang,1 Jianxian Lin,1 Dan Liang,1 Yongping Li1 1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, 2School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, People's Republic of China*These authors contributed equally to this workBackground: Celastrol, a Chinese herbal medicine, has shown antitumor activity against various tumor cell lines. However, the effect of celastrol on retinoblastoma has not yet been analyzed. Additionally, the poor water solubility of celastrol restricts further therapeutic applications. The goal of this study was to evaluate the effect of celastrol nanoparticles (CNPs on retinoblastoma and to investigate the potential mechanisms involved.Methods: Celastrol-loaded poly(ethylene glycol-block-poly(ε-caprolactone nanopolymeric micelles were developed to improve the hydrophilicity of celastrol. The 2-(2-methoxy-4-nitrophenyl-3-(4-nitrophenyl-5-(2,4-disulf-ophenyl-2H tetrazolium monosodium salt (WST-8 assay was used to determine the inhibitory effect of CNPs on SO-Rb 50 cell proliferation in vitro. Immunofluorescence was used to evaluate the apoptotic effect of CNPs on nuclear morphology, and flow cytometry was used to quantify cellular apoptosis. The expression of Bcl-2, Bax, NF-κB p65, and phospo-NF-κB p65 proteins was assessed by Western blotting. A human retinoblastoma xenograft model was used to evaluate the inhibitory effects of CNPs on retinoblastoma in NOD-SCID mice. Hematoxylin and eosin staining was used to assess the apoptotic effects of CNPs on retinoblastoma.Results: CNPs inhibit the proliferation of SO-Rb 50 cells in a dose- and time-dependent manner with an IC50 of 17.733 µg/mL (celastrol-loading content: 7.36% after exposure to CNPs for 48 hours. CNPs induce apoptosis in SO-Rb 50 cells in a dose-dependent manner. The expression of Bcl-2, NF-κB p65, and phospo-NF-κB p65

  7. A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with mutations in FUBP1, CIC, and IDH1.

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    Barbara Klink

    Full Text Available Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.

  8. Gamma Knife Surgery as Monotherapy with Clinically Relevant Doses Prolongs Survival in a Human GBM Xenograft Model

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    Bente Sandvei Skeie

    2013-01-01

    Full Text Available Object. Gamma knife surgery (GKS may be used for recurring glioblastomas (GBMs. However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. Methods. GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12 Gy or 18 Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test. Results. In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls (P<0.001. In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (P<0.006. Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment (P=0.04. Conclusion. GKS administered with clinically relevant doses prolongs survival in rats harboring GBM xenografts, and the associated toxicity is mild.

  9. A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts

    International Nuclear Information System (INIS)

    It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF–Cu complex. DSF–Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC–Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC–Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC–Cu(I)-treated group. Our data indicates that DDTC–Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer. - Highlights: • A new structure of DDTC–Cu(I) was reported for the first time. • DDTC–Cu(I) dissolved directly in water was for in vitro and in vivo uses. • DDTC–Cu(I) demonstrated significant anticancer effect in vitro and in vivo. • DDTC–Cu(I) is capable of inhibiting proteasome activity in vitro and in vivo

  10. A binuclear complex constituted by diethyldithiocarbamate and copper(I) functions as a proteasome activity inhibitor in pancreatic cancer cultures and xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Han, Jinbin, E-mail: hanjinbin@gmail.com [Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032 (China); Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Shanghai Clinical Center, Chinese Academy of Sciences/Xuhui Central Hospital, Shanghai 200031 (China); Liu, Luming, E-mail: llm1010@163.com [Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032 (China); Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Yue, Xiaoqiang [Department of Traditional Chinese Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433 (China); Chang, Jinjia [Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032 (China); Shi, Weidong; Hua, Yongqiang [Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032 (China); Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032 (China)

    2013-12-15

    It is a therapeutic strategy for cancers including pancreatic to inhibit proteasome activity. Disulfiram (DSF) may bind copper (Cu) to form a DSF–Cu complex. DSF–Cu is capable of inducing apoptosis in cancer cells by inhibiting proteasome activity. DSF is rapidly converted to diethyldithiocarbamate (DDTC) within bodies. Copper(II) absorbed by bodies is reduced to copper(I) when it enters cells. We found that DDTC and copper(I) could form a binuclear complex which might be entitled DDTC–Cu(I), and it had been synthesized by us in the laboratory. This study is to investigate the anticancer potential of this complex on pancreatic cancer and the possible mechanism. Pancreatic cancer cell lines, SW1990, PANC-1 and BXPC-3 were used for in vitro assays. Female athymic nude mice grown SW1990 xenografts were used as animal models. Cell counting kit-8 (cck-8) assay and flow cytometry were used for analyzing apoptosis in cells. A 20S proteasome assay kit was used in proteasome activity analysis. Western blot (WB) and immunohistochemistry (IHC) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays were used in tumor sample analysis. The results suggest that DDTC–Cu(I) inhibit pancreatic cancer cell proliferation and proteasome activity in vitro and in vivo. Accumulation of ubiquitinated proteins, and increased p27 as well as decreased NF-κB expression were detected in tumor tissues of DDTC–Cu(I)-treated group. Our data indicates that DDTC–Cu(I) is an effective proteasome activity inhibitor with the potential to be explored as a drug for pancreatic cancer. - Highlights: • A new structure of DDTC–Cu(I) was reported for the first time. • DDTC–Cu(I) dissolved directly in water was for in vitro and in vivo uses. • DDTC–Cu(I) demonstrated significant anticancer effect in vitro and in vivo. • DDTC–Cu(I) is capable of inhibiting proteasome activity in vitro and in vivo.

  11. Xenograft models for undifferentiated pleomorphic sarcoma not otherwise specified are essential for preclinical testing of therapeutic agents

    Science.gov (United States)

    Becker, Marc; Graf, Claudine; Tonak, Marcus; Radsak, Markus P.; Bopp, Tobias; Bals, Robert; Bohle, Rainer M.; Theobald, Matthias; Rommens, Pol-Maria; Proschek, Dirk; Wehler, Thomas C.

    2016-01-01

    Undifferentiated pleomorphic sarcoma not otherwise specified belongs to the heterogeneous group of soft tissue tumors. It is preferentially located in the upper and lower extremities of the body, and surgical resection remains the only curative treatment. Preclinical animal models are crucial to improve the development of novel chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma. However, this approach has been hampered by the lack of reproducible animal models. The present study established two xenograft animal models generated from stable non-clonal cell cultures, and investigated the difference in chemotherapeutic effects on tumor growth between undifferentiated pleomorphic sarcoma in vivo and in vitro. The cell cultures were generated from freshly isolated tumor tissues of two patients with undifferentiated pleomorphic sarcoma. For the in vivo analysis, these cells were injected subcutaneously into immunodeficient mice. The mice were monitored for tumor appearance and treated with the most common or innovative chemotherapeutic agents available to date. Furthermore, the same drugs were administered to in vitro cell cultures. The most effective tumor growth inhibition in vitro was observed with doxorubicin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as vorinostat. In the in vivo xenograft mouse model, the combination of doxorubicin and the tyrosine kinase inhibitor pazopanib induced a significant tumor reduction. By contrast, treatment with vorinostat did not reduce the tumor growth. Taken together, the results obtained from drug testing in vitro differed significantly from the in vivo results. Therefore, the novel and reproducible xenograft animal model established in the present study demonstrated that in vivo models are required to test potential chemotherapeutic agents for the treatment of undifferentiated pleomorphic sarcoma prior to clinical use, since animal models are more similar

  12. [18F]FDG and [18F]FLT positron emission tomography imaging following treatment with belinostat in human ovary cancer xenografts in mice

    International Nuclear Information System (INIS)

    Belinostat is a histone deacetylase inhibitor with anti-tumor effect in several pre-clinical tumor models and clinical trials. The aim of the study was to evaluate changes in cell proliferation and glucose uptake by use of 3’-deoxy-3’-[18F]fluorothymidine ([18F]FLT) and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) following treatment with belinostat in ovarian cancer in vivo models. In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) were studied after treatment with belinostat. Mice were divided in 2 groups receiving either belinostat (40 mg/kg ip twice daily Day 0–4 and 6–10) or vehicle. Baseline [18F]FLT or [18F]FDG scans were made before treatment (Day 0) and repeated at Day 3, 6 and 10. Tracer uptake was quantified using small animal PET/CT. Tumors in the belinostat group had volumes that were 462 ± 62% (640 mm3) at Day 10 relative to baseline which was significantly different (P = 0.011) from the control group 769 ± 74% (926 mm3). [18F]FLT SUVmax increased from baseline to Day 10 (+30 ± 9%; P = 0.048) in the control group. No increase was observed in the treatment group. [18F]FDG SUVmean was significantly different in the treatment group compared to the control group (P = 0.0023) at Day 10. Within treatment groups [18F]FDG uptake and to a lesser extent [18F]FLT uptake at Day 3 were significantly correlated with tumor growth at Day 10. [18F]FDG uptake early following treatment initiation predicted tumor sizes at Day 10, suggesting that [18F]FDG may be a valuable biomarker for non-invasive assessment of anti-tumor activity of belinostat

  13. Antitumor and Antiangiogenic Activities of Curcumin in Cervical Cancer Xenografts in Nude Mice

    Directory of Open Access Journals (Sweden)

    Pornphrom Yoysungnoen-Chintana

    2014-01-01

    Full Text Available To evaluate the effects of curcumin (CUR on tumor progression and angiogenesis in cervical cancer- (CaSki- implanted nude mice and on the angiogenic biomarkers: vascular endothelial growth factor (VEGF, cyclooxygenase-2 (COX-2, and epidermal growth factor receptor (EGFR. CaSki cells were subcutaneously injected in nude mice to establish subcutaneous tumors. One month after injection, mice were orally administered vehicle or 500, 1,000, and 1,500 mg/kg of CUR daily × 30 consecutive days. Tumor volume was measured every 3-4 days. At the end of the study, tumor microvasculature was observed under confocal microscope, and immunohistochemical analyses were performed to detect CD31, VEGF, COX-2, and EGFR. CUR at the doses of 1,000 and 1,500 mg/kg showed significant tumor growth retardation (21.03% and 35.57% versus CaSki + vehicle group. The microvascular density (MVD in CaSki + vehicle group was significantly increased versus Control + vehicle group and significantly reduced by CUR (1,000 and 1,500 mg/kg. VEGF, COX-2, and EGFR expressions were upregulated in CaSki + vehicle group and attenuated significantly by CUR (1,000 and 1,500 mg/kg. In conclusion, high dose CUR inhibited tumor growth and angiogenesis in CaSki-implanted mice probably mediated by the downregulation of VEGF, COX-2 and EGFR. CUR may have a role in treating human cervical cancer and should be explored further.

  14. Interleukin-12 Inhibits Tumor Growth in a Novel Angiogenesis Canine Hemangiosarcoma Xenograft Model1

    OpenAIRE

    Akhtar, Nasim; Padilla, Marcia L.; Dickerson, Erin B; Steinberg, Howard; Breen, Matthew; Auerbach, Robert; Helfand, Stuart C

    2004-01-01

    We established a canine hemangiosarcoma cell line derived from malignant endothelial cells comprising a spontaneous tumor in a dog to provide a renewable source of endothelial cells for studies of angiogenesis in malignancy. Pieces of the hemangiosarcoma biopsy were engrafted subcutaneously in a bg/nu/XID mouse allowing the tumor cells to expand in vivo. A cell line, SB-HSA, was derived from the xenograft. SB-HSA cells expressed vascular endothelial growth factor (VEGF) receptors 1 and 2, CD3...

  15. Interleukin-12 Inhibits Tumor Growth in a Novel Angiogenesis Canine Hemangiosarcoma Xenograft Model

    OpenAIRE

    Nasim Akhtar; Padilla, Marcia L.; Dickerson, Erin B; Howard Steinberg; Matthew Breent; Robert Auerbach; Helfand, Stuart C

    2004-01-01

    We established a canine hemangiosarcoma cell line derived from malignant endothelial cells comprising a spontaneous tumor in a dog to provide a renewable source of endothelial cells for studies of angiogenesis in malignancy. Pieces of the hemangiosarcoma biopsy were engrafted subcutaneously in a bg/nu/XID mouse allowing the tumor cells to expand in vivo. A cell line, SB-HSA, was derived from the xenograft. SB-HSA cells expressed vascular endothelial growth factor (VEGF) receptors 1 and 2, CD3...

  16. Methylselenol, a selenium metabolite, inhibits colon cancer cell growth and cancer xenografts in C57BL/6 mice

    Science.gov (United States)

    Data indicate that methylselenol is a critical selenium (Se) metabolite for anticancer activity in vivo but its role in colon cancer prevention remains to be characterized. This study tested the hypothesis that methylselenol inhibits the growth of colon cancer cells and tumors. We found that submicr...

  17. Comparative efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    International Nuclear Information System (INIS)

    these human lymphoma xenograft models

  18. Comparative efficacy of 177Lu and 90Y for anti-CD20 pretargeted radioimmunotherapy in murine lymphoma xenograft models.

    Directory of Open Access Journals (Sweden)

    Sofia H L Frost

    xenograft models.

  19. (212)Pb-radioimmunotherapy induces G(2) cell-cycle arrest and delays DNA damage repair in tumor xenografts in a model for disseminated intraperitoneal disease.

    Science.gov (United States)

    Yong, Kwon Joong; Milenic, Diane E; Baidoo, Kwamena E; Brechbiel, Martin W

    2012-03-01

    In preclinical studies, targeted radioimmunotherapy using (212)Pb-TCMC-trastuzumab as an in vivo generator of the high-energy α-particle emitting radionuclide (212)Bi is proving an efficacious modality for the treatment of disseminated peritoneal cancers. To elucidate mechanisms associated with this therapy, mice bearing human colon cancer LS-174T intraperitoneal xenografts were treated with (212)Pb-TCMC-trastuzumab and compared with the nonspecific control (212)Pb-TCMC-HuIgG, unlabeled trastuzumab, and HuIgG, as well as untreated controls. (212)Pb-TCMC-trastuzumab treatment induced significantly more apoptosis and DNA double-strand breaks (DSB) at 24 hours. Rad51 protein expression was downregulated, indicating delayed DNA double-strand damage repair compared with (212)Pb-TCMC-HuIgG, the nonspecific control. (212)Pb-TCMC-trastuzumab treatment also caused G(2)-M arrest, depression of the S phase fraction, and depressed DNA synthesis that persisted beyond 120 hours. In contrast, the effects produced by (212)Pb-TCMC-HuIgG seemed to rebound by 120 hours. In addition, (212)Pb-TCMC-trastuzumab treatment delayed open chromatin structure and expression of p21 until 72 hours, suggesting a correlation between induction of p21 protein and modification in chromatin structure of p21 in response to (212)Pb-TCMC-trastuzumab treatment. Taken together, increased DNA DSBs, impaired DNA damage repair, persistent G(2)-M arrest, and chromatin remodeling were associated with (212)Pb-TCMC-trastuzumab treatment and may explain its increased cell killing efficacy in the LS-174T intraperitoneal xenograft model for disseminated intraperitoneal disease. PMID:22238365

  20. Rapamycin and WYE-354 suppress human gallbladder cancer xenografts in mice.

    Science.gov (United States)

    Weber, Helga; Leal, Pamela; Stein, Stefan; Kunkel, Hana; García, Patricia; Bizama, Carolina; Espinoza, Jaime A; Riquelme, Ismael; Nervi, Bruno; Araya, Juan C; Grez, Manuel; Roa, Juan C

    2015-10-13

    Gallbladder cancer (GBC) is a highly malignant tumor characterized by a poor response to chemotherapy and radiotherapy. We evaluated the in vitro and in vivo antitumor efficacy of mTOR inhibitors, rapamycin and WYE-354. In vitro assays showed WYE-354 significantly reduced cell viability, migration and invasion and phospho-P70S6K expression in GBC cells. Mice harboring subcutaneous gallbladder tumors, treated with WYE-354 or rapamycin, exhibited a significant reduction in tumor mass. A short-term treatment with a higher dose of WYE-354 decreased the tumor size by 68.6% and 52.4%, in mice harboring G-415 or TGBC-2TKB tumors, respectively, compared to the control group. By contrast, treatment with a prolonged-low-dose regime of rapamycin almost abrogated tumor growth, exhibiting 92.7% and 97.1% reduction in tumor size, respectively, compared to control mice. These results were accompanied by a greater decrease in the phosphorylation status of P70S6K and a lower cell proliferation Ki67 index, compared to WYE-354 treated mice, suggesting a more effective mTOR pathway inhibition. These findings provide a proof of concept for the use of rapamycin or WYE-354 as potentially good candidates to be studied in clinical trials in GBC patients. PMID:26397134

  1. Biosynthesized Platinum Nanoparticles Inhibit the Proliferation of Human Lung-Cancer Cells in vitro and Delay the Growth of a Human Lung-Tumor Xenograft in vivo -In vitro and in vivo Anticancer Activity of bio-Pt NPs-

    Directory of Open Access Journals (Sweden)

    Bendale Yogesh

    2016-06-01

    Full Text Available Objectives: Lung cancer remains a deadly disease with unsatisfactory overall survival. Cisplatin, a standard platinum (Pt-based chemotherapeutic agent, has the potential to inhibit the growth of lung cancer. Its use, however, is occasionally limited by severe organ toxicity. However, until now, no systematic study has been conducted to verify its efficacy with proper experimental support in vivo. Therefore, we examined whether biosynthesized Pt nanoparticles (NPs inhibited human lung cancer in vitro and in vivo to validate their use in alternative and complementary medicine. Methods: We evaluated the in vitro and the in vivo anticancer efficiencies of biosynthesized Pt NPs in a subcutaneous xenograft model with A549 cells. Severe combined immune deficient mice (SCID were divided into four groups: group 1 being the vehicle control group and groups 2, 3 and 4 being the experimental groups. Once the tumor volume had reached 70 ─ 75 mm3, the progression profile of the tumor growth kinetics and the body weights of the mice were measured every week for 6 weeks after oral administration of Pt NPs. Doses of Pt NPs of 500, 1,000 and 2,000 mg/kg of body weight were administered to the experimental groups and a dose of honey was administered to the vehicle control group. The efficacy was quantified by using the delay in tumor growth following the administration of Pt NPs of A549 human-lung-cancer xenografts growing in SCID mice. Results: The in vitro cytotoxicity evaluation indicated that Pt NPs, in a dose-dependent manner, inhibited the growth of A549 cells, and the in vivo evaluation showed that Pt NPs at the mid and high doses effectively inhibited and delayed the growth of lung cancer in SCID mice. Conclusion: These findings confirm the antitumor properties of biosynthesized Pt NPs and suggest that they may be a cost-effective alternative for the treatment of patients with lung cancer.

  2. Human mammary fibroblasts stimulate invasion of breast cancer cells in a three-dimensional culture and increase stroma development in mouse xenografts

    International Nuclear Information System (INIS)

    Tumour phenotype is regulated in a complex fashion as a result of interactions between malignant cells and the tumour stroma. Fibroblasts are the most abundant and perhaps most active part of the tumour stroma. A better understanding of the changes that occur in fibroblasts in response to the presence of malignant cells may lead to the development of new strategies for cancer treatment. We explored the effects of fibroblasts on the growth and invasion of mammary carcinoma tumour cells in vitro and in vivo. In order to analyse secreted factors that affect invasive abilities of breast cancer cells we co-cultured human mammary fibroblasts (HMF3s) and cancer cells (MCF7S1) in three-dimensional (3D) growth conditions devoid of heterogeneous cell-cell contact. To study the possible influence of fibroblasts on MCF7S1 cancer cell growth in vivo we co-injected HMF3s and MCF7S1 cells in Balb/c nu/nu mice. In 3D co-culture both HMF3s and MCF7S1 cells demonstrated enhanced invasion into a Matrigel matrix. This was correlated with enhanced expression of the metastasis promoting S100A4 protein in fibroblasts, stimulation of the matrix metalloproteinase (MMP)-2 activity, and enhanced secretion of a range of different cytokines. Orthotopic injection of oestrogen-dependent MCF7S1 cancer cells together with fibroblasts showed stimulation of tumour growth in mice without an external oestrogen supply. The resulting tumours were characterized by increased development of extracellular matrix, as well as an increase of murine S100A4 concentration and activity of MMP-2 in the tumour interstitial fluid. Stimulation of the invasive phenotype of tumour cells in 3D co-cultures with fibroblasts could be correlated with increased production of S100A4 and MMP-2. We propose that enhanced development of mouse host-derived tumour stroma in a MCF7S1 co-injection xenograft model leads to oestrogen independency and is triggered by the initial presence of human fibroblasts

  3. Biodistribution of 131 I-Herceptin in Breast Cancer Xenograft%131I-Herceptin在乳腺癌裸鼠模型中的体内分布

    Institute of Scientific and Technical Information of China (English)

    杨志学; 蒋国勤; 邢春根; 危少华; 刘增礼

    2011-01-01

    目的 建立Her-2高表达乳腺癌动物模型,了解小鼠体内131 I-Herceptin的生物分布.方法 以对数生长期的SK-BR-3细胞皮下接种BALB/c-neu裸鼠建立动物模型.测量小鼠注射131I-Herceptin后4、12、24、48 h每克各组织每分钟的放射性计数(cpm/g),并计算肿瘤与非肿瘤组织放射性计数比值(T/NT)及每克组织放射性计数占注射剂量放射性计数的百分比(% ID/g).结果 SK-BR-3细胞皮下接种BALB/c-neu裸鼠后成瘤率96%.实验组与对照组T/NT值及%ID/g比较,差异有统计学意义(P<0.05或<0.01).结论 以SK-BR-3细胞皮下接种裸鼠成瘤率高,131 I-Herceptin在肿瘤组织中浓聚明显.%Objective To establish Her-2 positive SK-BR-3 human breast cance xenografts in athy-mic mice . To explore the biologic distribution of 131I-Herceptin in human breast cancer xenografts. Method Implant SK-BR-3 cells subcutaneously to BALB/c-neu athymic mice to establish animal model. To measure the radiocounting per minute (cpm) of every organ on a γ arithmometer at 4、12、24、48 h postin-jection of 131I-Herceptin or 131I-mIgG , then to gain the T/NT ratios and the uptakes percentage per gram of the injection dose (%ID/g). Results After subcutaneously planted, a 96% of tumor formming rate was achieved . Compared with the control group, bigger T/NT and % ID/g was obtained in the experimental group(P <0.05 and <0. 01). Conclusion A high tumor formming rate can be get by implanting SK-BR-3 cells subcutaneously to athymic mouse,131I-Herceptin is obviously concentrated in tumor tissues.

  4. Diversity of RGD radiotracers in monitoring antiangiogenesis of flavopiridol and paclitaxel in ovarian cancer xenograft-bearing mice

    International Nuclear Information System (INIS)

    Introduction: Although encouraging results had been shown in antiangiogenesis therapy monitoring, the underlying mechanism of RGD radiotracer accumulation needs to be further illustrated. This study was aimed to investigate the diversity of RGD radiotracers in monitoring antiangiogenic agent's effects and the underlying mechanism in ovarian cancer-bearing mice with a new agent flavopiridol compared with paclitaxel. Methods: Ovarian cancer SKOV-3 xenograft-bearing mice were established and divided into three groups, flavopiridol, paclitaxel and control. Flavopiridol (5 mg/kg body weight) and paclitaxel (20 mg/kg body weight) were administered every 3 days for 16 days. Tumor growth and proliferation were monitored by caliper measurements and immunofluorescence staining. Antiangiogenic effects were determined by tumor microvessel density (MVD) in vivo and by endothelial cell tube formation assay in vitro, respectively. 99mTc-3P-RGD2 was prepared, and its biodistribution studies were carried out. The effect of antiangiogenesis therapy on integrin αvβ3 expression was studied by immunohistochemical staining and flow cytometry. Results: Both paclitaxel and flavopiridol therapy could apparently inhibit tumor growth and proliferation, and antiangiogenic effects of therapy were validated in vivo and in vitro. However, compared with the control group, ID%/g tumor uptake of 99mTc-3P-RGD2 showed a significant decrease at 2 hours (by 39.96% ± 8.23%, P = 0.044) and at 4 hours (by 35.76% ± 11.42%, P = 0.024) post injection in the paclitaxel-treated group, but a slight increase of tumor uptake in the flavopiridol-treated group at 2 hours (by 4.42% ± 0.24%, p = 0.898) and at 4 hours (by 12.2% ± 1.84%, P = 0.702). The further studies indicated flavopiridol therapy has a dual-effect, reducing integrin αvβ3 expression on endothelial cells due to the reduction of tumor MVD and up-regulating the integrin αvβ3 expression on tumor cells. Conclusions: There is diversity in

  5. A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia

    International Nuclear Information System (INIS)

    Relevant preclinical mouse models are crucial to screen new therapeutic agents for acute myeloid leukemia (AML). Current in vivo models based on the use of patient samples are not easy to establish and manipulate in the laboratory. Our objective was to develop robust xenograft models of human AML using well-characterized cell lines as a more accessible and faster alternative to those incorporating the use of patient-derived AML cells. Five widely used AML cell lines representing various AML subtypes were transplanted and expanded into highly immunodeficient non-obese diabetic/LtSz-severe combined immunodeficiency IL2Rγcnull mice (for example, cell line-derived xenografts). We show here that bone marrow sublethal conditioning with busulfan or irradiation has equal efficiency for the xenotransplantation of AML cell lines. Although higher number of injected AML cells did not change tumor engraftment in bone marrow and spleen, it significantly reduced the overall survival in mice for all tested AML cell lines. On the basis of AML cell characteristics, these models also exhibited a broad range of overall mouse survival, engraftment, tissue infiltration and aggressiveness. Thus, we have established a robust, rapid and straightforward in vivo model based on engraftment behavior of AML cell lines, all vital prerequisites for testing new therapeutic agents in preclinical studies

  6. Patient-derived xenografts faithfully replicated clinical outcome in a phase II co-clinical trial of arsenic trioxide in relapsed small cell lung cancer

    OpenAIRE

    Owonikoko, Taofeek K.; Zhang, Guojing; Kim, Hyun S.; Stinson, Renea M.; Bechara, Rabih; Zhang, Chao; Chen, Zhengjia; Saba, Nabil F.; Pakkala, Suchita; Pillai, Rathi; Deng, Xingming; Sun, Shi-Yong; Rossi, Michael R.; Sica, Gabriel L.; Ramalingam, Suresh S.

    2016-01-01

    Background SCLC has limited treatment options and inadequate preclinical models. Promising activity of arsenic trioxide (ASO) recorded in conventional preclinical models of SCLC supported the clinical evaluation of ASO in patients. We assessed the efficacy of ASO in relapsed SCLC patients and in corresponding patient-derived xenografts (PDX). Methods Single arm, Simon 2-stage, phase II trial to enroll patients with relapsed SCLC who have failed at least one line of therapy. ASO was administer...

  7. Alkylator-Induced and Patient-Derived Xenograft Mouse Models of Therapy-Related Myeloid Neoplasms Model Clinical Disease and Suggest the Presence of Multiple Cell Subpopulations with Leukemia Stem Cell Activity

    Science.gov (United States)

    Johnson, Carl; Gratzinger, Dita; Majeti, Ravindra

    2016-01-01

    Acute myeloid leukemia (AML) is a heterogeneous group of aggressive bone marrow cancers arising from transformed hematopoietic stem and progenitor cells (HSPC). Therapy-related AML and MDS (t-AML/MDS) comprise a subset of AML cases occurring after exposure to alkylating chemotherapy and/or radiation and are associated with a very poor prognosis. Less is known about the pathogenesis and disease-initiating/leukemia stem cell (LSC) subpopulations of t-AML/MDS compared to their de novo counterparts. Here, we report the development of mouse models of t-AML/MDS. First, we modeled alkylator-induced t-AML/MDS by exposing wild type adult mice to N-ethyl-N-nitrosurea (ENU), resulting in several models of AML and MDS that have clinical and pathologic characteristics consistent with human t-AML/MDS including cytopenia, myelodysplasia, and shortened overall survival. These models were limited by their inability to transplant clinically aggressive disease. Second, we established three patient-derived xenograft models of human t-AML. These models led to rapidly fatal disease in recipient immunodeficient xenografted mice. LSC activity was identified in multiple HSPC subpopulations suggesting there is no canonical LSC immunophenotype in human t-AML. Overall, we report several new t-AML/MDS mouse models that could potentially be used to further define disease pathogenesis and test novel therapeutics. PMID:27428079

  8. Molecular Imaging of Bcr-Abl Phosphokinase in a Xenograft Model*

    OpenAIRE

    Wu, Ji Yuan; Yang, David J.; Angelo, Laura S.; Kohanim, Saady; Kurzrock, Razelle

    2009-01-01

    The purpose of this study was to determine whether the Bcr-Abl tyrosine kinase can be assessed by gamma imaging using an 111Indium-labeled anti-phosphotyrosine antibody, and if the response to treatment with imatinib could be detected using this imaging technique. Anti-phosphotyrosine antibody (APT) was labeled with indium (111In) using ethylenedicysteine (EC) as a chelator. To determine if 111In-EC-APT could assess a non-receptor tyrosine kinase, xenografts of the human chronic myelogenous l...

  9. Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models

    Energy Technology Data Exchange (ETDEWEB)

    Sakamoto, Toshiaki; Ozaki, Kei-ichi; Fujio, Kohsuke; Kajikawa, Shu-hei [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Uesato, Shin-ichi [Department of Biotechnology, Faculty of Engineering, Kansai University, Osaka 564-8680 (Japan); Watanabe, Kazushi [Proubase Technology Inc., Kanagawa 211-0063 (Japan); Tanimura, Susumu [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Koji, Takehiko [Department of Histology and Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kohno, Michiaki, E-mail: kohnom@nagasaki-u.ac.jp [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Proubase Technology Inc., Kanagawa 211-0063 (Japan); Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501 (Japan)

    2013-04-19

    Highlights: •Blockade of the ERK pathway enhances the anticancer efficacy of HDAC inhibitors. •MEK inhibitors sensitize human tumor xenografts to HDAC inhibitor cytotoxicity. •Such the enhanced efficacy is achieved by a transient blockade of the ERK pathway. •This drug combination provides a promising therapeutic strategy for cancer patients. -- Abstract: The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.

  10. Pseudotyped AAV vector-mediated gene transfer in a human fetal trachea xenograft model: implications for in utero gene therapy for cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    Sundeep G Keswani

    Full Text Available BACKGROUND: Lung disease including airway infection and inflammation currently causes the majority of morbidities and mortalities associated with cystic fibrosis (CF, making the airway epithelium and the submucosal glands (SMG novel target cells for gene therapy in CF. These target cells are relatively inaccessible to postnatal gene transfer limiting the success of gene therapy. Our previous work in a human-fetal trachea xenograft model suggests the potential benefit for treating CF in utero. In this study, we aim to validate adeno-associated virus serotype 2 (AAV2 gene transfer in a human fetal trachea xenograft model and to compare transduction efficiencies of pseudotyping AAV2 vectors in fetal xenografts and postnatal xenograft controls. METHODOLOGY/PRINCIPAL FINDINGS: Human fetal trachea or postnatal bronchus controls were xenografted onto immunocompromised SCID mice for a four-week engraftment period. After injection of AAV2/2, 2/1, 2/5, 2/7 or 2/8 with a LacZ reporter into both types of xenografts, we analyzed for transgene expression in the respiratory epithelium and SMGs. At 1 month, transduction by AAV2/2 and AAV2/8 in respiratory epithelium and SMG cells was significantly greater than that of AAV2/1, 2/5, and 2/7 in xenograft tracheas. Efficiency in SMG transduction was significantly greater in AAV2/8 than AAV2/2. At 3 months, AAV2/2 and AAV2/8 transgene expression was >99% of respiratory epithelium and SMG. At 1 month, transduction efficiency of AAV2/2 and AAV2/8 was significantly less in adult postnatal bronchial xenografts than in fetal tracheal xenografts. CONCLUSIONS/SIGNIFICANCE: Based on the effectiveness of AAV vectors in SMG transduction, our findings suggest the potential utility of pseudotyped AAV vectors for treatment of cystic fibrosis. The human fetal trachea xenograft model may serve as an effective tool for further development of fetal gene therapy strategies for the in utero treatment of cystic fibrosis.

  11. Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase

    Science.gov (United States)

    TSUJIMOTO, HIROAKI; TSUKIOKA, SAYAKA; ONO, SATORU; SAKAMOTO, ETSUKO; SAKAMOTO, KAZUKI; TSUTA, KOHJI; NAKAGAWA, FUMIO; SAITO, HITOSHI; UCHIDA, JUNJI; KINIWA, MAMORU; FUKUSHIMA, MASAKAZU

    2010-01-01

    The combination of oral tegafur-uracil (UFT) with leucovorin (LV) is used to treat patients with stage II to III colon cancer based on the results of postoperative randomized studies in which UFT/LV treatment showed an equivalent efficacy to intravenous 5-FU plus LV therapy. However, whether the addition of LV to UFT can elevate the antitumor activity of UFT in colorectal tumors with high expression levels of thymidylate synthase (TS), which affects 5-FU efficacy, remains to be clarified. This study investigated the effect of LV on the antitumor activity of UFT and/or 5-FU prodrugs in low folate diet-fed nude mice using human colorectal cancer xenografts with various expression levels of TS. The addition of LV to UFT resulted in a 55–79% inhibition of tumor growth among 11 types of colorectal tumor xenograft, whereas UFT alone showed 23–67% antitumor activity. Although there was an inverse relationship between the antitumor effect of UFT alone and UFT plus LV and tumoral TS activity, UFT plus LV appeared to have a more potent antitumor effect than UFT alone on colorectal tumors such as Co-3 and KM12C/5-FU with high expression levels of TS. This finding was confirmed by the significant positive correlation between the relative inhibition ratio of UFT/LV to UFT alone and TS levels in tumors. To investigate the reason for the higher efficacy of UFT/LV on colorectal cancer xenografts with high TS activity, intratumoral levels of reduced folates and a ternary complex of TS after oral UFT with or without LV were measured using Co-3 xenografts. Elevated levels of reduced folates and an increased ternary complex of TS in LV-treated tumors were noted. Our results indicate that a combined therapy of UFT with LV may contribute to the treatment of colorectal cancer patients with low and high expression levels of tumoral TS by increased formation of the ternary complex of TS leading to potentiated antitumor efficacy of UFT. PMID:22870097

  12. Comparison of the effects of vitamin D products in a psoriasis plaque test and a murine psoriasis xenograft model

    Directory of Open Access Journals (Sweden)

    Hoffmann Vibeke

    2009-12-01

    Full Text Available Abstract The aim of the present study was to compare the effects of Daivobet® and calcipotriol on clinical score and biomarker responses in a modified version of the Scholtz-Dumas psoriasis plaque assay. Furthermore, it was the aim to compare the effects of calcipotriol and betamethasone in the murine psoriasis xenograft model. Twenty four patients with psoriasis were treated topically once daily for three weeks, whereas the grafted mice were treated for four weeks. Clinical responses were scored twice weekly and biopsies were taken at the end of each study to analyse for skin biomarkers by histology and immunohistochemistry. The results clearly demonstrate effects on both clinical signs and biomarkers. In the patient study the total clinical score was reduced significantly with both Daivobet® and calcipotriol. Both treatments reduced epidermal thickness, Ki-67 and cytokeratin 16 expression. T cell infiltration was significantly reduced by Daivobet® but only marginally by calcipotriol. Both treatments showed strong effects on the epidermal psoriatic phenotype. Results from the xenograft model essentially showed the same results. However differences were observed when investigating subtypes of T cells. The study demonstrates the feasibility of obtaining robust biomarker data in the psoriasis plaque test that correlate well with those obtained in other clinical studies. Furthermore, the biomarker data from the plaque test correlate with biopsy data from the grafted mice.

  13. Radiation responses of human bladder cancer assessed in vitro or as xenografts in immune-deprived mice

    International Nuclear Information System (INIS)

    The response to radiation of cells derived from transitional cell carcinoma (TCC) of the human bladder has been studied. In vitro radiation survival curves for two established cell lines, RT-4 and MGH-U1, and for a cell line HB-10 derived recently from biopsy of a metastatic lymph node were characterized by values of D0 and anti n in the range of 1.1-1.5 Gy and 2-7 respectively. The oxygen enhancement ratio of HB-10 cells was 2.8. Xenografts derived from the line HB-10 were irradiated in vivo under both aerobic and hypoxic conditions and cell survival was assessed in agar. Both aerobic and hypoxic survival curves were similar to that obtained for irradiation of hypoxic HB-10 cells in culture. Another tumor line, HB-15, derived from a cystoscopic biopsy of primary TCC, was maintained by transplantation of xenografts. Regrowth curves for HB-15 xenografts after radiation doses of 10 or 20 Gy were parallel to the growth curve for untreated controls but with volume reduced by factors of about 5 and 20 respectively. Cells derived from TCC of the human bladder exhibit parameters of radiation survival similar to those of other mammalian cells, and that xenografts derived from such cells contain a high proportion of hypoxic cells

  14. The nude mouse as an in vivo model for human breast cancer invasion and metastasis

    DEFF Research Database (Denmark)

    Brünner, N; Boysen, B; Rømer, J; Spang-Thomsen, M

    1993-01-01

    Human breast cancer xenografts only rarely invade and metastasize in nude mice, and have therefore only had limited use as a model for studying mechanisms involved in breast cancer spreading. However, recent reports describe differences not only between various cell lines but also between strains...

  15. Bispecific antibody complex pre-targeting and targeted delivery of polymer drug conjugates for imaging and therapy in dual human mammary cancer xenografts. Targeted polymer drug conjugates for cancer diagnosis and therapy

    Energy Technology Data Exchange (ETDEWEB)

    Khaw, Ban-An; Gada, Keyur S.; Patil, Vishwesh; Panwar, Rajiv; Mandapati, Savitri [Northeastern University, Department of Pharmaceutical Sciences, Bouve College of Health Sciences, School of Pharmacy, Boston, MA (United States); Hatefi, Arash [Rutgers University, Department of Pharmaceutics, New Brunswick, NJ (United States); Majewski, Stan [West Virginia University, Department of Radiology, Morgantown, WV (United States); Weisenberger, Andrew [Thomas Jefferson National Accelerator Facility, Jefferson Lab, Newport News, VA (United States)

    2014-08-15

    Doxorubicin, a frontline chemotherapeutic agent, limited by its cardiotoxicity and other tissue toxicities, was conjugated to N-terminal DTPA-modified polyglutamic acid (D-Dox-PGA) to produce polymer pro-drug conjugates. D-Dox-PGA or Tc-99 m labeled DTPA-succinyl-polylysine polymers (DSPL) were targeted to HER2-positive human mammary carcinoma (BT-474) in a double xenografted SCID mouse model also hosting HER2-negative human mammary carcinoma (BT-20). After pretargeting with bispecific anti-HER2-affibody-anti-DTPA-Fab complexes (BAAC), anti-DTPA-Fab or only phosphate buffered saline, D-Dox-PGA or Tc-99 m DSPL were administered. Positive therapeutic control mice were injected with Dox alone at maximum tolerated dose (MTD). Only BT-474 lesions were visualized by gamma imaging with Tc-99 m-DSPL; BT-20 lesions were not. Therapeutic efficacy was equivalent in mice pretargeted with BAAC/targeted with D-Dox-PGA to mice treated only with doxorubicin. There was no total body weight (TBW) loss at three times the doxorubicin equivalent MTD with D-Dox-PGA, whereas mice treated with doxorubicin lost 10 % of TBW at 2 weeks and 16 % after the second MTD injection leading to death of all mice. Our cancer imaging and pretargeted therapeutic approaches are highly target specific, delivering very high specific activity reagents that may result in the development of a novel theranostic application. HER/2 neu specific affibody-anti-DTPA-Fab bispecific antibody pretargeting of HER2 positive human mammary xenografts enabled exquisite targeting of polymers loaded with radioisotopes for molecular imaging and doxorubicin for effective therapy without the associating non-tumor normal tissue toxicities. (orig.)

  16. Bispecific antibody complex pre-targeting and targeted delivery of polymer drug conjugates for imaging and therapy in dual human mammary cancer xenografts. Targeted polymer drug conjugates for cancer diagnosis and therapy

    International Nuclear Information System (INIS)

    Doxorubicin, a frontline chemotherapeutic agent, limited by its cardiotoxicity and other tissue toxicities, was conjugated to N-terminal DTPA-modified polyglutamic acid (D-Dox-PGA) to produce polymer pro-drug conjugates. D-Dox-PGA or Tc-99 m labeled DTPA-succinyl-polylysine polymers (DSPL) were targeted to HER2-positive human mammary carcinoma (BT-474) in a double xenografted SCID mouse model also hosting HER2-negative human mammary carcinoma (BT-20). After pretargeting with bispecific anti-HER2-affibody-anti-DTPA-Fab complexes (BAAC), anti-DTPA-Fab or only phosphate buffered saline, D-Dox-PGA or Tc-99 m DSPL were administered. Positive therapeutic control mice were injected with Dox alone at maximum tolerated dose (MTD). Only BT-474 lesions were visualized by gamma imaging with Tc-99 m-DSPL; BT-20 lesions were not. Therapeutic efficacy was equivalent in mice pretargeted with BAAC/targeted with D-Dox-PGA to mice treated only with doxorubicin. There was no total body weight (TBW) loss at three times the doxorubicin equivalent MTD with D-Dox-PGA, whereas mice treated with doxorubicin lost 10 % of TBW at 2 weeks and 16 % after the second MTD injection leading to death of all mice. Our cancer imaging and pretargeted therapeutic approaches are highly target specific, delivering very high specific activity reagents that may result in the development of a novel theranostic application. HER/2 neu specific affibody-anti-DTPA-Fab bispecific antibody pretargeting of HER2 positive human mammary xenografts enabled exquisite targeting of polymers loaded with radioisotopes for molecular imaging and doxorubicin for effective therapy without the associating non-tumor normal tissue toxicities. (orig.)

  17. Evaluation of 6-([18F] fluoroacetamido)-1-hexanoic-anilide (18F-FAHA) as imaging probe in tumor xenograft mice model

    Science.gov (United States)

    Li, Fiona; Cho, Sung Ju; Yu, Lihai; Hudson, Robert H. E.; Luyt, Leonard G.; Pin, Christopher L.; Kovacs, Michael S.; Koropatnick, James; Lee, Ting-Yim

    2016-03-01

    Alteration in genetic expression is as important as gene mutation in cancer development and proliferation. Epigenetic changes affect gene expression without altering the DNA sequence. Histone deacetylase (HDAC), an enzyme facilitating histone remodelling, can lead to silencing of tumor suppressor genes making HDAC inhibitors viable anticancer drugs against tumors with increased activity of the enzyme. In this study we evaluated 18F-fluroacetamido-1-hexanoicanilide (18F-FAHA), an artificial HDAC substrate, as imaging probe of HDAC activity of human tumor xenografts in immunocompromised host mice. Human breast and melanoma cell lines, MDA-MB-468 and MDA-MB-435 respectively, known to overexpress HDAC activity were xenografted into immunocompromised mice and HDAC activity was imaged using 18F-FAHA. The melanoma group was treated with saline, SAHA (suberoylanilide hydroxamic acid, an approved anticancer HDAC inhibitor) in DMSO, or DMSO as positive control. Tracer kinetic modelling and SUV were used to estimate HDAC activity from dynamic PET data. Both breast tumor and melanoma group showed great variability in binding rate constant (BRC) of 18F-FAHA suggesting highly variable inter- and intra-tumoral HDAC activity. For the SAHA treated melanoma group, HDAC activity, as monitored by BRC of 18F-FAHA, decreased more than the two (positive and negative) control groups but not tumor growth. Our preliminary study showed that noninvasive PET imaging with 18F-FAHA has the potential to identify patients for whom treatment with HDAC inhibitors are appropriate, to assess the effectiveness of that treatment as an early marker of target reduction, and also eliminate the need for invasive tissue biopsy to individualize treatment.

  18. Combination of Quercetin and 2-Methoxyestradiol Enhances Inhibition of Human Prostate Cancer LNCaP and PC-3 Cells Xenograft Tumor Growth.

    Directory of Open Access Journals (Sweden)

    Feiya Yang

    Full Text Available Quercetin and 2-Methoxyestradiol (2-ME are promising anti-cancer substances. Our previous in vitro study showed that quercetin synergized with 2-Methoxyestradiol exhibiting increased antiproliferative and proapoptotic activity in both androgen-dependent LNCaP and androgen-independent PC-3 human prostate cancer cell lines. In the present study, we determined whether their combination could inhibit LNCaP and PC-3 xenograft tumor growth in vivo and explored the underlying mechanism. Human prostate cancer LNCaP and PC-3 cells were inoculated subcutaneously in male BALB/c nude mice. When xenograft tumors reached about 100 mm3, mice were randomly allocated to vehicle control, quercetin or 2-Methoxyestradiol singly treated and combination treatment groups. After therapeutic intervention for 4 weeks, combination treatment of quercetin and 2-ME i significantly inhibited prostate cancer xenograft tumor growth by 46.8% for LNCaP and 51.3% for PC-3 as compared to vehicle control group, more effective than quercetin (28.4% for LNCaP, 24.8% for PC3 or 2-ME (32.1% for LNCaP, 28.9% for PC3 alone; ii was well tolerated by BALB/c mice and no obvious toxic reactions were observed; iii led to higher Bax/Bcl-2 ratio, cleaved caspase-3 protein expression and apoptosis rate; and iv resulted in lower phosphorylated AKT (pAKT protein level, vascular endothelial growth factor protein and mRNA expression, microvascular density and proliferation rate than single drug treatment. These effects were more remarkable compared to vehicle group. Therefore, combination of quercetin and 2-ME can serve as a novel clinical treatment regimen owning the potential of enhancing antitumor effect on prostate cancer in vivo and lessening the dose and side effects of either quercetin or 2-ME alone. These in vivo results will lay a further solid basis for subsequent researches on this novel therapeutic regimen in human prostate cancer.

  19. Uptake of verteporfin by orthotopic xenograft pancreas models with different levels of aggression

    Science.gov (United States)

    O'Hara, Julia; Samkoe, Kimberley S.; Chen, Alina; Hoopes, P. Jack; Rizvi, Imran; Hasan, Tayyaba; Pogue, Brian W.

    2009-06-01

    Pancreatic cancer is an aggressive disease with a poor prognosis, usually treated with chemoradiation therapy. Interstitial photodynamic therapy is a potentially effective adjuvant treatment that is under development. In the current study, two orthotopic pancreatic cancer models (AsPC-1 and Panc-1), have been characterized with respect to growth rates, morphology and liposomal drug (Verteporfin) uptake and distribution in SCID mice. Fluorescence of Verteporfin was measured in liver and tumor in vivo using a PDT fluorescence dosimeter with measurements taken before and up to one hour after tail vein injection. Fluorescence reached a plateau by about 15 minutes and did not decrease over the first hour. At time points from 15 minutes to 24 hrs, the internal organs (kidney, spleen, pancreas, tumor, muscle, lung, liver, and skin were excised and scanned on a Typhoon imager. The ratio of fluorescence in tumor versus normal tissues was analyzed with image processing, calculated at each time point and compared to in vivo results. Tissue distribution of Verteporfin in relation to functional vasculature marked by DiOc7 was carried out on frozen sections. Final analysis will result in determination of the ideal time point to administer light to achieve maximum tumor destruction while preserving normal tissue.

  20. Models of breast cancer: quo vadis, animal modeling?

    International Nuclear Information System (INIS)

    Rodent models for breast cancer have for many decades provided unparalleled insights into cellular and molecular aspects of neoplastic transformation and tumorigenesis. Despite recent improvements in the fidelity of genetically engineered mice, rodent models are still being criticized by many colleagues for not being 'authentic' enough to the human disease. Motives for this criticism are manifold and range from a very general antipathy against the rodent model system to well-founded arguments that highlight physiological variations between species. Newly proposed differences in genetic pathways that cause cancer in humans and mice invigorated the ongoing discussion about the legitimacy of the murine system to model the human disease. The present commentary intends to stimulate a debate on this subject by providing the background about new developments in animal modeling, by disputing suggested limitations of genetically engineered mice, and by discussing improvements but also ambiguous expectations on the authenticity of xenograft models to faithfully mimic the human disease

  1. Radioimmunoimaging and biodistribution of 131I-Herceptin in breast cancer xenograft BALB/c-neu mousse%131I-Herceptin在乳腺癌裸鼠模型中的显像及体内分布研究

    Institute of Scientific and Technical Information of China (English)

    杨志学; 危少华; 蒋国勤; 刘增礼

    2012-01-01

    Objective To study the biologic distribution of 131I-Herceptin in BALB/c-neu nude mice bearing HER-2 positive SK-BR-3 human breast cancer xenografts and the radioimmunoimaging characteristics of nude mouse bearing human SK-BR-3 breast cancer xenografts. Method SK-BR-3 breast cancer cells were implanted subcutaneously to athymic mice to establish animal model.Tumor bearing mice were continuously imaged with SPECT. The radiocounting per minute (cpm) of different organ on a γ-arithmometer was measured at 4,12,24,48 h postinjection of 131I-Herceptin or 131I-mlgG,and the T/NT ratios and the uptake percentages per gram of the injection dose (% ID/g) was gained. Results Model was established in 96% nude mouse.Compared with the control group,there was a significantly stronger contrast enhancement of tumor imaging,bigger T/NT and % ID/g in experimental group ( P < 0.0l ).Conclusions 131I-Herceptin concentrates obviously in implanting tumor tissues of nude mouse,hence it is a good radiopharmaceutical agent targeting SK-BR-3 xenografts.%目的 研究131I-Herceptin荷人乳腺癌裸鼠体内的生物学分布及荷人乳腺癌裸鼠的放射免疫显像特点.方法 以对数生长期的SK-BR-3乳腺癌细胞皮下接种BALB/c-neu裸鼠建立动物模型,对荷瘤小鼠模型进行SPECT连续显像.测量小鼠注药后的4、12、24、48 h各脏器每克组织每分钟的放射性计数(cpm/g),并计算T/NT以及每克组织的放射性计数占注射剂量放射性计数的百分比(% ID/g).结果 (1)SK-BR-3细胞皮下接种BALB/c-neu裸鼠后成瘤率96%.(2)实验组对比对照组,显像对比明显;实验组T/NT以及肿瘤组织%ID/g显著高于对照组(P<0.01).结论 131I-Herceptin在SK-BR-3乳腺癌裸鼠肿瘤组织中的浓聚明显,具有良好的靶向作用.

  2. Comparison of 131I- and 90Y-labeled monoclonal antibody 17-1A for treatment of human colon cancer xenografts

    International Nuclear Information System (INIS)

    The choice of radionuclide remains an important question in clinical radioimmunotherapy. Therefore, a study was initiated, using an in vivo model system, to assess the relative merits of 131I- and 90Y-labeled 17-1A monoclonal antibody as therapeutic agents in the treatment of colon cancer. 131I- and 90Y-labeled 17-1A were assessed in animal therapy trials using athymic nude mice bearing LS174T human colon cancer xenografts. 131I-labeled 17-1A decreased tumor growth in a dose-dependent fashion without lethality. In contrast, the doses of 90Y-labeled 17-1A which were required to produce a significant increase in tumor doubling time also caused marked toxicity. Although similar tumor growth inhibition was produced by 250 μCi 90Y- and 150 μCi 131I-labeled 17-1A, Medical Internal Radiation Dose calculations based on biodistribution data estimated that the dose delivered by 90Y was greater than that delivered by 131I. To investigate this discrepancy, 3-dimensional dose distributions within LS174T tumors were assessed using autoradiography and 3-dimensional calculational techniques. It was found that a greater fraction of the dose was deposited in the tumor after treatment with 131I- compared to 90Y-labeled 17-1A. When the Medical Internal Radiation Dose calculations were adjusted using the 3-dimensional dose distributions, 250 μCi of 90Y- and 150 μCi of 131I-labeled 17-1A were found to deliver similar tumor doses. These studies suggest that 131I-labeled 17-1A is superior to 90Y-labeled 17-1A, since 131I-labeled antibody produced less hematological and animal toxicity and was more effective at inhibiting LS174T tumor growth than 90Y-labeled antibody across the range of radionuclide doses tested. Furthermore, they suggest that it will be necessary to perform 3-dimensional dose calculations. 33 refs., 7 figs., 4 tabs

  3. Down-regulation of the nuclear factor-kappaB by lidamycin in association with inducing apoptosis in human pancreatic cancer cells and inhibiting xenograft growth.

    Science.gov (United States)

    Chen, Jing; Ouyang, Zhi-Gang; Zhang, Sheng-Hua; Zhen, Yong-Su

    2007-06-01

    Pancreatic cancer is now one of the most common causes of cancer death worldwide. K-ras mutations are present in up to 90% of pancreatic cancer cases. The expression of mutant K-ras activates the Akt/protein kinase B pathway, resulting in the activation of the nuclear factor-kappaB (NF-kappaB) transcriptional factor. Constitutive NF-kappaB activity plays a key role in pancreatic carcinoma. NF-kappaB has been shown to inhibit apoptosis in response to chemotherapeutic agents. In the present study, the effects of lidamycin (LDM), a member of the enediyne antibiotic family, were investigated on two established pancreatic cell lines, PANC-1 and SW1990. A dose-dependent inhibition of phospho-Akt and NF-kappaB activation was found in the cells treated with LDM as determined by Western blot analysis. Moreover, a down-regulation of K-ras mRNA and a protein expression by LDM were observed in both cell lines as determined by reverse transcription-PCR and Western blot analysis. By MTT assay, a remarkable difference in chemosensitivity to LDM, mitomycin, adriamycin, taxol, and gemcitabine was found in both cell lines. The IC50 values of LDM for the PANC-1 or SW1990 cells were 0.955+/-0.414 or 0.426+/-0.212 nM, respectively, lower than those of the other drugs. Growth inhibition, apoptosis induction and cell cycle arrest were observed in the LDM-treated cells. LDM decreased the invasive potential of pancreatic cancer cells by reducing matrix metalloproteinase-9 activity. Furthermore, LDM was found to suppress the growth of SW1990 xenografts in nude mice. Treatment with an i.v. injection of LDM at the dose of 0.02 and 0.04 mg/kg (once a week for two weeks) inhibited the growth of xenografts by 66 and 72%, respectively. By contrast, an i.p. injection of gemcitabine at the dose of 80 mg/kg inhibited the growth of xenografts by 38%. Our findings suggest that LDM is active in the down-regulation of NF-kappaB and could play a positive role in relevant targeted chemotherapy for

  4. Evaluation of meta-[211At]astatobenzylguanidine in an athymic mouse human neuroblastoma xenograft model

    International Nuclear Information System (INIS)

    A paired-label biodistribution was performed in athymic mice bearing SK-N-SH human neuroblastoma xenografts to compare the tissue uptake of meta-[211At]astatobenzylguanidine ([211At]MABG) and [131I]MIBG. Significantly higher (p 211At]MABG was seen in tumor (3.8 ± 0.8% ID/g vs. 3.1 ± 0.7% ID/g at 8 h) compared to [131I]MIBG. Desipramine reduced tumor uptake of [211At] MABG by 43%, suggesting that its accumulation was related to the specific uptake-1 mechanism. Higher uptake of [211At]MABG was also seen in normal tissue targets such as heart (6.0 ± 0.9% ID/g vs. 4.5 ± 0.8% ID/g at 8 h; p 211At]MABG by 1.5-fold while reducing uptake in heart and several other normal tissues. The vesicular uptake inhibitor tetrabenazine reduced heart uptake by 30% without reducing the tumor uptake. These results suggest such strategies might be useful for improving [211At]MABG tumor-to-normal tissue ratios

  5. Morphine modulates doxorubicin uptake and improves efficacy of chemotherapy in an intracranial xenograft model of human glioblastoma

    Science.gov (United States)

    da Ros, Martina; Iorio, Anna Lisa; Consolante, Dario; Cardile, Francesco; Muratori, Monica; Fantappiè, Ornella; Lucchesi, Maurizio; Guidi, Milena; Pisano, Claudio; Sardi, Iacopo

    2016-01-01

    Morphine may alter the permeability of Blood-Brain Barrier (BBB), enhancing the access of molecules normally unable to cross it, as Doxorubicin (Dox). In addition, morphine seems to mediate the uptake of Dox into the brain by its reduced efflux mediated by P-glycoprotein (P-gp). We evaluated the antitumor efficacy of Dox plus morphine treatment by an orthotopic glioblastoma xenograft model. Foxn1 mice were injected with U87MG-luc cells in the left lobe of the brain and treated with Dox (5 mg/kg and 2.5 mg/kg, weekly) with or without morphine pretreatment (10 mg/kg, weekly). Bioluminescence imaging (BLI) was used to monitoring tumor growth and response to therapy. Additionally, we investigated the role of morphine on the uptake of Dox by MDCKII cells transfected with human MDR1 gene encoding for P-gp. The data demonstrate that only Dox 5 mg/kg determined a significant tumor regression while the lower dose (2.5 mg/kg) was not effective. However, if combined with morphine, the group treated with Dox 2.5 mg/kg showed a decreasing tumor growth. The average BLI for Dox 2.5 mg/kg plus morphine was 5 fold lower than Dox 2.5 mg/kg alone (P=0.0053) and 8 fold lower than vehicle (P=0.0004). Additionally, Dox increased in MDCKII-P-gp transfected cells only in the presence of morphine with a significantly higher level comparing control group (3.84) vs Dox plus morphine group (12.29, P<0.05). Our results indicate that Dox alone and in combination with morphine appear to be effective in controlling the growth of glioblastoma in a xenograft mouse model. PMID:27152241

  6. Challenges in pre-clinical testing of anti-cancer drugs in cell culture and in animal models

    OpenAIRE

    HogenEsch, Harm; Yu Nikitin, Alexander

    2012-01-01

    Experiments with cultures of human tumor cell lines, xenografts of human tumors into immunodeficient mice, and mouse models of human cancer are important tools in the development and testing of anti-cancer drugs. Tumors are complex structures composed of genetically and phenotypically heterogeneous cancer cells that interact in a reciprocal manner with the stromal microenvironment and the immune system. Modeling the complexity of human cancers in cell culture and in mouse models for preclinic...

  7. Fractionated therapy of HER2-expressing breast and ovarian cancer xenografts in mice with targeted alpha emitting 227Th-DOTA-p-benzyl-trastuzumab.

    Directory of Open Access Journals (Sweden)

    Helen Heyerdahl

    Full Text Available BACKGROUND: The aim of this study was to investigate therapeutic efficacy and normal tissue toxicity of single dosage and fractionated targeted alpha therapy (TAT in mice with HER2-expressing breast and ovarian cancer xenografts using the low dose rate radioimmunoconjugate (227Th-DOTA-p-benzyl-trastuzumab. METHODOLOGY/PRINCIPAL FINDINGS: Nude mice carrying HER2-overexpressing subcutaneous SKOV-3 or SKBR-3 xenografts were treated with 1000 kBq/kg (227Th-trastuzumab as single injection or four injections of 250 kBq/kg with intervals of 4-5 days, 2 weeks, or 4 weeks. Control animals were treated with normal saline or unlabeled trastuzumab. In SKOV-3 xenografts tumor growth to 10-fold size was delayed (p<0.01 and survival with tumor diameter less than 16 mm was prolonged (p<0.05 in all TAT groups compared to the control groups. No statistically significant differences were seen among the treated groups. In SKBR-3 xenografts tumor growth to 10-fold size was delayed in the single injection and 4-5 days interval groups (p<0.001 and all except the 4 weeks interval TAT group showed improved survival to the control groups (p<0.05. Toxicity was assessed by blood cell counts, clinical chemistry measurements and body weight. Transient reduction in white blood cells was seen for the single injection and 4-5 days interval groups (p<0.05. No significant changes were seen in red blood cells, platelets or clinical chemistry parameters. Survival without life threatening loss of body weight was significantly prolonged in 4 weeks interval group compared to single injection group (p<0.05 for SKOV-3 animals and in 2 weeks interval group compared with the 4-5 days interval groups (p<0.05 for SKBR-3 animals. CONCLUSIONS/SIGNIFICANCE: The same concentration of radioactivity split into several fractions may improve toxicity of (227Th-radioimmunotherapy while the therapeutic effect is maintained. Thus, it might be possible to increase the cumulative absorbed radiation dose

  8. The utility of fecal corticosterone metabolites and animal welfare assessment protocols as predictive parameters of tumor development and animal welfare in a murine xenograft model

    DEFF Research Database (Denmark)

    Jacobsen, Kirsten Rosenmaj; Jørgensen, Pernille Schønning; Pipper, Christian Bressen;

    2013-01-01

    The aim of the present study was to evaluate the utility of various non-invasive parameters for the prediction of tumor development and animal welfare in a murine xenograft model in male C.B-17 SCID (C.B-Igh-1(b)/IcrTac-Prkdc(scid)) mice. The study showed that body weight, food and water...

  9. Abrogation of STAT3 signaling cascade by zerumbone inhibits proliferation and induces apoptosis in renal cell carcinoma xenograft mouse model.

    Science.gov (United States)

    Shanmugam, Muthu K; Rajendran, Peramaiyan; Li, Feng; Kim, Chulwon; Sikka, Sakshi; Siveen, Kodappully Sivaraman; Kumar, Alan Prem; Ahn, Kwang Seok; Sethi, Gautam

    2015-10-01

    Persistent activation of signal transducer and activator of transcription 3 (STAT3) is one of the characteristic features of renal cell carcinoma (RCC) and often linked to its deregulated proliferation, survival, and angiogenesis. In the present report, we investigated whether zerumbone, a sesquiterpene, exerts its anticancer effect through modulation of STAT3 activation pathway. The pharmacological effect of zerumbone on STAT3 activation, associated protein kinases and phosphatase, and apoptosis was investigated using both RCC cell lines and xenograft mouse model. We observed that zerumbone suppressed STAT3 activation in a dose- and time-dependent manner in RCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c-Src, Janus-activated kinase 1, and Janus-activated kinase 2. Pervanadate treatment reversed zerumbone-induced downregulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that zerumbone induced the expression of tyrosine phosphatase SHP-1 that correlated with its ability to inhibit STAT3 activation. Interestingly, deletion of SHP-1 gene by siRNA abolished the ability of zerumbone to inhibit STAT3 activation. The inhibition of STAT3 activation by zerumbone also caused the suppression of the gene products involved in proliferation, survival, and angiogenesis. Finally, when administered i.p., zerumbone inhibited STAT3 activation in tumor tissues and the growth of human RCC xenograft tumors in athymic nu/nu mice without any side effects. Overall, our results suggest for the first time that zerumbone is a novel blocker of STAT3 signaling cascade and thus has an enormous potential for the treatment of RCC and other solid tumors. PMID:24797723

  10. The Effects of Vandetanib on Paclitaxel Tumor Distribution and Antitumor Activity in a Xenograft Model of Human Ovarian Carcinoma

    Directory of Open Access Journals (Sweden)

    Marta Cesca

    2009-11-01

    Full Text Available This study was designed to determine the effects of vandetanib, a small-molecule receptor tyrosine kinase inhibitor of vascular endothelial growth factor and epidermal growth factor receptor, on paclitaxel (PTX tumor distribution and antitumor activity in xenograft models of human ovarian carcinoma. Nude mice bearing A2780-1A9 xenografts received daily (5, 10, or 15 days doses of vandetanib (50 mg/kg per os, combined with PTX (20 mg/kg intravenously. Morphologic and functional modifications associated with the tumor vasculature (CD31 and α-smooth muscle actin staining and Hoechst 33342 perfusion and PTX concentrations in plasma and tumor tissues were analyzed. Activity was evaluated as inhibition of tumor growth subcutaneously and spreading into the peritoneal cavity. Vandetanib treatment produced no significant change in tumor vessel density, although a reduced number of large vessels, an increased percentage of mature vessels, and diminished tumor perfusion were evident. Pretreatment with vandetanib led to decreased tumor PTX levels within 1 hour of PTX injection, although 24 hours later, tumor PTX levels were comparable with controls. In efficacy studies, the combination of vandetanib plus PTX improved antitumor activity compared with vandetanib or PTX alone, with greater effects being obtained when PTX was administered before vandetanib. The combination of PTX plus vandetanib reduced tumor burden in the peritoneal cavity of mice and significantly increased their survival. Analysis of vascular changes and PTX tumor uptake in vandetanib-treated tumors may help to guide the scheduling of vandetanib plus PTX combinations and may have implications for the design of clinical trials with these drugs.

  11. Chick embryo xenograft model reveals a novel perineural niche for human adipose-derived stromal cells

    Directory of Open Access Journals (Sweden)

    Ingrid R. Cordeiro

    2015-09-01

    Full Text Available Human adipose-derived stromal cells (hADSC are a heterogeneous cell population that contains adult multipotent stem cells. Although it is well established that hADSC have skeletal potential in vivo in adult organisms, in vitro assays suggest further differentiation capacity, such as into glia. Thus, we propose that grafting hADSC into the embryo can provide them with a much more instructive microenvironment, allowing the human cells to adopt diverse fates or niches. Here, hADSC spheroids were grafted into either the presumptive presomitic mesoderm or the first branchial arch (BA1 regions of chick embryos. Cells were identified without previous manipulations via human-specific Alu probes, which allows efficient long-term tracing of heterogeneous primary cultures. When grafted into the trunk, in contrast to previous studies, hADSC were not found in chondrogenic or osteogenic territories up to E8. Surprisingly, 82.5% of the hADSC were associated with HNK1+ tissues, such as peripheral nerves. Human skin fibroblasts showed a smaller tropism for nerves. In line with other studies, hADSC also adopted perivascular locations. When grafted into the presumptive BA1, 74.6% of the cells were in the outflow tract, the final goal of cardiac neural crest cells, and were also associated with peripheral nerves. This is the first study showing that hADSC could adopt a perineural niche in vivo and were able to recognize cues for neural crest cell migration of the host. Therefore, we propose that xenografts of human cells into chick embryos can reveal novel behaviors of heterogeneous cell populations, such as response to migration cues.

  12. Integrated genomics of ovarian xenograft tumor progression and chemotherapy response

    International Nuclear Information System (INIS)

    Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c. In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth. These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival. We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We propose that a combination of regulated expression and copy number

  13. Integrated genomics of ovarian xenograft tumor progression and chemotherapy response

    Directory of Open Access Journals (Sweden)

    Raphael Benjamin J

    2011-07-01

    Full Text Available Abstract Background Ovarian cancer is the most deadly gynecological cancer with a very poor prognosis. Xenograft mouse models have proven to be one very useful tool in testing candidate therapeutic agents and gene function in vivo. In this study we identify genes and gene networks important for the efficacy of a pre-clinical anti-tumor therapeutic, MT19c. Methods In order to understand how ovarian xenograft tumors may be growing and responding to anti-tumor therapeutics, we used genome-wide mRNA expression and DNA copy number measurements to identify key genes and pathways that may be critical for SKOV-3 xenograft tumor progression. We compared SKOV-3 xenografts treated with the ergocalciferol derived, MT19c, to untreated tumors collected at multiple time points. Cell viability assays were used to test the function of the PPARγ agonist, Rosiglitazone, on SKOV-3 cell growth. Results These data indicate that a number of known survival and growth pathways including Notch signaling and general apoptosis factors are differentially expressed in treated vs. untreated xenografts. As tumors grow, cell cycle and DNA replication genes show increased expression, consistent with faster growth. The steroid nuclear receptor, PPARγ, was significantly up-regulated in MT19c treated xenografts. Surprisingly, stimulation of PPARγ with Rosiglitazone reduced the efficacy of MT19c and cisplatin suggesting that PPARγ is regulating a survival pathway in SKOV-3 cells. To identify which genes may be important for tumor growth and treatment response, we observed that MT19c down-regulates some high copy number genes and stimulates expression of some low copy number genes suggesting that these genes are particularly important for SKOV-3 xenograft growth and survival. Conclusions We have characterized the time dependent responses of ovarian xenograft tumors to the vitamin D analog, MT19c. Our results suggest that PPARγ promotes survival for some ovarian tumor cells. We

  14. New peptide receptor radionuclide therapy of invasive cancer cells: in vivo studies using 177Lu-DOTA-AE105 targeting uPAR in human colorectal cancer xenografts

    DEFF Research Database (Denmark)

    Persson, Morten; Rasmussen, Palle; Madsen, Jacob;

    2012-01-01

    animals were treated day 0 and 7. A parallel 18F-FLT PET/CT study was performed on day 0, 1, 3 and 6. Dosimetry calculations were based on a biodistribution study, where organs and tissue of interest were collected 0.5, 1.0, 2.0, 4.0 and 24h post injection of 177Lu-DOTA-AE105. Toxicity was assessed by...... theranostic approach as treatment modality in a human xenograft colorectal cancer model. MethodsA DOTA-conjugated 9-mer high affinity uPAR binding peptide (DOTA-AE105) was radiolabeled with 64Cu and 177Lu, for PET imaging and targeted radionuclide therapy study, respectively. Human uPAR-positive CRC HT-29...... cells were inoculated in Nude mice and treated with 177Lu-DOTA-AE105 once a visible tumor had formed. To evaluate the true effect of the targeted radiotherapy, two controls groups were included in this study, one receiving a 177Lu-labeled non-binding control peptide and one receiving vehicle. All...

  15. Reproducibility study of [{sup 18}F]FPP(RGD){sub 2} uptake in murine models of human tumor xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Edwin; Liu, Shuangdong; Chin, Frederick; Cheng, Zhen [Stanford University, Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford, CA (United States); Gowrishankar, Gayatri; Yaghoubi, Shahriar [Stanford University, Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford, CA (United States); Stanford University, Molecular Imaging Program at Stanford, Department of Bioengineering, School of Medicine, Stanford, CA (United States); Wedgeworth, James Patrick [Stanford University, Molecular Imaging Program at Stanford, Department of Bioengineering, School of Medicine, Stanford, CA (United States); Berndorff, Dietmar; Gekeler, Volker [Bayer Schering Pharma AG, Global Drug Discovery, Berlin (Germany); Gambhir, Sanjiv S. [Stanford University, Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford, CA (United States); Stanford University, Molecular Imaging Program at Stanford, Department of Bioengineering, School of Medicine, Stanford, CA (United States); Canary Center at Stanford for Cancer Early Detection, Nuclear Medicine, Departments of Radiology and Bioengineering, Molecular Imaging Program at Stanford, Stanford, CA (United States)

    2011-04-15

    An {sup 18}F-labeled PEGylated arginine-glycine-aspartic acid (RGD) dimer [{sup 18}F]FPP(RGD){sub 2} has been used to image tumor {alpha}{sub v}{beta}{sub 3} integrin levels in preclinical and clinical studies. Serial positron emission tomography (PET) studies may be useful for monitoring antiangiogenic therapy response or for drug screening; however, the reproducibility of serial scans has not been determined for this PET probe. The purpose of this study was to determine the reproducibility of the integrin {alpha}{sub v}{beta}{sub 3}-targeted PET probe, [{sup 18}F ]FPP(RGD){sub 2} using small animal PET. Human HCT116 colon cancer xenografts were implanted into nude mice (n = 12) in the breast and scapular region and grown to mean diameters of 5-15 mm for approximately 2.5 weeks. A 3-min acquisition was performed on a small animal PET scanner approximately 1 h after administration of [{sup 18}F]FPP(RGD){sub 2} (1.9-3.8 MBq, 50-100 {mu}Ci) via the tail vein. A second small animal PET scan was performed approximately 6 h later after reinjection of the probe to assess for reproducibility. Images were analyzed by drawing an ellipsoidal region of interest (ROI) around the tumor xenograft activity. Percentage injected dose per gram (%ID/g) values were calculated from the mean or maximum activity in the ROIs. Coefficients of variation and differences in %ID/g values between studies from the same day were calculated to determine the reproducibility. The coefficient of variation (mean {+-}SD) for %ID{sub mean}/g and %ID{sub max}/g values between [{sup 18}F]FPP(RGD){sub 2} small animal PET scans performed 6 h apart on the same day were 11.1 {+-} 7.6% and 10.4 {+-} 9.3%, respectively. The corresponding differences in %ID{sub mean}/g and %ID{sub max}/g values between scans were -0.025 {+-} 0.067 and -0.039 {+-} 0.426. Immunofluorescence studies revealed a direct relationship between extent of {alpha}{sub {nu}}{beta}{sub 3} integrin expression in tumors and tumor vasculature

  16. Residual dormant cancer stem-cell foci are responsible for tumor relapse after antiangiogenic metronomic therapy in hepatocellular carcinoma xenografts.

    Science.gov (United States)

    Martin-Padura, Ines; Marighetti, Paola; Agliano, Alice; Colombo, Federico; Larzabal, Leyre; Redrado, Miriam; Bleau, Anne-Marie; Prior, Celia; Bertolini, Francesco; Calvo, Alfonso

    2012-07-01

    Hepatocellular carcinoma (HCC) is the fifth most common solid tumor and the third leading cause of cancer-related deaths. Currently available chemotherapeutic options are not curative due in part to tumor resistance to conventional therapies. We generated orthotopic HCC mouse models in immunodeficient NOD/SCID/IL2rγ null mice by injection of human alpha-feto protein (hAFP)- and/or luciferase-expressing HCC cell lines and primary cells from patients, where tumor growth and spread can be accurately monitored in a non-invasive way. In this model, low-dose metronomic administration of cyclophosphamide (LDM-CTX) caused complete regression of the tumor mass. A significant increase in survival (P<0.0001), reduced aberrant angiogenesis and hyperproliferation, and decrease in the number of circulating tumor cells were found in LDM-CTX-treated animals, in comparison with untreated mice. Co-administration of LDM-CTX with anti-VEGF therapy further improved the therapeutic efficacy. However, the presence of residual circulating hAFP levels suggested that some tumor cells were still present in livers of treated mice. Immunohistochemistry revealed that those cells had a hAFP+/CD13+/PCNA- phenotype, suggesting that they were dormant cancer stem cells (CSC). Indeed, discontinuation of therapy resulted in tumor regrowth. Moreover, in-vitro LDM-CTX treatment reduced hepatosphere formation in both number and size, and the resulting spheres were enriched in CD13+ cells indicating that these cells were particularly resistant to therapy. Co-treatment of the CD13-targeting drug, bestatin, with LDM-CTX leads to slower tumor growth and a decreased tumor volume. Therefore, combining a CD13 inhibitor, which targets the CSC-like population, with LDM-CTX chemotherapy may be used to eradicate minimal residual disease and improve the treatment of liver cancer. PMID:22546866

  17. Intratumoral pharmacokinetic analysis by 19F-magnetic resonance spectroscopy and cytostatic in vivo activity of gemcitabine (dFdC) in two small cell lung cancer xenografts

    DEFF Research Database (Denmark)

    Kristjansen, P E; Quistorff, B; Spang-Thomsen, M;

    1993-01-01

    small cell lung cancer (SCLC) tumor xenografts CPH SCCL 54A and 54B in nude mice. Non-invasive monitoring of the uptake and elimination of fluorine in the individual tumors was performed by in vivo 19F-magnetic resonance spectroscopy, using a 2.9 T magnet. Five dose levels in the range 5-80 mg/kg i...... therapy than 54A. This difference in sensitivity seems to be related to different delivery or uptake of the compound in the two tumor lines, since the 19F-MRS demonstrated a significantly higher antitumor accumulation of fluorine in 54B tumors compared with 54A (p < 0.05, Wilcoxons 2-sided test) following...

  18. Failure of a patient-derived xenograft for brain tumor model prepared by implantation of tissue fragments

    OpenAIRE

    Kim, Kyung-Min; Shim, Jin-Kyoung; Chang, Jong Hee; Lee, Ji-Hyun; Kim, Se-Hoon; Choi, Junjeong; Park, Junseong; Kim, Eui-Hyun; Kim, Sun Ho; Huh, Yong-Min; Lee, Su-Jae; Cheong, Jae-Ho; Kang, Seok-Gu

    2016-01-01

    Background With the continuing development of new anti-cancer drugs comes a need for preclinical experimental models capable of predicting the clinical activity of these novel agents in cancer patients. However existing models have a limited ability to recapitulate the clinical characteristics and associated drug sensitivity of tumors. Among the more promising approaches for improving preclinical models is direct implantation of patient-derived tumor tissue into immunocompromised mice, such a...

  19. Recent Technological Advances in Using Mouse Models to Study Ovarian Cancer

    OpenAIRE

    House, Carrie Danielle; Hernandez, Lidia; Annunziata, Christina Messineo

    2014-01-01

    Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered ...

  20. Peptides Derived from Type IV Collagen, CXC Chemokines, and Thrombospondin-1 Domain-Containing Proteins Inhibit Neovascularization and Suppress Tumor Growth in MDA-MB-231 Breast Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Jacob E. Koskimaki

    2009-12-01

    Full Text Available Angiogenesis or neovascularization, the process of new blood vessel formation from preexisting microvasculature, involves interactions among several cell types including parenchymal, endothelial cells, and immune cells. The formation of new vessels is tightly regulated by a balance between endogenous proangiogenic and antiangiogenic factors to maintain homeostasis in tissue; tumor progression and metastasis in breast cancer have been shown to be angiogenesis-dependent. We previously introduced a systematic methodology to identify putative endogenous antiangiogenic peptides and validated these predictions in vitro in human umbilical vein endothelial cell proliferation and migration assays. These peptides are derived from several protein families including type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins. On the basis of the results from the in vitro screening, we have evaluated the ability of one peptide selected from each family named pentastatin-1, chemokinostatin-1, and properdistatin, respectively, to suppress angiogenesis in an MDA-MB-231 human breast cancer orthotopic xenograft model in severe combined immunodeficient mice. Peptides were administered intraperitoneally once per day. We have demonstrated significant suppression of tumor growth in vivo and subsequent reductions in microvascular density, indicating the potential of these peptides as therapeutic agents for breast cancer.

  1. Anti-tumour activity of oncolytic Western Reserve vaccinia viruses in canine tumour cell lines, xenografts, and fresh tumour biopsies.

    Science.gov (United States)

    Autio, K; Knuuttila, A; Kipar, A; Ahonen, M; Parviainen, S; Diaconu, I; Kanerva, A; Hakonen, T; Vähä-Koskela, M; Hemminki, A

    2014-10-10

    Cancer is one of the most common reasons for death in dogs. One promising approach is oncolytic virotherapy. We assessed the oncolytic effect of genetically modified vaccinia viruses in canine cancer cells, in freshly excised tumour biopsies, and in mice harbouring canine tumour xenografts. Tumour transduction efficacy was assessed using virus expressing luciferase or fluorescent marker genes and oncolysis was quantified by a colorimetric cell viability assay. Oncolytic efficacy in vivo was evaluated in a nude mouse xenograft model. Vaccinia virus was shown to infect most tested canine cancer cell lines and primary surgical tumour tissues. Virus infection significantly reduced tumour growth in the xenograft model. Oncolytic vaccinia virus has antitumour effects against canine cancer cells and experimental tumours and is able to replicate in freshly excised patient tumour tissue. Our results suggest that oncolytic vaccinia virus may offer an effective treatment option for otherwise incurable canine tumours. PMID:25302859

  2. Diffuse large B-cell lymphoma patient-derived xenograft models capture the molecular and biological heterogeneity of the disease.

    Science.gov (United States)

    Chapuy, Bjoern; Cheng, Hongwei; Watahiki, Akira; Ducar, Matthew D; Tan, Yuxiang; Chen, Linfeng; Roemer, Margaretha G M; Ouyang, Jing; Christie, Amanda L; Zhang, Liye; Gusenleitner, Daniel; Abo, Ryan P; Farinha, Pedro; von Bonin, Frederike; Thorner, Aaron R; Sun, Heather H; Gascoyne, Randy D; Pinkus, Geraldine S; van Hummelen, Paul; Wulf, Gerald G; Aster, Jon C; Weinstock, David M; Monti, Stefano; Rodig, Scott J; Wang, Yuzhuo; Shipp, Margaret A

    2016-05-01

    Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined by transcriptional classifications, specific signaling and survival pathways, and multiple low-frequency genetic alterations. Preclinical model systems that capture the genetic and functional heterogeneity of DLBCL are urgently needed. Here, we generated and characterized a panel of large B-cell lymphoma (LBCL) patient-derived xenograft (PDX) models, including 8 that reflect the immunophenotypic, transcriptional, genetic, and functional heterogeneity of primary DLBCL and 1 that is a plasmablastic lymphoma. All LBCL PDX models were subjected to whole-transcriptome sequencing to classify cell of origin and consensus clustering classification (CCC) subtypes. Mutations and chromosomal rearrangements were evaluated by whole-exome sequencing with an extended bait set. Six of the 8 DLBCL models were activated B-cell (ABC)-type tumors that exhibited ABC-associated mutations such as MYD88, CD79B, CARD11, and PIM1. The remaining 2 DLBCL models were germinal B-cell type, with characteristic alterations of GNA13, CREBBP, and EZH2, and chromosomal translocations involving IgH and either BCL2 or MYC Only 25% of the DLBCL PDX models harbored inactivating TP53 mutations, whereas 75% exhibited copy number alterations of TP53 or its upstream modifier, CDKN2A, consistent with the reported incidence and type of p53 pathway alterations in primary DLBCL. By CCC criteria, 6 of 8 DLBCL PDX models were B-cell receptor (BCR)-type tumors that exhibited selective surface immunoglobulin expression and sensitivity to entospletinib, a recently developed spleen tyrosine kinase inhibitor. In summary, we have established and characterized faithful PDX models of DLBCL and demonstrated their usefulness in functional analyses of proximal BCR pathway inhibition. PMID:26773040

  3. Nilotinib and imatinib are comparably effective in reducing growth of human eosinophil leukemia cells in a newly established xenograft model.

    Directory of Open Access Journals (Sweden)

    Daniel Wicklein

    Full Text Available We developed a xenograft model of human Chronic Eosinophilic Leukemia (CEL to study disease progression and remission-induction under therapy with tyrosine kinase inhibitors using imatinib and nilotinib as examples. The FIP1L1/PDGFRA+ human CEL cell lineEOL-1 was injected intravenously into scid mice, and MR imaging and FACS analysis of mouse blood samples were performed to monitor disease development and the effects of imatinib and nilotinib. Organ infiltration was analyzed in detail by immunohistochemistry after sacrifice. All animals developed CEL and within one week of therapy, complete remissions were seen with both imatinib and nilotinib, resulting in reduced total tumor volumes by MR-imaging and almost complete disappearance of EOL-1 cells in the peripheral blood and in tissues. The new model system is feasible for the evaluation of new tyrosine kinase inhibitors and our data suggest that nilotinib may be a valuable additional targeted drug active in patients with FIP1L1/PDGFRA+ CEL.

  4. 5α-reductase inhibition suppresses testosterone-induced initial regrowth of regressed xenograft prostate tumors in animal models.

    Science.gov (United States)

    Masoodi, Khalid Z; Ramos Garcia, Raquel; Pascal, Laura E; Wang, Yujuan; Ma, Hei M; O'Malley, Katherine; Eisermann, Kurtis; Shevrin, Daniel H; Nguyen, Holly M; Vessella, Robert L; Nelson, Joel B; Parikh, Rahul A; Wang, Zhou

    2013-07-01

    Androgen deprivation therapy (ADT) is the standard treatment for patients with prostate-specific antigen progression after treatment for localized prostate cancer. An alternative to continuous ADT is intermittent ADT (IADT), which allows recovery of testosterone during off-cycles to stimulate regrowth and differentiation of the regressed prostate tumor. IADT offers patients a reduction in side effects associated with ADT, improved quality of life, and reduced cost with no difference in overall survival. Our previous studies showed that IADT coupled with 5α-reductase inhibitor (5ARI), which blocks testosterone conversion to DHT could prolong survival of animals bearing androgen-sensitive prostate tumors when off-cycle duration was fixed. To further investigate this clinically relevant observation, we measured the time course of testosterone-induced regrowth of regressed LuCaP35 and LNCaP xenograft tumors in the presence or absence of a 5ARI. 5α-Reductase inhibitors suppressed the initial regrowth of regressed prostate tumors. However, tumors resumed growth and were no longer responsive to 5α-reductase inhibition several days after testosterone replacement. This finding was substantiated by bromodeoxyuridine and Ki67 staining of LuCaP35 tumors, which showed inhibition of prostate tumor cell proliferation by 5ARI on day 2, but not day 14, after testosterone replacement. 5α-Reductase inhibitors also suppressed testosterone-stimulated proliferation of LNCaP cells precultured in androgen-free media, suggesting that blocking testosterone conversion to DHT can inhibit prostate tumor cell proliferation via an intracrine mechanism. These results suggest that short off-cycle coupled with 5α-reductase inhibition could maximize suppression of prostate tumor growth and, thus, improve potential survival benefit achieved in combination with IADT. PMID:23671262

  5. Imaging small human prostate cancer xenografts after pretargeting with bispecific bombesin-antibody complexes and targeting with high specific radioactivity labeled polymer-drug conjugates

    Energy Technology Data Exchange (ETDEWEB)

    Patil, Vishwesh; Gada, Keyur; Panwar, Rajiv; Ferris, Craig; Khaw, Ban-An [Northeastern University, School of Pharmacy, Department of Pharmaceutical Sciences, Boston, MA (United States); Varvarigou, Alexandra [Institute of Radioisotopes and Radiodiagnostics, National Centre for Scientific Research ' ' Demokritos' ' , Athens (Greece); Majewski, Stan [West Virginia University, Department of Radiology, Nuclear Medicine Imaging Instrumentation Program, Center for Advanced Imaging, Morgantown, WV (United States); Weisenberger, Andrew [Jefferson LA, Thomas Jefferson National Accelerator Facility, Newport News, VA (United States); Tekabe, Yared [Columbia University Medical Center, New York, NY (United States)

    2012-05-15

    Pretargeting with bispecific monoclonal antibodies (bsMAb) for tumor imaging was developed to enhance target to background activity ratios. Visualization of tumors was achieved by the delivery of mono- and divalent radiolabeled haptens. To improve the ability to image tumors with bsMAb, we have combined the pretargeting approach with targeting of high specific activity radiotracer labeled negatively charged polymers. The tumor antigen-specific antibody was replaced with bombesin (Bom), a ligand that binds specifically to the growth receptors that are overexpressed by many tumors including prostate cancer. Bom-anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody complexes were used to demonstrate pretargeting and imaging of very small human prostate cancer xenografts targeted with high specific activity {sup 111}In- or {sup 99m}Tc-labeled negatively charged polymers. Bispecific antibody complexes consisting of intact anti-DTPA antibody or Fab' linked to Bom via thioether bonds (Bom-bsCx or Bom-bsFCx, respectively) were used to pretarget PC-3 human prostate cancer xenografts in SCID mice. Negative control mice were pretargeted with Bom or anti-DTPA Ab. {sup 111}In-Labeled DTPA-succinyl polylysine (DSPL) was injected intravenously at 24 h (7.03 {+-} 1.74 or 6.88 {+-} 1.89 MBq {sup 111}In-DSPL) after Bom-bsCx or 50 {+-} 5.34 MBq of {sup 99m}Tc-DSPL after Bom-bsFCx pretargeting, respectively. Planar or single photon emission computed tomography (SPECT)/CT gamma images were obtained for up to 3 h and only planar images at 24 h. After imaging, all mice were killed and biodistribution of {sup 111}In or {sup 99m}Tc activities were determined by scintillation counting. Both planar and SPECT/CT imaging enabled detection of PC-3 prostate cancer lesions less than 1-2 mm in diameter in 1-3 h post {sup 111}In-DSPL injection. No lesions were visualized in Bom or anti-DTPA Ab pretargeted controls. {sup 111}In-DSPL activity in Bom-bsCx pretargeted tumors (1

  6. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity 86Y- or 177Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

    International Nuclear Information System (INIS)

    GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex. PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens 177Lu-or 86Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq 177Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm3) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm3 tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten 86Y-DOTA-Bn. We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. (orig.)

  7. Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity {sup 86}Y- or {sup 177}Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

    Energy Technology Data Exchange (ETDEWEB)

    Cheal, Sarah M.; Lee, Sang-gyu; Punzalan, Blesida; Larson, Steven M. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Xu, Hong; Guo, Hong-fen [Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, NY (United States); Chalasani, Sandhya; Carrasquillo, Jorge A. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Fung, Edward K. [Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Jungbluth, Achim [Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, NY (United States); Zanzonico, Pat B.; O' Donoghue, Joseph [Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Smith-Jones, Peter M. [Stony Brook University, Department of Psychiatry and Behavioral Science, Stony Brook, NY (United States); Stony Brook University, Department of Radiology, Stony Brook, NY (United States); Wittrup, K.D. [Massachusetts Institute of Technology, Department of Chemical Engineering, Cambridge, MA (United States); Massachusetts Institute of Technology, Department of Biological Engineering, Cambridge, MA (United States); Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Cambridge, MA (United States); Cheung, Nai-Kong V. [Memorial Sloan Kettering Cancer Center, Molecular Pharmacology and Chemistry Program, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Department of Pediatrics, New York, NY (United States)

    2016-05-15

    GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex. PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens {sup 177}Lu-or {sup 86}Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model. Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq {sup 177}Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm{sup 3}) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm{sup 3} tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten {sup 86}Y-DOTA-Bn. We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts. (orig.)

  8. Human skeletal muscle xenograft as a new preclinical model for muscle disorders

    OpenAIRE

    Zhang, Yuanfan; King, Oliver D.; Rahimov, Fedik; Jones, Takako I; Ward, Christopher W.; Kerr, Jaclyn P.; Liu, Naili; Emerson, Charles P.; Kunkel, Louis M; Partridge, Terence A.; Wagner, Kathryn R.

    2014-01-01

    Development of novel therapeutics requires good animal models of disease. Disorders for which good animal models do not exist have very few drugs in development or clinical trial. Even where there are accepted, albeit imperfect models, the leap from promising preclinical drug results to positive clinical trials commonly fails, including in disorders of skeletal muscle. The main alternative model for early drug development, tissue culture, lacks both the architecture and, usually, the metaboli...

  9. Monitoring of tumor growth and metastasis potential in MDA-MB-435s/tk-luc human breast cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Y.-F. [Department of Radiological Sciences, National Yang-Ming University, 155, Sec. 2, Li-Nong Street, Pei-tou 112, Taipei, Taiwan (China); Lin, Y.-Y. [Department of Radiological Sciences, National Yang-Ming University, 155, Sec. 2, Li-Nong Street, Pei-tou 112, Taipei, Taiwan (China); Wang, H.-E. [Department of Radiological Sciences, National Yang-Ming University, 155, Sec. 2, Li-Nong Street, Pei-tou 112, Taipei, Taiwan (China); Liu, R.-S. [Department of Nuclear Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Nuclear Medicine Department, Veterans General Hospital, Taipei, Taiwan (China); Pang Fei [Department of Veterinary Medicine, National Taiwan University, Taipei, Taiwan (China); Hwang, J.-J. [Department of Radiological Sciences, National Yang-Ming University, 155, Sec. 2, Li-Nong Street, Pei-tou 112, Taipei, Taiwan (China)]. E-mail: jjhwang@ym.edu.tw

    2007-02-01

    Molecular imaging of reporter gene expression provides a rapid, sensitive and non-invasive monitoring of tumor behaviors. In this study, we reported the establishment of a novel animal model for longitudinal examination of tumor growth kinetics and metastatic spreading in vivo. The highly metastatic human breast carcinoma MDA-MB-435s cell line was engineered to stably express herpes simplex virus type 1 thymidine kinase (HSV-1-tk) and luciferase (luc). Both {sup 131}I-FIAU and D-luciferin were used as reporter probes. For orthotopic tumor formation, MDA-MB-435s/tk-luc cells were implanted into the first nipple of 6-week-old female NOD/SCID mice. For metastatic study, cells were injected via the lateral tail vein. Mice-bearing MDA-MB-435s/tk-luc tumors were scanned for tumor growth and metastatsis using Xenogen IVIS50 system. Gamma scintigraphy and whole-body autoradiography were also applied to confirm the tumor localization. The results of bioluminescence imaging as well as histopathological finding showed that tumors could be detected in femur, spine, ovary, lungs, kidney, adrenal gland, lymph nodes and muscle at 16 weeks post i.v. injection, and correlated photons could be quantified. This MDA-MB-435s/tk-luc human breast carcinoma-bearing mouse model combined with multimodalities of molecular imaging may facilitate studies on the molecular mechanisms of cancer invasion and metastasis.

  10. Monitoring of tumor growth and metastasis potential in MDA-MB-435s/ tk-luc human breast cancer xenografts

    Science.gov (United States)

    Chang, Ya-Fang; Lin, Yi-Yu; Wang, Hsin-Ell; Liu, Ren-Shen; Pang, Fei; Hwang, Jeng-Jong

    2007-02-01

    Molecular imaging of reporter gene expression provides a rapid, sensitive and non-invasive monitoring of tumor behaviors. In this study, we reported the establishment of a novel animal model for longitudinal examination of tumor growth kinetics and metastatic spreading in vivo. The highly metastatic human breast carcinoma MDA-MB-435s cell line was engineered to stably express herpes simplex virus type 1 thymidine kinase (HSV-1- tk) and luciferase ( luc). Both 131I-FIAU and D-luciferin were used as reporter probes. For orthotopic tumor formation, MDA-MB-435s/ tk-luc cells were implanted into the first nipple of 6-week-old female NOD/SCID mice. For metastatic study, cells were injected via the lateral tail vein. Mice-bearing MDA-MB-435s/ tk-luc tumors were scanned for tumor growth and metastatsis using Xenogen IVIS50 system. Gamma scintigraphy and whole-body autoradiography were also applied to confirm the tumor localization. The results of bioluminescence imaging as well as histopathological finding showed that tumors could be detected in femur, spine, ovary, lungs, kidney, adrenal gland, lymph nodes and muscle at 16 weeks post i.v. injection, and correlated photons could be quantified. This MDA-MB-435s/ tk-luc human breast carcinoma-bearing mouse model combined with multimodalities of molecular imaging may facilitate studies on the molecular mechanisms of cancer invasion and metastasis.

  11. Artesunate induces oncosis-like cell death in vitro and has antitumor activity against pancreatic cancer xenografts in vivo

    OpenAIRE

    Du, Ji-Hui; Zhang, Hou-De; Ma, Zhen-Jian; Ji, Kun-Mei

    2009-01-01

    Pancreatic cancer is highly resistant to the currently available chemotherapeutic agents. Less than 5% of patients diagnosed with this disease could survive beyond 5 years. Thus, there is an urgent need for the development of novel, efficacious drugs that can treat pancreatic cancer. Herein we report the identification of artesunate (ART), a derivative of artemisinin, as a potent and selective antitumor agent against human pancreatic cancer cells in vitro and in vivo. ART exhibits selective c...

  12. External beam radiotherapy synergizes 188Re-liposome against human esophageal cancer xenograft and modulates 188Re-liposome pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Chang CH

    2015-05-01

    Full Text Available Chih-Hsien Chang,1,2 Shin-Yi Liu,3 Chih-Wen Chi,3 Hsiang-Lin Yu,1 Tsui-Jung Chang,1 Tung-Hu Tsai,4 Te-Wei Lee,1 Yu-Jen Chen3–5 1Isotope Application Division, Institute of Nuclear Energy Research, Taoyuan, Taiwan; 2Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, 3Department of Medical Research MacKay Memorial Hospital, 4Institute of Traditional Medicine, National Yang-Ming University, 5Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan Abstract: External beam radiotherapy (EBRT treats gross tumors and local microscopic diseases. Radionuclide therapy by radioisotopes can eradicate tumors systemically. Rhenium 188 (188Re-liposome, a nanoparticle undergoing clinical trials, emits gamma rays for imaging validation and beta rays for therapy, with biodistribution profiles preferential to tumors. We designed a combinatory treatment and examined its effects on human esophageal cancer xenografts, a malignancy with potential treatment resistance and poor prognosis. Human esophageal cancer cell lines BE-3 (adenocarcinoma and CE81T/VGH (squamous cell carcinoma were implanted and compared. The radiochemical purity of 188Re-liposome exceeded 95%. Molecular imaging by NanoSPECT/CT showed that BE-3, but not CE81T/VGH, xenografts could uptake the 188Re-liposome. The combination of EBRT and 188Re-liposome inhibited tumor regrowth greater than each treatment alone, as the tumor growth inhibition rate was 30% with EBRT, 25% with 188Re-liposome, and 53% with the combination treatment at 21 days postinjection. Combinatory treatment had no additive adverse effects and significant biological toxicities on white blood cell counts, body weight, or liver and renal functions. EBRT significantly enhanced the excretion of 188Re-liposome into feces and urine. In conclusion, the combination of EBRT with 188Re-liposome might be a potential treatment modality for esophageal cancer. Keywords: Radionuclide

  13. Monitoring tumor proliferative response to radiotherapy using 18F-fluorothymidine in human head and neck cancer xenograft in comparison with Ki-67

    International Nuclear Information System (INIS)

    Although radiotherapy is an important treatment strategy for head and neck cancers, it induces tumor repopulation which adversely affects therapeutic outcome. In this regard, fractionated radiotherapy is widely applied to prevent tumor repopulation. Evaluation of tumor proliferative activity using 18F-fluorothymidine (FLT), a noninvasive marker of tumor proliferation, may be useful for determining the optimal timing of and dose in the repetitive irradiation. Thus, to assess the potentials of FLT, we evaluated the sequential changes in intratumoral proliferative activity in head and neck cancer xenografts (FaDu) using FLT. FaDu tumor xenografts were established in nude mice and assigned to control and two radiation-treated groups (10 and 20 Gy). Tumor volume was measured daily. 3H-FLT was injected intravenously 2 h before killing. Mice were killed 6, 24, 48 h, and 7 days after the radiation treatment. Intratumoral 3H-FLT level was visually and quantitatively assessed by autoradiography. Ki-67 immunohistochemistry (IHC) was performed. In radiation-treated mice, the tumor growth was significantly suppressed compared with the control group, but the tumor volume in these mice gradually increased with time. In the visual assessment, intratumoral 3H-FLT level diffusely decreased 6 h after the radiation treatment and then gradually increased with time, whereas no apparent changes were observed in Ki-67 IHC. Six hours after the radiation treatment at 10 and 20 Gy, the intratumoral 3H-FLT level markedly decreased to 45 and 40% of the control, respectively (P3H-FLT levels at 48 h and on day 7 were significantly higher than that at 6 h. The intratumoral 3H-FLT levels in both treated groups were 68 and 60% at 24 h (P<0.001), 71 and 77% at 48 h (P<0.001), and 83 and 81% on day 7 (P=NS) compared with the control group. Intratumoral FLT uptake level markedly decreased at 6 h and then gradually increased with time. Sequential evaluation of intratumoral proliferative activity using

  14. Local Delivery of Cannabinoid-Loaded Microparticles Inhibits Tumor Growth in a Murine Xenograft Model of Glioblastoma Multiforme

    OpenAIRE

    Dolores Hernán Pérez de la Ossa; Mar Lorente; Maria Esther Gil-Alegre; Sofía Torres; Elena García-Taboada; María Del Rosario Aberturas; Jesús Molpeceres; Guillermo Velasco; Ana Isabel Torres-Suárez

    2013-01-01

    Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9)-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral a...

  15. Human primary ductal carcinoma in situ (DCIS) subtype-specific pathology is preserved in a mouse intraductal (MIND) xenograft model

    OpenAIRE

    Valdez, Kelli Elizabeth; Fang, Fan; Smith, William; Allred, D. Craig; Medina, Daniel; Behbod, Fariba

    2011-01-01

    Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. The current recognition that DCIS lesions exhibit inter- and intra-lesion diversity suggests that the process of evolution to invasive breast cancer is more complex than previously recognized. Here we demonstrate the reproducible growth of primary DCIS cells derived from patient’s surgical and biopsy samples by the mouse intraductal (MIND) model. MIND involves injection of cells into the NOD-SCID IL2Rgamman...

  16. Imaging of HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice using {sup 111}In-trastuzumab (Herceptin) Fab fragments

    Energy Technology Data Exchange (ETDEWEB)

    Tang Ying [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 2S2 (Canada); Wang, Judy [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Scollard, Deborah A. [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Mondal, Hridya [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada); Holloway, Claire [Sunnybrook and Women' s College Health Sciences Center, Toronto, Ontario, M4N 3M5 (Canada); Kahn, Harriette J. [Sunnybrook and Women' s College Health Sciences Center, Toronto, Ontario, M4N 3M5 (Canada); Reilly, Raymond M. [Division of Nuclear Medicine, University Health Network, Toronto, Ontario, M5G 2C4 (Canada) and Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, M5S 2S2 (Canada) and Department of Medical Imaging, University of Toronto, Toronto, Ontario, M5S 3E2 (Canada)]. E-mail: raymond.reilly@utoronto.ca

    2005-01-01

    Trastuzumab (Herceptin) Fab were prepared by digestion of intact IgG with immobilized papain, derivatized with diethylenetriaminepentaacetic acid (DTPA) and radiolabeled with {sup 111}In. The dissociation constant (K{sub d}) for binding of Fab to HER2/neu-positive SK-BR-3 human breast cancer cells was two- to threefold higher than for intact IgG (14-36 vs. 8-14 nM). The binding affinity was not significantly decreased after DTPA derivatization (K{sub d}=47 nM). {sup 111}In-trastuzumab Fab localized specifically in HER2/neu-positive BT-474 human breast cancer xenografts in athymic mice with tumor uptake of 7.8{+-}0.7% injected dose (ID)/g and tumor/blood ratio of 25.2{+-}1.6 at 72 h postinjection compared with 2.7{+-}0.7% ID/g and 7.0{+-}0.9 for {sup 111}In-HuM195 anti-CD33 Fab (significantly different, P<.001). Small (3-5 mm in diameter) BT-474 tumors were imaged with {sup 111}In-trastuzumab Fab as early as 24 h postinjection.

  17. CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models

    Science.gov (United States)

    Zhang, Shui-Jun; Zhao, Chen; Qiu, Bin-Song; Gu, Hai-Feng; Hong, Jian-Fei; Cao, Li; Chen, Yu; Xia, Bing; Bi, Qin; Wang, Ya-Ping

    2015-01-01

    Osteosarcoma is the most common bone tumors in children and adolescents. Despite intensive chemotherapy, patients with advanced disease still have a poor prognosis, illustrating the need for alternative therapies. In this study, we explored the use of antibodies that block CD47 with a tumor growth suppressive effect on osteosarcoma. We first found that up-regulation of CD47 mRNA levels in the tumorous tissues from eight patients with osteosarcoma when compared with that in adjacent non-tumorous tissues. Further western-blot (WB) and immunohistochemistry (IHC) demonstrated that CD47 protein level was highly expressed in osteosarcoma compared to normal osteoblastic cells and adjacent non-tumorous tissues. Osteosarcoma cancer stem cell markers staining shown that the majority of CD44+ cells expressed CD47 albeit with different percentages (ranging from 80% to 99%). Furthermore, high CD47 mRNA expression levels were associated with a decreased probability of progression-free and overall survival. In addition, blockade of CD47 by specific Abs suppresses the invasive ability of osteosarcoma tumor cells and further inhibits spontaneous pulmonary metastasis of KRIB osteosarcoma cells in vivo. Finally, CD47 blockade increases macrophage phagocytosis of osteosarcoma tumor cells. In conclusion, our findings demonstrate that CD47 is a critical regulator in the metastasis of osteosarcoma and suggest that targeted inhibition of this antigen by anti-CD47 may be a novel immunotherapeutic approach in the management of this tumor. PMID:26093091

  18. Magnetic Resonance Imaging Identifies Differential Response to Pro-Oxidant Chemotherapy in a Xenograft Model

    Directory of Open Access Journals (Sweden)

    Terry H. Landowski

    2016-06-01

    Full Text Available Induction of oxidative stress is a key component of cancer therapy. Pro-oxidant drugs have been demonstrated to enhance the efficacy of radiotherapy and chemotherapy. An emerging concept is that therapeutic outcomes are dictated by the differential redox buffering reserve in subpopulations of malignant cells, indicating the need for noninvasive biomarkers of tumor redox that can be used for dose identification and response assessment in a longitudinal setting. Magnetic resonance imaging (MRI enhanced with the thiol-binding contrast agent Gd-LC6-SH, and hemodynamic response imaging (HRI in combination with hypercapnia and hyperoxia were investigated as biomarkers of the pharmacodynamics of the small molecule pro-oxidant imexon (IMX. Human multiple myeloma cell lines 8226/S and an IMX-resistant variant, 8226/IM10, were established as contralateral tumors in SCID mice. T1slope, an MRI measure of the washout rate of Gd-LC6-SH, was significantly lower post-IMX therapy in 8226/S tumors compared with vehicle controls, indicating treatment-related oxidization of the tumor microenvironment, which was confirmed by analysis of tumor tissue for thiols. T1slope and ex vivo assays for thiols both indicated a more reduced microenvironment in 8226/IM10 tumors following IMX therapy. HRI with hypercapnia challenge revealed IMX inhibition of vascular dilation in 8226/S tumors but not 8226/IM10 tumors, consistent with decreased immunohistochemical staining for smooth muscle actin in treated 8226/S tumors. MRI enhanced with Gd-LC6-SH, and HRI coupled with a hypercapnic challenge provide noninvasive biomarkers of tumor response to the redox modulator imexon.

  19. Circadian rhythm characteristics of oral squamous cell carcinoma growth in an orthotopic xenograft model

    Directory of Open Access Journals (Sweden)

    Zhao NB

    2013-01-01

    Full Text Available Ningbo Zhao,* Hong Tang,* Kai Yang, Dan Chen Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China*These authors contributed equally to this workBackground: Recent studies show that circadian rhythm changes are closely related to the occurrence and development of various tumors, such as breast, liver, and prostate. However, there are significant differences in circadian rhythm between different tumors. At present, the circadian rhythm characteristics of oral cancer remain unknown. The purpose of this study is to investigate the circadian rhythm characteristics of the in vivo growth of oral squamous cell carcinoma (OSCC.Materials and methods: Thirty-two nude mice were placed under 12-hour light/12-hour dark cycles. The human OSCC cell line BcaCD885 was inoculated in the cheek of nude mice. After 3 weeks, eight mice were sacrificed at four time points, including 4 hours after light onset (HALO, 10 HALO, 16 HALO, and 22 HALO, during a period of 24 hours. The volume of excised tumors was measured and the proliferative index (PI and apoptotic index (AI of tumor cells were determined by flow cytometry. A cosine analysis method was used to determine whether the tumor volume, PI, and AI obeyed a circadian rhythm.Results: There was a significant circadian rhythm in the tumor volume and PI of OSCC cells. For the tumor volume, there were significant differences between the four time points. The peak and trough values of the tumor volume appeared at 3.23 HALO and 15.23 HALO, whereas the peak and trough values of PI appeared at 6.60 HALO and 18.16 HALO, respectively. However, there was no circadian rhythm in the AI of tumor cells, despite significant differences between the four time points.Conclusion: This study demonstrates, for the first time, that the tumor volume and PI of in vivo growing OSCC undergo circadian rhythms. These results support the assertion that time factor should be

  20. Review of Animal Models of Prostate Cancer Bone Metastasis

    Directory of Open Access Journals (Sweden)

    Jessica K. Simmons

    2014-06-01

    Full Text Available Prostate cancer bone metastases are associated with a poor prognosis and are considered incurable. Insight into the formation and growth of prostate cancer bone metastasis is required for development of new imaging and therapeutic strategies to combat this devastating disease. Animal models are indispensable in investigating cancer pathogenesis and evaluating therapeutics. Multiple animal models of prostate cancer bone metastasis have been developed, but few effectively model prostatic neoplasms and osteoblastic bone metastases as they occur in men. This review discusses the animal models that have been developed to investigate prostate cancer bone metastasis, with a focus on canine models and also includes human xenograft and rodent models. Adult dogs spontaneously develop benign prostatic hyperplasia and prostate cancer with osteoblastic bone metastases. Large animal models, such as dogs, are needed to develop new molecular imaging tools and effective focal intraprostatic therapy. None of the available models fully reflect the metastatic disease seen in men, although the various models have provided important insight into the metastatic process. As additional models are developed and knowledge from the different models is combined, the molecular mechanisms of prostate cancer bone metastasis can be deciphered and targeted for development of novel therapies and molecular diagnostic imaging.

  1. The resistance of delayed xenograft rejection to alpha(1,3)-galactosyltransferase gene inactivation and CD4 depletion in a mouse-to-rat model

    DEFF Research Database (Denmark)

    Hansen, Alastair B; Kirkeby, Svend; Aasted, Bent; Dahl, Kirsten; Hansen, Axel Kornerup; Dieperink, Hans; Kemp, Ejvind; Buschard, Karsten; D'Apice, Anthony J F

    2003-01-01

    Critical to the prevention of xenograft loss is the prevention of delayed xenograft rejection (DXR), due to its resistance to conventional immunosuppression. The role of the carbohydrate galactose-alpha1,3-galactose (alpha1,3Gal) has been a matter of great debate and it has been proposed that the......), generated by alpha1,3-galacto-syltransferase gene disruption, were transplanted to anti-alpha1,3Gal antibody-free Lew/Mol rats. This model consists of an alpha1,3Gal/alpha1,3Gal-antibody-free environment, eliminating a possible influence of this specific system on DXR. A subgroup of recipients were...... furthermore CD4 depleted in order to inhibit CD4-dependent B-cell antibody production. Rejected hearts were evaluated by light- and immunofluorescence microscopy. Treatment effects on recipient T-cell subsets and cytokine expression were analyzed by flow cytometry, while antibody production was measured by...

  2. The Influence of Tissue Ischemia Time on RNA Integrity and Patient-Derived Xenografts (PDX Engraftment Rate in a Non-Small Cell Lung Cancer (NSCLC Biobank.

    Directory of Open Access Journals (Sweden)

    Francesco Guerrera

    Full Text Available Bio-repositories are invaluable resources to implement translational cancer research and clinical programs. They represent one of the most powerful tools for biomolecular studies of clinically annotated cohorts, but high quality samples are required to generate reliable molecular readouts and functional studies. The objective of our study was to define the impact of cancer tissue ischemia time on RNA and DNA quality, and for the generation of Patient-Derived Xenografts (PDXs.One-hundred thirty-five lung cancer specimens were selected among our Institutional BioBank samples. Associations between different warm (surgical and cold (ex-vivo ischemia time ranges and RNA quality or PDXs engraftment rates were assessed. RNA quality was determined by RNA integrity number (RINs values. Fresh viable tissue fragments were implanted subcutaneously in NSG mice and serially transplanted.RNAs with a RIN>7 were detected in 51% of the sample (70/135, with values of RIN significantly lower (OR 0.08, P = 0.01 in samples preserved for more than 3 hours before cryopreservation. Higher quality DNA samples had a concomitant high RIN. Sixty-three primary tumors (41 adenocarcinoma were implanted with an overall engraftment rate of 33%. Both prolonged warm (>2 hours and ex-vivo ischemia time (>10 hours were associated to a lower engraftment rate (OR 0.09 P = 0.01 and OR 0.04 P = 0.008, respectively.RNA quality and PDXs engraftment rate were adversely affected by prolonged ischemia times. Proper tissue collection and processing reduce failure rate. Overall, NSCLC BioBanking represents an innovative modality, which can be successfully executed in routine clinical settings, when stringent Standard Operating Procedures are adopted.

  3. Lutetium-177-G250 radioimmunotherapy in an intraperitoneal clear cell renal cell carcinoma xenograft model

    International Nuclear Information System (INIS)

    Full text of publication follows. Aim: Despite the good results achieved with agents targeting the VEGF and mTOR pathways, the treatment of advanced clear cell renal cell carcinoma (ccRCC) still poses a great challenge. A new approach in the treatment of ccRCC is radioimmunotherapy (RIT) using anti-carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with Lutetium-177 (Lu177) labeled G250, we conducted protein dose escalation study and subsequently a RIT study with Lu177-G250 in an intraperitoneal ccRCC mouse model. Materials and methods: 25 athymic female BALB/c mice were injected intraperitoneally with 3 x 106 SK-RC-52 cells. To determine the optimal G250 protein dose, 3 weeks after inoculation the mice were injected with either 1, 3, 10, 30 or 100 μg G250 radiolabeled with 15 MBq indium-111 (In111). SPECT/CT images were made with the micro SPECT USPECT II camera 48 hours p.i. After imaging, the mice are killed and the biodistribution of In111-G250 was determined. The optimal protein dose was used in a subsequent therapy experiment in 3 groups of mice with i.p. SK-RC-52 tumors. One group (n=10) was injected with 13 MBq Lu177-G250, a control group received nonspecific antibody MOPC21 labeled with 13 MBq Lu177 (n=10) and the second control group received 20 MBq In111-G250 (n=10). Tumor growth was monitored with SPECT/CT imaging before treatment and with 3 week intervals. Primary endpoints were overall survival and toxicity. Results: The optimal G250 protein dose to target ccRCC in this model was 10 μg G250, as determined with SPECT/CT imaging and biodistribution. Treatment with 13 MBq Lu177-G250 was well tolerated. Treatment with Lu177-G250 resulted in significantly prolonged median survival of 139 days, in comparison with 49 days (Lu177-MOPC21) and 53 days In111-G250 (p=0.015). Conclusion: this is the first RIT study with radiolabeled G250 protein in mice with i.p. growing ccRCC. Treatment with Lu177-G250 resulted in significantly

  4. Platelets are associated with xenograft tumor growth and the clinical malignancy of ovarian cancer through an angiogenesis-dependent mechanism.

    Science.gov (United States)

    Yuan, Lei; Liu, Xishi

    2015-04-01

    Platelets are known to facilitate tumor metastasis and thrombocytosis has been associated with an adverse prognosis in ovarian cancer. However, the role of platelets in primary tumour growth remains to be elucidated. The present study demonstrated that the expression levels of various markers in platelets, endothelial adherence and angiogenesis, including, platelet glycoprotein IIb (CD41), platelet endothelial cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), lysyl oxidase, focal adhesion kinase and breast cancer anti‑estrogen resistance 1, were expressed at higher levels in patients with malignant carcinoma, compared with those with borderline cystadenoma and cystadenoma. In addition, the endothelial markers CD31 and VEGF were found to colocalize with the platelet marker CD41 in the malignant samples. Since mice transplanted with human ovarian cancer cells (SKOV3) demonstrated elevated tumor size and decreased survival rate when treated with thrombin or thrombopoietin (TPO), the platelets appeared to promote primary tumor growth. Depleting platelets using antibodies or by pretreating the cancer cells with hirudin significantly attenuated the transplanted tumor growth. The platelets contributed to late, but not early stages of tumor proliferation, as mice treated with platelet‑depleting antibody 1 day prior to and 11 days after tumor transplantation had the same tumor volumes. By contrast, tumor size in the early TPO‑injected group was increased significantly compared with the late TPO‑injected group. These findings suggested that the interplay between platelets and angiogenesis may contribute to ovarian cancer growth. Therefore, platelets and their associated signaling and adhesive molecules may represent potential therapeutic targets for ovarian cancer. PMID:25502723

  5. Magnetic Nanoparticle-Based Hyperthermia for Head & Neck Cancer in Mouse Models

    OpenAIRE

    Zhao, Qun; Wang, Luning; Cheng, Rui; Mao, Leidong; Arnold, Robert D.; Howerth, Elizabeth W.; Chen, Zhuo G; Platt, Simon

    2012-01-01

    In this study, magnetic iron oxide nanoparticle induced hyperthermia is applied for treatment of head and neck cancer using a mouse xenograft model of human head and neck cancer (Tu212 cell line). A hyperthermia system for heating iron oxide nanoparticles was developed by using alternating magnetic fields. Both theoretical simulation and experimental studies were performed to verify the thermotherapy effect. Experimental results showed that the temperature of the tumor center has dramatically...

  6. Radiosensitivity of small-cell lung cancer xenografts compared with activity of c-myc, N-myc, L-myc, c-raf-1 and K-ras proto-oncogenes

    DEFF Research Database (Denmark)

    Rygaard, K; Slebos, R J; Spang-Thomsen, M

    1991-01-01

    Oncogenes of the myc family c-raf-1 and K-ras have been reported to modulate radiosensitivity. We examined the possible relationship between in vivo radiosensitivity to single-dose irradiation with 3-10 Gy, and activity of these proto-oncogenes in 2 sets of small-cell lung cancer (SCLC) xenografts......-19 expressed identical amounts of c-raf-1 and high levels of c-myc mRNA, but neither expressed N-myc or L-myc. None of the tumours was mutated at codon 12 or K-ras. Our results show that SCLC xenografts with different radiosensitivity may express identical amounts of some of the proto-oncogenes...... reported to modulate radiosensitivity. Thus, factors other than activation of the examined proto-oncogenes must be involved in causing the differences in radiosensitivity found in the SCLC xenografts. Possible long-term effects of irradiation on proto-oncogene expression was examined in xenografts of GLC...

  7. Preliminary evaluation of 1′-[18F]fluoroethyl-β-D-lactose ([18F]FEL) for detection of pancreatic cancer in nude mouse orthotopic xenografts

    International Nuclear Information System (INIS)

    Introduction: Early detection of pancreatic cancer could save many thousands of lives. Non-invasive diagnostic imaging, including PET with [18F]FDG, has inadequate resolution for detection of small (2–3 mm) pancreatic tumours. We demonstrated the efficacy of PET imaging with an 18F-labelled lactose derivative, [18F]FEDL, that targets HIP/PAP, a biomarker that is overexpressed in the peritumoural pancreas. We developed another analogue, 1-[18F]fluoroethyl lactose ([18F]FEL), which is simpler to synthesise, for the same application. We conducted a preliminary evaluation of the new probe and its efficacy in detecting orthotopic pancreatic carcinoma xenografts in mice. Methods: Xenografts were developed in nude mice by injecting L3.6pl/GL+ pancreatic carcinoma cells into the pancreas of each mouse. Tumour growth was monitored by bioluminescence imaging (BLI); accuracy of BLI tumour size estimates was verified by MRI in two representative mice. When the tumour size reached approximately 2–3 mm, the animals were injected with [18F]FEL (3.7 MBq) and underwent static PET/CT scans. Blood samples were collected at 2, 5, 10, 20 and 60 min after [18F]FEL injection to track blood clearance. Following imaging, animals were sacrificed and their organs and tumours/pancreatic tissue were collected and counted on a gamma counter. Pancreas, including tumour, was frozen, sliced and used for autoradiography and immunohistochemical analysis of HIP/PAP expression. Results: Tumour growth was rapid, as observed by BLI and MRI. Blood clearance of [18F]FEL was bi-exponential, with half-lives of approximately 3.5 min and 40 min. Mean accumulation of [18F]FEL in the peritumoural pancreatic tissue was 1.29 ± 0.295 %ID/g, and that in the normal pancreas of control animals was 0.090 ± 0.101 %ID/g. [18F]FEL was cleared predominantly by the kidneys. Comparative analysis of autoradiographic images and immunostaining results demonstrated a correlation between [18F]FEL binding and HIP

  8. Lactaptin induces p53-independent cell death associated with features of apoptosis and autophagy and delays growth of breast cancer cells in mouse xenografts.

    Directory of Open Access Journals (Sweden)

    Olga A Koval

    Full Text Available Lactaptin, the proteolytic fragment of human milk kappa-casein, induces the death of various cultured cancer cells. The mechanisms leading to cell death after lactaptin treatment have not been well characterized. In this study the in vivo and in vitro effects of a recombinant analogue of lactaptin (RL2 were examined. Following treatment with the recombinant analogue of lactaptin strong caspase -3, -7 activation was detected. As a consequence of caspase activation we observed the appearance of a sub-G1 population of cells with subdiploid DNA content. Dynamic changes in the mRNA and protein levels of apoptosis-related genes were estimated. No statistically reliable differences in p53 mRNA level or protein level were found between control and RL2-treated cells. We observed that RL2 constitutively suppressed bcl-2 mRNA expression and down regulated Bcl-2 protein expression in MDA-MB-231 cells. We demonstrated that RL2 penetrates cancer and non-transformed cells. Identification of the cellular targets of the lactaptin analogue revealed that α/β-tubulin and α-actinin-1 were RL2-bound proteins. As the alteration in cellular viability in response to protein stimulus can be realized not only by way of apoptosis but also by autophagy, we examined the implications of autophagy in RL2-dependent cell death. We also found that RL2 treatment induces LC3-processing, which is a hallmark of autophagy. The autophagy inhibitor chloroquine enhanced RL2 cytotoxicity to MDA-MB-231 cells, indicating the pro-survival effect of RL2-dependent autophagy. The antitumour potential of RL2 was investigated in vivo in mouse xenografts bearing MDA-MB-231 cells. We demonstrated that the recombinant analogue of lactaptin significantly suppressed the growth of solid tumours. Our results indicate that lactaptin could be a new molecule for the development of anticancer drugs.

  9. Human Adipose Tissue-Derived Stromal/Stem Cells Promote Migration and Early Metastasis of Triple Negative Breast Cancer Xenografts

    OpenAIRE

    Rowan, Brian G.; Gimble, Jeffrey M; Sheng, Mei; Anbalagan, Muralidharan; Jones, Ryan K.; Frazier, Trivia P.; Asher, Majdouline; Lacayo, Eduardo A.; Friedlander, Paul L; Kutner, Robert; Chiu, Ernest S.

    2014-01-01

    Background Fat grafting is used to restore breast defects after surgical resection of breast tumors. Supplementing fat grafts with adipose tissue-derived stromal/stem cells (ASCs) is proposed to improve the regenerative/restorative ability of the graft and retention. However, long term safety for ASC grafting in proximity of residual breast cancer cells is unknown. The objective of this study was to determine the impact of human ASCs derived from abdominal lipoaspirates of three donors, on a ...

  10. Platelets are associated with xenograft tumor growth and the clinical malignancy of ovarian cancer through an angiogenesis-dependent mechanism

    OpenAIRE

    Yuan, Lei; Liu, Xishi

    2014-01-01

    Platelets are known to facilitate tumor metastasis and thrombocytosis has been associated with an adverse prognosis in ovarian cancer. However, the role of platelets in primary tumour growth remains to be elucidated. The present study demonstrated that the expression levels of various markers in platelets, endothelial adherence and angiogenesis, including, platelet glycoprotein IIb (CD41), platelet endothelial cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), lysyl o...

  11. Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kaylani, Samer Z. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Xu, Jianmin; Srivastava, Ritesh K. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda (United States); Pressey, Joseph G. [Division of Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, 1600 7th Avenue South, ACC 414, Birmingham, AL 35233 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-06-14

    Graphical abstract: Intervention of poorly differentiated RMS by rapamycin: In poorly differentiated RMS, rapamycin blocks mTOR and Hh signaling pathways concomitantly. This leads to dampening in cell cycle regulation and induction of apoptosis. This study provides a rationale for the therapeutic intervention of poorly differentiated RMS by treating patients with rapamycin alone or in combination with other chemotherapeutic agents. -- Highlights: •Rapamycin abrogates RMS tumor growth by modulating proliferation and apoptosis. •Co-targeting mTOR/Hh pathways underlie the molecular basis of effectiveness. •Reduction in mTOR/Hh pathways diminish EMT leading to reduced invasiveness. -- Abstract: Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis

  12. Dose-response relationship in cisplatin-treated breast cancer xenografts monitored with dynamic contrast-enhanced ultrasound

    OpenAIRE

    Chen, Yao; Han, Feng; Cao, Long-hui; Li, Cheng; Wang, Jian-Wei; Li, Qing; Zheng, Wei; Guo, Zhi-xing; Li, An-Hua; Zhou, Jian-Hua

    2015-01-01

    Background Exactly assessing tumor response to different dose of chemotherapy would help to tailor therapy for individual patients. This study was to determine the feasibility of dynamic contrast-enhanced ultrasound (CEUS) in the evaluation of tumor vascular response to different dose cisplatin. Methods MCF-7 breast cancer bearing mice were treated with different dose of cisplatin in group B (1 mg/kg) and group C (3 mg/kg). A control group A was given with saline. Sequential CEUS was performe...

  13. Effects of green-synthesized silver nanoparticles on lung cancer cells in vitro and grown as xenograft tumors in vivo

    OpenAIRE

    He Y; Du Z.; Ma S; Liu Y; Li D.; Huang H.; Jiang S; Cheng S; Wu W; Zhang K; Zheng X

    2016-01-01

    Yan He,1,* Zhiyun Du,1,* Shijing Ma,1 Yue Liu,2 Dongli Li,1 Huarong Huang,1 Sen Jiang,1 Shupeng Cheng,1 Wenjing Wu,1 Kun Zhang,1 Xi Zheng1,2 1Allan H Conney Laboratory for Anticancer Drug Research, School of Chemical Engineering and Light Industry, Guandong University of Technology, Guangzhou, People’s Republic of China; 2Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey...

  14. The effect of finasteride and dutasteride on the growth of WPE1-NA22 prostate cancer xenografts in nude mice.

    Directory of Open Access Journals (Sweden)

    Alexander B Opoku-Acheampong

    Full Text Available BACKGROUND: 5α-reductase 1 (5αR1 and 5α-reductase 2 (5αR2 convert testosterone into the more potent androgen dihydrotestosterone. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have increased 5αR1 and decreased 5αR2 expression. Previously, finasteride (5αR2 inhibitor treatment begun 3 weeks post-tumor implantation had no effect on Dunning R3327-H rat prostate tumor growth. We believe the tumor compensated for finasteride treatment by increasing tumor 5αR1 expression or activity. We hypothesize that finasteride treatment would not significantly alter tumor growth even if begun before tumor implantation, whereas dutasteride (5αR1 and 5αR2 inhibitor treatment would decrease tumor growth regardless of whether treatment was initiated before or after tumor implantation. METHODOLOGY/PRINCIPAL FINDINGS: Sixty 8-week-old male nude mice were randomized to Control, Pre- and Post-Finasteride, and Pre- and Post-Dutasteride (83.3 mg drug/kg diet diet groups. Pre- and post-groups began their treatment diets 1-2 weeks prior to or 3 weeks after subcutaneous injection of 1×10⁵ WPE1-NA22 human prostate cancer cells, respectively. Tumors were allowed to grow for 22 weeks; tumor areas, body weights, and food intakes were measured weekly. At study's conclusion, prostate and seminal vesicle weights were significantly decreased in all treatment groups versus the control; dutasteride intake significantly decreased seminal vesicle weights compared to finasteride intake. No differences were measured in final tumor areas or tumor weights between groups, likely due to poor tumor growth. In follow-up studies, proliferation of WPE1-NA22 prostate cancer cells and parent line RWPE-1 prostate epithelial cells were unaltered by treatment with testosterone, dihydrotestosterone, or mibolerone, suggesting that these cell lines are not androgen-sensitive. CONCLUSION: The lack of response of WPE1-NA22 prostate cancer cells to androgen

  15. Comparisons of [{sup 18}F]-1-deoxy-1-fluoro-scyllo-inositol with [{sup 18}F]-FDG for PET imaging of inflammation, breast and brain cancer xenografts in athymic mice

    Energy Technology Data Exchange (ETDEWEB)

    McLarty, Kristin; Moran, Matthew D. [Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8 (Canada); PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Scollard, Deborah A.; Chan, Conrad [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Sabha, Nesrin; Mukherjee, Joydeep; Guha, Abhijit [Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, ON, M5G 1X8 (Canada); McLaurin, JoAnne [Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, M5S 3H2 (Canada); Nitz, Mark [Department of Chemistry, University of Toronto, Toronto, ON, M5S 3H6 (Canada); Houle, Sylvain; Wilson, Alan A. [Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8 (Canada); PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada); Reilly, Raymond M., E-mail: raymond.reilly@utoronto.ca [Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Toronto General Research Institute, University Health Network, Toronto, ON, M5G 2M9 (Canada); Department of Medical Imaging, University of Toronto, Toronto, ON, M5S 3M2 (Canada); Vasdev, Neil, E-mail: neil.vasdev@utoronto.ca [Department of Psychiatry, University of Toronto, Toronto, ON, M5T 1R8 (Canada); PET Centre, Centre for Addiction and Mental Health, Toronto, ON, M5T 1R8 (Canada)

    2011-10-15

    Introduction: The aim of the study was to evaluate the uptake of [{sup 18}F]-1-deoxy-1-fluoro-scyllo-inositol ([{sup 18}F]-scyllo-inositol) in human breast cancer (BC) and glioma xenografts, as well as in inflammatory tissue, in immunocompromised mice. Studies of [{sup 18}F]-2-fluoro-2-deoxy-D-glucose ([{sup 18}F]-FDG) under the same conditions were also performed. Methods: Radiosynthesis of [{sup 18}F]-scyllo-inositol was automated using a commercial synthesis module. Tumour, inflammation and normal tissue uptakes were evaluated by biodistribution studies and positron emission tomography (PET) imaging using [{sup 18}F]-scyllo-inositol and [{sup 18}F]-FDG in mice bearing subcutaneous MDA-MB-231, MCF-7 and MDA-MB-361 human BC xenografts, intracranial U-87 MG glioma xenografts and turpentine-induced inflammation. Results: The radiosynthesis of [{sup 18}F]-scyllo-inositol was automated with good radiochemical yields (24.6%{+-}3.3%, uncorrected for decay, 65{+-}2 min, n=5) and high specific activities ({>=}195 GBq/{mu}mol at end of synthesis). Uptake of [{sup 18}F]-scyllo-inositol was greatest in MDA-MB-231 BC tumours and was comparable to that of [{sup 18}F]-FDG (4.6{+-}0.5 vs. 5.5{+-}2.1 %ID/g, respectively; P=.40), but was marginally lower in MDA-MB-361 and MCF-7 xenografts. Uptake of [{sup 18}F]-scyllo-inositol in inflammation was lower than [{sup 18}F]-FDG. While uptake of [{sup 18}F]-scyllo-inositol in intracranial U-87 MG xenografts was significantly lower than [{sup 18}F]-FDG, the tumour-to-brain ratio was significantly higher (10.6{+-}2.5 vs. 2.1{+-}0.6; P=.001). Conclusions: Consistent with biodistribution studies, uptake of [{sup 18}F]-scyllo-inositol was successfully visualized by PET imaging in human BC and glioma xenografts, with lower accumulation in inflammatory tissue than [{sup 18}F]-FDG. The tumour-to-brain ratio of [{sup 18}F]-scyllo-inositol was also significantly higher than that of [{sup 18}F]-FDG for visualizing intracranial glioma xenografts in

  16. Comparisons of [18F]-1-deoxy-1-fluoro-scyllo-inositol with [18F]-FDG for PET imaging of inflammation, breast and brain cancer xenografts in athymic mice

    International Nuclear Information System (INIS)

    Introduction: The aim of the study was to evaluate the uptake of [18F]-1-deoxy-1-fluoro-scyllo-inositol ([18F]-scyllo-inositol) in human breast cancer (BC) and glioma xenografts, as well as in inflammatory tissue, in immunocompromised mice. Studies of [18F]-2-fluoro-2-deoxy-D-glucose ([18F]-FDG) under the same conditions were also performed. Methods: Radiosynthesis of [18F]-scyllo-inositol was automated using a commercial synthesis module. Tumour, inflammation and normal tissue uptakes were evaluated by biodistribution studies and positron emission tomography (PET) imaging using [18F]-scyllo-inositol and [18F]-FDG in mice bearing subcutaneous MDA-MB-231, MCF-7 and MDA-MB-361 human BC xenografts, intracranial U-87 MG glioma xenografts and turpentine-induced inflammation. Results: The radiosynthesis of [18F]-scyllo-inositol was automated with good radiochemical yields (24.6%±3.3%, uncorrected for decay, 65±2 min, n=5) and high specific activities (≥195 GBq/μmol at end of synthesis). Uptake of [18F]-scyllo-inositol was greatest in MDA-MB-231 BC tumours and was comparable to that of [18F]-FDG (4.6±0.5 vs. 5.5±2.1 %ID/g, respectively; P=.40), but was marginally lower in MDA-MB-361 and MCF-7 xenografts. Uptake of [18F]-scyllo-inositol in inflammation was lower than [18F]-FDG. While uptake of [18F]-scyllo-inositol in intracranial U-87 MG xenografts was significantly lower than [18F]-FDG, the tumour-to-brain ratio was significantly higher (10.6±2.5 vs. 2.1±0.6; P=.001). Conclusions: Consistent with biodistribution studies, uptake of [18F]-scyllo-inositol was successfully visualized by PET imaging in human BC and glioma xenografts, with lower accumulation in inflammatory tissue than [18F]-FDG. The tumour-to-brain ratio of [18F]-scyllo-inositol was also significantly higher than that of [18F]-FDG for visualizing intracranial glioma xenografts in NOD SCID mice, giving a better contrast. -- Graphical Abstract: Display Omitted

  17. Effect of estrogen withdrawal on energy-rich phosphates and prediction of estrogen dependence monitored by in vivo 31P magnetic resonance spectroscopy of four human breast cancer xenografts

    DEFF Research Database (Denmark)

    Kristensen, C A; Kristjansen, P E; Brünner, N;

    1995-01-01

    The effect of estrogen withdrawal on energy metabolism was studied in four human breast cancer xenografts: the estrogen-dependent MCF-7 and ZR75-1 and the estrogen-independent ZR75/LCC-3 and MDA-MB-231. The tumors were grown in ovariectomized nude mice with a s.c. implanted estrogen pellet. After...... Gompertzian growth was verified, the estrogen pellet was removed from half of the animals. In vivo 31P magnetic resonance spectroscopy of the tumors was performed 1 day before and on days 2, 6, and 14 after estrogen removal. Estrogen withdrawal induced a significant increase in the nucleoside triphosphate......:Pi ratio in the two estrogen-dependent xenografts, whereas this ratio remained unchanged in the estrogen-independent tumors. In ZR75/LCC-3 tumors a slight decrease in nucleoside triphosphate:Pi was observed following onset of estrogen stimulation after initial growth without estrogen. Extracts of freeze...

  18. AZ17: a new bispecific drug targeting IL-6 and IL-23 with potential clinical use-improves psoriasis in a human xenograft transplantation model

    DEFF Research Database (Denmark)

    Stenderup, Karin; Kjeldsen, Cecilia Rosada; Shanebeck, K; Brady, W; Van Brunt, MP; King, G; Marelli, M; Slagle, P; Xu, H; Nairn, NW; Johnson, J; Wang, AA; Li, G; Thornton, KC; Dam, T.N.; Grabstein, KH

    yield. The bispecific molecule AZ17 was created by combining high affinity binding domains originating from monoclonal antibodies targeting human IL-6 and IL-23. To allow for high and efficient production, AZ17 was assembled by site-specific bioconjugation from two individual single chain fragment...... variables that were synthesized separately in Escherichia coli. To improve stability and extend pharmacokinetics, a flexible poly-ethylene glycol molecule was used as linker. In preclinical psoriasis models, AZ17 reduced IL-23-induced ear inflammation and improved psoriasis in a xenograft transplantation...

  19. Priceless GEMMs: genetically engineered mouse models for colorectal cancer drug development.

    Science.gov (United States)

    Roper, Jatin; Hung, Kenneth E

    2012-08-01

    To establish effective drug development for colorectal cancer (CRC), preclinical models that are robust surrogates for human disease are crucial. Mouse models are an attractive platform because of their relatively low cost, short life span, and ease of use. There are two main categories of mouse CRC models: xenografts derived from implantation of CRC cells or tumors in immunodeficient mice; and genetically engineered mouse models (GEMMs) derived from modification of human cancer predisposition genes, resulting in spontaneous tumor formation. Here, we review xenografts and GEMMs and focus on their potential application in translational research. Furthermore, we describe newer GEMMs for sporadic CRC that are particularly suitable for drug testing. Finally, we discuss recent advances in small-animal imaging, such as optical colonoscopy, which allow in vivo assessment of tumors. With the increasing sophistication of GEMMs, our preclinical armamentarium provides new hope for the ongoing war against CRC. PMID:22739258

  20. The Next Generation of Orthotopic Thyroid Cancer Models: Immunocompetent Orthotopic Mouse Models of BRAFV600E-Positive Papillary and Anaplastic Thyroid Carcinoma

    OpenAIRE

    Vanden Borre, Pierre; McFadden, David G.; Gunda, Viswanath; Sadow, Peter M.; Varmeh, Shohreh; Bernasconi, Maria; Jacks, Tyler; Parangi, Sareh

    2014-01-01

    Background: While the development of new treatments for aggressive thyroid cancer has advanced in the last 10 years, progress has trailed headways made with other malignancies. A lack of reliable authenticated human cell lines and reproducible animal models is one major roadblock to preclinical testing of novel therapeutics. Existing xenograft and orthotopic mouse models of aggressive thyroid cancer rely on the implantation of highly passaged human thyroid carcinoma lines in immunodeficient m...

  1. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    International Nuclear Information System (INIS)

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  2. Vorinostat, an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening mTOR signaling pathway in a human xenograft murine model

    Energy Technology Data Exchange (ETDEWEB)

    Kurundkar, Deepali; Srivastava, Ritesh K.; Chaudhary, Sandeep C. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Ballestas, Mary E. [Department of Pediatrics Infectious Disease, Children' s of Alabama, School of Medicine, University of Alabama at Birmingham, AL (United States); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, 6130 Executive Blvd., Suite 2114, Bethesda, MD 20892 (United States); Elmets, Craig A. [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States); Athar, Mohammad, E-mail: mathar@uab.edu [Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, 1530 3rd Avenue South, VH 509, Birmingham, AL 35294-0019 (United States)

    2013-01-15

    Histone deacetylase (HDAC) inhibitors are potent anticancer agents and show efficacy against various human neoplasms. Vorinostat is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors. However, its effect on the growth of skin neoplasm remains undefined. In this study, we show that vorinostat (2 μM) reduced expression of HDAC1, 2, 3, and 7 in epidermoid carcinoma A431 cells. Consistently, it increased acetylation of histone H3 and p53. Vorinostat (100 mg/kg body weight, IP) treatment reduced human xenograft tumor growth in highly immunosuppressed nu/nu mice. Histologically, the vorinostat-treated tumor showed features of well-differentiation with large necrotic areas. Based on proliferating cell nuclear antigen (PCNA) staining and expression of cyclins D1, D2, E, and A, vorinostat seems to impair proliferation by down-regulating the expression of these proteins. However, it also induced apoptosis. The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis, involved inhibition of mTOR signaling which was accompanied by reduction in cell survival AKT and extracellular-signal regulated kinase (ERK) signaling pathways. Our data provide a novel mechanism-based therapeutic intervention for cutaneous squamous cell carcinoma (SCC). Vorinostat may be utilized to cure skin neoplasms in organ transplant recipient (OTR). These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients, is difficult. -- Highlights: ► Vorinostat reduces SCC growth in a xenograft murine model. ► Vorinostat dampens proliferation and induces apoptosis in tumor cells. ► Diminution in mTOR, Akt and ERK signaling underlies inhibition in proliferation. ► Vorinostat by inhibiting HDACs inhibits epithelial–mesenchymal transition.

  3. Mouse models of colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    Yunguang Tong; Wancai Yang; H. Phillip Koeffler

    2011-01-01

    Colorectal cancer is one of the most common malignancies in the world. Many mouse models have been developed to evaluate features of colorectal cancer in humans. These can be grouped into genetically-engineered, chemically-induced, and inoculated models. However, none recapitulates all of the characteristics of human colorectal cancer. It is critical to use a specific mouse model to address a particular research question. Here, we review commonly used mouse models for human colorectal cancer.

  4. Chloroquine sensitizes cisplatin cytotoxicity in human gastric cancer xenografts%抗疟药氯喹增强胃癌裸鼠移植瘤对顺铂的化疗敏感性

    Institute of Scientific and Technical Information of China (English)

    方念; 张慧卿; 刘小梅; 何波; 万以叶; 程海涛; 谢桂生

    2014-01-01

    Objective To investigate the enhanced effect of cisplatin on chloroquine in SGC7901 xenografts. Methods The models of SGC7901 xenograft on athymic mouse were established and randomized to four groups with intraperitoneal injection of different drugs: control, cisplatin(DDP), chloroquine(CQ) and DDP+CQ. Drugs were injected once every 3 days, 10 times in all. The tumor volume were measured during the process of drug therapy. The mice were sacrificed 3 days after the last injection,and then the weight of tumor were measured. Western Blot was performed to detect the expression of beclin-1, LC3Ⅱ/Ⅰ, Caspase3 and P-gp, RT-PCR was performed to detect the expression of MDR1 mRNA. Results Compared to group control,the growth of tumor were more slowly and the tumor volume were much smaller in group DDP, the inhibition of tumor rate was 47.6%;and the expression of Beclin1 and LC3 were up-regulated. After combined with CQ, the inhibition of tumor rate was increased to 84.7%(P<0.01), and the ratio between LC3Ⅱ/Ⅰ was decreased;the expression of MDR1 and P-gp were also down-regulated. Conclusion Chloroquine can enhance the anti-tumor effect of cisplatin on gastric cancer xenografts, inhibition of autophagy and down-regulation of MDR1/P-gp expression are possibly the related mechanisms.%目的:探讨抗疟药氯喹(CQ)增强顺铂(DDP)抑制胃癌SGC7901细胞裸鼠移植瘤生长的作用。方法建立胃癌SGC7901细胞裸鼠异位移植瘤模型,将24只荷瘤鼠随机分为对照组、DDP组、CQ组和CQ+DDP组。腹腔注射给药,给药后每3日测量肿瘤体积。给药结束时处死裸鼠,剥离移植瘤,称重。Western Blot检测肿瘤组织beclin-1、LC3Ⅱ/Ⅰcaspase3和P-gp表达,RT-PCR技术检测MDR1 mRNA水平。结果与对照组相比,DDP组移植瘤生长缓慢,体积较小,抑瘤率为47.6%,而且Beclin1和LC3表达增加,LCⅠ转换LCⅡ增多。联合氯喹后,抑瘤率提高至84.7%(P<0.01),LC3

  5. Effect of Dys-psychological Stress on Expression of Dicer in Mice with Human Ovarian Cancer Xenografts%不良心理应激对小鼠人卵巢癌移植瘤dicer酶表达的影响

    Institute of Scientific and Technical Information of China (English)

    孙茜; 成晓洁; 喻小念

    2011-01-01

    目的 观察不良应激因素对小鼠人卵巢癌移植瘤dicer酶的表达影响.方法 将人卵巢癌组织采用背部皮下接种法移植裸鼠,建立人卵巢癌细胞裸鼠皮下移植瘤模型.成功造模后,取体质量及肿瘤大小相近的裸鼠按随机数字表法分为对照组和应激组,每组6只.对照组裸鼠自由供水和食物;应激组裸鼠采用束缚方法给予应激,束缚应激时将应激组裸鼠依次放入打孔通风的50 mL离心管,每天束缚6 h,5 d·周-1,束缚期间禁水、禁食,完成束缚应激后将裸鼠放出,恢复自由供水和食物,应激时间共2周.观察2组裸鼠生存状态、体质量及皮下移植瘤体积;完成应激后处死裸鼠,取皮下人卵巢癌组织,采用RT-PCR和免疫组织化学染色,比较2组人卵巢癌组织中dicer酶的表达水平.结果 应激组裸鼠摄食及活动不佳,与对照组相比,应激组裸鼠体质量明显下降(P<0.05);2组比较,肿瘤体积差异无统计学意义(P>0.05);RT-PCR和免疫组织化学染色结果表明:与对照组相比,应激组裸鼠卵巢癌组织中dicer酶的表达量明显下降(P<0.05).结论 不良心理应激因素能降低人卵巢癌移植瘤中dicer酶的表达.dicer酶的表达可成为研究不良心理应激对肿瘤生长影响的重要参考指标.%Objective To observe the effect of dys-psychological stress on the expression of dicer in mice with human ovarian cancer xenografts. Methods The subcutaneous tumor xenografts were established by implanting human ovarian cancer tissue into nude mice. After establishment of the model,the mice with similar weight and diameter of tumors were randomly divided into control group and stress group,with 6 mice in each group. The dys-psychological stress model was established by putting each nude mouse respectively into a 50 mL centrifuge tube with drilling for excellent ventilation. Six hours later,the mice were released from the tubes and then supplied with food and water. The

  6. Farnesol inhibits tumor growth and enhances the anticancer effects of bortezomib in multiple myeloma xenograft mouse model through the modulation of STAT3 signaling pathway.

    Science.gov (United States)

    Lee, Jong Hyun; Kim, Chulwon; Kim, Sung-Hoon; Sethi, Gautam; Ahn, Kwang Seok

    2015-05-01

    Aberrant activation of signal transducer and activator of transcription 3 (STAT3) is frequently observed in multiple myeloma (MM) cancer and can upregulate the expression of several genes involved in proliferation, survival, metastasis, and angiogenesis. The effect of farnesol (FOH) on STAT3 activation, associated protein kinases, its regulated gene products, cellular proliferation, and apoptosis was examined. The in vivo effect of FOH on the growth of human MM xenograft tumors alone and in combination with bortezomib (Bor) in athymic nu/nu female mice was also investigated. We found that FOH suppressed both constitutive and inducible STAT3 activation at Tyr705 in MM cells. The suppression of STAT3 was mediated through the inhibition of activation of upstream JAK1, JAK2, and c-Src kinases. Also, treatment with the protein tyrosine phosphatase (PTP) inhibitor, pervanadate treatment reversed the FOH-induced down-regulation of STAT3, possibly indicating the involvement of a PTP. Indeed, we found that FOH treatment induces the increased expression of SHP-2 protein and knockdown of the SHP-2 gene by small interfering RNA suppressed the ability of FOH to inhibit STAT3 activation. FOH inhibited proliferation and significantly potentiated the apoptotic effects of bortezomib (Bor) in U266 cells. When administered intraperitoneally, FOH enhanced Bor-induced growth suppression of human MM xenograft tumors in athymic nu/nu female mice. Our results suggest that FOH is a novel blocker of STAT3 signaling pathway and exerts both anti-proliferative and apoptotic activities in MM in vitro and in vivo. PMID:25697480

  7. MicroPET/CT imaging of patient-derived pancreatic cancer xenografts implanted subcutaneously or orthotopically in NOD-scid mice using 64Cu-NOTA-panitumumab F(ab')2 fragments

    International Nuclear Information System (INIS)

    Introduction: Our objective was to study microPET/CT imaging of patient-derived pancreatic cancer xenografts in NOD-scid mice using F(ab')2 fragments of the fully-human anti-EGFR monoclonal antibody, panitumumab (Vectibix) labeled with 64Cu. More than 90% of pancreatic cancers are EGFR-positive. Methods: F(ab')2 fragments were produced by proteolytic digestion of panitumumab IgG or non-specific human IgG, purified by ultrafiltration then modified with NOTA chelators for complexing 64Cu. Panitumumab IgG and Fab fragments were similarly labeled with 64Cu. EGFR immunoreactivity was determined in competition and direct (saturation) cell binding assays. The biodistribution of 64Cu-labeled panitumumab IgG, F(ab')2 and Fab was compared in non-tumor-bearing Balb/c mice. MicroPET/CT and biodistribution studies were performed in NOD-scid mice engrafted subcutaneously (s.c.) or orthotopically with patient-derived OCIP23 pancreatic tumors, or in NOD-scid with s.c. PANC-1 human pancreatic cancer xenografts. Results: Panitumumab F(ab')2 fragments were produced in high purity (> 90%), derivitized with 3.2 ± 0.7 NOTA/F(ab')2, and labeled with 64Cu (0.3–3.6 MBq/μg). The binding of 64Cu-NOTA-panitumumab F(ab')2 to OCIP23 or PANC-1 cells was decreased significantly by an excess of panitumumab IgG. The Kd for binding of 64Cu-NOTA-panitumumab F(ab')2 to EGFR on PANC-1 cells was 0.14 ± 0.05 nmol/L. F(ab')2 fragments exhibited more suitable normal tissue distribution for tumor imaging with 64Cu than panitumumab IgG or Fab. Tumor uptake at 48 h post injection (p.i.) of 64Cu-NOTA-panitumumab F(ab')2 was 12.0 ± 0.9% injected dose/g (ID/g) in s.c. and 11.8 ± 0.9% ID/g in orthotopic OCIP23 tumors vs. 6.1 ± 1.1% ID/g in s.c. PANC-1 xenografts. Tumor/Blood (T/B) ratios were 5:1 to 9:1 for OCIP23 and 2.4:1 for PANC-1 tumors. Tumor uptake of 64Cu-NOTA-non-specific F(ab')2 in OCIP23 xenografts was 5-fold lower than 64Cu-panitumumab F

  8. Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    Energy Technology Data Exchange (ETDEWEB)

    Frost, Sophia; Frayo, Shani; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; Back, Tom; Fisher, Darrell R.; Press, Oliver W.

    2015-03-01

    Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.

  9. Comparative distribution study of /sup 111/In-labelled DTPA and TTHA monoclonal antibody conjugates in a choriocarcinoma xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Buckley, R.G.; Barnett, P.; Searle, F.; Pedley, R.; Boden, J.A.

    1986-11-01

    Conjugates of the chelating agents DTPA and TTHA with a monoclonal anti-HCG were prepared. The tissue distribution of the /sup 111/In-Labelled conjugates and also /sup 111/In-citrate was studied in mice bearing human choriocarcinoma xenografts. The antibody conjugates both gave high liver and spleen radionuclide accumulation. Elevated femur levels were observed for the TTHA conjugate and /sup 111/In-citrate. Generally the DTPA conjugate showed the highest tumor-tissue ratios, although its tumor/blood ratio was lower than the other two materials. The results infer that the DTPA conjugate has the greatest utility as an imaging agent but that it would require a background subtraction technique.

  10. Antibody directed against human YKL-40 increases tumor volume in a human melanoma xenograft model in scid mice

    DEFF Research Database (Denmark)

    Salamon, Johannes; Hoffmann, Tatjana; Elies, Eva; Peldschus, Kersten; Johansen, Julia S; Lüers, Georg; Schumacher, Udo; Wicklein, Daniel

    2014-01-01

    (0.42 g). The effect of anti-YKL-40 on the increase of tumor volume started within hours after injection and was dose dependent. Intratumoral hemorrhage was observed in the treated animals. The strong effect on tumor size indicates important roles for YKL-40 in melanoma growth and argues for a......Induced overexpression of the secretory protein YKL-40 promotes tumor growth in xenograft experiments. We investigated if targeting YKL-40 with a monoclonal antibody could inhibit tumor growth. YKL-40 expressing human melanoma cells (LOX) were injected subcutenously in Balb/c scid mice. Animals...... were treated with intraperitoneal injections of anti-YKL-40, isoptype control or PBS. Non-YKL-40 expressing human pancreatic carcinoma cell line PaCa 5061 served as additional control. MR imaging was used for evaluation of tumor growth. Two days after the first injections of anti-YKL-40, tumor volume...

  11. Aspirin induces apoptosis in vitro and inhibits tumor growth of human hepatocellular carcinoma cells in a nude mouse xenograft model

    OpenAIRE

    HOSSAIN, MOHAMMAD AKBAR; Kim, Dong Hwan; JANG, JUNG YOON; KANG, YONG JUNG; YOON, JEONG-HYUN; Moon, Jeon-OK; Chung, Hae Young; Kim, Gi-Young; Choi, Yung Hyun; Copple, Bryan L.; Kim, Nam Deuk

    2011-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to induce apoptosis in a variety of cancer cells, including colon, prostate, breast and leukemia. Among them, aspirin, a classical NSAID, shows promise in cancer therapy in certain types of cancers. We hypothesized that aspirin might affect the growth of liver cancer cells since liver is the principal site for aspirin metabolism. Therefore, we investigated the effects of aspirin on the HepG2 human hepatocellular carcinoma cell line in vi...

  12. Animal Models of Colorectal Cancer

    Science.gov (United States)

    Johnson, Robert L.; Fleet, James C.

    2012-01-01

    Colorectal cancer is a heterogeneous disease that afflicts a large number of people in the United States. The use of animal models has the potential to increase our understanding of carcinogenesis, tumor biology, and the impact of specific molecular events on colon biology. In addition, animal models with features of specific human colorectal cancers can be used to test strategies for cancer prevention and treatment. In this review we provide an overview of the mechanisms driving human cancer, we discuss the approaches one can take to model colon cancer in animals, and we describe a number of specific animal models that have been developed for the study of colon cancer. We believe that there are many valuable animal models to study various aspects of human colorectal cancer. However, opportunities for improving upon these models exist. PMID:23076650

  13. Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Lohse, Ines; Lourenco, Corey; Ibrahimov, Emin; Pintilie, Melania [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Tsao, Ming-Sound [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Pathology, University Health Network, 200 Elizabeth Street, Toronto, ON M5G2C4 (Canada); Department of Laboratory Medicine and Pathobiology, 27 King’s College Circle, University of Toronto, Toronto, ON M5S1A1 (Canada); Hedley, David W., E-mail: david.hedley@uhn.ca [Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Center, University Health Network, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medical Biophysics University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Departments of Medicine, University of Toronto, 610 University Ave., Toronto, ON M5G2M9 (Canada); Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, 610 University Ave., Toronto, ON M5G2M9 (Canada)

    2014-02-26

    The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential.

  14. Assessment of Hypoxia in the Stroma of Patient-Derived Pancreatic Tumor Xenografts

    International Nuclear Information System (INIS)

    The unusually dense stroma of pancreatic cancers is thought to play an important role in their biological aggression. The presence of hypoxia is also considered an adverse prognostic factor. Although it is usually assumed that this is the result of effects of hypoxia on the epithelial component, it is possible that hypoxia exerts indirect effects via the tumor stroma. We therefore measured hypoxia in the stroma of a series of primary pancreatic cancer xenografts. Nine patient-derived pancreatic xenografts representing a range of oxygenation levels were labeled by immunohistochemistry for EF5 and analyzed using semi-automated pattern recognition software. Hypoxia in the tumor and stroma was correlated with tumor growth and metastatic potential. The extent of hypoxia varied from 1%–39% between the different models. EF5 labeling in the stroma ranged from 0–20% between models, and was correlated with the level of hypoxia in the tumor cell area, but not microvessel density. Tumor hypoxia correlated with spontaneous metastasis formation with the exception of one hypoxic model that showed disproportionately low levels of hypoxia in the stroma and was non-metastatic. Our results demonstrate that hypoxia exists in the stroma of primary pancreatic cancer xenografts and suggest that stromal hypoxia impacts the metastatic potential

  15. Inhibition of Human Pancreatic Tumor Growth by Cytokine-Induced Killer Cells in Nude Mouse Xenograft Model

    OpenAIRE

    Kim, Ji Sung; Park, Yun Soo; Kim, Ju Young; Kim, Yong Guk; Kim, Yeon Jin; Lee, Hong Kyung; Kim, Hyung Sook; Hong, Jin Tae; Kim, Youngsoo; Han, Sang-Bae

    2012-01-01

    Pancreatic cancer is the fourth commonest cause of cancer-related deaths in the world. However, no adequate therapy for pancreatic cancer has yet been found. In this study, the antitumor activity of cytokine-induced killer (CIK) cells against the human pancreatic cancer was evaluated in vitro and in vivo. Human peripheral blood mononuclear cells were cultured with IL-2-containing medium in anti-CD3 for 14 days. The resulting populations of CIK cells comprised 94% CD3+, 4% CD3-CD56+, 41% CD3+C...

  16. Scopoletin, an active principle of tree tobacco (Nicotiana glauca) inhibits human tumor vascularization in xenograft models and modulates ERK1, VEGF-A, and FGF-2 in computer model.

    Science.gov (United States)

    Tabana, Yasser M; Hassan, Loiy Elsir A; Ahamed, Mohamed B Khadeer; Dahham, Saad S; Iqbal, Muhammad Adnan; Saeed, Mohammed A A; Khan, Md Shamsuddin S; Sandai, Doblin; Majid, Aman S Abdul; Oon, Chern Ein; Majid, Amin Malik S A

    2016-09-01

    We recently reported the antineovascularization effect of scopoletin on rat aorta and identified its potential anti-angiogenic activity. Scopoletin could be useful as a systemic chemotherapeutic agent against angiogenesis-dependent malignancies if its antitumorigenic activity is investigated and scientifically proven using a suitable human tumor xenograft model. In the present study, bioassay-guided (anti-angiogenesis) phytochemical investigation was conducted on Nicotiana glauca extract which led to the isolation of scopoletin. Further, anti-angiogenic activity of scopoletin was characterized using ex vivo, in vivo and in silico angiogenesis models. Finally, the antitumorigenic efficacy of scopoletin was studied in human colorectal tumor xenograft model using athymic nude mice. For the first time, an in vivo anticancer activity of scopoletin was reported and characterized using xenograft models. Scopoletin caused significant suppression of sprouting of microvessels in rat aortic explants with IC50 (median inhibitory concentration) 0.06μM. Scopoletin (100 and 200mg/kg) strongly inhibited (59.72 and 89.4%, respectively) vascularization in matrigel plugs implanted in nude mice. In the tumor xenograft model, scopoletin showed remarkable inhibition on tumor growth (34.2 and 94.7% at 100 and 200mg/kg, respectively). Tumor histology revealed drastic reduction of the extent of vascularization. Further, immunostaining of CD31 and NG2 receptors in the histological sections confirmed the antivascular effect of scopoletin in tumor vasculature. In computer modeling, scopoletin showed strong ligand affinity and binding energies toward the following angiogenic factors: protein kinase (ERK1), vascular endothelial growth factor A (VEGF-A), and fibroblast growth factor 2 (FGF-2). These results suggest that the antitumor activity of scopoletin may be due to its strong anti-angiogenic effect, which may be mediated by its effective inhibition of ERK1, VEGF-A, and FGF-2. PMID:27133199

  17. High-dose stabilized chlorite matrix WF10 prolongs cardiac xenograft survival in the hamster-to-rat model without inducing ultrastructural or biochemical signs of cardiotoxicity

    DEFF Research Database (Denmark)

    Hansen, A; Kemp, K; Kemp, E;

    2001-01-01

    WF10 is a stabilized chlorite matrix with immunosuppressive effects. In vitro studies have demonstrated its ability to suppress T cells and delay or abolish antigen presentation. Hence, WF10 may prove useful to prolong graft survival after transplantation. In this study, we evaluated the use of...... high dose WF10 as a single drug regimen in the hamster-to-rat xenotransplantation model and searched for possible cardiotoxic side effects. WF10 prolonged cardiac xenograft survival, but did not induce tolerence or inhibit pathological signs of acute rejection. Hamsters from the donor population......, receiving high dose WF10 for 5 days, were compared with a matched control group. Ultrastructural examination of cardiac tissue as well as biochemical analysis of the cardiac enzymes troponin I, myoglobin and MB isoenzyme of creatine kinase showed no signs of damage. Thus, while prolonging graft survival...

  18. Functional Ginger Extracts from Supercritical Fluid Carbon Dioxide Extraction via In Vitro and In Vivo Assays: Antioxidation, Antimicroorganism, and Mice Xenografts Models

    Directory of Open Access Journals (Sweden)

    Chih-Chen Lee

    2013-01-01

    Full Text Available Supercritical fluid carbon dioxide extraction technology was developed to gain the active components from a Taiwan native plant, Zingiber officinale (ginger. We studied the biological effects of ginger extracts via multiple assays and demonstrated the biofunctions in each platform. Investigations of ginger extracts indicated antioxidative properties in dose-dependant manners on radical scavenging activities, reducing powers and metal chelating powers. We found that ginger extracts processed moderate scavenging values, middle metal chelating levels, and slight ferric reducing powers. The antibacterial susceptibility of ginger extracts on Staphylococcus aureus, Streptococcus sobrinus, S. mutans, and Escherichia coli was determined with the broth microdilution method technique. The ginger extracts had operative antimicroorganism potentials against both Gram-positive and Gram-negative bacteria. We further discovered the strong inhibitions of ginger extracts on lethal carcinogenic melanoma through in vivo xenograft model. To sum up, the data confirmed the possible applications as medical cosmetology agents, pharmaceutical antibiotics, and food supplements.

  19. Tumor Repression of VCaP Xenografts by a Pyrrole-Imidazole Polyamide.

    Directory of Open Access Journals (Sweden)

    Amanda E Hargrove

    Full Text Available Pyrrole-imidazole (Py-Im polyamides are high affinity DNA-binding small molecules that can inhibit protein-DNA interactions. In VCaP cells, a human prostate cancer cell line overexpressing both AR and the TMPRSS2-ERG gene fusion, an androgen response element (ARE-targeted Py-Im polyamide significantly downregulates AR driven gene expression. Polyamide exposure to VCaP cells reduced proliferation without causing DNA damage. Py-Im polyamide treatment also reduced tumor growth in a VCaP mouse xenograft model. In addition to the effects on AR regulated transcription, RNA-seq analysis revealed inhibition of topoisomerase-DNA binding as a potential mechanism that contributes to the antitumor effects of polyamides in cell culture and in xenografts. These studies support the therapeutic potential of Py-Im polyamides to target multiple aspects of transcriptional regulation in prostate cancers without genotoxic stress.

  20. Scanning Acoustic Microscopy-A Novel Noninvasive Method to Determine Tumor Interstitial Fluid Pressure in a Xenograft Tumor Model.

    Science.gov (United States)

    Hofmann, Matthias; Pflanzer, Ralph; Habib, Anowarul; Shelke, Amit; Bereiter-Hahn, Jürgen; Bernd, August; Kaufmann, Roland; Sader, Robert; Kippenberger, Stefan

    2016-06-01

    Elevated tumor interstitial fluid pressure (TIFP) is a prominent feature of solid tumors and hampers the transmigration of therapeutic macromolecules, for example, large monoclonal antibodies, from tumor-supplying vessels into the tumor interstitium. TIFP values of up to 40 mm Hg have been measured in experimental solid tumors using two conventional invasive techniques: the wick-in-needle and the micropuncture technique. We propose a novel noninvasive method of determining TIFP via ultrasonic investigation with scanning acoustic microscopy at 30-MHz frequency. In our experimental setup, we observed for the impedance fluctuations in the outer tumor hull of A431-vulva carcinoma-derived tumor xenograft mice. The gain dependence of signal strength was quantified, and the relaxation of tissue was calibrated with simultaneous hydrostatic pressure measurements. Signal patterns from the acoustical images were translated into TIFP curves, and a putative saturation effect was found for tumor pressures larger than 3 mm Hg. This is the first noninvasive approach to determine TIFP values in tumors. This technique can provide a potentially promising noninvasive assessment of TIFP and, therefore, can be used to determine the TIFP before treatment approach as well to measure therapeutic efficacy highlighted by lowered TFP values. PMID:27267834

  1. Scanning Acoustic Microscopy—A Novel Noninvasive Method to Determine Tumor Interstitial Fluid Pressure in a Xenograft Tumor Model1

    Science.gov (United States)

    Hofmann, Matthias; Pflanzer, Ralph; Habib, Anowarul; Shelke, Amit; Bereiter-Hahn, Jürgen; Bernd, August; Kaufmann, Roland; Sader, Robert; Kippenberger, Stefan

    2016-01-01

    Elevated tumor interstitial fluid pressure (TIFP) is a prominent feature of solid tumors and hampers the transmigration of therapeutic macromolecules, for example, large monoclonal antibodies, from tumor-supplying vessels into the tumor interstitium. TIFP values of up to 40 mm Hg have been measured in experimental solid tumors using two conventional invasive techniques: the wick-in-needle and the micropuncture technique. We propose a novel noninvasive method of determining TIFP via ultrasonic investigation with scanning acoustic microscopy at 30-MHz frequency. In our experimental setup, we observed for the impedance fluctuations in the outer tumor hull of A431-vulva carcinoma–derived tumor xenograft mice. The gain dependence of signal strength was quantified, and the relaxation of tissue was calibrated with simultaneous hydrostatic pressure measurements. Signal patterns from the acoustical images were translated into TIFP curves, and a putative saturation effect was found for tumor pressures larger than 3 mm Hg. This is the first noninvasive approach to determine TIFP values in tumors. This technique can provide a potentially promising noninvasive assessment of TIFP and, therefore, can be used to determine the TIFP before treatment approach as well to measure therapeutic efficacy highlighted by lowered TFP values.

  2. Anti-CD45 Pretargeted Radioimmunotherapy using Bismuth-213: High Rates of Complete Remission and Long-Term Survival in a Mouse Myeloid Leukemia Xenograft Model

    Energy Technology Data Exchange (ETDEWEB)

    Pagel, John M; Kenoyer, Aimee L; Back, Tom; Hamlin, Donald K; Wilbur, D Scott; Fisher, Darrell R; Park, Steven I; Frayo, Shani; Axtman, Amanda; Orgun, Nural; Orozoco, Johnnie; Shenoi, Jaideep; Lin, Yukang; Gopal, Ajay K; Green, Damian J; Appelbaum, Frederick R; Press, Oliver W

    2011-07-21

    Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and DOTA-biotin labeled with β-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. α-emitting radionuclides exhibit high cytotoxicity coupled with a short path-length, potentially increasing the therapeutic index and making them an attractive alternative to β-emitting radionuclides for patients with Acute Myeloid Leukemia (AML). Accordingly, we have used 213Bi in mice with human leukemia xenografts. Results demonstrated excellent localization of 213Bi-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5 ± 1.1% of the injected dose of 213Bi was delivered per gram of tumor. α imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after 213Bi-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a β-emitting radionuclide (90Y) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of 213Bi-DOTA-biotin given 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of 213Bi- or 90Y-DOTA-biotin, 80% and 20%, respectively, survived leukemia-free for >100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an α-emitting radionuclide may be highly effective and minimally toxic for treatment of AML.

  3. Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-κB regulated gene products in multiple myeloma xenograft mouse model.

    Science.gov (United States)

    Siveen, Kodappully Sivaraman; Mustafa, Nurulhuda; Li, Feng; Kannaiyan, Radhamani; Ahn, Kwang Seok; Kumar, Alan Prem; Chng, Wee-Joo; Sethi, Gautam

    2014-02-15

    Multiple myeloma (MM) is a B cell malignancy characterized by clonal proliferation of plasma cells in the bone marrow. With the advent of novel targeted agents, the median survival rate has increased to 5 -7 years. However, majority of patients with myeloma suffer relapse or develop chemoresistance to existing therapeutic agents. Thus, there is a need to develop novel alternative therapies for the treatment of MM. Thus in the present study, we investigated whether thymoquinone (TQ), a bioactive constituent of black seed oil, could suppress the proliferation and induce chemosensitization in human myeloma cells and xenograft mouse model. Our results show that TQ inhibited the proliferation of MM cells irrespective of their sensitivity to doxorubicin, melphalan or bortezomib. Interestingly, TQ treatment also resulted in a significant inhibition in the proliferation of CD138+ cells isolated from MM patient samples in a concentration dependent manner. TQ also potentiated the apoptotic effects of bortezomib in various MM cell lines through the activation of caspase-3, resulting in the cleavage of PARP. TQ treatment also inhibited chemotaxis and invasion induced by CXCL12 in MM cells. Furthermore, in a xenograft mouse model, TQ potentiated the antitumor effects of bortezomib (p<0.05, vehicle versus bortezomib + TQ; p<0.05, bortezomib versus bortezomib + TQ), and this correlated with modulation of various markers for survival and angiogenesis, such as Ki-67, vascular endothelial growth factor (VEGF), Bcl-2 and p65 expression. Overall, our results demonstrate that TQ can enhance the anticancer activity of bortezomib in vitro and in vivo and may have a substantial potential in the treatment of MM. PMID:24504138

  4. Establishment of animal model for the analysis of cancer cell metastasis during radiotherapy

    International Nuclear Information System (INIS)

    Γ-Ionizing radiation (IR) therapy is one of major therapeutic tools in cancer treatment. Nevertheless, γ-IR therapy failed due to occurrence of metastasis, which constitutes a significant obstacle in cancer treatment. The main aim of this investigation was to construct animal model which present metastasis during radiotherapy in a mouse system in vivo and establishes the molecular mechanisms involved. The C6L transfectant cell line expressing firefly luciferase (fLuc) was treated with γ-IR, followed by immunoblotting, zymography and invasion assay in vitro. We additionally employed the C6L transfectant cell line to construct xenografts in nude mice, which were irradiated with γ-IR. Irradiated xenograft-containing mice were analyzed via survival curves, measurement of tumor size, and bioluminescence imaging in vivo and ex vivo. Metastatic lesions in organs of mice were further assessed using RT-PCR, H & E staining and immunohistochemistry. γ-IR treatment of C6L cells induced epithelial-mesenchymal transition (EMT) and increased cell invasion. In irradiated xenograft-containing mice, tumor sizes were decreased dramatically and survival rates extended. Almost all non-irradiated xenograft-containing control mice had died within 4 weeks. However, we also observed luminescence signals in about 22.5% of γ-IR-treated mice. Intestines or lungs of mice displaying luminescence signals contained several lesions, which expressed the fLuc gene and presented histological features of cancer tissues as well as expression of EMT markers. These findings collectively indicate that occurrences of metastases during γ-IR treatment accompanied induction of EMT markers, including increased MMP activity. Establishment of a murine metastasis model during γ-IR treatment should aid in drug development against cancer metastasis and increase our understanding of the mechanisms underlying the metastatic process

  5. Engineered Swine Models of Cancer.

    Science.gov (United States)

    Watson, Adrienne L; Carlson, Daniel F; Largaespada, David A; Hackett, Perry B; Fahrenkrug, Scott C

    2016-01-01

    Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of cancer may be extremely valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Hence, the benefits of using swine as a large animal model in cancer research and the potential applications and future opportunities of utilizing pigs in cancer modeling are immense. In this review, we discuss how pigs have been and can be used as a biomedical models for cancer research, with an emphasis on current technologies. We have focused on applications of precision genetics that can provide models that mimic human cancer predisposition syndromes. In particular, we describe the advantages of targeted gene-editing using custom endonucleases, specifically TALENs and CRISPRs, and transposon systems, to make novel pig models of cancer with broad preclinical applications. PMID:27242889

  6. Engineered Swine Models of Cancer

    Science.gov (United States)

    Watson, Adrienne L.; Carlson, Daniel F.; Largaespada, David A.; Hackett, Perry B.; Fahrenkrug, Scott C.

    2016-01-01

    Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of cancer may be extremely valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Hence, the benefits of using swine as a large animal model in cancer research and the potential applications and future opportunities of utilizing pigs in cancer modeling are immense. In this review, we discuss how pigs have been and can be used as a biomedical models for cancer research, with an emphasis on current technologies. We have focused on applications of precision genetics that can provide models that mimic human cancer predisposition syndromes. In particular, we describe the advantages of targeted gene-editing using custom endonucleases, specifically TALENs and CRISPRs, and transposon systems, to make novel pig models of cancer with broad preclinical applications.

  7. Engineered Swine Models of Cancer

    Directory of Open Access Journals (Sweden)

    Adrienne L. Watson

    2016-05-01

    Full Text Available Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of cancer may be extremely valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Hence, the benefits of using swine as a large animal model in cancer research and the potential applications and future opportunities of utilizing pigs in cancer modeling are immense. In this review, we discuss how pigs have been and can be used as a biomedical models for cancer research, with an emphasis on current technologies. We have focused on applications of precision genetics that can provide models that mimic human cancer predisposition syndromes. In particular, we describe the advantages of targeted gene-editing using custom endonucleases, specifically TALENs and CRISPRs, and transposon systems, to make novel pig models of cancer with broad preclinical applications.

  8. Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models

    Science.gov (United States)

    Mazza, Tommaso; Panebianco, Concetta; Saracino, Chiara; Pereira, Stephen P.; Graziano, Paolo; Pazienza, Valerio

    2015-01-01

    Background/aims Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. Short-term fasting cycles have been shown to potentiate the efficacy of chemotherapy against glioma. The aim of this study was to assess the effect of fasting cycles on the efficacy of gemcitabine, a standard treatment for PC patients, in vitro and in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods BxPC-3, MiaPaca-2 and Panc-1 cells were cultured in standard and fasting mimicking culturing condition to evaluate the effects of gemcitabine. Pancreatic cancer xenograft mice were subjected to 24h starvation prior to gemcitabine injection to assess the tumor volume and weight as compared to mice fed ad libitum. Results Fasted pancreatic cancer cells showed increased levels of equilibrative nucleoside transporter (hENT1), the transporter of gemcitabine across the cell membrane, and decreased ribonucleotide reductase M1 (RRM1) levels as compared to those cultured in standard medium. Gemcitabine was more effective in inducing cell death on fasted cells as compared to controls. Consistently, xenograft pancreatic cancer mice subjected to fasting cycles prior to gemcitabine injection displayed a decrease of more than 40% in tumor growth. Conclusion Fasting cycles enhance gemcitabine effect in vitro and in the in vivo PC xenograft mouse model. These results suggest that restrictive dietary interventions could enhance the efficacy of existing cancer treatments in pancreatic cancer patients. PMID:26176887

  9. Imaging studies of breast cancer xenografts. Monoclonal anti-mucin antibodies BM-7 and 12H12 labeled with 99mTC

    International Nuclear Information System (INIS)

    The present study was undertaken to evaluate the correlation of the favourable in vitro characteristics of the anit-mucin Mabs 12H12 and BM-7 with high tumor accumulation in vivo. They were labeled with 99mTc; their biodistribution in nude mice bearing mammary tumor xenograft AR was examined and immunoscintigraphy was performed after 24 h. 99mTc-labeling of the Mabs 12H12 and BM-7 led to tumor uptakes of 20.7% and 8.8% ID/g, respectively, after 48 h. Tumor-to-muscle ratios were 31 (12H12) and 18 (BM-7). Tumor xenografts were clearly visualized in immunoscintigrams. Combination of Mab 12H12 and 99mTc provides high tumor-to-tissue ratios shortly after administration. (orig.)

  10. Pharmacokinetic modelling of N-(4-[18F]fluorobenzoyl)interleukin-2 binding to activated lymphocytes in an xenograft model of inflammation

    International Nuclear Information System (INIS)

    N-(4-[18F]Fluorobenzoyl)interleukin-2 ([18F]FB-IL2) specifically binds to interleukin-2 receptors (IL-2R) and thus may be used to detect inflammation processes using positron emission tomography (PET). We now validated whether [18F]FB-IL2 can be used to quantify activated human peripheral blood mononuclear cells (hPBMC) in rats by pharmacokinetic modelling. Eleven Wistar rats were subcutaneously inoculated in the shoulder with different amounts of phytohaemagglutinin (PHA) activated hPBMC 15 min before i.v. injection of [18F]FB-IL2. A 60-min dynamic PET scan was acquired and arterial blood sampling and metabolite analysis were performed. At the end of the scan, animals were terminated and the inflammatory lesion dissected. PET data were analysed using Logan and Patlak analysis as well as one-tissue and two-tissue compartment models. Model preferences according to the Akaike information criterion (AIC) and correlation between PET measurements and the number of CD25-positive cells were evaluated. A high correlation between ex vivo tracer uptake (standardized uptake value) in the xenograft and the number of inoculated CD25-positive cells was observed (R 2 = 0.90). Plasma time-activity curves showed a rapid washout of the radiopharmaceutical from blood, while the time-activity curves of the inflammatory lesions showed slower washout. Time-activity curves could be fitted well by the Logan analysis method, indicating that the binding between [18F]FB-IL2 and CD25 is reversible. AIC indicated that data could be modelled best by a two-tissue reversible compartment model. A high correlation was observed between the binding potential and the number of CD25-positive cells (R 2 = 0.876, p 18F]FB-IL2 kinetics in this animal model of inflammation could be best described by a reversible two-tissue compartment model. The [18F]FB-IL2 binding potential is a suitable measure for accurate quantification of lymphocytic infiltration in pathological conditions with PET. (orig.)

  11. Pharmacokinetic modelling of N-(4-[{sup 18}F]fluorobenzoyl)interleukin-2 binding to activated lymphocytes in an xenograft model of inflammation

    Energy Technology Data Exchange (ETDEWEB)

    di Gialleonardo, Valentina; Signore, Alberto [University, Nuclear Medicine Unit, Faculty of Medicine and Psychology, Rome (Italy); University, Medicina Nucleare, Ospedale S.Andrea, Rome (Italy); Willemsen, Antoon T.M.; Sijbesma, Jurgen W.A.; Dierckx, Rudi A.J.O.; Vries, Erik F.J. de [University, Nuclear Medicine Unit, Faculty of Medicine and Psychology, Rome (Italy)

    2012-10-15

    N-(4-[{sup 18}F]Fluorobenzoyl)interleukin-2 ([{sup 18}F]FB-IL2) specifically binds to interleukin-2 receptors (IL-2R) and thus may be used to detect inflammation processes using positron emission tomography (PET). We now validated whether [{sup 18}F]FB-IL2 can be used to quantify activated human peripheral blood mononuclear cells (hPBMC) in rats by pharmacokinetic modelling. Eleven Wistar rats were subcutaneously inoculated in the shoulder with different amounts of phytohaemagglutinin (PHA) activated hPBMC 15 min before i.v. injection of [{sup 18}F]FB-IL2. A 60-min dynamic PET scan was acquired and arterial blood sampling and metabolite analysis were performed. At the end of the scan, animals were terminated and the inflammatory lesion dissected. PET data were analysed using Logan and Patlak analysis as well as one-tissue and two-tissue compartment models. Model preferences according to the Akaike information criterion (AIC) and correlation between PET measurements and the number of CD25-positive cells were evaluated. A high correlation between ex vivo tracer uptake (standardized uptake value) in the xenograft and the number of inoculated CD25-positive cells was observed (R {sup 2} = 0.90). Plasma time-activity curves showed a rapid washout of the radiopharmaceutical from blood, while the time-activity curves of the inflammatory lesions showed slower washout. Time-activity curves could be fitted well by the Logan analysis method, indicating that the binding between [{sup 18}F]FB-IL2 and CD25 is reversible. AIC indicated that data could be modelled best by a two-tissue reversible compartment model. A high correlation was observed between the binding potential and the number of CD25-positive cells (R {sup 2} = 0.876, p < 0.0001). Based on binding potential measured by PET, the limit of detection was about 160,000 CD25-positive cells per 200 {mu}l lesion (95 % confidence). [{sup 18}F]FB-IL2 kinetics in this animal model of inflammation could be best described by a

  12. Tumor Accumulation of NIR Fluorescent PEG-PLA Nanoparticles: Impact of Particle Size and Human Xenograft Tumor Model

    DEFF Research Database (Denmark)

    Schädlich, Andreas; Caysa, Henrike; Mueller, Thomas;

    2011-01-01

    Cancer therapies are often terminated due to serious side effects of the drugs. The cause is the nonspecific distribution of chemotherapeutic agents to both cancerous and normal cells. Therefore, drug carriers which deliver their toxic cargo specific to cancer cells are needed. Size is one key......(lactide) block polymers were synthesized and used for the production of three defined, stable, and nontoxic near-infrared (NIR) dye-loaded nanoparticle batches. Size analysis based on asymmetrical field flow field fractionation coupled with multiangle laser light scattering and photon correlation spectroscopy...

  13. Mouse models for cancer research

    Institute of Scientific and Technical Information of China (English)

    Wei Zhang; Lynette Moore; Ping Ji

    2011-01-01

    Mouse models of cancer enable researchers to leamn about tumor biology in complicated and dynamic physiological systems. Since the development of gene targeting in mice, cancer biologists have been among the most frequent users of transgenic mouse models, which have dramatically increased knowledge about how cancers form and grow. The Chinese Joumnal of Cancer will publish a series of papers reporting the use of mouse models in studying genetic events in cancer cases. This editorial is an overview of the development and applications of mouse models of cancer and directs the reader to upcoming papers describing the use of these models to be published in coming issues, beginning with three articles in the current issue.

  14. The experimental study of radionuclide imaging and treatment of cervical cancer mediated by hNIS gene transfection

    International Nuclear Information System (INIS)

    Objective: To explore the feasibility of imaging and treatment of cervical cancer xenograft model using 131I mediated by hNIS gene transfection. Methods: The cervical cancer xenograft models were established with Hela-NIS( +) cells and Hela cells, respectively. Five Hela-NIS(+) xenograft models and five Hela xenograft models were dynamically imaged at 0.5, 1, 2, 4, 8, 16 and 20 h postinjection of 131I (7.4 MBq). Five Hela-NIS(+) xenograft models were imaged at 0.5, 1, 2, 4, 8, 16, 20 and 25 h postinjection of 99TcmO4- (11.1 MBq). Twenty Hela-NIS(+) cervical cancer xenograft models were randomly divided into four groups: Three 131I treating groups and one control group. The therapeutic effects of 131I at three levels (74, 111, 148 MBq) were investigated following intraperitoneal injection. Results: Hela-NIS(+)human cervical cancer xenografts were established successfully in nude mice. The Hela-NIS(+) xenografts significantly accumulated radioactivity after intraperitoneal injection of 131I, and the radioactivity was persistently present until 20 h postinjection, but Hela xenografts had no radioactive accumulation. The T/B value of the Hela-NIS(+) xenografts reached 17.34 at 8 h postinjection. The imaging with 99TcmO4- showed that the radioactivity was persistently present in Hela-NIS(+) xenografts for almost 25 h. The Hela-NIS(+)xenografts shrinked after 131I treatment. The inhibition ratios of tumor growth in 111 MBq and 148 MBq groups were both significantly higher than that of 74 MBq group (t: 2.74-5.75, P131I and 99TcmO4- and could be treated successfully with 131I. 131I treatment mediated by hNIS gene transfection could be a promising cancer treatment method. (authors)

  15. Effects of Cyclooxygenase Inhibitors in Combination with Taxol on Expression of Cyclin D1 and Ki-67 in a Xenograft Model of Ovarian Carcinoma

    Directory of Open Access Journals (Sweden)

    Liang Wan

    2012-08-01

    Full Text Available The present study was designed to investigate the effects of cyclooxygenase (COX inhibitors in combination with taxol on the expression of cyclin D1 and Ki-67 in human ovarian SKOV-3 carcinoma cells xenograft-bearing mice. The animals were treated with 100 mg/kg celecoxib (a COX-2 selective inhibitor alone, 3 mg/kg SC-560 (a COX-1 selective inhibitor alone by gavage twice a day, 20 mg/kg taxol alone by intraperitoneally (i.p. once a week, or celecoxib/taxol, SC-560/celecoxib, SC-560/taxol or SC-560/celecoxib/taxol, for three weeks. To test the mechanism of the combination treatment, the index of cell proliferation and expression of cyclin D1 in tumor tissues were determined by immunohistochemistry. The mean tumor volume in the treated groups was significantly lower than control (p < 0.05, and in the three-drug combination group, tumor volume was reduced by 58.27% (p < 0.01; downregulated cell proliferation and cyclin D1 expression were statistically significant compared with those of the control group (both p < 0.01. This study suggests that the effects of COX selective inhibitors on the growth of tumors and decreased cell proliferation in a SKOV-3 cells mouse xenograft model were similar to taxol. The three-drug combination showing a better decreasing tendency in growth-inhibitory effect during the experiment may have been caused by suppressing cyclin D1 expression.

  16. Spatial and temporal mapping of heterogeneity in liposome uptake and microvascular distribution in an orthotopic tumor xenograft model.

    Science.gov (United States)

    Ekdawi, Sandra N; Stewart, James M P; Dunne, Michael; Stapleton, Shawn; Mitsakakis, Nicholas; Dou, Yannan N; Jaffray, David A; Allen, Christine

    2015-06-10

    Existing paradigms in nano-based drug delivery are currently being challenged. Assessment of bulk tumor accumulation has been routinely considered an indicative measure of nanomedicine potency. However, it is now recognized that the intratumoral distribution of nanomedicines also impacts their therapeutic effect. At this time, our understanding of the relationship between the bulk (i.e., macro-) tumor accumulation of nanocarriers and their intratumoral (i.e., micro-) distribution remains limited. Liposome-based drug formulations, in particular, suffer from diminished efficacy in vivo as a result of transport-limiting properties, combined with the heterogeneous nature of the tumor microenvironment. In this report, we perform a quantitative image-based assessment of macro- and microdistribution of liposomes. Multi-scalar assessment of liposome distribution was enabled by a stable formulation which co-encapsulates an iodinated contrast agent and a near-infrared fluorescence probe, for computed tomography (CT) and optical microscopy, respectively. Spatio-temporal quantification of tumor uptake in orthotopic xenografts was performed using CT at the bulk tissue level, and within defined sub-volumes of the tumor (i.e., rim, periphery and core). Tumor penetration and relative distribution of liposomes were assessed by fluorescence microscopy of whole tumor sections. Microdistribution analysis of whole tumor images exposed a heterogeneous distribution of both liposomes and tumor vasculature. Highest levels of liposome uptake were achieved and maintained in the well-vascularized tumor rim over the study period, corresponding to a positive correlation between liposome and microvascular density. Tumor penetration of liposomes was found to be time-dependent in all regions of the tumor however independent of location in the tumor. Importantly, a multi-scalar comparison of liposome distribution reveals that macro-accumulation in tissues (e.g., blood, whole tumor) may not reflect

  17. Prevalence of Endogenous CD34+ Adipose Stem Cells Predicts Human Fat Graft Retention in a Xenograft Model

    Science.gov (United States)

    Philips, Brian J.; Grahovac, Tara L.; Valentin, Jolene E.; Chung, Christopher W.; Bliley, Jacqueline M.; Pfeifer, Melanie E.; Roy, Sohini B.; Dreifuss, Stephanie; Kelmendi-Doko, Arta; Kling, Russell E.; Ravuri, Sudheer K.; Marra, Kacey G.; Donnenberg, Vera S.; Donnenberg, Albert D.; Rubin, J. Peter

    2014-01-01

    Background Fat grafting is a promising technique for soft-tissue augmentation, although graft retention is highly unpredictable and factors that affect graft survival have not been well defined. Because of their capacity for differentiation and growth factor release, adipose-derived stem cells may have a key role in graft healing. The authors’ objective was to determine whether biological properties of adipose-derived stem cells present within human fat would correlate with in vivo outcomes of graft volume retention. Methods Lipoaspirate from eight human subjects was processed using a standardized centrifugation technique and then injected subcutaneously into the flanks of 6-week-old athymic nude mice. Graft masses and volumes were measured, and histologic evaluation, including CD31+ staining for vessels, was performed 8 weeks after transplantation. Stromal vascular fraction isolated at the time of harvest from each subject was analyzed for surface markers by multi-parameter flow cytometry, and also assessed for proliferation, differentiation capacity, and normoxic/hypoxic vascular endothelial growth factor secretion. Results Wide variation in percentage of CD34+ progenitors within the stromal vascular fraction was noted among subjects and averaged 21.3 ± 15 percent (mean ± SD). Proliferation rates and adipogenic potential among stromal vascular fraction cells demonstrated moderate interpatient variability. In mouse xenograft studies, retention volumes ranged from approximately 36 to 68 percent after 8 weeks, with an overall average of 52 ± 11 percent. A strong correlation (r = 0.78, slope = 0.76, p < 0.05) existed between stromal vascular fraction percentage of CD34+ progenitors and high graft retention. Conclusion Inherent biological differences in adipose tissue exist between patients. In particular, concentration of CD34+ progenitor cells within the stromal vascular fraction may be one of the factors used to predict human fat graft retention. (Plast

  18. Radiosynthesis, biodistribution and imaging of [11C]YM155, a novel survivin suppressant, in a human prostate tumor-xenograft mouse model

    International Nuclear Information System (INIS)

    Introduction: Sepantronium bromide (YM155) is an antitumor drug in development and is a first-in-class chemical entity, which is a survivin suppressant. We developed a radiosynthesis of [11C]YM155 to non-invasively evaluate its tissue and tumor distribution in mice bearing human prostate tumor xenografts. Methods: Methods utilizing [11C]acetyl chloride and [11C]methyl triflate, both accessible with automated radiosynthesis boxes, were evaluated. The O-methylation of ethanolamine-alkolate with [11C]methyl triflate proved to be the key development toward a rapid and efficient process. The whole-body distribution of [11C]YM155 in PC-3 xenografted mice was examined using a planar positron imaging system (PPIS). Results: Sufficient quantities of radiopharmaceutical grade [11C]YM155 were produced for our PET imaging and distribution studies. The decay corrected (EOB) radiochemical yield was 16–22%, within a synthesis time of 47 min. The radiochemical purity was higher than 99%, and the specific activity was 29–60 GBq/μmol (EOS). High uptake levels of radioactivity (%ID/g, mean ± SE) were observed in tumor (0.0613 ± 0.0056), kidneys (0.0513 ± 0.0092), liver (0.0368 ± 0.0043) and cecum (0.0623 ± 0.0070). The highest tumor uptake was observed at an early time point (from 10 min after) following injection. Tumor-to-blood and tumor-to-muscle uptake ratios of [11C]YM155, at 40 min after injection, were 26.5 (± 2.9) and 25.6 (± 3.6), respectively. Conclusion: A rapid method for producing a radiopharmaceutical grade [11C]YM155 was developed. An in vivo distribution study using PPIS showed high uptake of [11C]YM155 in tumor tissue. Our methodology may facilitate the evaluation and prediction of response to YM155, when given as an anti-cancer agent

  19. Application of proteomics in the study of rodent models of cancer

    DEFF Research Database (Denmark)

    Terp, Mikkel Green; Ditzel, Henrik J

    tumor development from highly matched disease cases and controls with identical environmental and genetic backgrounds, thus providing an excellent method for biomarker discovery. Xenograft and genetically engineered mouse models have been widely used to identify proteomic patterns in tumor tissues and...... plasma samples associated with different stages of human cancer, including early cancer detection and development of metastasis. Here, we review proteomic strategies to identify proteins involved in key cancer processes within such animal models as well as biomarkers for diagnosis, prognosis, and...... monitoring of cancer progression and treatment response. Central to such studies is the ability to ensure at an early stage that the identified proteins are of clinical relevance by examining relevant specimens from larger cohorts of cancer patients....

  20. Animal models and therapeutic molecular targets of cancer: utility and limitations

    Directory of Open Access Journals (Sweden)

    Cekanova M

    2014-10-01

    Full Text Available Maria Cekanova, Kusum Rathore Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA Abstract: Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for patients depends on the selection of appropriate animal experimental models. Cancer research uses animal and human cancer cell lines in vitro to study biochemical pathways in these cancer cells. In this review, we summarize the important animal models of cancer with focus on their advantages and limitations. Mouse cancer models are well known, and are frequently used for cancer research. Rodent models have revolutionized our ability to study gene and protein functions in vivo and to better understand their molecular pathways and mechanisms. Xenograft and chemically or genetically induced mouse cancers are the most commonly used rodent cancer models. Companion animals with spontaneous neoplasms are still an underexploited tool for making rapid advances in human and veterinary cancer therapies by testing new drugs and delivery systems that have shown promise in vitro and in vivo in mouse models. Companion animals have a relatively high incidence of cancers, with biological behavior, response to therapy, and response to cytotoxic agents similar to those in humans. Shorter overall lifespan and more rapid disease progression are factors contributing to the advantages of a companion animal model. In addition, the current focus is on discovering molecular targets for new therapeutic drugs to improve survival and quality of life in cancer patients. Keywords: mouse cancer model, companion animal cancer model, dogs, cats, molecular targets

  1. Longitudinal evaluation of the metabolic response of a tumor xenograft model to single fraction radiation therapy using magnetic resonance spectroscopy

    Science.gov (United States)

    Tessier, A. G.; Yahya, A.; Larocque, M. P.; Fallone, B. G.; Syme, A.

    2014-09-01

    Proton magnetic resonance spectroscopy (MRS) was used to evaluate the metabolic profile of human glioblastoma multiform brain tumors grown as xenografts in nude mice before, and at multiple time points after single fraction radiation therapy. Tumors were grown over the thigh in 16 mice in this study, of which 5 served as untreated controls and 11 had their tumors treated to 800 cGy with 200 kVp x-rays. Spectra were acquired within 24 h pre-treatment, and then at 3, 7 and 14 d post-treatment using a 9.4 T animal magnetic resonance (MR) system. For the untreated control tumors, spectra (1-2 per mouse) were acquired at different stages of tumor growth. Spectra were obtained with the PRESS pulse sequence using a 3  ×  3 × 3 mm3 voxel. Analysis was performed with the LCModel software platform. Six metabolites were profiled for this analysis: alanine (Ala), myo-inositol (Ins), taurine (Tau), creatine and phosphocreatine (Cr + PCr), glutamine and glutamate (Glu + Gln), and total choline (glycerophosphocholine + phosphocholine) (GPC + PCh). For the treated cohort, most metabolite/water concentration ratios were found to decrease in the short term at 3 and 7 d post-treatment, followed by an increase at 14 d post-treatment toward pre-treatment values. The lowest concentrations were observed at 7 d post-treatment, with magnitudes (relative to pre-treatment concentration ratios) of: 0.42  ±  24.6% (Ala), 0.43  ±  15.3% (Ins), 0.68  ±  27.9% (Tau), 0.52  ±  14.6% (GPC+PCh), 0.49  ±  21.0% (Cr + PCr) and 0.78  ±  24.5% (Glu + Gln). Control animals did not demonstrate any significant correlation between tumor volume and metabolite concentration, indicating that the observed kinetics were the result of the therapeutic intervention. We have demonstrated the feasibility of using MRS to follow multiple metabolic markers over time for the purpose of evaluating therapeutic response of tumors to radiation therapy. This study provides

  2. Longitudinal evaluation of the metabolic response of a tumor xenograft model to single fraction radiation therapy using magnetic resonance spectroscopy

    International Nuclear Information System (INIS)

    Proton magnetic resonance spectroscopy (MRS) was used to evaluate the metabolic profile of human glioblastoma multiform brain tumors grown as xenografts in nude mice before, and at multiple time points after single fraction radiation therapy. Tumors were grown over the thigh in 16 mice in this study, of which 5 served as untreated controls and 11 had their tumors treated to 800 cGy with 200 kVp x-rays. Spectra were acquired within 24 h pre-treatment, and then at 3, 7 and 14 d post-treatment using a 9.4 T animal magnetic resonance (MR) system. For the untreated control tumors, spectra (1–2 per mouse) were acquired at different stages of tumor growth. Spectra were obtained with the PRESS pulse sequence using a 3  ×  3 × 3 mm3 voxel. Analysis was performed with the LCModel software platform. Six metabolites were profiled for this analysis: alanine (Ala), myo-inositol (Ins), taurine (Tau), creatine and phosphocreatine (Cr + PCr), glutamine and glutamate (Glu + Gln), and total choline (glycerophosphocholine + phosphocholine) (GPC + PCh). For the treated cohort, most metabolite/water concentration ratios were found to decrease in the short term at 3 and 7 d post-treatment, followed by an increase at 14 d post-treatment toward pre-treatment values. The lowest concentrations were observed at 7 d post-treatment, with magnitudes (relative to pre-treatment concentration ratios) of: 0.42  ±  24.6% (Ala), 0.43  ±  15.3% (Ins), 0.68  ±  27.9% (Tau), 0.52  ±  14.6% (GPC+PCh), 0.49  ±  21.0% (Cr + PCr) and 0.78  ±  24.5% (Glu + Gln). Control animals did not demonstrate any significant correlation between tumor volume and metabolite concentration, indicating that the observed kinetics were the result of the therapeutic intervention. We have demonstrated the feasibility of using MRS to follow multiple metabolic markers over time for the purpose of evaluating therapeutic response of tumors to radiation therapy

  3. Magnetic Nanoparticle-Based Hyperthermia for Head & Neck Cancer in Mouse Models

    Directory of Open Access Journals (Sweden)

    Qun Zhao, Luning Wang, Rui Cheng, Leidong Mao, Robert D. Arnold, Elizabeth W. Howerth, Zhuo G. Chen, Simon Platt

    2012-01-01

    Full Text Available In this study, magnetic iron oxide nanoparticle induced hyperthermia is applied for treatment of head and neck cancer using a mouse xenograft model of human head and neck cancer (Tu212 cell line. A hyperthermia system for heating iron oxide nanoparticles was developed by using alternating magnetic fields. Both theoretical simulation and experimental studies were performed to verify the thermotherapy effect. Experimental results showed that the temperature of the tumor center has dramatically elevated from around the room temperature to about 40oC within the first 5-10 minutes. Pathological studies demonstrate epithelial tumor cell destruction associated with the hyperthermia treatment.

  4. Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with 111In using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts

    International Nuclear Information System (INIS)

    In disseminated prostate cancer, expression of human epidermal growth factor receptor type 2 (HER2) is one of the pathways to androgen independence. Radionuclide molecular imaging of HER2 expression in disseminated prostate cancer might identify patients for HER2-targeted therapy. Affibody molecules are small (7 kDa) targeting proteins with high potential as tracers for radionuclide imaging. The goal of this study was to develop an optimal Affibody-based tracer for visualization of HER2 expression in prostate cancer. A synthetic variant of the anti-HER2 ZHER2:342 Affibody molecule, ZHER2:S1, was N-terminally conjugated with the chelators DOTA, NOTA and NODAGA. The conjugated proteins were biophysically characterized by electrospray ionization mass spectroscopy (ESI-MS), circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis. After labelling with 111In, the biodistribution was assessed in normal mice and the two most promising conjugates were further evaluated for tumour targeting in mice bearing DU-145 prostate cancer xenografts. The HER2-binding equilibrium dissociation constants were 130, 140 and 90 pM for DOTA-ZHER2:S1, NOTA-ZHER2:S1 and NODAGA-ZHER2:S1, respectively. A comparative study of 111In-labelled DOTA-ZHER2:S1, NOTA-ZHER2:S1 and NODAGA-ZHER2:S1 in normal mice demonstrated a substantial influence of the chelators on the biodistribution properties of the conjugates. 111In-NODAGA-ZHER2:S1 had the most rapid clearance from blood and healthy tissues. 111In-NOTA-ZHER2:S1 showed high hepatic uptake and was excluded from further evaluation. 111In-DOTA-ZHER2:S1 and 111In-NODAGA-ZHER2:S1 demonstrated specific uptake in DU-145 prostate cancer xenografts in nude mice. The tumour uptake of 111In-NODAGA-ZHER2:S1, 5.6 ± 0.4%ID/g, was significantly lower than the uptake of 111In-DOTA-ZHER2:S1, 7.4 ± 0.5%ID/g, presumably because of lower bioavailability due to more rapid clearance. 111In-NODAGA-ZHER2:S1 provided higher tumour

  5. Genetic Modification of Cancer Cells Using Non-Viral, Episomal S/MAR Vectors for In Vivo Tumour Modelling

    OpenAIRE

    Orestis Argyros; Suet Ping Wong; Kate Gowers; Richard Paul Harbottle

    2012-01-01

    The development of genetically marked animal tumour xenografts is an area of ongoing research to enable easier and more reliable testing of cancer therapies. Genetically marked tumour models have a number of advantages over conventional tumour models, including the easy longitudinal monitoring of therapies and the reduced number of animals needed for trials. Several different methods have been used in previous studies to mark tumours genetically, however all have limitations, such as genotoxi...

  6. Distinct population of highly malignant cells in a head and neck squamous cell carcinoma cell line established by xenograft model

    Directory of Open Access Journals (Sweden)

    Jan Chia-Ing

    2009-11-01

    Full Text Available Abstract The progression and metastasis of solid tumors, including head and neck squamous cell carcinoma (HNSCC, have been related to the behavior of a small subpopulation of cancer stem cells. Here, we have established a highly malignant HNSCC cell line, SASVO3, from primary tumors using three sequential rounds of xenotransplantation. SASVO3 possesses enhanced tumorigenic ability both in vitro and in vivo. Moreover, SASVO3 exhibits properties of cancer stem cells, including that increased the abilities of sphere-forming, the number of side population cells, the potential of transplanted tumor growth and elevated expression of the stem cell marker Bmi1. Injection of SASVO3 into the tail vein of nude mice resulted in lung metastases. These results are consistent with the postulate that the malignant and/or metastasis potential of HNSCC cells may reside in a stem-like subpopulation.

  7. 5α-Reductase Inhibition Suppresses Testosterone-Induced Initial Regrowth of Regressed Xenograft Prostate Tumors in Animal Models

    OpenAIRE

    Masoodi, Khalid Z.; Ramos Garcia, Raquel; Pascal, Laura E.; Wang, Yujuan; Ma, Hei M.; O'Malley, Katherine; Eisermann, Kurtis; Shevrin, Daniel H.; Nguyen, Holly M.; Vessella, Robert L; Nelson, Joel B.; Parikh, Rahul A.; Wang, Zhou

    2013-01-01

    Androgen deprivation therapy (ADT) is the standard treatment for patients with prostate-specific antigen progression after treatment for localized prostate cancer. An alternative to continuous ADT is intermittent ADT (IADT), which allows recovery of testosterone during off-cycles to stimulate regrowth and differentiation of the regressed prostate tumor. IADT offers patients a reduction in side effects associated with ADT, improved quality of life, and reduced cost with no difference in overal...

  8. Early Treatment Response Monitoring Using 2-Deoxy-2-[18F]fluoro-D-glucose Positron Emission Tomography Imaging during Fractionated Radiotherapy of Head Neck Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Jiayi Huang

    2014-01-01

    Full Text Available Background. To determine the optimal timing and analytic method of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (PET imaging during fractionated radiotherapy (RT to predict tumor control. Methods. Ten head neck squamous cell carcinoma xenografts derived from the UT-14-SCC cell line were irradiated with 50 Gy at 2 Gy per day over 5 weeks. Dynamic PET scans were acquired over 70 minutes at baseline (week 0 and weekly for seven weeks. PET data were analyzed using standard uptake value (SUV, retention index (RI, sensitivity factor (SF, and kinetic index (Ki. Results. Four xenografts had local failure (LF and 6 had local control. Eighty scans from week 0 to week 7 were analyzed. RI and SF after 10 Gy appeared to be the optimal predictors for LF. In contrast, SUV and Ki during RT were not significant predictors for LF. Conclusion. RI and SF of PET obtained after the first week of fractionated RT were the optimal methods and timing to predict tumor control.

  9. Localization of 131I-labelled monoclonal antibody ERIC1 in a subcutaneous xenograft model of neuroblastoma in SCID mice

    International Nuclear Information System (INIS)

    Our purpose was to evaluate a novel strategy of immunolocalization of human neuroblastoma by targeting the neural cell adhesion molecule (NCAM), which is over-expressed on neuroblastoma. Neuroblastoma is the most frequent solid extracranial childhood tumour and also the most common neoplasm in the first year of life. The most frequent metastatic sites are bone, bone marrow and liver. The neural cell adhesion molecule (NCAM) is constitutively expressed on nearly 100% of all neuroblastomas. NCAM has been successfully used as a target for immunotoxines and bi-specific antibodies in multiple myeloma, small cell lung cancer, glioma or neuroblastoma, in vitro and in vivo. NCAM expression was quantified on established neuroblastoma cells by real time PCR and NCAM expression on the cell surface shown by flow cytometry. A SCID mouse model using IMR5-75 neuroblastoma cells to induce subcutaneous tumour growth was established. 131I was used to label monoclonal NCAM specific ERIC1 antibodies generating the 131I-ERIC1 antibody, which shows a high affinity to NCAM also after labelling (KD= 9 x 10-8). Groups of five to six mice received intravenous injections of 3-9 MBq of 131I-ERIC1 on day 0 into the tail vein. At time points 2.5 h, 24 h, 48 h, 72 h and 96 h post injection mice were sacrificed by cervical dislocation. Blood, liver, spleen, kidneys, muscle, femur, thyroid, intestines, lung, tumour and urine were removed and weighed. Organ-specific radioactivity was measured in a well-counter as well as that of the tail and remnant cadavers. Data were calculated as dose per gram of tissue (%ID/g) and tumour to non-tumour ratios (T/NT ratio). For blocking experiments mice were pre-injected with 140μg of unlabelled ERIC1 into the tail vein 24 h prior 131I-ERIC1 application. Mice from these blocking experiments were measured after 72 h. Measurement of organ-specific radioactivity showed low organ-specific uptake (5.33 %ID/g after 72 h), which continuously decreased over the 96 hour

  10. Intracellular Doppler Signatures of Platinum Sensitivity Captured by Biodynamic Profiling in Ovarian Xenografts

    Science.gov (United States)

    Merrill, Daniel; An, Ran; Sun, Hao; Yakubov, Bakhtiyor; Matei, Daniela; Turek, John; Nolte, David

    2016-01-01

    Three-dimensional (3D) tissue cultures are replacing conventional two-dimensional (2D) cultures for applications in cancer drug development. However, direct comparisons of in vitro 3D models relative to in vivo models derived from the same cell lines have not been reported because of the lack of sensitive optical probes that can extract high-content information from deep inside living tissue. Here we report the use of biodynamic imaging (BDI) to measure response to platinum in 3D living tissue. BDI combines low-coherence digital holography with intracellular Doppler spectroscopy to study tumor drug response. Human ovarian cancer cell lines were grown either in vitro as 3D multicellular monoculture spheroids or as xenografts in nude mice. Fragments of xenografts grown in vivo in nude mice from a platinum-sensitive human ovarian cell line showed rapid and dramatic signatures of induced cell death when exposed to platinum ex vivo, while the corresponding 3D multicellular spheroids grown in vitro showed negligible response. The differences in drug response between in vivo and in vitro growth have important implications for predicting chemotherapeutic response using tumor biopsies from patients or patient-derived xenografts.

  11. Hypoxia-induced alteration of tracer accumulation in cultured cancer cells and xenografts in mice: implications for pre-therapeutic prediction of treatment outcomes with 99mTc-sestamibi, 201Tl chloride and 99mTc-HL91

    International Nuclear Information System (INIS)

    Weak visualization of tumours in pre-therapeutic scintigrams with technetium-99m sestamibi (MIBI) is likely a predictive sign of unfavourable tumour response to radiotherapy and chemotherapy. However, factors relating to this scintigraphic finding are not well understood. The presence of hypoxic tumour cells is one of the major reasons for therapeutic failure; consequently, we attempted to determine whether oxygenation status affects 99mTc-MIBI accumulation in tumour cells. LS180 human colon cancer and T24 human bladder cancer cells were incubated in air or N2 gas at 37 C. Cellular uptake of 99mTc-MIBI was subsequently determined at 15, 60 and 120 min. Uptake of thallium-201 chloride was also assessed. Uptake of 99mTc-HL91 was assessed as a hypoxic marker. Accumulation of the tracers in LS180 xenografts was observed in mice treated with 5 mg/kg hydralazine and compared with that in untreated mice. pO2 in the medium and tumours was measured with O2 microelectrodes. N2 gas flow gradually reduced pO2 in the cell suspension to 1-2 mmHg in 60 min. Cellular uptake of 99mTc-MIBI in LS180 cells decreased by approximately 30% in N2 gas in comparison to that in air throughout the study. Hypoxia had a more prominent influence on 201Tl uptake, which displayed a reduction of approximately 60% in N2 gas at 120 min, than on 99mTc-MIBI uptake. On the other hand, N2 gas induced an increase of 170% in 99mTc-HL91 uptake at 120 min, indicating the hypoxic condition of cells. The results of in vitro assays employing the T24 cell line were similar to those obtained with the LS180 cell line. Hydralazine treatment markedly reduced 99mTc-MIBI and 201Tl accumulation in LS180 xenografts; moreover, intratumoural pO2 decreased from 14.5±6.6 mmHg to 7.6±6.2 mmHg. 99mTc-HL91 accumulation in xenografts was markedly increased by hydralazine. In conclusion, hypoxia reduced accumulation of 99mTc-MIBI and 201Tl in tumour cells. Accordingly, hypoxia may be an important factor in terms of the

  12. 辣椒素抑制胰腺癌裸鼠皮下移植瘤生长的实验研究%Capsaicin enhances the anti-tumor effect of gemcitabine on pancreatic cancer cell xenograft

    Institute of Scientific and Technical Information of China (English)

    刘南; 张兆伟; 孙刚

    2013-01-01

    目的 探讨辣椒素增强吉西他滨对胰腺癌T3M4细胞裸鼠移植瘤化疗作用及其机制.方法 建立耐药胰腺癌T3M4细胞的裸鼠皮下移植瘤动物模型,将荷瘤鼠随机分为:N组(生理盐水组),G组(吉西他滨,125 mg/kg),C组(辣椒素,20 mg/kg),G+C组(联合用药,吉西他滨80 mg/kg,辣椒素20 mg/kg).各组给药均采用腹腔注射的方法,每3d一次,共8次.实验过程中测量肿瘤体积.免疫组织化学法检测细胞增殖因子Ki-67、多药耐药蛋白P-gp和核转录因子NF-κB的表达.采用RT-PCR检测核转录因子NF-κB和多药耐药基因MDR1的表达.结果 末次用药1周后G+C组肿瘤体积和质量明显小于其他各组.免疫组织化学染色结果显示C组和G+C组的NF-κB和P-gp蛋白的表达量明显低于N组和G组.G+C组Ki-67的表达量明显低于其他各组.RT-PCR结果显示C组MDR1和NF-κB的表达水平明显低于N组和G组,G+C组NF-κB和MDR1的表达水平明显低于N组和G组.结论 辣椒素可以通过下调NF-κB的表达,抑制MDR1基因表达,有效地增强吉西他滨对胰腺癌T3M4细胞移植瘤的化疗作用.%Objective To investigate the enhanced effect of gemcitabine by capsaicin on T3M4 cell xenograft on athymic.Meethods The models of T3M4 cell xenograft on athymic mouse were established and randomized to four groups with intraperitoneal (IP)injection of different drugs (group N 0.9% sodium chloride),group G(gemcitabine,125 mg/kg),group C (capsaicin 20 mg/kg) and group G + C (gemcitabine 80 mg/kg and capsaicin 20 mg/kg in combination).The drugs were injected once every 3 days,8 times in all.The mice were sacrificed 1 week after the last injection.The tumor volume and tumor weight were measured during the drug therapy.Immunohistochemistry(IHC) was performed to detect the expression of NF-κB,P-gp and Ki-67,RT-PCR was performed to detect the expression of NF-κB and MDR1 mRNA.Results One week after the last administration,the mean tumor volume and tumor

  13. Lung Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing lung cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  14. Prostate Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing prostate cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  15. Breast Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing breast cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  16. Ovarian Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing ovarian cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  17. Cervical Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing cervical cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  18. Liver Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing liver cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  19. Pancreatic Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing pancreatic cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  20. Colorectal Cancer Risk Prediction Models

    Science.gov (United States)

    Developing statistical models that estimate the probability of developing colorectal cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  1. Monitoring the Effects of Anti-angiogenesis on the Radiation Sensitivity of Pancreatic Cancer Xenografts Using Dynamic Contrast-Enhanced Computed Tomography

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Ning [School of Health Sciences, Purdue University, West Lafayette, Indiana (United States); Radiation Oncology, University of Washington, Seattle, Washington (United States); Cao, Minsong [Radiation Oncology, University of California–Los Angeles, Los Angeles, California (United States); Chin-Sinex, Helen; Mendonca, Marc; Ko, Song-Chu [Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana (United States); Stantz, Keith M., E-mail: kstantz@purdue.edu [School of Health Sciences, Purdue University, West Lafayette, Indiana (United States); Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana (United States)

    2014-02-01

    Purpose: To image the intratumor vascular physiological status of pancreatic tumors xenografts and their response to anti-angiogenic therapy using dynamic contrast-enhanced computed tomography (DCE-CT), and to identify parameters of vascular physiology associated with tumor x-ray sensitivity after anti-angiogenic therapy. Methods and Materials: Nude mice bearing human BxPC-3 pancreatic tumor xenografts were treated with 5 Gy of radiation therapy (RT), either a low dose (40 mg/kg) or a high dose (150 mg/kg) of DC101, the anti-VEGF receptor-2 anti-angiogenesis antibody, or with combination of low or high dose DC101 and 5 Gy RT (DC101-plus-RT). DCE-CT scans were longitudinally acquired over a 3-week period post-DC101 treatment. Parametric maps of tumor perfusion and fractional plasma volume (F{sub p}) were calculated and their averaged values and histogram distributions evaluated and compared to controls, from which a more homogeneous physiological window was observed 1-week post-DC101. Mice receiving a combination of DC101-plus-RT(5 Gy) were imaged baseline before receiving DC101 and 1 week after DC101 (before RT). Changes in perfusion and F{sub p} were compared with alternation in tumor growth delay for RT and DC101-plus-RT (5 Gy)-treated tumors. Results: Pretreatment with low or high doses of DC101 before RT significantly delayed tumor growth by an average 7.9 days compared to RT alone (P ≤ .01). The increase in tumor growth delay for the DC101-plus-RT-treated tumors was strongly associated with changes in tumor perfusion (ΔP>−15%) compared to RT treated tumors alone (P=.01). In addition, further analysis revealed a trend linking the tumor's increased growth delay to its tumor volume-to-DC101 dose ratio. Conclusions: DCE-CT is capable of monitoring changes in intratumor physiological parameter of tumor perfusion in response to anti-angiogenic therapy of a pancreatic human tumor xenograft that was associated with enhanced radiation response.

  2. Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy

    Directory of Open Access Journals (Sweden)

    Liu Hui

    2009-07-01

    Full Text Available Abstract Background GLV-1h68 is an attenuated recombinant vaccinia virus (VACV that selectively colonizes established human xenografts inducing their complete regression. Results Here, we explored xenograft/VACV/host interactions in vivo adopting organism-specific expression arrays and tumor cell/VACV in vitro comparing VACV replication patterns. There were no clear-cut differences in vitro among responding and non-responding tumors, however, tumor rejection was associated in vivo with activation of interferon-stimulated genes (ISGs and innate immune host's effector functions (IEFs correlating with VACV colonization of the xenografts. These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD that causes tumor or allograft rejection, autoimmunity or clearance of pathogens. We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR. Conclusion This study provides the first prospective validation of a universal mechanism associated with TSD. Thus, xenograft infection by oncolytic VACV, beyond offering a promising therapy of established cancers, may represent a reliable pre-clinical model to test therapeutic strategies aimed at modulating the central pathways leading to TSD; this information may lead to the identification of principles that could refine the treatment of cancer and chronic infection by immune stimulation or autoimmunity and allograft rejection through immune tolerance.

  3. Assessing Metabolic Changes in Response to mTOR Inhibition in a Mantle Cell Lymphoma Xenograft Model Using AcidoCEST MRI.

    Science.gov (United States)

    Akhenblit, Paul J; Hanke, Neale T; Gill, Alexander; Persky, Daniel O; Howison, Christine M; Pagel, Mark D; Baker, Amanda F

    2016-01-01

    AcidoCEST magnetic resonance imaging (MRI) has previously been shown to measure tumor extracellular pH (pHe) with excellent accuracy and precision. This study investigated the ability of acidoCEST MRI to monitor changes in tumor pHe in response to therapy. To perform this study, we used the Granta 519 human mantle cell lymphoma cell line, which is an aggressive B-cell malignancy that demonstrates activation of the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. We performed in vitro and in vivo studies using the Granta 519 cell line to investigate the efficacy and associated changes induced by the mTOR inhibitor, everolimus (RAD001). AcidoCEST MRI studies showed a statistically significant increase in tumor pHe of 0.10 pH unit within 1 day of initiating treatment, which foreshadowed a decrease in tumor growth of the Granta 519 xenograft model. AcidoCEST MRI then measured a decrease in tumor pHe 7 days after initiating treatment, which foreshadowed a return to normal tumor growth rate. Therefore, this study is a strong example that acidoCEST MRI can be used to measure tumor pHe that may serve as a marker for therapeutic efficacy of anticancer therapies. PMID:27140422

  4. Inhibition of p300 lysine acetyltransferase activity by luteolin reduces tumor growth in head and neck squamous cell carcinoma (HNSCC) xenograft mouse model.

    Science.gov (United States)

    Selvi, Ruthrotha B; Swaminathan, Amrutha; Chatterjee, Snehajyoti; Shanmugam, Muthu K; Li, Feng; Ramakrishnan, Gowsica B; Siveen, Kodappully Sivaraman; Chinnathambi, Arunachalam; Zayed, M Emam; Alharbi, Sulaiman Ali; Basha, Jeelan; Bhat, Akshay; Vasudevan, Madavan; Dharmarajan, Arunasalam; Sethi, Gautam; Kundu, Tapas K

    2015-12-22

    Chromatin acetylation is attributed with distinct functional relevance with respect to gene expression in normal and diseased conditions thereby leading to a topical interest in the concept of epigenetic modulators and therapy. We report here the identification and characterization of the acetylation inhibitory potential of an important dietary flavonoid, luteolin. Luteolin was found to inhibit p300 acetyltransferase with competitive binding to the acetyl CoA binding site. Luteolin treatment in a xenografted tumor model of head and neck squamous cell carcinoma (HNSCC), led to a dramatic reduction in tumor growth within 4 weeks corresponding to a decrease in histone acetylation. Cells treated with luteolin exhibit cell cycle arrest and decreased cell migration. Luteolin treatment led to an alteration in gene expression and miRNA profile including up-regulation of p53 induced miR-195/215, let7C; potentially translating into a tumor suppressor function. It also led to down-regulation of oncomiRNAs such as miR-135a, thereby reflecting global changes in the microRNA network. Furthermore, a direct correlation between the inhibition of histone acetylation and gene expression was established using chromatin immunoprecipitation on promoters of differentially expressed genes. A network of dysregulated genes and miRNAs was mapped along with the gene ontology categories, and the effects of luteolin were observed to be potentially at multiple levels: at the level of gene expression, miRNA expression and miRNA processing. PMID:26517526

  5. Effect of endocrine therapy on growth of T61 human breast cancer xenografts is directly correlated to a specific down-regulation of insulin-like growth factor II (IGF-II)

    DEFF Research Database (Denmark)

    Brünner, N; Yee, D; Kern, F G;

    1993-01-01

    Insulin-like growth factors I and II (IGF-I and IGF-II) are potent mitogens for some human breast cancer cell lines, and expression of IGF-II mRNA in the oestrogen receptor-positive (ER+) and oestradiol (E2) stimulated human breast cancer cell line T47D is increased by E2, suggesting a role for IGF......-II in the mitogenic response to E2. Very little information is available from the literature on the relation between growth inhibition by endocrine therapy and cellular production of IGF-II. Here we report on the effect of E2 and tamoxifen (TAM) on IGF-II mRNA and protein expression in the ER+T61 human...... breast cancer xenograft. Growth of the T61 tumour is inhibited by treatment with E2 and TAM. Ribonuclease (RNAse) protection assays with human- and mouse-specific IGF-II antisense probes were used to study the regulation of IGF-II mRNA by E2 and TAM in the tumour. IGF-II protein expression was studied by...

  6. Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models: an effect mediated by EGFR inhibition, p53 acetylation and oxidative stress

    OpenAIRE

    Huang, Liqun; WONG, CHI C.; Mackenzie, Gerardo G; Sun, Yu; Cheng, Ka Wing; Vrankova, Kvetoslava; Alston, Ninche; Ouyang, Nengtai; Rigas, Basil

    2014-01-01

    Background The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its chemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC). Methods Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic stud...

  7. Engineered Swine Models of Cancer

    OpenAIRE

    Watson, Adrienne L; Carlson, Daniel F.; Largaespada, David A; Hackett, Perry B; Fahrenkrug, Scott C.

    2016-01-01

    Over the past decade, the technology to engineer genetically modified swine has seen many advancements, and because their physiology is remarkably similar to that of humans, swine models of cancer may be extremely valuable for preclinical safety studies as well as toxicity testing of pharmaceuticals prior to the start of human clinical trials. Hence, the benefits of using swine as a large animal model in cancer research and the potential applications and future opportunities of utilizing pigs...

  8. WNT signaling enhances breast cancer cell motility and blockade of the WNT pathway by sFRP1 suppresses MDA-MB-231 xenograft growth

    OpenAIRE

    Matsuda, Yutaka; Schlange, Thomas; Oakeley, Edward J.; Boulay, Anne; Nancy E Hynes

    2009-01-01

    Introduction In breast cancer, deregulation of the WNT signaling pathway occurs by autocrine mechanisms. WNT ligands and Frizzled receptors are coexpressed in primary breast tumors and cancer cell lines. Moreover, many breast tumors show hypermethylation of the secreted Frizzled-related protein 1 (sFRP1) promoter region, causing low expression of this WNT antagonist. We have previously shown that the WNT pathway influences proliferation of breast cancer cell lines via activation of canonical ...

  9. Generation of human/rat xenograft animal model for the study of human donor stem cell behaviors in vivo

    OpenAIRE

    Sun, Yan; Xiao, Dong; Pan, Xing-hua; Zhang, Ruo-Shuang; Cui, Guang-Hui; Chen, Xi-Gu

    2007-01-01

    AIM: To accurately and realistically elucidate human stem cell behaviors in vivo and the fundamental mechanisms controlling human stem cell fates in vivo, which is urgently required in regenerative medicine and treatments for some human diseases, a surrogate human-rat chimera model was developed.

  10. EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

    Directory of Open Access Journals (Sweden)

    Hongsheng Miao

    Full Text Available Glioblastoma (GBM is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.

  11. Mouse models of pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Marta Herreros-Villanueva; Elizabeth Hijona; Angel Cosme; Luis Bujanda

    2012-01-01

    Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States,and potent therapeutic options are lacking.Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer,currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed.In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes.In the last few years,several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed.These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer.Genetic alterations such as activating mutations in KRas,or TGFb and/or inactivation of tumoral suppressors such as p53,INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice.These mouse models have a spectrum of pathologic changes,from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system.These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches,chemopreventive and/or anticancer treatments.Here,we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments.

  12. Mouse models for colorectal cancer

    OpenAIRE

    KARIM, BAKTIAR O.; Huso, David L.

    2013-01-01

    Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States, with the number of affected people increasing. There are many risk factors that increase CRC risk, including family or personal history of CRC, smoking, consumption of red meat, obesity, and alcohol consumption. Conversely, increased screening, maintaining healthy body weight, not smoking, and limiting intake of red meat are all associated with reduced CRC morbidity and mortality. Mouse models of ...

  13. Successful high-resolution animal positron emission tomography of human Ewing tumours and their metastases in a murine xenograft model

    Energy Technology Data Exchange (ETDEWEB)

    Franzius, Christiane; Hermann, Sven; Schaefers, Klaus; Schober, Otmar; Schaefers, Michael [University Hospital Muenster, Department of Nuclear Medicine, Muenster (Germany); Hotfilder, Marc; Juergens, Heribert [University Hospital Muenster, Department of Pediatric Hematology and Oncology, Muenster (Germany); Poremba, Christopher; Gabbert, Helmut E. [Heinrich-Heine-University, Institute of Pathology, Duesseldorf (Germany); Vormoor, Josef [University Hospital Muenster, Department of Pediatric Hematology and Oncology, Muenster (Germany); University of Newcastle upon Tyne, Northern Institute for Cancer Research, Newcastle (United Kingdom)

    2006-12-15

    As primary osseous metastasis is the main adverse prognostic factor in patients with Ewing tumours, a NOD/scid mouse model for human Ewing tumour metastases has been established to examine the mechanisms of metastasis. The aim of this study was to evaluate the feasibility of diagnostic molecular imaging by small animal PET in this mouse model. Human Ewing tumour cells were transplanted into immune-deficient NOD/scid mice via s.c injection (n=17) or i.v. injection (n=17). The animals (mean weight 23.2 g) were studied 2-7 weeks after transplantation using a submillimetre resolution animal PET scanner. To assess glucose utilisation and bone metabolism, mice were scanned after intravenous injection of 9.6 MBq (mean) 2-[{sup 18}F]fluoro-2-deoxy-D-glucose (FDG) or 9.4 MBq (mean) [{sup 18}F]fluoride. Whole-body PET images were analysed visually and semi-quantitatively [%ID/g, tumour to non-tumour ratio (T/NT)]. Foci of pathological uptake were identified with respect to the physiological organ uptake in corresponding regions. Subcutaneously transplanted Ewing tumours demonstrated a moderately increased glucose uptake (median %ID/g 2.5; median T/NT 2.2). After i.v. transplantation, the pattern of metastasis was similar to that in patients with metastases in lung, bone and soft tissue. These metastases showed an increased FDG uptake (median %ID/g 3.6; median T/NT 2.7). Osseous metastases were additionally visible on [{sup 18}F]fluoride PET by virtue of decreased [{sup 18}F]fluoride uptake (osteolysis; median %ID/g 8.4; median T/NT 0.59). Metastases were confirmed immunohistologically. Diagnostic molecular imaging of Ewing tumours and their small metastases in an in vivo NOD/scid mouse model is feasible using a submillimetre resolution PET scanner. (orig.)

  14. Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Manbok, E-mail: manbok66@dankook.ac.kr [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Rahman, Masmudur M. [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States); Cogle, Christopher R. [Department of Hematology/Oncology, University of Florida, Gainesville, FL 32610 (United States); McFadden, Grant [Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610 (United States)

    2015-07-10

    Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases.

  15. Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease

    International Nuclear Information System (INIS)

    Epstein–Barr virus (EBV) has been associated with a variety of epithelial and hematologic malignancies, including B-, T- and NK cell-lymphomas, Hodgkin's disease (HD), post-transplant lymphoproliferative diseases (LPDs), nasopharyngeal and gastric carcinomas, smooth muscle tumors, and HIV-associated lymphomas. Currently, treatment options for EBV-associated malignancies are limited. We have previously shown that myxoma virus specifically targets various human solid tumors and leukemia cells in a variety of animal models, while sparing normal human or murine tissues. Since transplant recipients of bone marrow or solid organs often develop EBV-associated post-transplant LPDs and lymphoma, myxoma virus may be of utility to prevent EBV-associated malignancies in immunocompromised transplant patients where treatment options are frequently limited. In this report, we demonstrate the safety and efficacy of myxoma virus purging as a prophylactic strategy for preventing post-transplant EBV-transformed human lymphomas, using a highly immunosuppressed mouse xenotransplantation model. This provides support for developing myxoma virus as a potential oncolytic therapy for preventing EBV-associated LPDs following transplantation of bone marrow or solid organ allografts. - Highlights: • Myxoma virus effectively infects and purges EBV lymphoma cells in vivo. • Oncolytic myxoma virus effectively eradicates oncogenic EBV tumorigenesis. • Ex vivo pre-treatment of myxoma virus can be effective as a preventive treatment modality for post-transplant lymphoproliferative diseases

  16. Imaging and histological characterization of a human brain xenograft in pig: the first induced glioma model in a large animal.

    Science.gov (United States)

    Selek, Laurent; Seigneuret, Eric; Nugue, Guillaume; Wion, Didier; Nissou, Marie France; Salon, Caroline; Seurin, Marie José; Carozzo, Claude; Ponce, Frédérique; Roger, Thierry; Berger, François

    2014-01-15

    The prognosis of glioblastoma remains poor despite significant improvement in cytoreductive surgery, external irradiation and new approach of systemic treatment as antiangiogenic therapy. One of the issues is the low concentration in the infiltrated parenchyma of therapeutic agent administered intravenously mainly due to the blood-brain barrier. An intracerebral injection is advocated to overpass this barrier, this kind of administration need a low flow and continuous injection. The development of sophisticated implanted devices for convection-enhanced delivery is a mandatory step to have a controlled released of a therapeutic agent in glioblastoma treatment. Before testing such a device in a clinical trial a serious preclinical studies are required, in order to test it in realistic conditions we have develop the first induced high grade glioma model in a non-rodent animal: the pig. 21 pigs have been implanted in the parietal lobe with human glioblastoma cell lineage under a chemical immunosuppression by ciclosporine. A MRI follow up was then realized. 15 pigs have been implanted with U87MG, 14 have presented a macroscopic significant tumor, with radiological and anatomapathological characteristics of high grade glioma. 6 pigs were implanted with G6, stem-like cells tumors of glioblastoma, 1 pig develops a macroscopic tumor. This is the first reproducible glioma model in a large animal described, it open the way to preclinical studies to test implanted devices in anatomic realistic conditions, without the ethical issues of a primate use. PMID:24126047

  17. Investigation of the origin of stromal and endothelial cells at the desmoplastic interface in xenograft tumor in mice.

    Science.gov (United States)

    Jung, Minsun; Ryu, Young-joon; Kang, Gu

    2015-12-01

    Carcinoma-associated fibroblasts found at the interface between a tumor and the normal stroma play several roles in the development of cancer, including cancer initiation, growth, and progression, thereby also affecting patient prognosis. Although recent studies have focused on carcinoma-associated fibroblasts as potential treatment targets, the origin of these fibroblasts remains unclear. One theory suggests that these cells arise from tumor cells undergoing the epithelial-mesenchymal transition, i.e., tumor cells transform into carcinoma-associated fibroblasts. Therefore, in this study, we aimed to elucidate the cellular origin of carcinoma-associated fibroblasts in a mouse xenograft model. Mice were transplanted with human lung cancer cells (H226 and A549 cells). After sacrifice, tumor masses and surrounding tissues were excised. Interestingly, the excised xenograft tissues contained a significant proportion of desmoplastic fibroblasts that exhibited strong expression of α-smooth muscle actin (SMA). Immunohistochemical staining with pan-cytokeratin, vimentin, β-catenin, E-cadherin, and CD34 showed no evidence of the epithelial-mesenchymal transition. Additional evaluation using dual-color silver in situ hybridization with dinitrophenyl-labeled human epidermal growth factor receptor 2 (HER2) and digoxigenin-labeled chromosome 17 centromere probes also showed similar results. In conclusion, our results revealed that the epithelial-mesenchymal transition may not occur in tumor xenograft models, regardless of evidence supporting this phenomenon in humans. PMID:26564105

  18. Establishment of a human multiple myeloma xenograft model in the chicken to study tumor growth, invasion and angiogenesis.

    Science.gov (United States)

    Martowicz, Agnieszka; Kern, Johann; Gunsilius, Eberhard; Untergasser, Gerold

    2015-01-01

    Multiple myeloma (MM), a malignant plasma cell disease, remains incurable and novel drugs are required to improve the prognosis of patients. Due to the lack of the bone microenvironment and auto/paracrine growth factors human MM cells are difficult to cultivate. Therefore, there is an urgent need to establish proper in vitro and in vivo culture systems to study the action of novel therapeutics on human MM cells. Here we present a model to grow human multiple myeloma cells in a complex 3D environment in vitro and in vivo. MM cell lines OPM-2 and RPMI-8226 were transfected to express the transgene GFP and were cultivated in the presence of human mesenchymal cells and collagen type-I matrix as three-dimensional spheroids. In addition, spheroids were grafted on the chorioallantoic membrane (CAM) of chicken embryos and tumor growth was monitored by stereo fluorescence microscopy. Both models allow the study of novel therapeutic drugs in a complex 3D environment and the quantification of the tumor cell mass after homogenization of grafts in a transgene-specific GFP-ELISA. Moreover, angiogenic responses of the host and invasion of tumor cells into the subjacent host tissue can be monitored daily by a stereo microscope and analyzed by immunohistochemical staining against human tumor cells (Ki-67, CD138, Vimentin) or host mural cells covering blood vessels (desmin/ASMA). In conclusion, the onplant system allows studying MM cell growth and angiogenesis in a complex 3D environment and enables screening for novel therapeutic compounds targeting survival and proliferation of MM cells. PMID:25993267

  19. Current status and evolution of preclinical drug development models of epithelial ovarian cancer

    Directory of Open Access Journals (Sweden)

    Panagiotis A Konstantinopoulos

    2013-12-01

    Full Text Available Epithelial ovarian cancer (EOC is the most lethal gynecologic malignancy and the fifth most common cause of female cancer death in the United States. Although important advances in surgical and chemotherapeutic strategies over the last three decades have significantly improved the median survival of EOC patients, the plateau of the survival curve has not changed appreciably. Given that EOC is a genetically and biologically heterogeneous disease, identification of specific molecular abnormalities that can be targeted in each individual ovarian cancer on the basis of predictive biomarkers promises to be an effective strategy to improve outcome in this disease. However, for this promise to materialize, appropriate preclinical experimental platforms that recapitulate the complexity of these neoplasms and reliably predict antitumor activity in the clinic are critically important. In this review, we will present the current status and evolution of preclinical models of EOC, including cell lines, immortalized normal cells, xenograft models, patient-derived xenografts and animal models, and will discuss their potential for oncology drug development.

  20. Generation of human/rat xenograft animal model for the study of human donor stem cell behaviors in vivo

    Institute of Scientific and Technical Information of China (English)

    Yan Sun; Dong Xiao; Xing-Hua Pan; Ruo-Shuang Zhang; Guang-Hui Cui; Xi-Gu Chen

    2007-01-01

    AIM: To accurately and realistically elucidate human stem cell behaviors In vivo and the fundamental mechanisms controlling human stem cell fates in vivo, which is urgently required in regenerative medicine and treatments for some human diseases, a surrogate human-rat chimera model was developed.METHODS: Human-rat chimeras were achieved by in utero transplanting low-density mononuclear cells from human umbilical cord blood into the fetal rats at 9-11 d of gestation, and subsequently, a variety of methods, including flow cytometry, PCR as well as immunohistochemical assay, were used to test the human donor contribution in the recipients.RESULTS: Of 29 live-born recipients, 19 had the presence of human CD45+ cells in peripheral blood (PB) detected by flow cytometry, while PCR analysis on genomic DNA from 11 different adult tissues showed that 14 selected from flow cytometry-positive 19 animals possessed of donor-derived human cell engraftment in multiple tissues (i.e. liver, spleen, thymus, heart, kidney, blood, lung, muscle, gut and skin) examined at the time of tissue collection, as confirmed by detecting human β2-microglobulin expression using immunohistochemistry.In this xenogeneic system, the engrafted donor-derived human cells persisted in multiple tissues for at least 6 mo after birth. Moreover, transplanted human donor cells underwent site-specific differentiation into CK18-positive human cells in chimeric liver and CD45-positive human cells in chimeric spleen and thymus of recipients.CONCLUSION: Taken together, these findings suggest that we successfully developed human-rat chimeras, in which xenogeneic human cells exist up to 6 mo later. This humanized small animal model, which offers an in vivo environment more closely resembling to the situations in human, provides an invaluable and effective approach for in vivo investigating human stem cell behaviors, and further in vivo examining fundamental mechanisms controlling human stem cell fates in the future

  1. Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with {sup 111}In using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Malmberg, Jennie; Varasteh, Zohreh; Orlova, Anna [Uppsala University, Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala (Sweden); Perols, Anna; Braun, Alexis; Eriksson Karlstroem, Amelie [AlbaNova University Centre, Division of Molecular Biotechnology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm (Sweden); Altai, Mohamed; Tolmachev, Vladimir [Uppsala University, Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala (Sweden); Sandstroem, Mattias [Uppsala University Hospital, Section of Medical Physics, Department of Oncology, Uppsala (Sweden); Garske, Ulrike [Uppsala University Hospital, Department of Medical Sciences, Section of Nuclear Medicine, Uppsala (Sweden)

    2012-03-15

    In disseminated prostate cancer, expression of human epidermal growth factor receptor type 2 (HER2) is one of the pathways to androgen independence. Radionuclide molecular imaging of HER2 expression in disseminated prostate cancer might identify patients for HER2-targeted therapy. Affibody molecules are small (7 kDa) targeting proteins with high potential as tracers for radionuclide imaging. The goal of this study was to develop an optimal Affibody-based tracer for visualization of HER2 expression in prostate cancer. A synthetic variant of the anti-HER2 Z{sub HER2:342} Affibody molecule, Z{sub HER2:S1}, was N-terminally conjugated with the chelators DOTA, NOTA and NODAGA. The conjugated proteins were biophysically characterized by electrospray ionization mass spectroscopy (ESI-MS), circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis. After labelling with {sup 111}In, the biodistribution was assessed in normal mice and the two most promising conjugates were further evaluated for tumour targeting in mice bearing DU-145 prostate cancer xenografts. The HER2-binding equilibrium dissociation constants were 130, 140 and 90 pM for DOTA-Z{sub HER2:S1}, NOTA-Z{sub HER2:S1} and NODAGA-Z{sub HER2:S1}, respectively. A comparative study of {sup 111}In-labelled DOTA-Z{sub HER2:S1}, NOTA-Z{sub HER2:S1} and NODAGA-Z{sub HER2:S1} in normal mice demonstrated a substantial influence of the chelators on the biodistribution properties of the conjugates. {sup 111}In-NODAGA-Z{sub HER2:S1} had the most rapid clearance from blood and healthy tissues. {sup 111}In-NOTA-Z{sub HER2:S1} showed high hepatic uptake and was excluded from further evaluation. {sup 111}In-DOTA-Z{sub HER2:S1} and {sup 111}In-NODAGA-Z{sub HER2:S1} demonstrated specific uptake in DU-145 prostate cancer xenografts in nude mice. The tumour uptake of {sup 111}In-NODAGA-Z{sub HER2:S1}, 5.6 {+-} 0.4%ID/g, was significantly lower than the uptake of {sup 111}In-DOTA-Z{sub HER2:S1

  2. Total lymphoid irradiation and discordant cardiac xenografts

    International Nuclear Information System (INIS)

    Total lymphoid irradiation can prolong concordant cardiac xenografts. The effects of total lymphoid irradiation in a discordant xenograft model (guinea pig to rat) were studied with and without adjuvant pharmacologic immunosuppression. Inbred Lewis rats were randomly allocated to one of four groups. Group 1 (n = 6) served as a control group and rats received no immunosuppression. Group 2 (n = 5) received triple-drug therapy that consisted of intraperitoneal azathioprine (2 mg/kg), cyclosporine (20 mg/kg), and methylprednisolone (1 mg/kg) for 1 week before transplantation. Group 3 animals (n = 5) received 15 Gy of total lymphoid irradiation in 12 divided doses over a 3-week period. Group 4 (n = 6) received both triple-drug therapy and total lymphoid irradiation as described for groups 2 and 3. Complement-dependent cytotoxicity assay was performed to determine if a correlation between complement-dependent cytotoxicity and rejection-free interval existed. Rejection was defined as cessation of graft pulsation and was confirmed by histologic test results. Only groups 1 and 2 showed a difference in survival (group 1, 6.9 +/- 1.0 minutes; group 2, 14.2 +/- 2.7 minutes, p = 0.02). Although total lymphoid irradiation did decrease complement-dependent cytotoxicity, linear regression revealed no correlation between complement-dependent cytotoxicity and graft survival (coefficient of correlation, 0.30). Unlike concordant cardiac xenografts, total lymphoid irradiation with or without triple-drug therapy does not prolong graft survival

  3. Total lymphoid irradiation and discordant cardiac xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Kaplan, E.; Dresdale, A.R.; Diehl, J.T.; Katzen, N.A.; Aronovitz, M.J.; Konstam, M.A.; Payne, D.D.; Cleveland, R.J. (Tufts Univ. School of Medicine, Boston, MA (USA))

    1990-01-01

    Total lymphoid irradiation can prolong concordant cardiac xenografts. The effects of total lymphoid irradiation in a discordant xenograft model (guinea pig to rat) were studied with and without adjuvant pharmacologic immunosuppression. Inbred Lewis rats were randomly allocated to one of four groups. Group 1 (n = 6) served as a control group and rats received no immunosuppression. Group 2 (n = 5) received triple-drug therapy that consisted of intraperitoneal azathioprine (2 mg/kg), cyclosporine (20 mg/kg), and methylprednisolone (1 mg/kg) for 1 week before transplantation. Group 3 animals (n = 5) received 15 Gy of total lymphoid irradiation in 12 divided doses over a 3-week period. Group 4 (n = 6) received both triple-drug therapy and total lymphoid irradiation as described for groups 2 and 3. Complement-dependent cytotoxicity assay was performed to determine if a correlation between complement-dependent cytotoxicity and rejection-free interval existed. Rejection was defined as cessation of graft pulsation and was confirmed by histologic test results. Only groups 1 and 2 showed a difference in survival (group 1, 6.9 +/- 1.0 minutes; group 2, 14.2 +/- 2.7 minutes, p = 0.02). Although total lymphoid irradiation did decrease complement-dependent cytotoxicity, linear regression revealed no correlation between complement-dependent cytotoxicity and graft survival (coefficient of correlation, 0.30). Unlike concordant cardiac xenografts, total lymphoid irradiation with or without triple-drug therapy does not prolong graft survival.

  4. Radiation effects on S-phase duration, labelling index, potential doubling time and DNA distribution in head and neck cancer xenografts

    International Nuclear Information System (INIS)

    The effect of irradiation on S-phase duration (Ts), labelling index (LI), potential doubling time (Tpot), and cell cycle phase distributions was determined by DNA flow cytometry in xenografted human squamous cell carcinoma of the head and neck (SCCHN). Tumours were treated with a single dose of 3 Gy, and excised at intervals over a 90-h period. Six hours before each excision the tumours were labelled in vivo with bromodeoxyuridine (BrdUrd). Although the growth rate of irradiated tumours was comparable with that of untreated controls, analysis of BrdUrd uptake revealed a transient reduction of LI and a prolongation of Ts in irradiated tumours. Maximum mean Tpot was 931 days in irradiated tumours as compared to 13 days in untreated controls. The variations in Ts, LI and Tpot all occurred within the first hours after irradiation; during the remainder of the observation time, the values of the variables did not differ from those of untreated controls. In irradiated tumours the distribution of cells according to DNA content changed significantly on three occasions during the observation period: 1. Parallel to the initial lowering of LI and prolongation of Ts there was a transient increase in the proportion of cells in G0/G1 and a decrease in the proportion of cells in S and G2; 2. at 18 h, the most pronounced cell cycle phase redistribution occurred when the G0/G1 fraction decreased and the S and G2 phase fractions increased; 3. at 66 h (i.e., approximately one cell cycle later), the pattern was the same as that after 18 h. The findings suggest that the transient prolongation of DNA replication seen in SCCHN cells immediately after a single radiation dose is a symptom of DNA damage inflicted during late G1 or early S-phase, and that this disturbance in DNA synthesis is associated with the subsequent accumulation of cells in G2 phase. (orig.)

  5. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death

    OpenAIRE

    Raimondo, S; Naselli, F; S.; Fontana; Monteleone, F.; A. Lo Dico; Saieva, L; Zito, G.; Flugy, A; Manno, M; Di Bella, M; Leo, G.; ALESSANDRO, R

    2015-01-01

    Nanosized vesicles are considered key players in cell to cell communication, thus influencing physiological and pathological processes, including cancer. Nanovesicles have also been found in edible-plants and have shown therapeutic activity in inflammatory bowel diseases; however information on their role in affecting cancer progression is missing. Our study identify for the first time a fraction of vesicles from lemon juice (Citrus limon L.), obtained as a result of different ultracentrifuga...

  6. Photo activation of HPPH encapsulated in “Pocket” liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts

    OpenAIRE

    Sine J; Urban C.; Thayer D; Charron H; Valim N; Tata DB; Schiff R; Blumenthal R; Joshi A; Puri A

    2014-01-01

    Jessica Sine,1,* Cordula Urban,2,* Derek Thayer,1 Heather Charron,2 Niksa Valim,2 Darrell B Tata,3 Rachel Schiff,4 Robert Blumenthal,1 Amit Joshi,2 Anu Puri1 1Membrane Structure and Function Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute – Frederick, Frederick, MD, USA; 2Department of Radiology, Baylor College of Medicine, Houston, TX, USA; 3US Food and Drug Administration, CDRH/OSEL/Division of Physics, White Oak Campus, MD, USA; 4Lester and ...

  7. Photo activation of HPPH encapsulated in “Pocket” liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts

    OpenAIRE

    Puri, Anu

    2014-01-01

    Jessica Sine,1,* Cordula Urban,2,* Derek Thayer,1 Heather Charron,2 Niksa Valim,2 Darrell B Tata,3 Rachel Schiff,4 Robert Blumenthal,1 Amit Joshi,2 Anu Puri1 1Membrane Structure and Function Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute – Frederick, Frederick, MD, USA; 2Department of Radiology, Baylor College of Medicine, Houston, TX, USA; 3US Food and Drug Administration, CDRH/OSEL/Division of Physics, White Oak Campus, MD, USA; 4Lester ...

  8. In vitro and in vivo evaluation of tubulin inhibitors with non-small cell lung cancer pre-clinical models

    Directory of Open Access Journals (Sweden)

    Lama R

    2015-05-01

    Full Text Available Synthetic small molecule tubulin inhibitors have many advantages as novel anti-cancer agents compared to the current tubulin inhibitors generated from natural products. Our previous studies led to the design and synthesis of a series of novel tubulin inhibitors. Some of these compounds also inhibited heat shock protein 27 (Hsp27, and showed promising in vitro anti-cancer activities in several breast cancer cell lines at sub nano-molar concentrations. However, whether these compounds could suppress tumor growth in animals was not investigated yet. In the current study, to identify the best drug candidates, therapeutic efficacy of the representative compounds from previous analyses was evaluated using non-small cell lung cancer preclinical models. These agents dose-dependently inhibited the growth of lung cancer cells in both monolayer cultures and three-dimensional multicellular spheroids. Several compounds also showed promising tumor growth suppressive activity in nude mice xenograft model

  9. Design, Synthesis, and Validation of Axl-Targeted Monoclonal Antibody Probe for microPET Imaging in Human Lung Cancer Xenograft

    OpenAIRE

    Liu, Shuanglong; Li, Dan; Guo, Jiacong; Canale, Nicolette; Li, Xiuqing; Liu, Ren; Krasnoperov, Valery; Gill, Parkash S.; Conti, Peter S.; Shan, Hong; Li, Zibo

    2014-01-01

    Accumulating experimental evidence indicates that overexpression of the oncogenic receptor tyrosine kinase, Axl, plays a key role in the tumorigenesis and metastasis of various types of cancer. The objective of this study is to design a novel imaging probe based on the monoclonal antibody, h173, for microPET imaging of Axl expression in human lung cancer. A bifunctional chelator, DOTA, was conjugated to h173, followed by radiolabeling with 64Cu. The binding of DOTA-h173 to the Axl receptor wa...

  10. The 2-oxoglutarate analog 3-oxoglutarate decreases normoxic hypoxia-inducible factor-1α in cancer cells, induces cell death, and reduces tumor xenograft growth

    Directory of Open Access Journals (Sweden)

    Koivunen P

    2016-03-01

    Full Text Available Peppi Koivunen,1 Stuart M Fell,2,3 Wenyun Lu,4 Joshua D Rabinowitz,4 Andrew L Kung,5,6 Susanne Schlisio,2,7 1Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland; 2Ludwig Institute for Cancer Research Ltd, Stockholm, Sweden; 3Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden; 4Department of Chemistry and Integrative Genomics, Princeton University, Princeton, NJ, 5Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 6Department of Pediatrics, Columbia University Medical Center, New York, NY, USA; 7Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden Abstract: The cellular response to hypoxia is primarily regulated by the hypoxia-inducible factors (HIFs. HIF-1α is also a major mediator of tumor physiology, and its abundance is correlated with therapeutic resistance in a broad range of cancers. Accumulation of HIF-1α under hypoxia is mainly controlled by the oxygen-sensing HIF prolyl 4-hydroxylases (EGLNs, also known as PHDs. Here, we identified a high level of normoxic HIF-1α protein in various cancer cell lines. EGLNs require oxygen and 2-oxoglutarate for enzymatic activity. We tested the ability of several cell-permeable 2-oxoglutarate analogs to regulate the abundance of HIF-1α protein. We identified 3-oxoglutarate as a potent regulator of HIF-1α in normoxic conditions. In contrast to 2-oxoglutarate, 3-oxoglutarate decreased the abundance of HIF-1α protein in several cancer cell lines in normoxia and diminished HIF-1α levels independent of EGLN enzymatic activity. Furthermore, we observed that 3-oxoglutarate was detrimental to cancer cell survival. We show that esterified 3-oxoglutarate, in combination with the cancer chemotherapeutic drug vincristine, induces apoptosis and inhibits tumor growth in vitro and in vivo. Our data

  11. Imaging of treatment response to the combination of carboplatin and paclitaxel in human ovarian cancer xenograft tumors in mice using FDG and FLT PET

    DEFF Research Database (Denmark)

    Munk Jensen, Mette; Erichsen, Kamille Dumong; Björkling, Fredrik;

    2013-01-01

    A combination of carboplatin and paclitaxel is often used as first line chemotherapy for treatment of ovarian cancer. Therefore the use of imaging biomarkers early after initiation of treatment to determine treatment sensitivity would be valuable in order to identify responders from non-responder......A combination of carboplatin and paclitaxel is often used as first line chemotherapy for treatment of ovarian cancer. Therefore the use of imaging biomarkers early after initiation of treatment to determine treatment sensitivity would be valuable in order to identify responders from non...... carboplatin and paclitaxel....

  12. Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model

    OpenAIRE

    Kim, Chulwon; Lee, Jong Hyun; Kim, Sung-Hoon; Sethi, Gautam; Ahn, Kwang Seok

    2015-01-01

    Artesunate (ART), a semi-synthetic derivative of artemisinin, is one of the most commonly used anti-malarial drugs. Also, ART possesses anticancer potential albeit through incompletely understood molecular mechanism(s). Here, the effect of ART on various protein kinases, associated gene products, cellular response, and apoptosis was investigated. The in vivo effect of ART on the growth of human CML xenograft tumors in athymic nu/nu mice was also examined. In our preliminary experiments, we fi...

  13. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death.

    Science.gov (United States)

    Raimondo, Stefania; Naselli, Flores; Fontana, Simona; Monteleone, Francesca; Lo Dico, Alessia; Saieva, Laura; Zito, Giovanni; Flugy, Anna; Manno, Mauro; Di Bella, Maria Antonietta; De Leo, Giacomo; Alessandro, Riccardo

    2015-08-14

    Nanosized vesicles are considered key players in cell to cell communication, thus influencing physiological and pathological processes, including cancer. Nanovesicles have also been found in edible-plants and have shown therapeutic activity in inflammatory bowel diseases; however information on their role in affecting cancer progression is missing.Our study identify for the first time a fraction of vesicles from lemon juice (Citrus limon L.), obtained as a result of different ultracentrifugation, with density ranging from 1,15 to 1,19 g/ml and specific proteomic profile. By using an in vitro approach, we show that isolated nanovesicles inhibit cancer cell proliferation in different tumor cell lines, by activating a TRAIL-mediated apoptotic cell death. Furthermore, we demonstrate that lemon nanovesicles suppress CML tumor growth in vivo by specifically reaching tumor site and by activating TRAIL-mediated apoptotic cell processes. Overall, this study suggests the possible use of plant-edible nanovesicles as a feasible approach in cancer treatment. PMID:26098775

  14. ANIMAL MODELS OF CANCER: A REVIEW

    OpenAIRE

    Archana M Navale

    2013-01-01

    Cancer is the second leading cause of death worldwide. In USA three persons out of five will develop some type of cancer. Beyond these statistics of mortality, the morbidity due to cancer presents a real scary picture. Last 50 years of research has rendered some types of cancer curable, but still the major fear factor associated with this disease is unchanged. Animal models are classified according to the method of induction of cancer in the animal. Spontaneous tumor models are the most primi...

  15. PET Imaging of Serotonin Transporters With 4-[(18)F]-ADAM in a Parkinsonian Rat Model With Porcine Neural Xenografts.

    Science.gov (United States)

    Chiu, Chuang-Hsin; Li, I-Hsun; Weng, Shao-Ju; Huang, Yuahn-Sieh; Wu, Shinn-Chih; Chou, Ta-Kai; Huang, Wen-Sheng; Liao, Mei-Hsiu; Shiue, Chyng-Yann; Cheng, Cheng-Yi; Ma, Kuo-Hsing

    2016-01-01

    Parkinson's disease (PD) is a neurodegenerative disease characterized by a loss of dopaminergic neurons in the nigrostriatal pathway. Apart from effective strategies to halt the underlying neuronal degeneration, cell replacement now offers novel prospects for PD therapy. Porcine embryonic neural tissue has been considered an alternative source to human fetal grafts in neurodegenerative disorders because its use avoids major practical and ethical issues. This study was undertaken to evaluate the effects of embryonic day 27 (E27) porcine mesencephalic tissue transplantation in a PD rat model using animal positron emission tomography (PET) coupled with 4-[(18)F]-ADAM, a serotonin transporter (SERT) imaging agent. The parkinsonian rat was induced by injecting 6-hydroxydopamine into the medial forebrain bundle (MFB) of the right nigrostriatal pathway. The apomorphine-induced rotation behavioral test and 4-[(18)F]-ADAM/animal PET scanning were carried out following 6-OHDA lesioning. At the second week following 6-OHDA lesioning, the parkinsonian rat rotates substantially on apomorphine-induced contralateral turning. In addition, the mean striatal-specific uptake ratio (SUR) of 4-[(18)F]-ADAM decreased by 44%. After transplantation, the number of drug-induced rotations decreased markedly, and the mean SUR of 4-[(18)F]-ADAM and the level of SERT immunoreactivity (SERT-ir) in striatum were partially restored. The mean SUR level was restored to 71% compared to that for the contralateral intact side, which together with the abundant survival of tyrosine hydroxylase (TH) neurons accounted for functional recovery at the fourth week postgraft. In regard to the extent of donor-derived cells, we found the neurons of the xenografts from E27 transgenic pigs harboring red fluorescent protein (RFP) localized with TH-ir cells and SERT-ir in the grafted area. Thus, transplanted E27 porcine mesencephalic tissue may restore dopaminergic and serotonergic systems in the parkinsonian rat

  16. Fish Oil Slows Prostate Cancer Xenograft Growth Relative to Other Dietary Fats and is Associated with Decreased Mitochondrial and Insulin Pathway Gene Expression

    OpenAIRE

    Lloyd, Jessica C.; Masko, Elizabeth M.; Wu, Chenwei; Keenan, Melissa M; Pilla, Danielle M.; Aronson, William J.; Chi, Jen-Tsan A.; Freedland, Stephen J.

    2013-01-01

    Background Previous mouse studies suggest that decreasing dietary fat content can slow prostate cancer (PCa) growth. To our knowledge, no study has yet compared the effect of multiple different fats on PCa progression. We sought to systematically compare the effect of fish oil, olive oil, corn oil, and animal fat on PCa progression. Methods A total of 96 male SCID mice were injected with LAPC-4 human PCa cells. Two weeks following injection, mice were randomized to a fish oil, olive oil, corn...

  17. Developing a Novel Embryo-Larval Zebrafish Xenograft Assay to Prioritize Human Glioblastoma Therapeutics.

    Science.gov (United States)

    Wehmas, Leah Christine; Tanguay, Robert L; Punnoose, Alex; Greenwood, Juliet A

    2016-08-01

    Glioblastoma is an aggressive brain cancer requiring improved treatments. Existing methods of drug discovery and development require years before new therapeutics become available to patients. Zebrafish xenograft models hold promise for prioritizing drug development. We have developed an embryo-larval zebrafish xenograft assay in which cancer cells are implanted in a brain microenvironment to discover and prioritize compounds that impact glioblastoma proliferation, migration, and invasion. We illustrate the utility of our assay by evaluating the well-studied, phosphatidylinositide 3-kinase inhibitor LY294002 and zinc oxide nanoparticles (ZnO NPs), which demonstrate selective cancer cytotoxicity in cell culture, but the in vivo effectiveness has not been established. Exposures of 3.125-6.25 μM LY294002 significantly decreased proliferation up to 34% with concentration-dependent trends. Exposure to 6.25 μM LY294002 significantly inhibited migration/invasion by ∼27% within the glioblastoma cell mass (0-80 μm) and by ∼32% in the next distance region (81-160 μm). Unexpectedly, ZnO enhanced glioblastoma proliferation by ∼19% and migration/invasion by ∼35% at the periphery of the cell mass (161+ μm); however, dissolution of these NPs make it difficult to discern whether this was a nano or ionic effect. These results demonstrate that we have a short, relevant, and sensitive zebrafish-based assay to aid glioblastoma therapeutic development. PMID:27158859

  18. 13A. Integrative Cancer Care: The Life Over Cancer Model

    OpenAIRE

    Block, Keith; Block, Penny; Gyllenhaal, Charlotte; Shoham, Jacob

    2013-01-01

    Focus Areas: Integrative Algorithms of Care Integrative cancer treatment fully blends conventional cancer treatment with integrative therapies such as diet, supplements, exercise and biobehavioral approaches. The Life Over Cancer model comprises three spheres of intervention: improving lifestyle, improving biochemical environment (terrain), and improving tolerance of conventional treatment. These levels are applied within the context of a life-affirming approach to cancer patients and treatme...

  19. Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Purcell, James W; Davis, Jefferson; Reddy, Mamatha; Martin, Shamra; Samayoa, Kimberly; Vo, Hung; Thomsen, Karen; Bean, Peter; Kuo, Wen Lin; Ziyad, Safiyyah; Billig, Jessica; Feiler, Heidi S; Gray, Joe W; Wood, Kenneth W; Cases, Sylvaine

    2009-06-10

    Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein (KSP), a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have demonstrated a 9% response rate in patients with locally advanced or metastatic breast cancer, and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer we explored the activity of ispinesib alone and in combination several therapies approved for the treatment of breast cancer. We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo, and tested the ability of ispinesib to enhance the anti-tumor activity of approved therapies. In vitro, ispinesib displayed broad anti-proliferative activity against a panel of 53 breast cell-lines. In vivo, ispinesib produced regressions in each of five breast cancer models, and tumor free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the anti-tumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine, and exhibited activity comparable to paclitaxel and ixabepilone. These findings support further clinical exploration of KSP inhibitors for the treatment of breast cancer.

  20. Enhancement of tumor initiation and expression of KCNMA1, MORF4L2 and ASPM genes in the adenocarcinoma of lung xenograft after vorinostat treatment.

    Science.gov (United States)

    Kuo, Wei-Ying; Wu, Chun-Yi; Hwu, Luen; Lee, Jhih-Shian; Tsai, Cheng-Han; Lin, Kang-Ping; Wang, Hsin-Ell; Chou, Teh-Ying; Tsai, Chun-Ming; Gelovani, Juri; Liu, Ren-Shyan

    2015-04-20

    Cancer stem cells (CSCs) are usually tolerant to chemotherapy and radiotherapy and associated with tumor relapse. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), is currently being used in clinical trials of lung cancer. However, SAHA facilitates the formation of induced pluripotent stem cells from somatic cells. We hypothesized that SAHA would mediate the CSCs properties and subsequently confer a more malignant phenotype in lung cancer. Transfected H1299 lung cancer cells, which stably expresses a triple fused reporter gene (DsRedm-Fluc-tTKsr39) under the control of CMV promoter was used to establish a xenograft mouse model. After the treatment of SAHA, H1299 cell line and tumor xenografts were sorted by fluorescence-activated cell sorting (FACS) based on aldehyde dehydrogenase (ALDH) activity. We found that SAHA could suppress the growth of xenografted H1299 tumors with decreased proportion of ALDHbr lung cancer cells indicating that SAHA may target CSCs. However, SAHA significantly enhanced the tumor initiating capacity and the expression of malignant genes such as KCNMA1, MORF4L2 and ASPM in the remaining living ALDHbr cells. These findings suggested that SAHA treatment created a more drug-resistant state in residual ALDHbr cells. The in vivo imaging technique may facilitate searching and characterization of CSCs. PMID:25796627

  1. Effect of leucovorin on the antitumor efficacy of the 5-FU prodrug, tegafur-uracil, in human colorectal cancer xenografts with various expression levels of thymidylate synthase

    OpenAIRE

    TSUJIMOTO, HIROAKI; TSUKIOKA, SAYAKA; ONO, Satoru; Sakamoto, Etsuko; Sakamoto, Kazuki; TSUTA, KOHJI; Nakagawa, Fumio; Saito, Hitoshi; Uchida, Junji; Kiniwa, Mamoru; Fukushima, Masakazu

    2010-01-01

    The combination of oral tegafur-uracil (UFT) with leucovorin (LV) is used to treat patients with stage II to III colon cancer based on the results of postoperative randomized studies in which UFT/LV treatment showed an equivalent efficacy to intravenous 5-FU plus LV therapy. However, whether the addition of LV to UFT can elevate the antitumor activity of UFT in colorectal tumors with high expression levels of thymidylate synthase (TS), which affects 5-FU efficacy, remains to be clarified. Thi...

  2. mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft

    Directory of Open Access Journals (Sweden)

    Ramaswamy Krishna

    2008-11-01

    Full Text Available Abstract Background Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. However, the effects mitochondrial DNA (mtDNA levels have on the nuclear transcriptome have not been defined under physiological conditions. In order to address this issue, we characterized the gene expression profiles of A549 lung cancer cells and their mtDNA-depleted ρ0 counterparts grown in culture and as tumor xenografts in immune-deficient mice. Results Cultured A549 ρ0 cells were respiration-deficient and showed enhanced levels of transcripts relevant to metal homeostasis, initiation of the epithelial-mesenchymal transition, and glucuronidation pathways. Several well-established HIF-regulated transcripts showed increased or decreased abundance relative to the parental cell line. Furthermore, growth in culture versus xenograft has a significantly greater influence on expression profiles, including transcripts involved in mitochondrial structure and both aerobic and anaerobic energy metabolism. However, both in vitro and in vivo, mtDNA levels explained the majority of the variance observed in the expression of transcripts in glucuronidation, tRNA synthetase, and immune surveillance related pathways. mtDNA levels in A549 xenografts also affected the expression of genes, such as AMACR and PHYH, involved in peroxisomal lipid metabolic pathways. Conclusion We have identified mtDNA-dependent gene expression profiles that are shared in cultured cells and in xenografts. These profiles indicate that mtDNA-depleted cells could provide informative model systems for the testing the efficacy of select classes of therapeutics, such as anti-angiogenesis agents. Furthermore, mtDNA-depleted cells grown culture and in xenografts provide a powerful means to investigate possible relationships between mitochondrial activity and gene expression profiles in normal and pathological cells.

  3. Characterization of the Tumor-Microenvironment in Patient-Derived Cervix Xenografts (OCICx)

    International Nuclear Information System (INIS)

    Rationale: The tumor microenvironment (TME) is heterogeneous including both malignant and host cell components as well as regions of hypoxia, elevated interstitial fluid pressure (IFP) and poor nutrient supply. The quantitative extent to which the microenvironmental properties of primary tumors are recapitulated in xenograft models is not well characterized. Methods: Xenografts were generated by implanting tumor biopsies directly into the cervix of mice to create a panel of orthotopically-passaged xenografts (OCICx). Tumors were grown to ~1 cm (diameter) and IFP measurements recorded prior to sacrifice. Enlarged para-aortic lymph nodes (>1–2 mm) were excised for histologic confirmation of metastatic disease. Quantitative histological analysis was used to evaluate hypoxia, proliferation, lymphatic and blood vessels in the epithelial and stromal regions of the xenografts and original patient tumour. Results: IFP and nodal disease were not correlated with tumor engraftment. IFP measurements in the xenografts were generally lower than those in the patient’s tumor. Lymphatic metastasis increased with passage number as did levels of hypoxia in the epithelial component of the xenografts. The blood vessel density in the stromal component of the xenografts increased in parallel. When all the markers were compared between the biopsy and the respective 3rd generation xenograft 10 of 11 tumors showed a good correlation. Conclusions: This ongoing study provides characterization about tumoral and stromal heterogeneity in a unique orthotopic xenograft model

  4. Characterization of the Tumor-Microenvironment in Patient-Derived Cervix Xenografts (OCICx)

    Energy Technology Data Exchange (ETDEWEB)

    Chaudary, Naz [Ontario Cancer Institute/Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Pintilie, Melania [Biostatistics Department, Ontario Cancer Institute/Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Schwock, Joerg [Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Dhani, Neesha [Ontario Cancer Institute/Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Clarke, Blaise [Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Department of Pathology, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Milosevic, Michael; Fyles, Anthony [Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Hill, Richard P., E-mail: hill@uhnres.utoronto.ca [Ontario Cancer Institute/Princess Margaret Cancer Centre and Campbell Family Institute for Cancer Research, University Health Network, Toronto, Ontario M5G 2M9 (Canada); Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9 (Canada); Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2M9 (Canada)

    2012-08-29

    Rationale: The tumor microenvironment (TME) is heterogeneous including both malignant and host cell components as well as regions of hypoxia, elevated interstitial fluid pressure (IFP) and poor nutrient supply. The quantitative extent to which the microenvironmental properties of primary tumors are recapitulated in xenograft models is not well characterized. Methods: Xenografts were generated by implanting tumor biopsies directly into the cervix of mice to create a panel of orthotopically-passaged xenografts (OCICx). Tumors were grown to ~1 cm (diameter) and IFP measurements recorded prior to sacrifice. Enlarged para-aortic lymph nodes (>1–2 mm) were excised for histologic confirmation of metastatic disease. Quantitative histological analysis was used to evaluate hypoxia, proliferation, lymphatic and blood vessels in the epithelial and stromal regions of the xenografts and original patient tumour. Results: IFP and nodal disease were not correlated with tumor engraftment. IFP measurements in the xenografts were generally lower than those in the patient’s tumor. Lymphatic metastasis increased with passage number as did levels of hypoxia in the epithelial component of the xenografts. The blood vessel density in the stromal component of the xenografts increased in parallel. When all the markers were compared between the biopsy and the respective 3rd generation xenograft 10 of 11 tumors showed a good correlation. Conclusions: This ongoing study provides characterization about tumoral and stromal heterogeneity in a unique orthotopic xenograft model.

  5. Dietary phenethyl isothiocyanate inhibition of androgen-responsive LNCaP prostate cancer cell tumor growth correlates with decreased angiogenesis

    Science.gov (United States)

    Phenethyl isothiocyanate (PEITC), found in certain cruciferous vegetables, has antitumor activity in several cancer models, including prostate cancer. In our xenograft model, dietary administration of PEITC (100-150 mg/kg/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth...

  6. Dynamic {sup 18}F-FDG PET for Assessment of Tumor Physiology in Two Breast Carcinoma Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Kristian, Alexandr; Nilsen, Line B.; Roe, Kathrine; Revheim, Monaelisabeth; Engebraten, Olav; Maelandsmo, Gunhild M.; Holm, Ruth; Malinen Eirik; Seierstad, Therese [Oslo Univ. Hospital, Oslo (Norway)

    2013-09-15

    To compare dynamic 2-deoxy-2-[{sup 18}F]fluoro-D-glucose positron emission tomography ({sup 18}F-FDG PET) parameters in two selected human breast cancer xenografts and to evaluate associations with immunohistochemistry and histology. Dynamic {sup 18}F-FDG PET of luminal-like MAS98.06 and basal-like MAS98.12 xenografts was performed, and the compartmental transfer rates (k{sub 1}, k{sub 2}, k{sub 3}), blood volume fraction (v{sub B}) and metabolic rate of {sup 18}F-FDG(MR{sub FDG}) were estimated from pharmacokinetic model analysis. After sacrifice, analyses of hypoxia (pimonidazole), proliferation (Ki-67), vascularization (CD31), glucose transport receptor (GLUT1) and necrosis (HE) was performed. The level of hexokinase 2 (HK2) was estimated from Western blot analysis. The {sup 18}F-FDG uptake curves for the two xenografts were significantly different (p<0.05). k{sub 1} and v{sub B} were higher for MAS98.12 (p<0.01), while k{sub 3} was higher for MAS98.06 (p<0.01). MAS98.12 had a higher fraction of stromal tissue and higher microvessel density (MVD), and it was less necrotic and hypoxic than MAS98.06 MAS98.12 had stronger positive GLUT1 staining and lower Ki-67 than MAS98.06. In both models significant correlations were found between k{sub 1} and the GLUT1 score, between k{sub 3} and the level of HK2, and between v{sub B} and MVD. Significant differences in dynamic {sup 18}F-FDG parameters between the two human breast cancer xenografts were found. The differences could be explained by underlying histological and physiological characteristics.

  7. A Mouse Model for Human Anal Cancer

    OpenAIRE

    Stelzer, Marie K.; Pitot, Henry C.; Liem, Amy; Schweizer, Johannes; Mahoney, Charles; Lambert, Paul F.

    2010-01-01

    Human anal cancers are associated with high-risk human papillomaviruses (HPVs) that cause other anogenital cancers and head and neck cancers. As with other cancers, HPV16 is the most common high-risk HPV in anal cancers. We describe the generation and characterization of a mouse model for human anal cancer. This model makes use of K14E6 and K14E7 transgenic mice in which the HPV16 E6 and E7 genes are directed in their expression to stratified squamous epithelia. HPV16 E6 and E7 possess oncoge...

  8. 不同化疗方案对MCF-7乳腺癌荷瘤裸鼠的抑瘤作用及对PCNA表达的影响%The effects of various chemotherapy regimens on the expression of PCNA and human breast cancer xenograft (MCF-7) transplanted in nude mice

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: To investigate the antitumor activity of different combination regimens to human breast cancer xenograft (MCF-7) transplanted in nude mice and the effects on the expression of PCNA, and to evaluate the value of PCNA as predictive factor for the response of chemotherapy and individualized treatment. Methods: (1) 88 nude mice models of human breast cancer xenograft (MCF-7) were established, and then were randomly divided into control group and 10 chemotherapy groups (each group, n = 8). Among them, the mice of 5 chemotherapy groups were treated intraperitoneally/orally by 5 combination chemotherapy regimens (CMF, CAF, NP, TP, Xeloda) respectively at 1/3 LD10 dosage schedule (dose lethal to 10%of the mice), and that in another 5 chemotherapy groups were treated at 2/3 LD10 dosage schedule. Control animals were administered intraperitoneally with normal saline. (2) The body weight of nude mice and transplanted tumor growth were observed and recorded, then inhibition rate of tumor growth was calculated. (3) The pathological features of transplanted tumor were studied under microscope. The expression of proliferating cell nuclear antigen (PCNA) was comparatively studied in chemotherapy group and control group by SP immunohistochemical method and flow cytometry analysis. Results: (1) Body weight, tumor weight and inhibition rate of tumor growth of athymic mice bearing cancer: Body weights and tumor weights of nude mice in every 2/3 LD10 chemotherapy group were significantly lower than those of the control group (P < 0.05), and the inhibition rates of tumor growth were 83.1%, 75.5%, 84.6%, 87.9% and 91.0%, respectively. Body weights of athymic mice in every 1/3 LD10 chemotherapy group were lower than that of the control (P < 0.05). The results showed that the 2/3 LD10chemotherapy groups could reflect the effect of combination chemotherapy on the nude mice and the clinical dependability was better. So the data of 2/3 LD10 chemotherapy groups were appropriated

  9. Artesunate suppresses tumor growth and induces apoptosis through the modulation of multiple oncogenic cascades in a chronic myeloid leukemia xenograft mouse model.

    Science.gov (United States)

    Kim, Chulwon; Lee, Jong Hyun; Kim, Sung-Hoon; Sethi, Gautam; Ahn, Kwang Seok

    2015-02-28

    Artesunate (ART), a semi-synthetic derivative of artemisinin, is one of the most commonly used anti-malarial drugs. Also, ART possesses anticancer potential albeit through incompletely understood molecular mechanism(s). Here, the effect of ART on various protein kinases, associated gene products, cellular response, and apoptosis was investigated. The in vivo effect of ART on the growth of human CML xenograft tumors in athymic nu/nu mice was also examined. In our preliminary experiments, we first observed that phosphorylation of p38, ERK, CREB, Chk-2, STAT5, and RSK proteins were suppressed upon ART exposure. Interestingly, ART induced the expression of SOCS-1 protein and depletion of SOCS-1 using siRNA abrogated the STAT5 inhibitory effect of the drug. Also various dephosphorylations caused by ART led to the suppression of various survival gene products and induced apoptosis through caspase-3 activation. Moreover, ART also substantially potentiated the apoptosis induced by chemotherapeutic agents. Finally, when administered intraperitoneally, ART inhibited p38, ERK, STAT5, and CREB activation in tumor tissues and the growth of human CML xenograft tumors in mice without exhibiting any significant adverse effects. Overall, our results suggest that ART exerts its anti-proliferative and pro-apoptotic effects through suppression of multiple signaling cascades in CML both in vitro and in vivo. PMID:25738364

  10. Photo activation of HPPH encapsulated in “Pocket” liposomes triggers multiple drug release and tumor cell killing in mouse breast cancer xenografts

    Directory of Open Access Journals (Sweden)

    Sine J

    2014-12-01

    Full Text Available Jessica Sine,1,* Cordula Urban,2,* Derek Thayer,1 Heather Charron,2 Niksa Valim,2 Darrell B Tata,3 Rachel Schiff,4 Robert Blumenthal,1 Amit Joshi,2 Anu Puri1 1Membrane Structure and Function Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute – Frederick, Frederick, MD, USA; 2Department of Radiology, Baylor College of Medicine, Houston, TX, USA; 3US Food and Drug Administration, CDRH/OSEL/Division of Physics, White Oak Campus, MD, USA; 4Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA *These authors contributed equally to this work Abstract: We recently reported laser-triggered release of photosensitive compounds from liposomes containing dipalmitoylphosphatidylcholine (DPPC and 1,2 bis(tricosa-10,12-diynoyl-sn-glycero-3-phosphocholine (DC8,9PC. We hypothesized that the permeation of photoactivated compounds occurs through domains of enhanced fluidity in the liposome membrane and have thus called them “Pocket” liposomes. In this study we have encapsulated the red light activatable anticancer photodynamic therapy drug 2-(1-Hexyloxyethyl-2-devinyl pyropheophorbide-a (HPPH (Ex/Em410/670 nm together with calcein (Ex/Em490/517 nm as a marker for drug release in Pocket liposomes. A mole ratio of 7.6:1 lipid:HPPH was found to be optimal, with >80% of HPPH being included in the liposomes. Exposure of liposomes with a cw-diode 660 nm laser (90 mW, 0–5 minutes resulted in calcein release only when HPPH was included in the liposomes. Further analysis of the quenching ratios of liposome-entrapped calcein in the laser treated samples indicated that the laser-triggered release occurred via the graded mechanism. In vitro studies with MDA-MB-231-LM2 breast cancer cell line showed significant cell killing upon treatment of cell-liposome suspensions with the laser. To assess in vivo efficacy, we implanted MDA-MB-231-LM2 cells containing the luciferase gene along the mammary fat pads

  11. Titanium wire implants with nanotube arrays: A study model for localized cancer treatment.

    Science.gov (United States)

    Kaur, Gagandeep; Willsmore, Tamsyn; Gulati, Karan; Zinonos, Irene; Wang, Ye; Kurian, Mima; Hay, Shelley; Losic, Dusan; Evdokiou, Andreas

    2016-09-01

    Adverse complications associated with systemic administration of anti-cancer drugs are a major problem in cancer therapy in current clinical practice. To increase effectiveness and reduce side effects, localized drug delivery to tumour sites requiring therapy is essential. Direct delivery of potent anti-cancer drugs locally to the cancer site based on nanotechnology has been recognised as a promising alternative approach. Previously, we reported the design and fabrication of nano-engineered 3D titanium wire based implants with titania (TiO2) nanotube arrays (Ti-TNTs) for applications such as bone integration by using in-vitro culture systems. The aim of present study is to demonstrate the feasibility of using such Ti-TNTs loaded with anti-cancer agent for localized cancer therapy using pre-clinical cancer models and to test local drug delivery efficiency and anti-tumour efficacy within the tumour environment. TNF-related apoptosis-inducing ligand (TRAIL) which has proven anti-cancer properties was selected as the model drug for therapeutic delivery by Ti-TNTs. Our in-vitro 2D and 3D cell culture studies demonstrated a significant decrease in breast cancer cell viability upon incubation with TRAIL loaded Ti-TNT implants (TRAIL-TNTs). Subcutaneous tumour xenografts were established to test TRAIL-TNTs implant performance in the tumour environment by monitoring the changes in tumour burden over a selected time course. TRAIL-TNTs showed a significant regression in tumour burden within the first three days of implant insertion at the tumour site. Based on current experimental findings these Ti-TNTs wire implants have shown promising capacity to load and deliver anti-cancer agents maintaining their efficacy for cancer treatment. PMID:27289379

  12. A folate receptor-targeting nanoparticle minimizes drug res