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Sample records for cancer therapeutic efficacy

  1. Enhancing the Therapeutic Efficacy of Cancer Treatment With Cannabinoids

    Sayeda Yasmin-Karim

    2018-04-01

    Full Text Available Over the years, many in vitro and in vivo studies have shown the antineoplastic effects of cannabinoids (CBDs, with reports advocating for investigations of combination therapy approaches that could better leverage these effects in clinical translation. This study explores the potential of combination approaches employing CBDs with radiotherapy (RT or smart biomaterials toward enhancing therapeutic efficacy during treatment of pancreatic and lung cancers. In in vitro studies, clonogenic assay results showed greater effective tumor cell killing, when combining CBDs and RT. Meanwhile, in vivo study results revealed major increase in survival when employing smart biomaterials for sustained delivery of CBDs to tumor cells. The significance of these findings, considerations for further research, and viable roadmap to clinical translation are discussed.

  2. Nanodiamonds enhance therapeutic efficacy of doxorubicin in treating metastatic hormone-refractory prostate cancer.

    Salaam, Amanee D; Hwang, Patrick T J; Poonawalla, Aliza; Green, Hadiyah N; Jun, Ho-wook; Dean, Derrick

    2014-10-24

    Enhancing therapeutic efficacy is essential for successful treatment of chemoresistant cancers such as metastatic hormone-refractory prostate cancer (HRPC). To improve the efficacy of doxorubicin (DOX) for treating chemoresistant disease, the feasibility of using nanodiamond (ND) particles was investigated. Utilizing the pH responsive properties of ND, a novel protocol for complexing NDs and DOX was developed using a pH 8.5 coupling buffer. The DOX loading efficiency, loading on the NDs, and pH responsive release characteristics were determined utilizing UV-Visible spectroscopy. The effects of the ND-DOX on HRPC cell line PC3 were evaluated with MTS and live/dead cell viability assays. ND-DOX displayed exceptional loading efficiency (95.7%) and drug loading on NDs (23.9 wt%) with optimal release at pH 4 (80%). In comparison to treatment with DOX alone, cell death significantly increased when cells were treated with ND-DOX complexes demonstrating a 50% improvement in DOX efficacy. Of the tested treatments, ND-DOX with 2.4 μg mL(-1) DOX exhibited superior efficacy (60% cell death). ND-DOX with 1.2 μg mL(-1) DOX achieved 42% cell death, which was comparable to cell death in response to 2.4 μg mL(-1) of free DOX, suggesting that NDs aid in decreasing the DOX dose necessary to achieve a chemotherapeutic efficacy. Due to its enhanced efficacy, ND-DOX can be used to successfully treat HRPC and potentially decrease the clinical side effects of DOX.

  3. The Novel IκB Kinase β Inhibitor, IMD-0560, Has Potent Therapeutic Efficacy in Ovarian Cancer Xenograft Model Mice.

    Sawada, Ikuko; Hashimoto, Kae; Sawada, Kenjiro; Kinose, Yasuto; Nakamura, Koji; Toda, Aska; Nakatsuka, Erika; Yoshimura, Akihiko; Mabuchi, Seiji; Fujikawa, Tomoyuki; Itai, Akiko; Kimura, Tadashi

    2016-05-01

    Aberrant activation of nuclear factor-kappa β (NF-κB) signaling has been correlated with poor outcome among patients with ovarian cancer. Although the therapeutic potential of NF-κB pathway disruption in cancers has been extensively studied, most classical NF-κB inhibitors are poorly selective, exhibit off-target effects, and have failed to be applied in clinical use. IMD-0560, N-[2,5-bis (trifluoromethyl) phenyl]-5-bromo-2-hydroxybenzamide, is a novel low-molecular-weight compound that selectively inhibits the IκB kinase complex and works as an inhibitor of NF-κB signaling. The aim of this study was to assess the therapeutic potential of IMD-0560 against ovarian cancer in vitro and in vivo. NF-κB activity (phosphorylation) was determined in 9 ovarian cancer cell lines and the inhibitory effect of IMD-0560 on NF-κB activation was analyzed by Western blotting. Cell viability, cell cycle, vascular endothelial growth factor (VEGF) expression, and angiogenesis were assessed in vitro to evaluate the effect of IMD-0560 on ovarian cancer cells. In vivo efficacy of IMD-0560 was also investigated using an ovarian cancer xenograft mouse model. The NF-κB signaling pathway was constitutively activated in 8 of 9 ovarian cancer cell lines. IMD-0560 inhibited NF-κB activation and suppressed ovarian cancer cell proliferation by inducing G1 phase arrest. IMD-0560 decreased VEGF secretion from cancer cells and inhibited the tube formation of human umbilical vein endothelial cells. IMD-0560 significantly inhibited peritoneal metastasis and prolonged the survival in an ovarian cancer xenograft mice model. Immunohistochemical staining of excised tumors revealed that IMD-0560 suppressed VEGF expression, tumor angiogenesis, and cancer cell proliferation. IMD-0560 showed promising therapeutic efficacy against ovarian cancer xenograft mice by inducing cell cycle arrest and suppressing VEGF production from cancer cells. IMD-0560 may be a potential future option in regimens for the

  4. Tumor blood vessel "normalization" improves the therapeutic efficacy of boron neutron capture therapy (BNCT) in experimental oral cancer

    D. W. Nigg

    2012-01-01

    We previously demonstrated the efficacy of BNCT mediated by boronophenylalanine (BPA) to treat tumors in a hamster cheek pouch model of oral cancer with no normal tissue radiotoxicity and moderate, albeit reversible, mucositis in precancerous tissue around treated tumors. It is known that boron targeting of the largest possible proportion of tumor cells contributes to the success of BNCT and that tumor blood vessel normalization improves drug delivery to the tumor. Within this context, the aim of the present study was to evaluate the effect of blood vessel normalization on the therapeutic efficacy and potential radiotoxicity of BNCT in the hamster cheek pouch model of oral cancer.

  5. Tumor blood vessel 'normalization' improves the therapeutic efficacy of boron neutron capture therapy (BNCT) in experimental oral cancer

    Nigg, D.W.

    2012-01-01

    We previously demonstrated the efficacy of BNCT mediated by boronophenylalanine (BPA) to treat tumors in a hamster cheek pouch model of oral cancer with no normal tissue radiotoxicity and moderate, albeit reversible, mucositis in precancerous tissue around treated tumors. It is known that boron targeting of the largest possible proportion of tumor cells contributes to the success of BNCT and that tumor blood vessel normalization improves drug delivery to the tumor. Within this context, the aim of the present study was to evaluate the effect of blood vessel normalization on the therapeutic efficacy and potential radiotoxicity of BNCT in the hamster cheek pouch model of oral cancer.

  6. Comparison of therapeutic efficacy and biodistribution of 213Bi- and 211At-labeled monoclonal antibody MX35 in an ovarian cancer model

    Gustafsson, Anna M E; Bäck, Tom; Elgqvist, Jörgen

    2012-01-01

    The purpose of this study was to compare the therapeutic efficacy and biodistribution of the monoclonal antibody MX35 labeled with either (213)Bi or (211)At, both α-emitters, in an ovarian cancer model.......The purpose of this study was to compare the therapeutic efficacy and biodistribution of the monoclonal antibody MX35 labeled with either (213)Bi or (211)At, both α-emitters, in an ovarian cancer model....

  7. Therapeutic Efficacy of Ginger, Cisplatin and Radiation on Chemically-Induced Cancer in Male Albino Rats

    El-Beih, N.M.; Galal, S.M.; Fahmy, N.M.; Abd El-Azime, M.G.

    2015-01-01

    This study aimed to investigate the in vivo effect of dietary supplementation with ginger to evaluate its therapeutic effect against lung and kidney cancer and in combination with cisplatin as chemotherapy and radiotherapy in male albino rats. 54 male albino rats were divided into nine groups of 6 animals each, all animals were allowed to food and water ad libitum . Group I was treated with 0.5 ml saline, orlly for 12 consecutive weeks serve as con - trol group Group II injected with N-nitrosodimethylamine (NDMA) and carbon tetrachloride (CCl 4 ); all groups were injected with NDMA + CCl 4 for 6 weeks. Group III were given ginger for 6 consecutive weeks (200 mg/kg, b.wt./day). Group IV animals received cisplatin, group V irradiated with 2 Gy, group VI treated with ginger then irradiated, group VII treated with ginger then injected with cisplatin, group VIII injected with cisplatin then irradiated and group IX treated with ginger and cisplatin then irradiated. Antioxidant status in both kidney and lung tissues were estimated by determining the activity of antioxidant enzyme superoxide dismutase (SOD); as well as the level of reduced glutathione (GSH), Malondialdehyde (MDA) and Nitric oxide (NO). In parallel to histopathological investigations of lung and kidney tissues. In addition, Tumor Necrosis Factor Alpha (TNF-α) level, advanced oxidative protein product (AOPP), urea, creatinine and uric acid. Remarkable disturbances were observed in the levels of all tested parameters in NDMA + CCl 4 group. On the other hand, rats injected with the cancer agents then treated with cisplatin+radiation showed moderate improvements in the studied parameters while, treatment with ginger + cisplatin + radiation ameliorated the levels of the disturbed bio

  8. Anticancer Drug-Incorporated Layered Double Hydroxide Nanohybrids and Their Enhanced Anticancer Therapeutic Efficacy in Combination Cancer Treatment

    Tae-Hyun Kim

    2014-01-01

    Full Text Available Objective. Layered double hydroxide (LDH nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles. Method. Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML, 5-FU/LDH (FL, and (MTX + 5-FU/LDH (MFL nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy. Conclusion. All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy.

  9. TC > 0.05 as a Pharmacokinetic Parameter of Paclitaxel for Therapeutic Efficacy and Toxicity in Cancer Patients.

    Xin, D S; Zhou, L; Li, C Z; Zhang, S Q; Huang, H Q; Qiu, G D; Lin, L F; She, Y Q; Zheng, J T; Chen, C; Fang, L; Chen, Zhe-Sheng; Zhang, S Y

    2018-03-05

    Paclitaxel (PTX) has remarkable anti-tumor activity, but it causes severe toxicities. There is an urgent need to seek an appropriate pharmacokinetic parameter of PTX to improve treatment efficacy and reduce adverse effects. To evaluate the association of pharmacokinetic parameter TC>0.05 of paclitaxel (PTX) and its therapeutic efficacy and toxicity in patients with solid tumors. A total of 295 patients with ovarian cancer, esophageal cancer, breast cancer, and non-small cell lung cancer (NSCLC), who were admitted to the Tumor Hospital of Shantou University Medical College, China, were recruited for this study. Patients received 3 weeks of PTX chemotherapy. The plasma concentrations of PTX were examined using the MyPaclitaxelTM kit. The patients' PTX TC>0.05 (the time during which PTX plasma concentration exceed 0.05 μmol/L) were calculated based on pharmacokinetic analysis. The results showed that: (1) the concentrations of PTX in these 295 patients ranged from 0.0358-0.127 μmol/L; (2) the PTX TC> 0.05 ranged from 14 to 38 h with a median time of 27 h; (3) among all treatment cycles, there was a statistically significant difference in the PTX TC>0.05 between CR+PR and SD+PD; (4) with the increasing value of TC>0.05, level of leukopenia and leukopenic fever increased; (5) high PTX TC>0.05 led to the occurrence of neutropenia, neutropenic fever, severe anemia, and severe peripheral neurotoxicity. Taken together, our results indicated that the pharmacokinetic parameter PTX TC>0.05 was an effective measure of treatment efficacy and toxicity in patients with solid tumors. Maintaining PTX TC>0.05 at 26 to 30 h could improve its efficacy and reduce the incidence of leukopenia, neutropenia, anemia, and peripheral neurotoxicity in these patients. PTX TC>0.05 is a key pharmacokinetic parameter of PTX which should be monitored to optimize individual treatment in patients with solid tumors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Diffusion MRI: A New Strategy for Assessment of Cancer Therapeutic Efficacy

    Thomas L. Chenevert; Charles R. Meyer; Bradford A. Moffat; Alnawaz Rehemtulla; Suresh K. Mukherji; Stephen S. Gebarski; Douglas J. Quint; Patricia L. Robertson; Theodore S. Lawrence; Larry Junck; Jeremy M. G. Taylor; Timothy D. Johnson; Qian Dong; Karin M. Muraszko; James A. Brunberg

    2002-01-01

    The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular ...

  11. Correlation between paclitaxel Tc > 0.05 and its therapeutic efficacy and severe toxicities in ovarian cancer patients

    Shuyao Zhang

    2016-01-01

    Conclusion: These results indicated that the PTX Tc > 0.05 correlated with therapeutic efficacy and drug toxicity. Therefore, monitoring the PTX Tc > 0.05 other than blood concentration of PTX is necessary to optimize individual treatment.

  12. Diffusion MRI: A New Strategy for Assessment of Cancer Therapeutic Efficacy

    Thomas L. Chenevert

    2002-10-01

    Full Text Available The use of anatomical imaging in clinical oncology practice traditionally relies on comparison of patient scans acquired before and following completion of therapeutic intervention. Therapeutic success is typically determined from inspection of gross anatomical images to assess changes in tumor size. Imaging could provide significant additional insight into therapeutic impact if a specific parameter or combination of parameters could be identified which reflect tissue changes at the cellular or physiologic level. This would provide an early indicator of treatment response/outcome in an individual patient before completion of therapy. Moreover, response of a tumor to therapeutic intervention may be heterogeneous. The use of imaging could assist in delineating therapeutic-induced spatial heterogeneity within a tumor mass by providing information related to specific regions that are resistant or responsive to treatment. Largely untapped potential resides in exploratory methods such as diffusion MRI, which is a non-volumetric intravoxel measure of tumor response based upon water molecular mobility. Alterations in water mobility reflect changes in tissue structure at the cellular level. While the clinical utility of diffusion MRI for oncologic practice is still under active investigation, this overview on the use of diffusion MRI for the evaluation of brain tumors will serve to introduce how this approach may be applied in the future for the management of patients with solid tumors.

  13. Therapeutic Efficacy of Orally Delivered Doxorubicin Nanoparticles in Rat Tongue Cancer Induced by 4-Nitroquinoline 1-Oxide

    Monir Moradzadeh Khiavi

    2015-06-01

    Full Text Available Purpose: Oral cancer is one of the most significant cancers in the world, and squamous cell carcinoma makes up about 94% of oral malignancies. The aim of the present study was to compare the efficacy of doxorubicin plus methotrexate - loaded nanoparticles on tongue squamous cell carcinoma induced by 4NQO and compare it with the commercial doxorubicin and methotrexate delivered orally on seventy SD male rats. Methods: 70 rats were divided into five groups. During the study, the animals were weighed by a digital scale once a week. Number of mortalities was recorded in the data collection forms. At the end of the treatment, biopsy samples were taken from rat tongues in order to evaluate the severity of dysplasia and the extent of cell proliferation. The results were analyzed using ANOVA, descriptive statistics and chi-square test. Results: No statistically significant difference was found in the mean weight of five groups (p>0.05. No significant relationship was found between groups and mortality rate (P = 0. 39. In addition, there was a significant relationship between groups and the degree of dysplasia (P <0.001. The statistical analysis showed a significant relationship between groups and the rate of cell proliferation (p <0.001. Conclusion: The results of the present study showed that the use of doxorubicin plus methotrexate - loaded nanoparticles orally had more therapeutic effects than commercial doxorubicin plus methotrexate.

  14. Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer

    2016-06-01

    breast cancer subtypes, potentially including antigens preferentially expressed by breast cancer stem cells. We will identify both MHC-I- and MHC...two of them were previously identified as targets of T cells in chronic lymphocytic leukemia ( CLL ) patients. This analysis demonstrated that both...IFN- release CDCA7L protein [CDA7L] (422-430) HLA-A*03, HLA-C*03, HLA-C*12 chronic lymphocytic leukemia ( CLL ) 7 + CLLs (23%) Table 4

  15. Therapeutic Cancer Vaccines in Combination with Conventional Therapy

    Andersen, Mads Hald; Junker, N.; Ellebaek, E.

    2010-01-01

    The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...

  16. Therapeutic cancer vaccines in combination with conventional therapy

    Andersen, Mads Hald; Junker, Niels; Ellebaek, Eva

    2010-01-01

    The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...

  17. Therapeutic efficacy of MUC1-specific cytotoxic T lymphocytes and CD137 co-stimulation in a spontaneous breast cancer model.

    Mukherjee, Pinku; Tinder, Teresa L; Basu, Gargi D; Pathangey, Latha B; Chen, Lieping; Gendler, Sandra J

    2004-01-01

    To study immunology in breast tumors, we have utilized a mammary gland adenocarcinoma model in which mice develop spontaneous tumors of the mammary gland which are initiated at puberty and express a human tumor antigen, MUC1. MUC1 (CD227) is over-expressed in 90% of human breast cancers and its glycosylation status and pattern of expression in cancer cells is altered. Humoral and cellular responses to MUC1 have been reported in breast cancer patients and therefore, MUC1 is being evaluated as a target for immune intervention. This mouse model of spontaneous breast cancer allows the evaluation of anti-MUC1 immune responses at all stages of the disease. In this report, we review the model as it pertains to a) the development of the tumor, b) MUC1 expression, and the native immune responses against MUC1 as tumors progress, and c) the immune suppressive microenvironment within the developing tumor. Finally, we report our latest findings describing the therapeutic efficacy of adoptively transferred MUC1-specific cytotoxic T lymphocytes (MUC1-CTL) in these mice and discuss ways to increase their effectiveness by agonistic monoclonal antibody against CD137 T cell costimulatory molecule.

  18. H-Ferritin Enriches the Curcumin Uptake and Improves the Therapeutic Efficacy in Triple Negative Breast Cancer Cells.

    Pandolfi, Laura; Bellini, Michela; Vanna, Renzo; Morasso, Carlo; Zago, Andrea; Carcano, Sofia; Avvakumova, Svetlana; Bertolini, Jessica Armida; Rizzuto, Maria Antonietta; Colombo, Miriam; Prosperi, Davide

    2017-10-09

    Triple negative breast cancer (TNBC) is a highly aggressive, invasive, and metastatic tumor. Although it is reported to be sensitive to cytotoxic chemotherapeutics, frequent relapse and chemoresistance often result in treatment failure. In this study, we developed a biomimetic nanodrug consisting of a self-assembling variant (HFn) of human apoferritin loaded with curcumin. HFn nanocage improved the solubility, chemical stability, and bioavailability of curcumin, allowing us to reliably carry out several experiments in the attempt to establish the potential of this molecule as a therapeutic agent and elucidate the mechanism of action in TNBC. HFn biopolymer was designed to bind selectively to the TfR1 receptor overexpressed in TNBC cells. HFn-curcumin (CFn) proved to be more effective in viability assays compared to the drug alone using MDA-MB-468 and MDA-MB-231 cell lines, representative of basal and claudin-low TNBC subtypes, respectively. Cellular uptake of CFn was demonstrated by flow cytometry and label-free confocal Raman imaging. CFn could act as a chemosensitizer enhancing the cytotoxic effect of doxorubicin by interfering with the activity of multidrug resistance transporters. In addition, CFn exhibited different cell cycle effects on these two TNBC cell lines, blocking MDA-MB-231 in G0/G1 phase, whereas MDA-MB-468 accumulated in G2/M phase. CFn was able to inhibit the Akt phosphorylation, suggesting that the effect on the proliferation and cell cycle involved the alteration of PI3K/Akt pathway.

  19. Optimizing therapeutic efficacy of chemopreventive agents: A critical review of delivery strategies in oral cancer chemoprevention clinical trials

    Andrew S Holpuch; Kashappa-Goud H Desai; Steven P Schwendeman; Susan R Mallery

    2011-01-01

    Due to its characterized progression from recognized premalignant oral epithelial changes (i.e., oral epithelial dysplasia) to invasive cancer, oral squamous cell carcinoma represents an optimal disease for chemopreventive intervention prior to malignant transformation. The primary goal of oral cancer chemoprevention is to reverse, suppress, or inhibit the progression of premalignant lesions to cancer. Over the last several decades, numerous oral cancer chemoprevention clinical trials have as...

  20. Comparison of Efficacy and Safety of Different Therapeutic Regimens as 
Second-line Treatment for Small Cell Lung Cancer

    Zhihua LI

    2015-05-01

    Full Text Available Background and objective Small-cell lung cancer (SCLC is an aggressive disease for which the mainstay of treatment is cytotoxic chemotherapy. Despite good initial responses most patients will relapse or progress after the first-line therapy. The evidence of a benefit from second-line chemotherapy is limited in patients with relapsed/advanced SCLC. Some drugs are recommended by guidelines, but more regimens are formulated based on experience in clinical. So we conducted this retrospective study in order to compare the efficacy and safety of different second-line treatment regimens. Methods We totally analyzed 309 patients received second-line treatment in our retrospective study. 157 patients received best supportive care (BSC, and the rest 152 patients received second-line chemotherapy. The Kaplan-Meier method survival curves and Log-rank test were used to analysis the differences among different groups. The endpoints were objective response rate (ORR, disease control rate (DCR, progression-free survival (PFS, and overall survival (OS. Results Patients administered second-line chemotherapy lived significantly longer, with a total OS from first-line therapy of 11.5 mo compared to 6.0 mo in patients with best supportive care alone (P<0.001, and the ORR, DCR, PFS and OS of the former (including the sensitive disease and resistance/refractory disease patients were obviously better than that of the latter. The ORR and DCR of the patients who received second-line chemotherapy is 39.5% and 59.2%, respectively. The median PFS and OS from second-line chemotherapy were 3.3 mo and 5.3 mo. The patients who received second-line chemotherapy were divided by types of second-line regimens. The sensitive disease patients were from group A (VP-16-based rechallenge and group B1 (CPT-11-based regimen. The ORR of the two groups were 48.6% and 35.3%, and the DCR were 68.6% and 58.8%, respectively. There was no statistically significant difference (P=0.264; P=0

  1. Profiling Prostate Cancer Therapeutic Resistance

    Cameron A. Wade; Natasha Kyprianou

    2018-01-01

    The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival ...

  2. Therapeutic Vaccination for HPV Induced Cervical Cancers

    Joeli A. Brinkman

    2007-01-01

    Full Text Available Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.

  3. Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer.

    Šišić, Ibrahim; Pojskić, Belma; Mekić Abazović, Alma; Kovčin, Vladimir

    2015-08-01

    To compare efficacy and toxicity of bolus application of chemotherapy protocol, oxaliplatin, fluorouracil (bolus), leucovorin (folfox) between two groups of patients in the therapy of metastatic colorectal carcinoma (mCRC). A total of 63 patients were treated for mCRC in the period January 2009 - January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients) and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 - January 2006 (second group, 33 patients). The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D), 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS), progression free survival, hematological and non-hematological toxicity . Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy. Copyright© by the Medical Assotiation of Zenica-Doboj Canton.

  4. Therapeutic efficacy and toxicity of bolus application of chemotherapy protocol in the treatment of metastatic colorectal cancer

    Ibrahim Šišić

    2015-08-01

    Full Text Available Aim To compare efficacy and toxicity of bolus application of chemotherapy protocol, oxaliplatin, fluorouracil (bolus, leucovorin (folfox between two groups of patients in the therapy of metastatic colorectal carcinoma (mCRC. Methods A total of 63 patients were treated for mCRC in the period January 2009 – January 2010 at the Department of Oncology of the Cantonal Hospital Zenica, Bosnia and Herzegovina (first group, 30 patients and at the Department of Oncology of the Clinical Hospital Centre Bežanijska kosa in Belgrade, Serbia, in the period January 2005 – January 2006 (second group, 33 patients. The patients were treated according the same protocol, i.v. bolus infusion, but in different day intervals (D, 1, 8, 15/28 days or D1-D5/28 days, respectively. In all patients the following factors were analyzed: tumor response, overall survival (OS, progression free survival, hematological and non-hematological toxicity. Results Colon was the primary localization in almost two thirds of patients. There was no statistically significant difference between the groups according to the age, hematological and non-hematological toxicity, as well as in achieved OS. Progression free survival expressed in months was in average 5 months though with a large range between minimal and maximal survival time. Conclusion Both groups have shown equivalent efficacy to applied chemotherapy protocols. Overall survival in the two groups matched data from the literature. Further research should confirm success of the combination of chemotherapy protocols and their combination with the biological therapy.

  5. #3653 Sequencing of plasma cfDNA from patients with locally advanced bladder cancer for surveillance and therapeutic efficacy monitoring

    Birkenkamp-Demtröder, Karin; Christensen, Emil; Sharma, Shruti

    ), 340 (67-2838) moderate and 223 (29-2955) low-impact SNVs or insertion-deletions (InDels) per tumor. High-impact mutations in known cancer genes such as TP53 (60%), KDM6A (34%), ARID1A (32%), RB1 (28%), BRCA2 (26%), FGFR3 (22%) and ERCC2 (20%) were identified with no significant difference between......, 50 patients diagnosed with locally advanced muscle-invasive bladder cancer (MIBC) and scheduled for chemotherapy were prospectively recruited between 2013 and 2017. In total, 42 patients received four cycles of cisplatin-based NAC prior to cystectomy and 82% showed response (pathologic downstaging......). Eight patients received 2-6 cycles of cisplatin-based first-line chemotherapy due to diagnosis of T4b or lymph node metastasis prior to cystectomy (3CR, 2PR, 2PD, 1 ongoing). So far, 8/50 patients (16%) experienced disease relapse and three patients had metastatic progression. The mean follow-up time...

  6. Therapeutic antitumor efficacy of tumor-derived autophagosome (DRibble vaccine on head and neck cancer

    Su H

    2015-03-01

    DC cross-presenting antigens on upregulated MHC-I, suggesting that DRibbles be deployed as an effective antitumor vaccine for head and neck cancer immunotherapy in clinical trials. Keywords: autophagy, nanoparticles, dendritic cells, antitumor immunity, head and neck cancer

  7. Poly(ethylene glycol-block-poly(ε-caprolactone– and phospholipid-based stealth nanoparticles with enhanced therapeutic efficacy on murine breast cancer by improved intracellular drug delivery

    He XD

    2015-03-01

    Full Text Available Xiaodan He,1 Li Li,2 Hong Su,1 Dinglun Zhou,3 Hongmei Song,4 Ling Wang,1 Xuehua Jiang1 1West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3West China School of Public Health, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 4HitGen Ltd., Chengdu, Sichuan, People’s Republic of China Background: Effective anticancer drug delivery to the tumor site without rapid body clearance is a prerequisite for successful chemotherapy. 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-N-(methoxy[polyethyleneglycol]-2000 (DSPE-PEG2000 has been widely used in the preparation of stealth liposomes. Although PEG chains can efficiently preserve liposomes from rapid clearance by the reticuloendothelial system (RES, its application has been hindered by poor cellular uptake and unsatisfactory therapeutic effect.Methods: To address the dilemma, we presented a facile approach to fabricate novel stealth nanoparticles generated by poly(ethylene glycol-block-poly(ε-caprolactone (PEG-b-PCL, soybean phosphatidylcholine (SPC, and cholesterol, namely LPPs (L represented lipid and PP represented PEG-b-PCL, for the delivery of anticancer drug paclitaxel (PTX. LPPs were prepared using the thin film hydration method. Two PEG-b-PCL polymers with different molecular weights (MW; PEG2000-b-PCL2000, MW: 4,000 Da and PEG5000-b-PCL5000, MW: 10,000 Da were used to fabricate stealth nanoparticles. Conventional PEGylated liposome (LDP2000, L represented lipid and DP2000 represented DSPE-PEG2000 composed of SPC, cholesterol, and DSPE-PEG2000 was used as the control. The physical properties, cellular uptake, endocytosis pathway, cytotoxicity, pharmacokinetics, tumor accumulation, and anticancer efficacy of free PTX, PTX-loaded LPPs, and LDP2000 were systemically investigated after injection into 4T1

  8. Graphene-based platforms for cancer therapeutics

    Patel, Sunny C; Lee, Stephen; Lalwani, Gaurav; Suhrland, Cassandra; Chowdhury, Sayan Mullick; Sitharaman, Balaji

    2016-01-01

    Graphene is a multifunctional carbon nanomaterial and could be utilized to develop platform technologies for cancer therapies. Its surface can be covalently and noncovalently functionalized with anticancer drugs and functional groups that target cancer cells and tissue to improve treatment efficacies. Furthermore, its physicochemical properties can be harnessed to facilitate stimulus responsive therapeutics and drug delivery. This review article summarizes the recent literature specifically focused on development of graphene technologies to treat cancer. We will focus on advances at the interface of graphene based drug/gene delivery, photothermal/photodynamic therapy and combinations of these techniques. We also discuss the current understanding in cytocompatibility and biocompatibility issues related to graphene formulations and their implications pertinent to clinical cancer management. PMID:26769305

  9. Guidelines for Rational Cancer Therapeutics

    Byunghee Yoo

    2017-12-01

    Full Text Available Traditionally, cancer therapy has relied on surgery, radiation therapy, and chemotherapy. In recent years, these interventions have become increasingly replaced or complemented by more targeted approaches that are informed by a deeper understanding of the underlying biology. Still, the implementation of fully rational patient-specific drug design appears to be years away. Here, we present a vision of rational drug design for cancer that is defined by two major components: modularity and image guidance. We suggest that modularity can be achieved by combining a nanocarrier and an oligonucleotide component into the therapeutic. Image guidance can be incorporated into the nanocarrier component by labeling with a specific imaging reporter, such as a radionuclide or contrast agent for magnetic resonance imaging. While limited by the need for additional technological advancement in the areas of cancer biology, nanotechnology, and imaging, this vision for the future of cancer therapy can be used as a guide to future research endeavors.

  10. Therapeutic efficacy of stereotactic radiotherapy with gamma knife on early-stage non-small-cell lung cancer and life quality of patients

    Ren Zhengting; Cui Di; Ren Ye; Dai Zhuojie; Su Xiaoming; Fan Jingjing; Shen Yulong; Ma Huizhen; Wang Zongye

    2012-01-01

    Objective: To evaluate the therapeutic efficacy of stereotactic body radiotherapy (SBRT) with gamma knife on stage Ⅰ-Ⅱ non-small-cell lung cancer (NSCLC)and the quality of life of the patients undergoing this therapy. Methods: Twenty NSCLC patients with the median age of 76, 10 at stage Ⅰ and 10 at stage Ⅱ who were unable or unwilling to undergo surgery were given SBRT with gamma knife at the doses of 3-6 Gy in 8-15 fractions,finished within 2 to 3 weeks. The prescription isodose line was 50%,the marginal dose was 39-56 Gy, the central dose was 78-112 Gy, and the total biologically effective dose was 51-83 Gy. The patients were observed after admission and followed up by chest CT 1, 3, 6, and 12 months after treatment until progressive disease or death. EORTC QLQ-LC43 questionnaire was used to investigate the changes in quality of life. Results: The 20 patients were followed up for 24 (12-46) months. At six months after the treatment,the overall response rate was 80%, and the complete response rate was 35%. The 1, 2 and 3-year local control rates were 100%, 95% and 95%, respectively. The 1, 2 and 3-year overall survival rates were 95%, 80% and 50% respectively; The 1, 2, and 3-year progression free survival rates were 85%, 64% and 33%, respectively. The failure rate was 20% and the rate of progress within the planning target volume was 5%. No acute toxicity at grade 3 and over occurred in any patient during the treatment. 15% of the patients developed grade 1-2 radiation pneumonia. Age, gender, pathologic index or not were weakly correlated with the overall survival. The emotional function was improved significantly after treatment (P<0.05), dyspnea and cough were improved at different degrees, however, not significantly. There were no significant changes in the physical function and symptoms, such as fatigue,lack of appetite, insomnia, etc. Conclusions: Significantly improving the motional function and maintaining the quality of life, SBRT with gamma knife

  11. Comparison of therapeutic efficacy and clinical parameters between recombinant human thyroid stimulating hormone and thyroid hormone withdrawal in high-dose radioiodine treatment with differentiated thyroid cancer

    Choi, Se Hun; Na, Chang Ju; Kim, Jeong Hun; Han, Yeon Hee; KIm, Hee Kwon; Jeong, Hwan Jeong; Sohn, Myung Hee; Lim, Seok Tae [Dept. of Nuclear Medicine, Chonbuk National University Medical School and Hospital, Jeonju (Korea, Republic of)

    2015-06-15

    High-dose radioiodine treatment (HD-RIT) after injection of recombinant human thyroid stimulating hormone (rh-TSH) has become widely used. This study compared the therapeutic efficacy of HD-RIT and clinical parameters between rh-TSH supplement and thyroid hormone withdrawal (THW) after total thyroidectomy in patients with differentiated thyroid cancer. We retrospectively reviewed 266 patients (47 male and 219 female; age, 49.0 ± 10.9 years) with differentiated thyroid cancer detected from September 2011 to September 2012. Patients comprised THW (217, 81.6 %) and rh-TSH (49, 18.4 %). Inclusion criteria were: first HD-RIT; any TN stage; absence of distant metastasis. To evaluate the complete ablation of the remnant thyroid tissue or metastasis, we reviewed stimulated serum thyroglobulin (sTg), I-123 whole-body scan (RxWBS) on T4 off-state, and thyroid ultrasonography (US) or [F-18]-fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) 6–8 months after HD-RIT. We defined a complete ablation state when all three of the follow-up conditions were satisfied; <2.0 ng/ml of the sTg, I-123 RxWBS (−), and thyroid US or F-18 FDG PET/CT (−). If one of the three was positive, ablation was considered incomplete. We also compared various clinical biomarkers (body weight, body mass index, liver and kidney function) between THW and rh-TSH groups. The rates of complete ablation were 73.7 % (160/217) for the THW group and 73.5 % (36/49) for the rh-TSH group. There was no significant difference between the two groups (p = 0.970). The follow-up aspartate transaminase (p = 0.001) and alanine transaminase (p = 0.001) were significantly higher in the THW group. The renal function parameters of blood urea nitrogen (p = 0.001) and creatinine (p = 0.005) tended to increase in the THW group. The change of body weight was + Δ0.96 (±1.9) kg for the THW group and was decreased by -Δ1.39 (±1.5) kg for the rh-TSH group. The change

  12. Colorectal cancer: diagnostic and therapeutic strategies

    Vaillant, J.C.

    1996-01-01

    Technical advances that has been achieved during the past two decades have not dramatically improved the 35 % five-year rate observed in patients with colorectal cancer. These tumours remain one of the most challenging problems in public health policies in western countries. Screening applies to some subgroups of high-risk individuals and the general population aged over 50. In order to improve their efficacy, such screening programs imply large-scale information campaigns and a strong cooperation with the general physicians. The diagnosis is strongly suggested by any recent modification of bowel habits ad by rectal bleeding. It has to be confirmed by rectal examination and by colonoscopy which allows sampling to the tumour. Loco-regional and distant metastatic tumour spread must be assessed precisely before any therapeutic strategy is decided. Surgery, which resects the tumour en bloc with the corresponding lymphatic territories, is the only treatment that can achieve long term cure. In localized tumours, surgery alone can provide patients with 5-years survival rates close to 95 %. On the other hand, surgery alone is not sufficient to cure patients with advances cancers. In recent years, several adjuvant therapeutic modalities have been shown to improve the results of surgery in these cases (rectal cancer: pre-operative radiotherapy or post-operative radio-chemotherapy, colon cancer with nodal metastases: post-operative chemotherapy). There is a hope that a better use of our diagnostic and therapeutic armementarium would be able to avoid or to cure up to 75 % of the colorectal cancers we are dealing with. (author)

  13. Therapeutic Efficacy Comparison of 5 Major EGFR-TKIs in Advanced EGFR-positive Non-Small-cell Lung Cancer: A Network Meta-analysis Based on Head-to-Head Trials.

    Zhang, Yaxiong; Zhang, Zhonghan; Huang, Xiaodan; Kang, Shiyang; Chen, Gang; Wu, Manli; Miao, Siyu; Huang, Yan; Zhao, Hongyun; Zhang, Li

    2017-09-01

    Five major first- and second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), including erlotinib, gefitinib, icotinib, afatinib, and dacomitinib, are currently optional for patients with advanced non-small-cell lung cancer (NSCLC) who harbor EGFR mutations. However, there was no head-to-head-based network meta-analysis among all the TKIs in EGFR-mutated populations. Eligible literature was searched from an electronic database. Data of objective response rate, disease control rate, progression-free survival, and overall survival were extracted from enrolled studies. Multiple treatment comparisons based on Bayesian network integrated the efficacy of all included treatments. Six phase III randomized trials involving 1055 EGFR-mutated patients with advanced NSCLC were enrolled. Multiple treatment comparisons showed that 5 different EGFR-TKIs shared equivalent therapeutic efficacy in terms of all outcome measures. Rank probabilities indicated that dacomitinib and afatinib had potentially better efficacy compared with erlotinib, gefitinib, and icotinib in the EGFR-mutated patients. When compared with other agents, potential survival benefits (progression-free and overall survival) were observed in dacomitinib, whereas afatinib showed a better rank probability in overall response rate and disease control rate. Our study indicated a preferable therapeutic efficacy in the second-generation TKIs (dacomitinib and afatinib) when compared with the first-generation TKIs (erlotinib, gefitinib, and icotinib). Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Therapeutic Silencing of Bcl-2 by Systemically Administered siRNA Nanotherapeutics Inhibits Tumor Growth by Autophagy and Apoptosis and Enhances the Efficacy of Chemotherapy in Orthotopic Xenograft Models of ER (− and ER (+ Breast Cancer

    Ibrahim Tekedereli

    2013-01-01

    Full Text Available Bcl-2 is overexpressed in about a half of human cancers and 50–70% of breast cancer patients, thereby conferring resistance to conventional therapies and making it an excellent therapeutic target. Small interfering RNA (siRNA offers novel and powerful tools for specific gene silencing and molecularly targeted therapy. Here, we show that therapeutic silencing of Bcl-2 by systemically administered nanoliposomal (NL-Bcl-2 siRNA (0.15 mg siRNA/kg, intravenous twice a week leads to significant antitumor activity and suppression of growth in both estrogen receptor-negative (ER(− MDA-MB-231 and ER-positive (+ MCF7 breast tumors in orthotopic xenograft models (P < 0.05. A single intravenous injection of NL-Bcl-2-siRNA provided robust and persistent silencing of the target gene expression in xenograft tumors. NL-Bcl-2-siRNA treatment significantly increased the efficacy of chemotherapy when combined with doxorubicin in both MDA-MB-231 and MCF-7 animal models (P < 0.05. NL-Bcl-2-siRNA treatment-induced apoptosis and autophagic cell death, and inhibited cyclin D1, HIF1α and Src/Fak signaling in tumors. In conclusion, our data provide the first evidence that in vivo therapeutic targeting Bcl-2 by systemically administered nanoliposomal-siRNA significantly inhibits growth of both ER(− and ER(+ breast tumors and enhances the efficacy of chemotherapy, suggesting that therapeutic silencing of Bcl-2 by siRNA is a viable approach in breast cancers.

  15. Curcumin Nanomedicine: A Road to Cancer Therapeutics

    Yallapu, Murali M.; Jaggi, Meena; Chauhan, Subhash C.

    2013-01-01

    Cancer is the second leading cause of death in the United States. Conventional therapies cause widespread systemic toxicity and lead to serious side effects which prohibit their long term use. Additionally, in many circumstances tumor resistance and recurrence is commonly observed. Therefore, there is an urgent need to identify suitable anticancer therapies that are highly precise with minimal side effects. Curcumin is a natural polyphenol molecule derived from the Curcuma longa plant which exhibits anticancer, chemo-preventive, chemo- and radio-sensitization properties. Curcumin’s widespread availability, safety, low cost and multiple cancer fighting functions justify its development as a drug for cancer treatment. However, various basic and clinical studies elucidate curcumin’s limited efficacy due to its low solubility, high rate of metabolism, poor bioavailability and pharmacokinetics. A growing list of nanomedicine(s) using first line therapeutic drugs have been approved or are under consideration by the Food and Drug Administration (FDA) to improve human health. These nanotechnology strategies may help to overcome challenges and ease the translation of curcumin from bench to clinical application. Prominent research is reviewed which shows that advanced drug delivery of curcumin (curcumin nanoformulations or curcumin nanomedicine) is able to leverage therapeutic benefits by improving bioavailability and pharmacokinetics which in turn improves binding, internalization and targeting of tumor(s). Outcomes using these novel drug delivery systems have been discussed in detail. This review also describes the tumor-specific drug delivery system(s) that can be highly effective in destroying tumors. Such new approaches are expected to lead to clinical trials and to improve cancer therapeutics. PMID:23116309

  16. Therapeutic efficacy of Traditional Chinese medicine, "Kuan-Sin-Yin", in patients undergoing chemotherapy for advanced colon cancer - A controlled trial.

    Chien, Tsai-Ju; Liu, Chia-Yu; Lu, Ruey-Hwa; Kuo, Chin-Wei; Lin, Yang-Chao; Hsu, Chung-Hua

    2016-12-01

    Traditional Chinese Medicine (TCM) has been used increasingly as complementary medicine in cancer care. Kuan-Sin-Yin (KSY) is a TCM decoction containing seven herbs known to cause immunomodulation or anticancer activity, and which are associated with the TCM concept of Qi and energy supply. Kuan-Sin-Yin has cytostatic effects on cancer cells in animal models. The aim of this study is to evaluate the level of improvement in meridian energy and heart-rate variability (HRV) and to assess whether these observations are compatible with TCM theory. A non-randomized controlled trial was designed with monitoring of the meridian electro-conductivity and heart-rate variability (HRV) to compare the efficacy of Kuan-Sin-Yin in the control and experimental groups. 52 patients were enrolled in this study. We also measured cancer-related symptoms and quality of life as secondary outcomes. We found that colon cancer patients who received KSY as complementary therapy benefitted with enhancement of meridian energy (Yin meridian: 27.90:35.45μA; p=0.014; Yang meridian: 27.09:33.55μA; p=0.024) and increases in HRV activity (78.40:129.04ms; SDNN: p=0.001) and parasympathetic tone(HF:1644.80:3217.92 ms 2 ; p=0.003; RMMSD:99.76:164.52ms; p=0.002). Cancer-related symptoms decreased (ECOG>1:46.2:7.7%; p=0.0001), and quality of life (KSY group: PCS 35.46:42.12, p=0.0001; MCS: 44.50:47.55, p=0.209) was improved with statistical significance. The correlation of positive results reflected in meridian energy and HRV activity confirms the positive role of complementary medicine of Kuan-Sin-Yin in cancer care. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Novel approach to cancer therapeutics using comparative cancer biology

    Revi, Bhindu

    2018-01-01

    Developing personalized cancer therapies based on cancer genomics methodologies forms the basis for future cancer therapeutics. A genomics platform was developed based on canine cancer to produce a proof-of-concept for personalized genomics led therapeutic choices but also developing personalized therapeutics for canine cancer patients themselves. The platform identified the genetic state of a canine cancer patient within two drugable pathways; p53 and HSP90/IRF1. The former ge...

  18. Therapeutic efficacy of PD-L1 blockade in a breast cancer model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored IL-12.

    Bozeman, Erica N; He, Sara; Shafizadeh, Yalda; Selvaraj, Periasamy

    2016-01-01

    Immunotherapeutic approaches have emerged as promising strategies to treat various cancers, including breast cancer. A single approach, however, is unlikely to effectively combat the complex, immune evasive strategies found within the tumor microenvironment, thus novel, effective combination treatments must be explored. In this study, we investigated the efficacy of a combination therapy consisting of PD-L1 immune checkpoint blockade and whole cell vaccination in a HER-2 positive mouse model of breast cancer. We demonstrate that tumorigenicity is completely abrogated when adjuvanted with immune stimulatory molecules (ISMs) B7-1 and a cell-surface anchored (GPI) form of IL-12 or GM-CSF. Irradiated cellular vaccines expressing the combination of adjuvants B7-1 and GPI-IL-12 completely inhibited tumor formation which was correlative with robust HER-2 specific CTL activity. However, in a therapeutic setting, both cellular vaccination and PD-L1 blockade induced only 10-20% tumor regression when administered alone but resulted in 50% tumor regression as a combination therapy. This protection was significantly hindered following CD4 or CD8 depletion indicating the essential role played by cellular immunity. Collectively, these pre-clinical studies provide a strong rationale for further investigation into the efficacy of combination therapy with tumor cell vaccines adjuvanted with membrane-anchored ISMs along with PD-L1 blockade for the treatment of breast cancer.

  19. Therapeutic efficacy of sulfadoxine-pyrimethamine in uncomplicated ...

    Therapeutic efficacy of sulfadoxine-pyrimethamine in uncomplicated Plasmodium falciparum malaria 3 years after introduction in Mpumalanga. Aaron Mabuza, John Govere, David Durrheim, Nicros Mangomezulu, Barry Bredenkamp, Karen Barnes, Brian Sharp ...

  20. Therapeutic efficacy of traditional Chinese medicine, Shen-Mai San, in cancer patients undergoing chemotherapy or radiotherapy: study protocol for a randomized, double-blind, placebo-controlled trial

    Lo Lun-Chien

    2012-12-01

    Full Text Available Abstract Background Cancer is one of the major health issues worldwide. An increasing number of cancer patients are offered treatment with surgery, chemotherapy and radiotherapy. Traditional Chinese medicine (TCM is one of the most common complementary therapies offered to cancer patients in Taiwan. We designed a randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy of TCM in patients with cancer. Methods/design In this study, inclusion criteria are postoperative patients with histologically confirmed cancer within 3 years who are undergoing chemotherapy or radiotherapy, more than 18 years old, have given signed informed consent, have the ability to read Chinese, and the ability for oral intake. Exclusion criteria include being pregnant, breast feeding, having completed chemotherapy or radiotherapy, brain metastasis with Eastern Cooperative Oncology Group (ECOG performance status of two to four, delusion or hallucinations, acute infection, and have received medications under other clinical trials. The patients were separated into an intervention group (Shen-Mai-San, SMS and a placebo group for four weeks using a randomized, double-blind procedure. The European Organization for Research and Treatment of Cancer (EORTC Quality of Life questionnaire (QOL-C30 was used to evaluate the quality of life. General data, hemoglobin (Hb, hematocrit (Hct, glutamic-oxalacetic transaminase (GOT, glutamic-pyruvic transaminase (GPT, blood urea nitrogen (BUN, creatinine, carcinoembryonic antigen (CEA, TCM diagnosis data and heart rate variability (HRV were also recorded. These data were collected at baseline, two weeks and four weeks after receiving medication. The patients were prescribed granules which contained therapeutic medicines or placebo. Paired-T test was used for statistical analysis. Discussion Shen-Mai-San is composed of processed Ginseng radis, Liriope spicata, and Schizandrae fructus. It was found to be effective for

  1. Predictive and therapeutic markers in ovarian cancer

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  2. Design of clinical trials for therapeutic cancer vaccines development.

    Mackiewicz, Jacek; Mackiewicz, Andrzej

    2009-12-25

    Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.

  3. Neurodevelopmental Treatment (NDT): Therapeutic Intervention and Its Efficacy.

    Stern, Francine Martin; Gorga, Delia

    1988-01-01

    Use of neurodevelopmental treatment, also known as the Bobath method, is discussed, including its history, philosophy, goals, and treatment emphasis with infants and children with movement disorders. Examples of children before and after therapeutic intervention illustrate use of the technique, and controversies in measuring therapy efficacy are…

  4. Understanding Music's Therapeutic Efficacy with Implications for Why Music Matters

    Thram, Diane

    2015-01-01

    In this essay, I focus on how attention to music's therapeutic efficacy is important to the praxial music education philosophy espoused by Elliott and Silverman. I note, despite the use of the term praxis from Aristotle's philosophy dating back to antiquity, there is no mention in Music Matters 2 of what historical evidence tells us about how…

  5. Therapeutic Efficacy Of Cotecxin (R) alone and Its Combination with ...

    The therapeutic efficacy of Cotecxin(R) (Dihydroartemisinin) alone and its combination with diminazene aceturate (Berenil(R)) was studied in rats infected with Federe strain of Trypanosoma brucei brucei. Fifty healthy adult albino rats of both sexes weighing between 100-180g used were divided into five groups (A-E) of 10 ...

  6. THERAPEUTIC OPTIONS FOR BREAST CANCER

    Milena Georgescu

    2011-12-01

    Full Text Available Breast cancer remains a major public health problem, being the second cause of cancer death in women. There is a marked tendency to restrict the extension of surgical gesture, which directly leads to two different attitudes: radical surgery and conservative surgery, to which, at least in our country, there are still some delays. Prospective and retrospective studies have shown that, in 20 years, conservative and radical therapy had about the same rate of survival and disease-free interval, at least for stage I and II breast cancer, the only real counterargument against conservative surgery being that, in principle, the higher rate of recurrence local constraint can be solved by postoperative radiotherapy. Finally, the survival rate is the main parameter of evaluation, assessing the effectiveness of the treatment in breast cancer, and in all its other forms.

  7. Targeting mitochondrial respiration as a therapeutic strategy for cervical cancer.

    Tian, Shenglan; Chen, Heng; Tan, Wei

    2018-05-23

    Targeting mitochondrial respiration has been documented as an effective therapeutic strategy in cancer. However, the impact of mitochondrial respiration inhibition on cervical cancer cells are not well elucidated. Using a panel of cervical cancer cell lines, we show that an existing drug atovaquone is active against the cervical cancer cells with high profiling of mitochondrial biogenesis. Atovaquone inhibited proliferation and induced apoptosis with varying efficacy among cervical cancer cell lines regardless of HPV infection, cellular origin and their sensitivity to paclitaxel. We further demonstrated that atovaquone acts on cervical cancer cells via inhibiting mitochondrial respiration. In particular, atovaquone specifically inhibited mitochondrial complex III but not I, II or IV activity, leading to respiration inhibition and energy crisis. Importantly, we found that the different sensitivity of cervical cancer cell lines to atovaquone were due to their differential level of mitochondrial biogenesis and dependency to mitochondrial respiration. In addition, we demonstrated that the in vitro observations were translatable to in vivo cervical cancer xenograft mouse model. Our findings suggest that the mitochondrial biogenesis varies among patients with cervical cancer. Our work also suggests that atovaquone is a useful addition to cervical cancer treatment, particularly to those with high dependency on mitochondrial respiration. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Therapeutic efficacy of Chymotrypsin in acute bovine mastitis

    Marco Leal G

    2016-05-01

    Full Text Available Objective. To evaluate the therapeutic efficacy of a proteolytic drug “chymotrypsin” combined with beta-lactam antibiotics in cows with acute mastitis. Material and Methods. Fourteen cows with acute mastitis. Three cows were treated with a beta-latam antibiotic (BLA and the other eleven cows were treated with chymotrypsin plus beta-lactam antibiotic (C+BLA. The response was evaluated according to the semiological findings, somatic cell count (SCC and a microbiological culture. Results. There was a therapeutic efficacy comparing the pre and post treatment period (SCC reduction, p<0.01 and a reduction of clinical signs in 84.7% of treated quarters in the first day of treatment (C+BLA compared with (BLA. Conclusions. Chymotrypsin improves the treatment of acute mastitis when is combined with BLA, controlling the infected mammary glands, compared with the group treated only with amoxicilina and clavulanic acid.

  9. IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

    Liefers-Visser, J A L; Meijering, R A M; Reyners, A K L; van der Zee, A G J; de Jong, S

    2017-11-01

    The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  10. Therapeutic Implications of Targeting Energy Metabolism in Breast Cancer

    Meena K. Sakharkar

    2013-01-01

    Full Text Available PPARs are ligand activated transcription factors. PPARγ agonists have been reported as a new and potentially efficacious treatment of inflammation, diabetes, obesity, cancer, AD, and schizophrenia. Since cancer cells show dysregulation of glycolysis they are potentially manageable through changes in metabolic environment. Interestingly, several of the genes involved in maintaining the metabolic environment and the central energy generation pathway are regulated or predicted to be regulated by PPARγ. The use of synthetic PPARγ ligands as drugs and their recent withdrawal/restricted usage highlight the lack of understanding of the molecular basis of these drugs, their off-target effects, and their network. These data further underscores the complexity of nuclear receptor signalling mechanisms. This paper will discuss the function and role of PPARγ in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer.

  11. Individualised cancer therapeutics: dream or reality? Therapeutics construction.

    Shen, Yuqiao; Senzer, Neil; Nemunaitis, John

    2005-11-01

    The analysis of DNA microarray and proteomic data, and the subsequent integration into functional expression sets, provides a circuit map of the hierarchical cellular networks responsible for sustaining the viability and environmental competitiveness of cancer cells, that is, their robust systematics. These technologies can be used to 'snapshot' the unique patterns of molecular derangements and modified interactions in cancer, and allow for strategic selection of therapeutics that best match the individual profile of the tumour. This review highlights technology that can be used to selectively disrupt critical molecular targets and describes possible vehicles to deliver the synthesised molecular therapeutics to the relevant cellular compartments of the malignant cells. RNA interference (RNAi) involves a group of evolutionarily conserved gene silencing mechanisms in which small sequences of double-stranded RNA or intrinsic antisense RNA trigger mRNA cleavage or translational repression, respectively. Although RNAi molecules can be synthesised to 'silence' virtually any gene, even if upregulated, a mechanism for selective delivery of RNAi effectors to sites of malignant disease remains challenging. The authors will discuss gene-modified conditionally replicating viruses as candidate vehicles for the delivery of RNAi.

  12. Radioiodination of cyclin dependent kinase inhibitor Olomoucine loaded Fe rate at Au nanoparticle and evaluation of the therapeutic efficacy on cancerous cells

    Takan, Gokhan; Guldu, Ozge Kozgus; Medine, Emin Ilker [Ege Univ., Izmir (Turkey). Dept. of Nuclear Applications

    2017-06-01

    Magnetic nanoparticles have promising biomedical applications such as drug delivery, novel therapeutics and diagnostic imaging. Magnetic drug delivery combination works on the delivery of magnetic nanoparticles loaded with drug to the target tissue by means of an external magnetic field. Gold coated iron oxide (Fe rate at Au) nanoparticles can provide useful surface chemistry and biological reactivity. Covalent conjugation to the Fe rate at Au nanoparticles through cleavable linkages can be used to deliver drugs to tumor cells, then the drug can be released by an external. In this paper, purine based cyclin dependent kinases (CDKs) inhibitor Olomoucine (Olo) [2-(Hydroxyethylamino)-6-benzylamino-9-methylpurine] was loaded on gold coated iron oxide (Fe rate at Au) nanoparticles and radiolabeled with {sup 131}I to combine magnetic targeted drug delivery and radiotherapy. Fe rate at Au nanoparticles were synthesized by microemulsion method. The characterization of nanoparticles was examined by TEM, VSM and XRD. Amine activation was utilized by cysteamine hydrochloride and then CDI was used for conjugation of Olomoucine. Antiproliferative effect and cytotoxicity of Olomoucine loaded Fe rate at Au nanoparticles (Fe rate at Au-Olo) were investigated on MCF7 and A549 cell lines. Proliferation rate was decreased while uptake of Fe rate at Au-Olo on both cell lines was high in comparison with Olomoucine. Also, enhanced incorporation ratio was observed under external magnetic field.

  13. Radioiodination of cyclin dependent kinase inhibitor Olomoucine loaded Fe rate at Au nanoparticle and evaluation of the therapeutic efficacy on cancerous cells

    Takan, Gokhan; Guldu, Ozge Kozgus; Medine, Emin Ilker

    2017-01-01

    Magnetic nanoparticles have promising biomedical applications such as drug delivery, novel therapeutics and diagnostic imaging. Magnetic drug delivery combination works on the delivery of magnetic nanoparticles loaded with drug to the target tissue by means of an external magnetic field. Gold coated iron oxide (Fe rate at Au) nanoparticles can provide useful surface chemistry and biological reactivity. Covalent conjugation to the Fe rate at Au nanoparticles through cleavable linkages can be used to deliver drugs to tumor cells, then the drug can be released by an external. In this paper, purine based cyclin dependent kinases (CDKs) inhibitor Olomoucine (Olo) [2-(Hydroxyethylamino)-6-benzylamino-9-methylpurine] was loaded on gold coated iron oxide (Fe rate at Au) nanoparticles and radiolabeled with "1"3"1I to combine magnetic targeted drug delivery and radiotherapy. Fe rate at Au nanoparticles were synthesized by microemulsion method. The characterization of nanoparticles was examined by TEM, VSM and XRD. Amine activation was utilized by cysteamine hydrochloride and then CDI was used for conjugation of Olomoucine. Antiproliferative effect and cytotoxicity of Olomoucine loaded Fe rate at Au nanoparticles (Fe rate at Au-Olo) were investigated on MCF7 and A549 cell lines. Proliferation rate was decreased while uptake of Fe rate at Au-Olo on both cell lines was high in comparison with Olomoucine. Also, enhanced incorporation ratio was observed under external magnetic field.

  14. Therapeutic efficacy of boron neutron capture therapy mediated by boron-rich liposomes for oral cancer in the hamster cheek pouch model

    Heber, Elisa M. [Comision Nacional de Energia Atomica (CNEA), Buenos Aires (Argentina); Hawthorne, M. Frederick [Univ. of Missouri, Columbia, MO (United States). International Inst. of Nano and Molecular Medicine; Kueffer, Peter J. [Univ. of Missouri, Columbia, MO (United States). International Inst. of Nano and Molecular Medicine; Garabalino, Marcela A. [Comision Nacional de Energia Atomica (CNEA), Buenos Aires (Argentina); Thorp, Silvia I. [Comision Nacional de Energia Atomica (CNEA), Buenos Aires (Argentina); Pozzi, Emiliano C. C. [Comision Nacional de Energia Atomica (CNEA), Buenos Aires (Argentina); Hughes, Andrea Monti [Comision Nacional de Energia Atomica (CNEA), Buenos Aires (Argentina); Maitz, Charles A. [Univ. of Missouri, Columbia, MO (United States). International Inst. of Nano and Molecular Medicine; Jalisatgi, Satish S. [Univ. of Missouri, Columbia, MO (United States). International Inst. of Nano and Molecular Medicine; Nigg, David W. [Idaho National Lab. (INL), Idaho Falls, ID (United States); Curotto, Paula [Comision Nacional de Energia Atomica (CNEA), Buenos Aires (Argentina); Trivillin, Verónica A. [Comision Nacional de Energia Atomica (CNEA), Buenos Aires (Argentina); Schwint, Amanda E. [Comision Nacional de Energia Atomica (CNEA), Buenos Aires (Argentina)

    2014-11-11

    Unilamellar liposomes formulated with an equimolar mixture of cholesterol and 1,2-distearoyl-sn-glycero-3-phosphocholine, incorporating K[nido-7-CH3(CH2)15-7,8-C2B9H11] in the lipid bilayer, and encapsulating Na3[1-(2’-B10-H9)-2-NH3B10H8] were prepared by probe sonication and investigated in vivo. Microwave assisted digestion followed by inductively coupled plasma-optical emission spectroscopy was utilized to determine the biodistribution of boron in various tissues following either a single tail vein injection or two identical injections (separated by 24 hours) of the liposomal suspension in BALB/c mice bearing EMT6 mammary adenocarcinomas in their right flank. Double-injection protocols resulted in a boron content in the tumor exceeding 50 µg of boron per gram of tissue for 48 to 72 hours subsequent to the initial injection while tumor:blood boron ratios were more ideal from 54 hours (1.9:1) to 96 hours (5.7:1) subsequent to the initial injection. Tumor bearing mice were given a double-injection of liposomes containing the 10B-enriched analogs of the aforementioned agents and subjected to a 30 minute irradiation by thermal neutrons with a flux of 8.8 x 108 (±7%) neutrons/cm2 s integrated over the energy range of 0.0 – 0.414 eV. Significant tumor response for a single BNCT treatment was demonstrated by growth curves versus a control group. Vastly diminished tumor growth was witnessed at 14 days (186% increase versus 1551% in controls) in mice that were given a second injection/radiation treatment 7 days after the first. Mice given a one hour neutron irradiation following the double-injection of liposomes had a similar response (169% increase at 14 days) suggesting that neutron fluence is the limiting factor towards BNCT efficacy in this study.

  15. Hedgehog signaling and therapeutics in pancreatic cancer.

    Kelleher, Fergal C

    2012-02-01

    OBJECTIVE: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. METHOD: PubMed search (2000-2010) and literature based references. RESULTS: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. CONCLUSIONS: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer.

  16. Therapeutic efficacy of self-ligating brackets: A systematic review.

    Dehbi, Hasnaa; Azaroual, Mohamed Faouzi; Zaoui, Fatima; Halimi, Abdelali; Benyahia, Hicham

    2017-09-01

    Over the last few years, the use of self-ligating brackets in orthodontics has progressed considerably. These systems have been the subject of numerous studies with good levels of evidence making it possible to evaluate their efficacy and efficiency compared to conventional brackets. The aim of this study was to evaluate the therapeutic efficacy of self-ligating brackets by means of a systematic review of the scientific literature. A systematic study was undertaken in the form of a recent search of the electronic Pubmed database, oriented by the use of several keywords combined by Boolean operators relating to the therapeutic efficacy of self-ligating brackets through the study of tooth alignment, space closure, expansion, treatment duration and degree of discomfort. The search was limited to randomized controlled studies, and two independent readers identified studies corresponding to the selection criteria. The chosen articles comprised 20 randomized controlled trials. The studies analyzed revealed the absence of significant differences between the two types of system on the basis of the clinical criteria adopted, thereby refuting the hypothesis of the superiority of self-ligating brackets over conventional systems. Copyright © 2017 CEO. Published by Elsevier Masson SAS. All rights reserved.

  17. Therapeutic efficacy of uterine arterial embolization for intractable uterine hemorrhage

    Liu Lang; Lu Lianwei; Ke Mengjia; Zhao Ru'en; Zeng Shaolan

    2010-01-01

    Objective: To evaluate the therapeutic efficacy of uterine arterial embolization (UAE) for intractable uterine hemorrhage. Methods: 16 patients with intractable uterine hemorrhage underwent bilateral UAE after failed conventional conservative treatment. Results: Uterine hemorrhage ceased within 12 hours in 15 patients (93.8%) after bilateral super-selective UAE. Internal iliac artery embolization was performed on one patient (6.2%) and hysterectomy was eventually carried out because of recurrent hemorrhage. Conclusion: UAE is a rapid and effective treatment method obviating hysterectomy for intractable uterine hemorrhage. (authors)

  18. Immune evasion in cancer: Mechanistic basis and therapeutic strategies.

    Vinay, Dass S; Ryan, Elizabeth P; Pawelec, Graham; Talib, Wamidh H; Stagg, John; Elkord, Eyad; Lichtor, Terry; Decker, William K; Whelan, Richard L; Kumara, H M C Shantha; Signori, Emanuela; Honoki, Kanya; Georgakilas, Alexandros G; Amin, Amr; Helferich, William G; Boosani, Chandra S; Guha, Gunjan; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I; Azmi, Asfar S; Keith, W Nicol; Bilsland, Alan; Bhakta, Dipita; Halicka, Dorota; Fujii, Hiromasa; Aquilano, Katia; Ashraf, S Salman; Nowsheen, Somaira; Yang, Xujuan; Choi, Beom K; Kwon, Byoung S

    2015-12-01

    Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Therapeutic efficacy of a therapeutic cooking group from the patients' perspective.

    Hill, Kimberly H; O'Brien, Kimberly A; Yurt, Roger W

    2007-01-01

    The purpose of this study was to evaluate the therapeutic efficacy of the cooking group from the burn survivors' perspective. By incorporating concepts of kitchen skills, energy conservation, and desensitization techniques, the cooking group can assist patients with the functional use of their hands, standing tolerance, return to former vocational activities, and socialization with other patients. A questionnaire was developed based on commonly expressed benefits of cooking group. Areas of interest included decreasing anxiety in the kitchen, distraction from their burns, socializing with other burn survivors, and the physical benefits of participating in the group. The results of this study indicate that participants regard the therapeutic cooking group as a valuable treatment modality that effectively combines functional activities with socialization to decrease burn related anxiety and increase motion in a supportive environment for patients with burns.

  20. Aptamer nanomedicine for cancer therapeutics: barriers and potential for translation.

    Lao, Yeh-Hsing; Phua, Kyle K L; Leong, Kam W

    2015-03-24

    Aptamer nanomedicine, including therapeutic aptamers and aptamer nanocomplexes, is beginning to fulfill its potential in both clinical trials and preclinical studies. Especially in oncology, aptamer nanomedicine may perform better than conventional or antibody-based chemotherapeutics due to specificity compared to the former and stability compared to the latter. Many proof-of-concept studies on applying aptamers to drug delivery, gene therapy, and cancer imaging have shown promising efficacy and impressive safety in vivo toward translation. Yet, there remains ample room for improvement and critical barriers to be addressed. In this review, we will first introduce the recent progress in clinical trials of aptamer nanomedicine, followed by a discussion of the barriers at the design and in vivo application stages. We will then highlight recent advances and engineering strategies proposed to tackle these barriers. Aptamer cancer nanomedicine has the potential to address one of the most important healthcare issues of the society.

  1. Agonist anti-GITR antibody significantly enhances the therapeutic efficacy of Listeria monocytogenes-based immunotherapy.

    Shrimali, Rajeev; Ahmad, Shamim; Berrong, Zuzana; Okoev, Grigori; Matevosyan, Adelaida; Razavi, Ghazaleh Shoja E; Petit, Robert; Gupta, Seema; Mkrtichyan, Mikayel; Khleif, Samir N

    2017-08-15

    We previously demonstrated that in addition to generating an antigen-specific immune response, Listeria monocytogenes (Lm)-based immunotherapy significantly reduces the ratio of regulatory T cells (Tregs)/CD4 + and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Since Lm-based immunotherapy is able to inhibit the immune suppressive environment, we hypothesized that combining this treatment with agonist antibody to a co-stimulatory receptor that would further boost the effector arm of immunity will result in significant improvement of anti-tumor efficacy of treatment. Here we tested the immune and therapeutic efficacy of Listeria-based immunotherapy combination with agonist antibody to glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) in TC-1 mouse tumor model. We evaluated the potency of combination on tumor growth and survival of treated animals and profiled tumor microenvironment for effector and suppressor cell populations. We demonstrate that combination of Listeria-based immunotherapy with agonist antibody to GITR synergizes to improve immune and therapeutic efficacy of treatment in a mouse tumor model. We show that this combinational treatment leads to significant inhibition of tumor-growth, prolongs survival and leads to complete regression of established tumors in 60% of treated animals. We determined that this therapeutic benefit of combinational treatment is due to a significant increase in tumor infiltrating effector CD4 + and CD8 + T cells along with a decrease of inhibitory cells. To our knowledge, this is the first study that exploits Lm-based immunotherapy combined with agonist anti-GITR antibody as a potent treatment strategy that simultaneously targets both the effector and suppressor arms of the immune system, leading to significantly improved anti-tumor efficacy. We believe that our findings depicted in this manuscript provide a promising and translatable strategy that can enhance the overall

  2. Integrins as Therapeutic Targets: Successes and Cancers

    Sabine Raab-Westphal

    2017-08-01

    Full Text Available Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments.

  3. Cancer chemopreventive and therapeutic effects of diosgenin, a food saponin.

    Raju, Jayadev; Mehta, Rekha

    2009-01-01

    Cancer chemoprevention is a strategy taken to retard, regress, or resist the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal-preneoplasia-neoplasia-metastasis. For several reasons, including safety, minimal (or no) toxicity and side-effects, and better availability, alternatives such as naturally occurring phytochemicals that are found in foods are becoming increasingly popular over synthetic drugs. Food saponins have been used in complimentary and traditional medicine against a variety of diseases including several cancers. Diosgenin, a naturally occurring steroid saponin found abundantly in legumes and yams, is a well-known precursor of various synthetic steroidal drugs that are extensively used in the pharmaceutical industry. Over the past decade, a series of preclinical and mechanistic studies have been conducted to understand the role of diosgenin as a chemopreventive/therapeutic agent against several cancers. This review highlights the biological activity of diosgenin that contributes to cancer chemoprevention and control. The anticancer mode of action of diosgenin has been demonstrated via modulation of multiple cell signaling events involving critical molecular candidates associated with growth, differentiation, apoptosis, and oncogenesis. Altogether, these preclinical and mechanistic findings strongly implicate the use of diosgenin as a novel, multitarget-based chemopreventive or therapeutic agent against several cancer types. Future research in this field will help to establish not only whether diosgenin is safe and efficacious as a chemopreventive agent against several human cancers, but also to develop and evaluate standards of evidence for health claims for diosgenin-containing foods as they become increasingly popular and enter the marketplace labeled as functional foods and nutraceuticals.

  4. Therapeutic strategies with oral fluoropyrimidine anticancer agent, S-1 against oral cancer.

    Harada, Koji; Ferdous, Tarannum; Ueyama, Yoshiya

    2017-08-01

    Oral cancer has been recognized as a tumor with low sensitivity to anticancer agents. However, introduction of S-1, an oral cancer agent is improving treatment outcome for patients with oral cancer. In addition, S-1, as a main drug for oral cancer treatment in Japan can be easily available for outpatients. In fact, S-1 exerts high therapeutic effects with acceptable side effects. Moreover, combined chemotherapy with S-1 shows higher efficacy than S-1 alone, and combined chemo-radiotherapy with S-1 exerts remarkable therapeutic effects. Furthermore, we should consider the combined therapy of S-1 and molecular targeting agents right now as these combinations were reportedly useful for oral cancer treatment. Here, we describe our findings related to S-1 that were obtained experimentally and clinically, and favorable therapeutic strategies with S-1 against oral cancer with bibliographic considerations.

  5. Therapeutic efficacy of different Hemodialysis prescriptions in canine azotemia

    Ekta Atul Thakkar

    2014-12-01

    Full Text Available Aim: The aim was to determine therapeutic efficacy of different Hemodialysis prescriptions in canine azotemia. Materials and Methods: Patients (n=9 with acute onset of renal dysfunction or chronic patients with superimposed acute factor (component or patients with known chronic nature of the disease were dialyzed with Fresenius 4008S hemodialysis machine after jugular catheterization. Patients were randomly divided into two groups, one group (n=3 was dialyzed every day and second (n=4 was dialyzed on alternate days. The patients were evaluated for following parameters to compare the efficacy of the dialysis prescription: Urea reduction ratio (URR, creatinine reduction ratio (CRR, Kt/V, time averaged concentration of urea (TAC urea. Result and Discussion: Increasing both dialysis frequency and duration is the superior dialysis schedule. Patient dialyzed every day with total processed blood volume 1.79 L/Kg for 4 h 26 min/session had the lowest TAC of 36.82 mg/dl, thereby was considered it as a better prescription.

  6. Development of the Fibulin-3 protein therapeutics of non small cell lung cancer stem cells

    Kim, In Gyu; Kim, Kugchan; Jung, Il Lae; Kim, Seo Yeon; Choi, Su Im; Lee, Jae Ha

    2013-09-15

    This study focuses on developing an efficient bioprocess for large-scale production of fibulin-3 using Chinese Hamster Ovary cell expression system and evaluating its therapeutic potential for the treatment of cancer. The specific aims are as follows: Isolation and establishment of CSCs using FACS based on cell surface markers and high ALDH1 activity. Identification and characterization of lung cancer stem cells that acquire features of CSC upon exposure to ionizing radiation. Evaluation of the fibulin-3 effects on the stem traits and signaling pathways required for the generation and maintenance of CSCs. In vivo validation of fivulin-3 for tumor prognosis and therapeutic efficacy against lung cancer using animal model.

  7. Therapeutic Strategies to Enhance the Anticancer Efficacy of Histone Deacetylase Inhibitors

    Claudia P. Miller

    2011-01-01

    Full Text Available Histone acetylation is a posttranslational modification that plays a role in regulating gene expression. More recently, other nonhistone proteins have been identified to be acetylated which can regulate their function, stability, localization, or interaction with other molecules. Modulating acetylation with histone deacetylase inhibitors (HDACi has been validated to have anticancer effects in preclinical and clinical cancer models. This has led to development and approval of the first HDACi, vorinostat, for the treatment of cutaneous T cell lymphoma. However, to date, targeting acetylation with HDACi as a monotherapy has shown modest activity against other cancers. To improve their efficacy, HDACi have been paired with other antitumor agents. Here, we discuss several combination therapies, highlighting various epigenetic drugs, ROS-generating agents, proteasome inhibitors, and DNA-damaging compounds that together may provide a therapeutic advantage over single-agent strategies.

  8. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer.

    Kamerkar, Sushrut; LeBleu, Valerie S; Sugimoto, Hikaru; Yang, Sujuan; Ruivo, Carolina F; Melo, Sonia A; Lee, J Jack; Kalluri, Raghu

    2017-06-22

    The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic Kras G12D , a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Our results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes.

  9. TRAIL: A Novel Therapeutic Agent for Prostate Cancer

    Li, Honglin

    2002-01-01

    This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...

  10. TRAIL: A Novel Therapeutic Agent for Prostate Cancer

    Li, Honglin

    2004-01-01

    This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...

  11. TRAIL: A Novel Therapeutic Agent for Prostate Cancer

    Li, Honglin

    2003-01-01

    This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...

  12. Cancer Stem Cell Plasticity Drives Therapeutic Resistance

    Mary R. Doherty

    2016-01-01

    Full Text Available The connection between epithelial-mesenchymal (E-M plasticity and cancer stem cell (CSC properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence.

  13. Therapeutic potential of bryophytes and derived compounds against cancer

    Abhijit Dey

    2015-08-01

    Full Text Available Bryophytes, taxonomically placed between the algae and the pteridophytes, are divided into three classes such as Liverworts, Hornworts and Mosses. Indigenous use involves this small group of plants to treat various diseases. Bryophytes have been investigated pharmacologically for active biomolecules. Several constituents with therapeutic potential have been isolated, characterized and investigated for antibacterial, antifungal, antiviral, antioxidative, antiinflamatory and anticancerous efficacy. The present review deals with the literature covering the anticancerous potential of bryophytes. Apart from the examples of the compounds and the containing bryophyte genera, the authors have tried to include the examples of cancer cell lines on which the efficacy have been tested and the mode of action of certain cytotoxic agents. Crude extracts and isolated compounds from bryophytes were found to possess potent cytotoxic properties. Different types of terpenoids and bibenzyls have been reported among the most potent cytotoxic compounds. Most of these compounds were found to induce apoptosis by activating a number of genes and enzymes. Biochemical markers such as DNA fragmentation, nuclear condensation, proteolysis of poly (ADP-ribose polymerase, activation of caspases, inhibition of antiapoptotic nuclear transcriptional factor-kappaB, activation of p38 mitogen-activated protein kinase etc. have been found to be associated with apoptotic and necrotic response. This review summarizes recent scientific findings and suggests further investigations to evaluate the cytotoxic efficacy of bryophytes.

  14. Stealth Properties to Improve Therapeutic Efficacy of Drug Nanocarriers

    Stefano Salmaso

    2013-01-01

    Full Text Available Over the last few decades, nanocarriers for drug delivery have emerged as powerful tools with unquestionable potential to improve the therapeutic efficacy of anticancer drugs. Many colloidal drug delivery systems are underdevelopment to ameliorate the site specificity of drug action and reduce the systemic side effects. By virtue of their small size they can be injected intravenously and disposed into the target tissues where they release the drug. Nanocarriers interact massively with the surrounding environment, namely, endothelium vessels as well as cells and blood proteins. Consequently, they are rapidly removed from the circulation mostly by the mononuclear phagocyte system. In order to endow nanosystems with long circulation properties, new technologies aimed at the surface modification of their physicochemical features have been developed. In particular, stealth nanocarriers can be obtained by polymeric coating. In this paper, the basic concept underlining the “stealth” properties of drug nanocarriers, the parameters influencing the polymer coating performance in terms of opsonins/macrophages interaction with the colloid surface, the most commonly used materials for the coating process and the outcomes of this peculiar procedure are thoroughly discussed.

  15. The Slaying of a Beautiful Hypothesis: The Efficacy of Counseling and the Therapeutic Process

    Hauser, Mike; Hays, Danica G.

    2010-01-01

    Although the efficacy of counseling has been empirically linked to the therapeutic process, the emphasis in much of the literature remains on technique use. This article discusses 3 components of therapeutic efficacy (i.e., common factors, working alliance, and counselor attributes) and provides implications for counselors and counselor training.…

  16. Metformin exhibits preventive and therapeutic efficacy against experimental cystic echinococcosis

    Loos, Julia A.; Dávila, Valeria A.; Rodrígues, Christian R.; Petrigh, Romina; Zoppi, Jorge A.; Crocenzi, Fernando A.; Cumino, Andrea C.

    2017-01-01

    Metformin (Met) is an anti-hyperglycemic and potential anti-cancer agent which may exert its anti-proliferative effects via the induction of energetic stress. In this study we investigated the in vitro and in vivo efficacy of Met against the larval stage of Echinococcus granulosus. Metformin showed significant dose- and time-dependent killing effects on in vitro cultured protoscoleces and metacestodes. Notably, the combination of Met together with the minimum effective concentration of ABZSO had a synergistic effect after days 3 and 12 on metacestodes and protoscoleces, respectively. Oral administration of Met (50 mg/kg/day) in E. granulosus-infected mice was highly effective in reducing the weight and number of parasite cysts, yet its combination with the lowest recommended dose of ABZ (5 mg/kg/day) was even more effective. Coincidentally, intracystic Met accumulation was higher in animals treated with both drugs compared to those administered Met alone. Furthermore, the safe plant-derived drug Met exhibited remarkable chemopreventive properties against secondary hydatidosis in mice. In conclusion, based on our experimental data, Met emerges as a promising anti-echinococcal drug as it has proven to efficiently inhibit the development and growth of the E. granulosus larval stage and its combination with ABZ may improve the current anti-parasitic therapy. PMID:28182659

  17. Metformin exhibits preventive and therapeutic efficacy against experimental cystic echinococcosis.

    Julia A Loos

    2017-02-01

    Full Text Available Metformin (Met is an anti-hyperglycemic and potential anti-cancer agent which may exert its anti-proliferative effects via the induction of energetic stress. In this study we investigated the in vitro and in vivo efficacy of Met against the larval stage of Echinococcus granulosus. Metformin showed significant dose- and time-dependent killing effects on in vitro cultured protoscoleces and metacestodes. Notably, the combination of Met together with the minimum effective concentration of ABZSO had a synergistic effect after days 3 and 12 on metacestodes and protoscoleces, respectively. Oral administration of Met (50 mg/kg/day in E. granulosus-infected mice was highly effective in reducing the weight and number of parasite cysts, yet its combination with the lowest recommended dose of ABZ (5 mg/kg/day was even more effective. Coincidentally, intracystic Met accumulation was higher in animals treated with both drugs compared to those administered Met alone. Furthermore, the safe plant-derived drug Met exhibited remarkable chemopreventive properties against secondary hydatidosis in mice. In conclusion, based on our experimental data, Met emerges as a promising anti-echinococcal drug as it has proven to efficiently inhibit the development and growth of the E. granulosus larval stage and its combination with ABZ may improve the current anti-parasitic therapy.

  18. Transient Treg depletion enhances therapeutic anti‐cancer vaccination

    Aston, Wayne J.; Chee, Jonathan; Khong, Andrea; Cleaver, Amanda L.; Solin, Jessica N.; Ma, Shaokang; Lesterhuis, W. Joost; Dick, Ian; Holt, Robert A.; Creaney, Jenette; Boon, Louis; Robinson, Bruce; Lake, Richard A.

    2016-01-01

    Abstract Introduction Regulatory T cells (Treg) play an important role in suppressing anti‐ immunity and their depletion has been linked to improved outcomes. To better understand the role of Treg in limiting the efficacy of anti‐cancer immunity, we used a Diphtheria toxin (DTX) transgenic mouse model to specifically target and deplete Treg. Methods Tumor bearing BALB/c FoxP3.dtr transgenic mice were subjected to different treatment protocols, with or without Treg depletion and tumor growth and survival monitored. Results DTX specifically depleted Treg in a transient, dose‐dependent manner. Treg depletion correlated with delayed tumor growth, increased effector T cell (Teff) activation, and enhanced survival in a range of solid tumors. Tumor regression was dependent on Teffs as depletion of both CD4 and CD8 T cells completely abrogated any survival benefit. Severe morbidity following Treg depletion was only observed, when consecutive doses of DTX were given during peak CD8 T cell activation, demonstrating that Treg can be depleted on multiple occasions, but only when CD8 T cell activation has returned to base line levels. Finally, we show that even minimal Treg depletion is sufficient to significantly improve the efficacy of tumor‐peptide vaccination. Conclusions BALB/c.FoxP3.dtr mice are an ideal model to investigate the full therapeutic potential of Treg depletion to boost anti‐tumor immunity. DTX‐mediated Treg depletion is transient, dose‐dependent, and leads to strong anti‐tumor immunity and complete tumor regression at high doses, while enhancing the efficacy of tumor‐specific vaccination at low doses. Together this data highlight the importance of Treg manipulation as a useful strategy for enhancing current and future cancer immunotherapies. PMID:28250921

  19. Annotating cancer variants and anti-cancer therapeutics in reactome.

    Milacic, Marija; Haw, Robin; Rothfels, Karen; Wu, Guanming; Croft, David; Hermjakob, Henning; D'Eustachio, Peter; Stein, Lincoln

    2012-11-08

    Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of "cancer" pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics.

  20. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

    Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

    2015-12-29

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

  1. Cooperative nanomaterials systems for cancer diagnosis and therapeutics

    Park, Ji Ho

    developed. Gold nanorods localized through vascular circulation to the tumor region, where they reported their location and converted near infrared (NIR) radiation to thermal energy. The local photothermal heating enabled to enhance tumor-specific drug release from thermally labile therapeutic liposomes or induce more binding sites for targeted therapeutic liposomes. The combination of local hyperthermia and chemotherapy in the cooperative nanosystems significantly enhanced therapeutic efficacy relative to individual therapies.

  2. Exogenous Restoration of TUSC2 Expression Induces Responsiveness to Erlotinib in Wildtype Epidermal Growth Factor Receptor (EGFR Lung Cancer Cells through Context Specific Pathways Resulting in Enhanced Therapeutic Efficacy.

    Bingbing Dai

    Full Text Available Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC cell lines resistant to the epidermal growth factor receptor (EGFR tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR.

  3. Annotating Cancer Variants and Anti-Cancer Therapeutics in Reactome

    Milacic, Marija; Haw, Robin, E-mail: robin.haw@oicr.on.ca; Rothfels, Karen; Wu, Guanming [Informatics and Bio-computing Platform, Ontario Institute for Cancer Research, Toronto, ON, M5G0A3 (Canada); Croft, David; Hermjakob, Henning [European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD (United Kingdom); D’Eustachio, Peter [Department of Biochemistry, NYU School of Medicine, New York, NY 10016 (United States); Stein, Lincoln [Informatics and Bio-computing Platform, Ontario Institute for Cancer Research, Toronto, ON, M5G0A3 (Canada)

    2012-11-08

    Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics.

  4. Annotating Cancer Variants and Anti-Cancer Therapeutics in Reactome

    Milacic, Marija; Haw, Robin; Rothfels, Karen; Wu, Guanming; Croft, David; Hermjakob, Henning; D’Eustachio, Peter; Stein, Lincoln

    2012-01-01

    Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics

  5. Therapeutic efficacy of hydro-kinesiotherapy Programs in lumbar spondylosis

    Ana-Maria BOTEZAN

    2015-12-01

    Full Text Available Lumbar spondylarthrosis is a degenerative disease that affects the joint structures of the lumbar spine. In the course of time, numerous studies on the role of hydro-kinesiotherapy in the treatment of lumbar spondylosis have been conducted. The aim of this research is motivated by the significantly high number of patients with chronic pain in the lumbar spine due to lumbar spondylosis, as well as by the negative impact on their quality of life through the impairment of the activities of daily living. The prospective longitudinal study was carried out at the Clinical Rehabilitation Hospital Cluj-Napoca. The study included 35 patients with chronic low back pain and mobility limitation in the lumbar spine. The patients were assigned to two groups: the study group formed by 20 patients and the control group consisting of 15 patients aged between 40-70 years. The treatment of the patients included in the study was performed over a two week period and consisted of a hydro-kinesiotherapy program, for the patients of the study group, the duration of a treatment session being 40 minutes. Both the subjects of the study group and of the control group also benefited from sedative massage of the lumbosacral spine, kinesiotherapy, laser therapy of the lumbar spine. The patients were evaluated using Schober’s test, the Visual Analogue Scale, the Oswestry index. These evaluation methods were applied to the patients of both groups at the beginning of the rehabilitation programs and after two weeks. The results of the study demonstrated the therapeutic efficacy of the medical rehabilitation programs that included hydro-kinesiotherapy programs. The patients of both groups had improvements through a decrease of lumbar pain, an increase in lumbar spine mobility, as well as in the patients’ ability to organize themselves in the activities of daily living. However, the patients of the study group, with a hydro-kinesiotherapy program performed for two weeks, had

  6. Efficacy of radiotherapy of oral mucosa cancer

    Vorob'ev, Yu.I.; Garbuzov, M.I.; Sarantseva, I.P.; Popov, N.V.; Pereslegin, O.I.

    1986-01-01

    An analysis of 10-year experience of a radiological department (962 patients) indicated late admission of oral mucosa cancer patients for specialized treatment: 75-85% of the patients were admitted with Stage 2-4 disease. The assessment of the efficacy of radiotherapy according to the 3 ad 5-year survival rates showed that better results were obtained for buccal mucosa cancer and the worst for mouth fundus cancer. Regional metastates are a poor prognostic sign, particularly fixed metastases in patients with tongue and mouth fundus cancer. Combined therapy turned out be the most effective in tongue cancer. In different variants of dose delivery in time the most favorable results were obtained with small fractionation (a conventional course). However it should be noted that a split course was usually applied to weak elderly patients with advanced stages of disease

  7. Intracellular delivery of potential therapeutic genes: prospects in cancer gene therapy.

    Bakhtiar, Athirah; Sayyad, Mustak; Rosli, Rozita; Maruyama, Atsushi; Chowdhury, Ezharul H

    2014-01-01

    Conventional therapies for malignant cancer such as chemotherapy and radiotherapy are associated with poor survival rates owing to the development of cellular resistance to cancer drugs and the lack of targetability, resulting in unwanted adverse effects on healthy cells and necessitating the lowering of therapeutic dose with consequential lower efficacy of the treatment. Gene therapy employing different types of viral and non-viral carriers to transport gene(s) of interest and facilitating production of the desirable therapeutic protein(s) has tremendous prospects in cancer treatments due to the high-level of specificity in therapeutic action of the expressed protein(s) with diminished off-target effects, although cancer cell-specific delivery of transgene(s) still poses some challenges to be addressed. Depending on the potential therapeutic target genes, cancer gene therapy could be categorized into tumor suppressor gene replacement therapy, immune gene therapy and enzyme- or prodrug-based therapy. This review would shed light on the current progress of delivery of potentially therapeutic genes into various cancer cells in vitro and animal models utilizing a variety of viral and non-viral vectors.

  8. Androgen Receptor: A Complex Therapeutic Target for Breast Cancer

    Narayanan, Ramesh; Dalton, James T.

    2016-01-01

    Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER) and human epidermal growth factor receptor (HER2) are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR) is evolving as a molecular target for cancers that have developed resistance to conventional treatments. The high expression of AR in breast cancer and recent discovery and development of new nonsteroidal drugs targeting the AR provide a strong rationale for exploring it again as a therapeutic target in this disease. Ironically, both nonsteroidal agonists and antagonists for the AR are undergoing clinical trials, making AR a complicated target to understand in breast cancer. This review provides a detailed account of AR’s therapeutic role in breast cancer. PMID:27918430

  9. Androgen Receptor: A Complex Therapeutic Target for Breast Cancer

    Ramesh Narayanan

    2016-12-01

    Full Text Available Molecular and histopathological profiling have classified breast cancer into multiple sub-types empowering precision treatment. Although estrogen receptor (ER and human epidermal growth factor receptor (HER2 are the mainstay therapeutic targets in breast cancer, the androgen receptor (AR is evolving as a molecular target for cancers that have developed resistance to conventional treatments. The high expression of AR in breast cancer and recent discovery and development of new nonsteroidal drugs targeting the AR provide a strong rationale for exploring it again as a therapeutic target in this disease. Ironically, both nonsteroidal agonists and antagonists for the AR are undergoing clinical trials, making AR a complicated target to understand in breast cancer. This review provides a detailed account of AR’s therapeutic role in breast cancer.

  10. Ghrelin receptor agonists as novel breast cancer therapeutics

    CHEUK MAN CHERIE AU

    2017-01-01

    The human cell studies and the live mouse studies are intended to provide the information that is needed to apply therapies to treat breast cancer patients, based on our novel discoveries. We believe that des-acyl ghrelin-like compounds will be novel breast cancer therapeutics while avoiding well-documented serious side effects, including joint pain, osteoporosis or endometrial cancer. Our findings could therefore improve the quality of life of women treated for breast cancer, improve complia...

  11. Therapeutic Strategies for Hereditary Kidney Cancer.

    Sidana, Abhinav; Srinivasan, Ramaprasad

    2016-08-01

    The study of hereditary forms of kidney cancer has vastly increased our understanding of metabolic and genetic pathways involved in the development of both inherited and sporadic kidney cancers. The recognition that diverse molecular events drive different forms of kidney cancers has led to the preclinical and clinical development of specific pathway-directed strategies tailored to treat distinct subgroups of kidney cancer. Here, we describe the molecular mechanisms underlying the pathogenesis of several different types of hereditary renal cancers, review their clinical characteristics, and summarize the treatment strategies for the management of these cancers.

  12. [The Functional Role of Exosomes in Cancer Biology and Their Potential as Biomarkers and Therapeutic Targets of Cancer].

    Naito, Yutaka; Yoshioka, Yusuke; Ochiya, Takahiro

    2015-06-01

    Intercellular communication plays an important role in the regulation of various cellular events. In particular, cancer cells and the surrounding cells communicate with each other, and this intercellular communication triggers cancer initiation and progression through the secretion of molecules, including growth factors and cytokines. Recent advances in cancer biology have indicated that small membrane vesicles, termed exosomes, also serve as regulatory agents in intercellular communications. Exosomes contain functional cellular components, including proteins and microRNAs (miRNAs), and they transfer these components to recipient cells. This exosome-mediated intercellular communication leads to increased growth, invasion, and metastasis of cancer. Thus, researchers regard exosomes as important cues to understanding the molecular mechanisms of cancer biology. Indeed, several lines of evidence have demonstrated that exosomes can explain multiple aspects of cancer biology. In addition, increasing evidence suggests that exosomes and their specific molecules are also attractive for use as biomarkers and therapeutic targets in cancer. Recent reports showed the efficacy of a novel diagnosis by detecting component molecules of cancer-derived exosomes, including miRNAs and membrane proteins. Furthermore, clinical trials that test the application of exosomes for cancer therapy have already been reported. From these points of view, we will summarize experimental data that support the role of exosomes in cancer progression and the potential of exosomes for use in novel diagnostic and therapeutic approaches for cancer.

  13. FDA Approves First Therapeutic Cancer Vaccine

    Sipuleucel-T (Provenge) is a relatively nontoxic treatment option for men with hormone-resistant or castration-resistant prostate cancer. The FDA's approval of the vaccine represented the first proof of principle that immunotherapy can work in cancer.

  14. Therapeutic resistance and cancer recurrence mechanisms

    Cancer recurrence is believed to be one of the major reasons for the failure of cancer treatment strategies. Thisbiological phenomenon could arise from the incomplete eradication of tumour cells after chemo- and radiotherapy.Recent developments in the design of models reflecting cancer recurrence and in vivo imaging ...

  15. Gastric cancer stem cells: A novel therapeutic target

    Singh, Shree Ram

    2013-01-01

    Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow–derived mesenchymal cells, and that gastric tumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironment with normal niche, which play an important role in gastric cancer and tumor growth. This mini-review presents a brief overview of the recent developments in gastric cancer stem cell research. The knowledge gained by studying cancer stem cells in gastric mucosa will support the development of novel therapeutic strategies for gastric cancer. PMID:23583679

  16. HemoHIM enhances the therapeutic efficacy of ionizing radiation treatment in tumor-bearing mice.

    Park, Hae-Ran; Ju, Eun-Jin; Jo, Sung-Kee; Jung, Uhee; Kim, Sung-Ho

    2010-02-01

    Although radiotherapy is commonly used for a variety of cancers, radiotherapy alone does not achieve a satisfactory therapeutic outcome. In this study, we examined the possibility that HemoHIM can enhance the anticancer effects of ionizing radiation (IR) in melanoma-bearing mice. The HemoHIM was prepared by adding the ethanol-insoluble fraction to the total water extract of a mixture of three edible herbs-Angelica Radix, Cnidium Rhizoma, and Paeonia Radix. Anticancer effects of HemoHIM were evaluated in melanoma-bearing mice exposed to IR. IR treatment (5 Gy at 7 days after melanoma cell injection) reduced the weight of the solid tumors, and HemoHIM supplementation with IR enhanced the decreases in tumor weight (P HemoHIM administration also increased the activity of natural killer cells and cytotoxic T cells, although the proportions of these cells in spleen were not different. In addition, HemoHIM administration increased the interleukin-2 and tumor necrosis factor-alpha secretion from lymphocytes stimulated with concanavalin A, which seemed to contribute to the enhanced efficacy of HemoHIM in tumor-bearing mice treated with IR. In conclusion, HemoHIM may be a beneficial supplement during radiotherapy for enhancing the antitumor efficacy.

  17. Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo.

    Bardhan, Rizia; Chen, Wenxue; Bartels, Marc; Perez-Torres, Carlos; Botero, Maria F; McAninch, Robin Ward; Contreras, Alejandro; Schiff, Rachel; Pautler, Robia G; Halas, Naomi J; Joshi, Amit

    2010-12-08

    Nanoparticle-based therapeutics with local delivery and external electromagnetic field modulation holds extraordinary promise for soft-tissue cancers such as breast cancer; however, knowledge of the distribution and fate of nanoparticles in vivo is crucial for clinical translation. Here we demonstrate that multiple diagnostic capabilities can be introduced in photothermal therapeutic nanocomplexes by simultaneously enhancing both near-infrared fluorescence and magnetic resonance imaging (MRI). We track nanocomplexes in vivo, examining the influence of HER2 antibody targeting on nanocomplex distribution over 72 h. This approach provides valuable, detailed information regarding the distribution and fate of complex nanoparticles designed for specific diagnostic and therapeutic functions.

  18. Virus-Targeted Therapeutic for Breast Cancer

    Faller, Douglas

    1997-01-01

    .... Our approach initially involves investigation of EBV sequences in breast cancer cell lines and specimens, determination of whether treatment with Arginine Butyrate will induce the viral thymidine...

  19. Efficacy of therapeutic ultrasound and exercise therapy in the ...

    Results: Findings of the study revealed no significant difference in VAS, ROM and WOMAC scores in the study and control groups. Conclusions: This study confirms that therapeutic ultrasound is of no additional benefit to exercise therapy in the management of chronic osteoarthritis. Key words: Ultrasound; Exercise; ...

  20. Therapeutic Efficacy of Intermittent Cryotherapy in the Management ...

    This study was therefore, designed to investigate the efficacy of intermittent cryotherapy in the management of pain among human subjects who sustained closed soft tissue injuries (CSTIs). Subjects' pre- and post-treatment pain perception scores (PPS) using visual analogue scale (VAS) and the sessions of treatment were ...

  1. Cancer Stem Cells and Their Microenvironment: Biology and Therapeutic Implications

    Eunice Yuen-Ting Lau

    2017-01-01

    Full Text Available Tumor consists of heterogeneous cancer cells including cancer stem cells (CSCs that can terminally differentiate into tumor bulk. Normal stem cells in normal organs regulate self-renewal within a stem cell niche. Likewise, accumulating evidence has also suggested that CSCs are maintained extrinsically within the tumor microenvironment, which includes both cellular and physical factors. Here, we review the significance of stromal cells, immune cells, extracellular matrix, tumor stiffness, and hypoxia in regulation of CSC plasticity and therapeutic resistance. With a better understanding of how CSC interacts with its niche, we are able to identify potential therapeutic targets for the development of more effective treatments against cancer.

  2. Dana-Farber Cancer Institute: Identification of Therapeutic Targets Across Cancer Types | Office of Cancer Genomics

    The Dana Farber Cancer Institute CTD2 Center focuses on the use of high-throughput genetic and bioinformatic approaches to identify and credential oncogenes and co-dependencies in cancers. This Center aims to provide the cancer research community with information that will facilitate the prioritization of targets based on both genomic and functional evidence, inform the most appropriate genetic context for downstream mechanistic and validation studies, and enable the translation of this information into therapeutics and diagnostics.

  3. Lactobionic acid-conjugated TPGS nanoparticles for enhancing therapeutic efficacy of etoposide against hepatocellular carcinoma

    Tsend-Ayush, Altansukh; Zhu, Xiumei; Ding, Yu; Yao, Jianxu; Yin, Lifang; Zhou, Jianping; Yao, Jing

    2017-05-01

    Many effective anti-cancer drugs have limited use in hepatocellular carcinoma (HCC) therapy due to the drug resistance mechanisms in liver cells. In recent years, tumor-targeted drug delivery and the inhibition of drug-resistance-related mechanisms has become an integrated strategy for effectively combating chemo-resistant cancer. Herein, lactobionic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-LA conjugate) has been developed as a potential asialoglycoprotein receptor (ASGPR)-targeted nanocarrier and an efficient inhibitor of P-glycoprotein (P-gp) to enhance etoposide (ETO) efficacy against HCC. The main properties of ETO-loaded TPGS-LA nanoparticles (NPs) were tested through in vitro and in vivo studies after being prepared using the nanoprecipitation method and characterized by dynamic light scattering (DLS). According to the results, smaller (˜141.43 nm), positively charged ETO-loaded TPGS-LA NPs were more suitable for providing efficient delivery to hepatoma cells by avoiding the clearance mechanisms. It was found that ETO-loaded TPGS-LA NPs were noticeably able to enhance the cytotoxicity of ETO in HepG2 cells. Besides this, markedly higher internalization by the ASGPR-overexpressed HepG2 cells and efficient accumulation at the tumor site in vivo were revealed in the TPGS-LA NP group. More importantly, animal studies confirmed that ETO-loaded TPGS-LA NPs achieved the highest therapeutic efficacy against HCC. Interestingly, ETO-loaded TPGS-LA NPs also exhibited a great inhibitory effect on P-gp compared to the ETO-loaded TPGS NPs. These results suggest that TPGS-LA NPs could be used as a potential ETO delivery system against HCC.

  4. Understanding music’s therapeutic efficacy: Implications for music education

    Diane Thram

    2014-11-01

    Full Text Available In the current era of electronic domination of human experience, be it via cell phone and/or computer addiction, or the ubiquitous television, actual participation in music- making is less and less common for the average person, child or adult. Passive participation through listening is most often cited by people as their major experience with music in their lives. When asked if listening has therapeutic effects, it is rare for anyone to respond in the negative. Likewise, for performers/active participants in music- making, be it solitary or as part of a group, invariably an enhanced sense of well-being from the act of making music is reported. This paper addresses therapeutic aspects of musical participation (singing, clapping, playing an instrument, dancing, listening by providing a historical overview (12th c to present of attitudes toward music’s therapeutic effects. It argues that music exists through the interaction of our biological capacity to make music with our cultural circumstances. How individuals benefit in all aspects their being – physical, mental and emotional – from engaging in the act of making music is illustrated with examples from field research in southern Africa. Finally implications for Music Education are explored which emphasize how more comprehensive integration of music into the curriculum can serve as an antidote to the increasing isolation and alienation of modern life.

  5. FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study

    Geva, Ravit; Vecchione, Loredana; Kalogeras, Konstantinos T

    2015-01-01

    OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled. DESIGN: To show a HR advantage ...

  6. The intersection of cancer, cancer stem cells, and the immune system: therapeutic opportunities.

    Silver, Daniel J; Sinyuk, Maksim; Vogelbaum, Michael A; Ahluwalia, Manmeet S; Lathia, Justin D

    2016-02-01

    During brain neoplasia, malignant cells subjugate the immune system to provide an environment that favors tumor growth. These mechanisms capitalize on tumor-promoting functions of various immune cell types and typically result in suppression of tumor immune rejection. Immunotherapy efforts are underway to disrupt these mechanisms and turn the immune system against developing tumors. While many of these therapies are already in early-stage clinical trials, understanding how these therapies impact various tumor cell populations, including self-renewing cancer stem cells, may help to predict their efficacy and clarify their mechanisms of action. Moreover, interrogating the biology of glioma cell, cancer stem cell, and immune cell interactions may provide additional therapeutic targets to leverage against disease progression. In this review, we begin by highlighting a series of investigations into immune cell-mediated tumor promotion that do not parse the tumor into stem and non-stem components. We then take a closer look at the immune-suppressive mechanisms derived specifically from cancer stem cell interactions with the immune system and end with an update on immunotherapy and cancer stem cell-directed clinical trials in glioblastoma. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Novel Therapeutic Approaches Toward Treating Prostate Cancer

    2013-05-01

    Kinases, Prostate Cancer, AKT inhibition, Mouse, Prostate Stem Cells 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES...Bearss 0, Wierda WG, Gandhi V (2009) Pim kinase inhibitor, 5GI-1776, induces apoptosis in CLL lymphocytes. Blood 114:4150--4157. 27. Grey R, et aL...PIM1 expression predict outcome in mantle cell lymphoma treated with high dose therapy, stem eel! transplantation and rituximab: a Cancer and Leukemia

  8. Experimental study of plasmapheresis therapeutic efficacy in severe radiation damage

    Legeza, V.I.; Abdul', Yu.A.; Chigareva, N.G.; Petkevich, N.V.; Myasoedov, A.F.; Andryukhin, V.I.; Artemenko, A.G.

    1994-01-01

    In experiments with dogs exposed to 2.9 Gy (LD 80/45 ) it was found that plasmapheresis treatment 4-6 h after irradiation reduce the severity of the radiation sickness clinical manifestations and post-radiation toxemia thus increasing the rate of animal survival up to 60 %. Sham plasmapheresis included all the manipulations of plasmapheretic treatment except plasma substitution and had no detoxication effect and did not affect the irradiated animals survival. This is evidence for leading role of detoxiation in the mechanisms of th therapeutic action of plasmapheresis in acute irradiation

  9. Host manipulation by cancer cells: Expectations, facts, and therapeutic implications.

    Tissot, Tazzio; Arnal, Audrey; Jacqueline, Camille; Poulin, Robert; Lefèvre, Thierry; Mery, Frédéric; Renaud, François; Roche, Benjamin; Massol, François; Salzet, Michel; Ewald, Paul; Tasiemski, Aurélie; Ujvari, Beata; Thomas, Frédéric

    2016-03-01

    Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research. © 2016 WILEY Periodicals, Inc.

  10. EMMPRIN in gynecologic cancers: pathologic and therapeutic aspects.

    Liu, Dan-tong

    2015-07-01

    The highly glycosylated transmembrane protein extracellular matrix metalloproteinase inducer (EMMPRIN) is associated with several pathological conditions, including various types of cancers. In different gynecological malignancies, such as ovarian, cervical, and endometrial cancers, EMMPRIN plays significant roles in cell adhesion modulation, tumor growth, invasion, angiogenesis, and metastasis by inducing the production of various molecules, including matrix metalloproteinases and vascular endothelial growth factor. Because of its high level of expression, EMMPRIN can possibly be used as a diagnostic marker of gynecological cancers. Recent studies have showed that targeting EMMPRIN, especially by RNA interference (RNAi) technology, has promising therapeutic potential in basic research on gynecological cancer treatments, which make a platform for the future clinical success. This review study focused on the association of EMMPRIN in gynecological cancers in the perspectives of pathogenesis, diagnosis, and therapeutics.

  11. Nano-Engineered Mesenchymal Stem Cells Increase Therapeutic Efficacy of Anticancer Drug Through True Active Tumor Targeting.

    Layek, Buddhadev; Sadhukha, Tanmoy; Panyam, Jayanth; Prabha, Swayam

    2018-06-01

    Tumor-targeted drug delivery has the potential to improve therapeutic efficacy and mitigate non-specific toxicity of anticancer drugs. However, current drug delivery approaches rely on inefficient passive accumulation of the drug carrier in the tumor. We have developed a unique, truly active tumor-targeting strategy that relies on engineering mesenchymal stem cells (MSC) with drug-loaded nanoparticles. Our studies using the A549 orthotopic lung tumor model show that nano-engineered MSCs carrying the anticancer drug paclitaxel (PTX) home to tumors and create cellular drug depots that release the drug payload over several days. Despite significantly lower doses of PTX, nano-engineered MSCs resulted in significant inhibition of tumor growth and superior survival. Anticancer efficacy of nano-engineered MSCs was confirmed in immunocompetent C57BL/6 albino female mice bearing orthotopic Lewis Lung Carcinoma (LL/2-luc) tumors. Furthermore, at doses that resulted in equivalent therapeutic efficacy, nano-engineered MSCs had no effect on white blood cell count, whereas PTX solution and PTX nanoparticle treatments caused leukopenia. Biodistribution studies showed that nano-engineered MSCs resulted in greater than 9-fold higher AUC lung of PTX (1.5 μg.day/g) than PTX solution and nanoparticles (0.2 and 0.1 μg.day/g tissue, respectively) in the target lung tumors. Furthermore, the lung-to-liver and the lung-to-spleen ratios of PTX were several folds higher for nano-engineered MSCs relative to those for PTX solution and nanoparticle groups, suggesting that nano-engineered MSCs demonstrate significantly less off-target deposition. In summary, our results demonstrate that nano-engineered MSCs can serve as an efficient carrier for tumor-specific drug delivery and significantly improved anti-cancer efficacy of conventional chemotherapeutic drugs. Mol Cancer Ther; 17(6); 1196-206. ©2018 AACR . ©2018 American Association for Cancer Research.

  12. MicroRNA-targeted therapeutics for lung cancer treatment.

    Xue, Jing; Yang, Jiali; Luo, Meihui; Cho, William C; Liu, Xiaoming

    2017-02-01

    Lung cancer is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs) are endogenous non-coding small RNAs that repress the expression of a broad array of target genes. Many efforts have been made to therapeutically target miRNAs in cancer treatments using miRNA mimics and miRNA antagonists. Areas covered: This article summarizes the recent findings with the role of miRNAs in lung cancer, and discusses the potential and challenges of developing miRNA-targeted therapeutics in this dreadful disease. Expert opinion: The development of miRNA-targeted therapeutics has become an important anti-cancer strategy. Results from both preclinical and clinical trials of microRNA replacement therapy have shown some promise in cancer treatment. However, some obstacles, including drug delivery, specificity, off-target effect, toxicity mediation, immunological activation and dosage determination should be addressed. Several delivery strategies have been employed, including naked oligonucleotides, liposomes, aptamer-conjugates, nanoparticles and viral vectors. However, delivery remains a main challenge in miRNA-targeting therapeutics. Furthermore, immune-related serious adverse events are also a concern, which indicates the complexity of miRNA-based therapy in clinical settings.

  13. Podoplanin - an emerging cancer biomarker and therapeutic target.

    Krishnan, Harini; Rayes, Julie; Miyashita, Tomoyuki; Ishii, Genichiro; Retzbach, Edward P; Sheehan, Stephanie A; Takemoto, Ai; Chang, Yao-Wen; Yoneda, Kazue; Asai, Jun; Jensen, Lasse; Chalise, Lushun; Natsume, Atsushi; Goldberg, Gary S

    2018-03-25

    Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts (CAFs), and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition (EMT), migration, invasion, metastasis, and inflammation. Antibodies, CAR-T cells, biologics, and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer including glioma, squamous cell carcinoma, mesothelioma, and melanoma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  14. Therapeutic considerations in Dukes C colon cancer

    Bleeker, Willem Aldert

    2001-01-01

    Colon cancer is one of the main health issues in the western world. In the Netherlands more than 7000 patients are diagnosed yearly with this disease and half of them will die from it. Prognosis largely depends on tumor stage, which is estimated by radiological, clinical and histological

  15. Effect of Therapeutic Touch in Patients with Cancer: a Literature Review.

    Tabatabaee, Amir; Tafreshi, Mansoureh Zagheri; Rassouli, Maryam; Aledavood, Seyed Amir; AlaviMajd, Hamid; Farahmand, Seyed Kazem

    2016-04-01

    The use of complementary and alternative medicine (CAM) techniques has been growing. The National Center for Complementary and Alternative Medicine places therapeutic touch (TT) into the category of bio field energy. This literature review is aimed at critically evaluating the data from clinical trials examining the clinical efficacy of therapeutic touch as a supportive care modality in adult patients with cancer. Electronic databases (PubMed, Scopus, Scholar Google, and Science Direct) were searched from the year 1990 to 2015 to locate potentially relevant peer-reviewed articles using the key words therapeutic touch, touch therapy, neoplasm, cancer, and CAM. Additionally, relevant journals and references of all the located articles were manually searched for other potentially relevant studies. The number of 334 articles was found on the basis of the key words, of which 17 articles related to the clinical trial were examined in accordance with the objectives of the study. A total of 6 articles were in the final dataset in which several examples of the positive effects of healing touch on pain, nausea, anxiety and fatigue, and life quality and also on biochemical parameters were observed. Based on the results of this study, an affirmation can be made regarding the use of TT, as a non-invasive intervention for improving the health status in patients with cancer. Moreover, therapeutic touch was proved to be a useful strategy for adult patients with cancer.

  16. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice

    Judge, Adam D.; Robbins, Marjorie; Tavakoli, Iran; Levi, Jasna; Hu, Lina; Fronda, Anna; Ambegia, Ellen; McClintock, Kevin; MacLachlan, Ian

    2009-01-01

    siRNAs that specifically silence the expression of cancer-related genes offer a therapeutic approach in oncology. However, it remains critical to determine the true mechanism of their therapeutic effects. Here, we describe the preclinical development of chemically modified siRNA targeting the essential cell-cycle proteins polo-like kinase 1 (PLK1) and kinesin spindle protein (KSP) in mice. siRNA formulated in stable nucleic acid lipid particles (SNALP) displayed potent antitumor efficacy in b...

  17. Cancer stem cell markers in common cancers - therapeutic implications

    Klonisch, Thomas; Wiechec, Emilia; Hombach-Klonisch, Sabine

    2008-01-01

    Rapid advance in the cancer stem cell field warrants optimism for the development of more reliable cancer therapies within the next 2-3 decades. Below, we characterize and compare the specific markers that are present on stem cells, cancer cells and cancer stem cells (CSC) in selected tissues...

  18. Therapeutic Approaches to Target Cancer Stem Cells

    Diaz, Arlhee; Leon, Kalet

    2011-01-01

    The clinical relevance of cancer stem cells (CSC) remains a major challenge for current cancer therapies, but preliminary findings indicate that specific targeting may be possible. Recent studies have shown that these tumor subpopulations promote tumor angiogenesis through the increased production of VEGF, whereas the VEGF neutralizing antibody bevacizumab specifically inhibits CSC growth. Moreover, nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR) with a potent antiangiogenic activity, has been shown by our group to reduce the frequency of CSC-like subpopulations in mouse models of brain tumors when combined with ionizing radiation. These studies and subsequent reports from other groups support the relevance of approaches based on molecular-targeted therapies to selectively attack CSC. This review discusses the relevance of targeting both the EGFR and angiogenic pathways as valid approaches to this aim. We discuss the relevance of identifying better molecular markers to develop drug screening strategies that selectively target CSC

  19. The Therapeutic Efficacy of Domestic Violence Victim Interventions.

    Hackett, Shannon; McWhirter, Paula T; Lesher, Susan

    2016-04-01

    A meta-analysis on domestic violence interventions was conducted to determine overall effectiveness of mental health programs involving women and children in joint treatment. These interventions were further analyzed to determine whether outcomes are differentially affected based on the outcome measure employed. To date, no meta-analyses have been published on domestic violence victim intervention efficacy. The 17 investigations that met study criteria yielded findings indicating that domestic violence interventions have a large effect size (d = .812), which decreases to a medium effect size when compared to control groups (d = .518). Effect sizes were assessed to determine whether treatment differed according to the focus of the outcome measure employed: (a) external stress (behavioral problems, aggression, or alcohol use); (b) psychological adjustment (depression, anxiety, or happiness); (c) self-concept (self-esteem, perceived competence, or internal locus of control); (d) social adjustment (popularity, loneliness, or cooperativeness); (e) family relations (mother-child relations, affection, or quality of interaction); and (f) maltreatment events (reoccurrence of violence, return to partner). Results reveal that domestic violence interventions across all outcome categories yield effects in the medium to large range for both internalized and externalized symptomatology. Implications for greater awareness and support for domestic violence treatment and programming are discussed. © The Author(s) 2015.

  20. Recombinant IκBα-loaded curcumin nanoparticles for improved cancer therapeutics

    Banerjee, Subhamoy; Sahoo, Amaresh Kumar; Chattopadhyay, Arun; Sankar Ghosh, Siddhartha

    2014-08-01

    The field of recombinant protein therapeutics has been evolving rapidly, making significant impact on clinical applications for several diseases, including cancer. However, the functional aspects of proteins rely exclusively on their structural integrity, in which nanoparticle mediated delivery offers unique advantages over free proteins. In the present work, a novel strategy has been developed where the nanoparticles (NPs) used for the delivery of the recombinant protein could contribute to enhancing the therapeutic efficacy of the recombinant protein. The transcription factor, NFκB, involved in cell growth and its inhibitor, IκBα, regulates its proliferation. Another similar naturally available molecule, which inhibits the function of NFκB, is curcumin. Hence, we have developed a ‘green synthesis’ method for preparing water-soluble curcumin nanoparticles to stabilize recombinant IκBα protein. The NPs were characterized by UV-vis and fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering before administration into human cervical carcinoma (HeLa) and glioblastoma (U87MG) cells. Experimental results demonstrated that this combined module had enhanced therapeutic efficacy, causing apoptotic cell death, which was confirmed by cytotoxicity assay and flowcytometry analyses. The expression of apoptotic genes studied by semi-quantitative reverse transcription PCR delineated the molecular pathways involved in cell death. Thus, our study revealed that the functional delivery of recombinant IκBα-loaded curcumin NPs has promise as a natural-product-based protein therapeutics against cancer cells.

  1. Recombinant IκBα-loaded curcumin nanoparticles for improved cancer therapeutics

    Banerjee, Subhamoy; Ghosh, Siddhartha Sankar; Sahoo, Amaresh Kumar; Chattopadhyay, Arun

    2014-01-01

    The field of recombinant protein therapeutics has been evolving rapidly, making significant impact on clinical applications for several diseases, including cancer. However, the functional aspects of proteins rely exclusively on their structural integrity, in which nanoparticle mediated delivery offers unique advantages over free proteins. In the present work, a novel strategy has been developed where the nanoparticles (NPs) used for the delivery of the recombinant protein could contribute to enhancing the therapeutic efficacy of the recombinant protein. The transcription factor, NFκB, involved in cell growth and its inhibitor, IκBα, regulates its proliferation. Another similar naturally available molecule, which inhibits the function of NFκB, is curcumin. Hence, we have developed a ‘green synthesis’ method for preparing water-soluble curcumin nanoparticles to stabilize recombinant IκBα protein. The NPs were characterized by UV–vis and fluorescence spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering before administration into human cervical carcinoma (HeLa) and glioblastoma (U87MG) cells. Experimental results demonstrated that this combined module had enhanced therapeutic efficacy, causing apoptotic cell death, which was confirmed by cytotoxicity assay and flowcytometry analyses. The expression of apoptotic genes studied by semi-quantitative reverse transcription PCR delineated the molecular pathways involved in cell death. Thus, our study revealed that the functional delivery of recombinant IκBα-loaded curcumin NPs has promise as a natural-product-based protein therapeutics against cancer cells. (paper)

  2. Breast cancer lung metastasis: Molecular biology and therapeutic implications.

    Jin, Liting; Han, Bingchen; Siegel, Emily; Cui, Yukun; Giuliano, Armando; Cui, Xiaojiang

    2018-03-26

    Distant metastasis accounts for the vast majority of deaths in patients with cancer. Breast cancer exhibits a distinct metastatic pattern commonly involving bone, liver, lung, and brain. Breast cancer can be divided into different subtypes based on gene expression profiles, and different breast cancer subtypes show preference to distinct organ sites of metastasis. Luminal breast tumors tend to metastasize to bone while basal-like breast cancer (BLBC) displays a lung tropism of metastasis. However, the mechanisms underlying this organ-specific pattern of metastasis still remain to be elucidated. In this review, we will summarize the recent advances regarding the molecular signaling pathways as well as the therapeutic strategies for treating breast cancer lung metastasis.

  3. Therapeutic management of locally unresectable pancreatic cancer

    Lombard-Bohas, C.; Saurin, J.C.; Mornex, F.

    1997-01-01

    Pancreatic cancer still have bad prognosis. At the time of diagnosis, less than 10 % of patients can undergo surgery with an overall 5-year survival rate of less than 2 %. For patients with localized pancreatic adenocarcinoma, the combination of radiation therapy and chemotherapy has been shown to control symptoms and to enhance patient survival. This treatment should be proposed to all the patients with good performance status and without icterus. Pain management should be optimized and often need morphinic and co-antalgic (anticonvulsants, steroids) consumption. The celiac plexus block with alcohol gives an excellent pain relief and should be more frequently used. (author)

  4. Epigenetic Modifications: Therapeutic Potential in Cancer

    Manisha Sachan

    2015-08-01

    Full Text Available Epigenetic modifications and alterations in chromatin structure and function contribute to the cumulative changes observed as normal cells undergo malignant transformation. These modifications and enzymes (DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases related to them have been deeply studied to develop new drugs, epigenome-targeted therapies and new diagnostic tools. Epigenetic modifiers aim to restore normal epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. Four of them (azacitidine, decitabine, vorinostat and romidepsin are approved by the U.S. Food and Drug Administration. This article provides an overview about the known functional roles of epigenetic enzymes in cancer development.

  5. B metastases in breast cancer. Clinical, diagnostic and therapeutic aspects

    Ferrigno, R.; Petitto, J.V.

    1989-01-01

    Osseous metastases are the most frequent sites of dissemination in breast cancer and diminish the quality of patients life, being one of the most serious problems of the disease. The authors discuss the clinical, diagnosis and therapeutic aspects, based on their own experience and data from the literature. (author)

  6. Host-guest supramolecular nanosystems for cancer diagnostics and therapeutics.

    Wang, Lei; Li, Li-li; Fan, Yun-shan; Wang, Hao

    2013-07-26

    Extensive efforts have been devoted to the construction of functional supramolecular nanosystems for applications in catalysis, energy conversion, sensing and biomedicine. The applications of supramolecular nanosystems such as liposomes, micelles, inorganic nanoparticles, carbon materials for cancer diagnostics and therapeutics have been reviewed by other groups. Here, we will focus on the recent momentous advances in the implementation of typical supramolecular hosts (i.e., cyclodextrins, calixarenes, cucurbiturils and metallo-hosts) and their nanosystems in cancer diagnostics and therapeutics. We discuss the evolutive process of supramolecular nanosystems from the structural control and characterization to their diagnostic and therapeutic function exploitation and even the future potentials for clinical translation. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Nanotechnology based approaches in cancer therapeutics

    Biswas, Amit Kumer; Islam, Md Reazul; Choudhury, Zahid Sadek; Kadir, Mohammad Fahim; Mostafa, Asif

    2014-01-01

    The current decades are marked not by the development of new molecules for the cure of various diseases but rather the development of new delivery methods for optimum treatment outcome. Nanomedicine is perhaps playing the biggest role in this concern. Nanomedicine offers numerous advantages over conventional drug delivery approaches and is particularly the hot topic in anticancer research. Nanoparticles (NPs) have many unique criteria that enable them to be incorporated in anticancer therapy. This topical review aims to look at the properties and various forms of NPs and their use in anticancer treatment, recent development of the process of identifying new delivery approaches as well as progress in clinical trials with these newer approaches. Although the outcome of cancer therapy can be increased using nanomedicine there are still many disadvantages of using this approach. We aim to discuss all these issues in this review. (review)

  8. TRAIL death receptors and cancer therapeutics

    Huang Ying; Sheikh, M. Saeed

    2007-01-01

    Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) also known as Apo2L is an apoptotic molecule that belongs to the tumor necrosis factor superfamily of cytokines. It mediates its apoptotic effects via its cognate death receptors including DR4 and DR5. Agonistic monoclonal antibodies have also been developed that selectively activate TRAIL death receptors to mediate apoptosis. Multiple clinically relevant agents also upregulate the expression of TRAIL death receptors, and cooperate with TRAIL as well as DR4 and DR5-specific agonistic antibodies to exhibit tumor cell killing. TRAIL is currently in phase I clinical trials, whereas DR4 and DR5-specific agonistic antibodies have been tested in phase I and II studies. Thus, TRAIL has clearly distinguished itself from the other family members including TNF-alpha and FasL both of which could not make it to the clinic due to their toxic nature. It is therefore, evident that the future of TRAIL-based therapeutic approaches looks brighter

  9. Chemotherapy and novel therapeutics before radical prostatectomy for high-risk clinically localized prostate cancer.

    Cha, Eugene K; Eastham, James A

    2015-05-01

    Although both surgery and radiation are potential curative options for men with clinically localized prostate cancer, a significant proportion of men with high-risk and locally advanced disease will demonstrate biochemical and potentially clinical progression of their disease. Neoadjuvant systemic therapy before radical prostatectomy (RP) is a logical strategy to improve treatment outcomes for men with clinically localized high-risk prostate cancer. Furthermore, delivery of chemotherapy and other systemic agents before RP affords an opportunity to explore the efficacy of these agents with pathologic end points. Neoadjuvant chemotherapy, primarily with docetaxel (with or without androgen deprivation therapy), has demonstrated feasibility and safety in men undergoing RP, but no study to date has established the efficacy of neoadjuvant chemotherapy or neoadjuvant chemohormonal therapies. Other novel agents, such as those targeting the vascular endothelial growth factor receptor, epidermal growth factor receptor, platelet-derived growth factor receptor, clusterin, and immunomodulatory therapeutics, are currently under investigation. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy.

    Chirmule, Narendra; Jawa, Vibha; Meibohm, Bernd

    2012-06-01

    The development of therapeutic proteins requires the understanding of the relationship between the dose, exposure, efficacy, and toxicity of these molecules. Several intrinsic and extrinsic factors contribute to the challenges for measuring therapeutic proteins in a precise and accurate manner. In addition, induction of an immune response to therapeutic protein results in additional complexities in the analysis of the pharmacokinetic profile, toxicity, safety, and efficacy of this class of molecules. Assessment of immunogenicity of therapeutic proteins is a required aspect of regulatory filings for a licensing application and for the safe and efficacious use of these compounds. A systematic strategy and well-defined criteria for measuring anti-drug antibodies (ADA) have been established, to a large extent, through coordinated efforts. These recommendations are based on risk assessment and include the determination of ADA content (concentration/titer), affinity, immunoglobulin isotype/subtype, and neutralization capacity. This manuscript reviews the requirements necessary for understanding the nature of an ADA response in order to discern the impact of immunogenicity on pharmacokinetics/pharmacodynamics and efficacy.

  11. The Influence of Antithyroid Drug Discontinuation to the Therapeutic Efficacy of 131I in Hyperthyroidism

    Kartamihardja, A. Hussein Sundawa; Massora, Stepanus

    2016-01-01

    The influence of antithyroid drugs (ATDs) on the therapeutic efficacy of radioactive iodine in hyperthyroidism is still controversial. The aim of this study was to evaluate the effect of ATD discontinuation to the therapeutic efficacy of I-131 in hyperthyroidism patients with long-term ATD treatment. Retrospective study was done to 39 subjects with hyperthyroidism who had been treated with doses of 300 MBq radioactive iodine. The subjects were divided into three groups: Group I (n = 14) had been using ATDs for more than one year and discontinued more than three days; group II (n = 14) had been using ATDs for more than one year but discontinued only for three days or less, and group III (n = 11) has never been used any ATD before radioactive iodine treatment. There was a significant difference in the therapeutic efficacy after three months of radioactive iodine treatment between group I and group II (P = 0.018), group II and group III (P = 0.017), but not between group I and group III (P = 1.0). There was no observed difference on the therapeutic efficacy between the three groups at 6 months after radioactive iodine therapy (P = 0.143). Administration of ATDs more than 1 year without discontinuation decreased response of radioactive iodine treatment in 3 months follow-up. Discontinuation of ATDs for more than 3 days before radioactive iodine treatment is recommended

  12. The Influence of Antithyroid Drug Discontinuation to the Therapeutic Efficacy of (131)I in Hyperthyroidism.

    Kartamihardja, A Hussein Sundawa; Massora, Stepanus

    2016-01-01

    The influence of antithyroid drugs (ATDs) on the therapeutic efficacy of radioactive iodine in hyperthyroidism is still controversial. The aim of this study was to evaluate the effect of ATD discontinuation to the therapeutic efficacy of I-131 in hyperthyroidism patients with long-term ATD treatment. Retrospective study was done to 39 subjects with hyperthyroidism who had been treated with doses of 300 MBq radioactive iodine. The subjects were divided into three groups: Group I (n = 14) had been using ATDs for more than one year and discontinued more than three days; group II (n = 14) had been using ATDs for more than one year but discontinued only for three days or less, and group III (n = 11) has never been used any ATD before radioactive iodine treatment. There was a significant difference in the therapeutic efficacy after three months of radioactive iodine treatment between group I and group II (P = 0.018), group II and group III (P = 0.017), but not between group I and group III (P = 1.0). There was no observed difference on the therapeutic efficacy between the three groups at 6 months after radioactive iodine therapy (P = 0.143). Administration of ATDs more than 1 year without discontinuation decreased response of radioactive iodine treatment in 3 months follow-up. Discontinuation of ATDs for more than 3 days before radioactive iodine treatment is recommended.

  13. The Influence of Antithyroid Drug Discontinuation to the Therapeutic Efficacy of 131I in Hyperthyroidism

    Kartamihardja, A. Hussein Sundawa; Massora, Stepanus

    2016-01-01

    The influence of antithyroid drugs (ATDs) on the therapeutic efficacy of radioactive iodine in hyperthyroidism is still controversial. The aim of this study was to evaluate the effect of ATD discontinuation to the therapeutic efficacy of I-131 in hyperthyroidism patients with long-term ATD treatment. Retrospective study was done to 39 subjects with hyperthyroidism who had been treated with doses of 300 MBq radioactive iodine. The subjects were divided into three groups: Group I (n = 14) had been using ATDs for more than one year and discontinued more than three days; group II (n = 14) had been using ATDs for more than one year but discontinued only for three days or less, and group III (n = 11) has never been used any ATD before radioactive iodine treatment. There was a significant difference in the therapeutic efficacy after three months of radioactive iodine treatment between group I and group II (P = 0.018), group II and group III (P = 0.017), but not between group I and group III (P = 1.0). There was no observed difference on the therapeutic efficacy between the three groups at 6 months after radioactive iodine therapy (P = 0.143). Administration of ATDs more than 1 year without discontinuation decreased response of radioactive iodine treatment in 3 months follow-up. Discontinuation of ATDs for more than 3 days before radioactive iodine treatment is recommended. PMID:27134556

  14. Self-Efficacy for Therapeutic Mode Use among Occupational Therapy Students in Norway

    Opseth, Thea Moos; Carstensen, Tove; Yazdani, Farzaneh; Ellingham, Brian; Thørrisen, Mikkel Magnus; Bonsaksen, Tore

    2017-01-01

    Background: The intentional relationship model (IRM) proposes six distinct ways of relating to clients. A new instrument for measuring self-efficacy for using the therapeutic modes in occupational therapy practice was recently found to have good psychometric properties. To date, however, no research has investigated factors associated with…

  15. Inhibiting DNA Polymerases as a Therapeutic Intervention against Cancer

    Anthony J. Berdis

    2017-11-01

    Full Text Available Inhibiting DNA synthesis is an important therapeutic strategy that is widely used to treat a number of hyperproliferative diseases including viral infections, autoimmune disorders, and cancer. This chapter describes two major categories of therapeutic agents used to inhibit DNA synthesis. The first category includes purine and pyrmidine nucleoside analogs that directly inhibit DNA polymerase activity. The second category includes DNA damaging agents including cisplatin and chlorambucil that modify the composition and structure of the nucleic acid substrate to indirectly inhibit DNA synthesis. Special emphasis is placed on describing the molecular mechanisms of these inhibitory effects against chromosomal and mitochondrial DNA polymerases. Discussions are also provided on the mechanisms associated with resistance to these therapeutic agents. A primary focus is toward understanding the roles of specialized DNA polymerases that by-pass DNA lesions produced by DNA damaging agents. Finally, a section is provided that describes emerging areas in developing new therapeutic strategies targeting specialized DNA polymerases.

  16. Therapeutic Applications of Herbal Medicines for Cancer Patients

    Shu-Yi Yin

    2013-01-01

    Full Text Available Medicinal herbs and their derivative phytocompounds are being increasingly recognized as useful complementary treatments for cancer. A large volume of clinical studies have reported the beneficial effects of herbal medicines on the survival, immune modulation, and quality of life (QOL of cancer patients, when these herbal medicines are used in combination with conventional therapeutics. Here, we briefly review some examples of clinical studies that investigated the use of herbal medicines for various cancers and the development of randomized controlled trials (RCTs in this emerging research area. In addition, we also report recent studies on the biochemical and cellular mechanisms of herbal medicines in specific tumor microenvironments and the potential application of specific phytochemicals in cell-based cancer vaccine systems. This review should provide useful technological support for evidence-based application of herbal medicines in cancer therapy.

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

    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.

  18. [Therapeutic education in oncology: involving patient in the management of cancer].

    Pérol, David; Toutenu, Pauline; Lefranc, Anne; Régnier, Véronique; Chvetzoff, Gisèle; Saltel, Pierre; Chauvin, Franck

    2007-03-01

    The notion of therapeutic education was only recently introduced in cancer. Although the term is commonly used, no standard definition exists for the concept and principles of therapeutic education and its efficacy remains to be assessed. Therapeutic education is complementary to the healthcare approach and aims to get the patients more involved in their disease and the treatment decision-making process. This discipline, placed at the interface of human and social sciences, was first developed for the management of chronic diseases (diabetes, asthma). It derives from the principle that involving patients in their own care and management can help them better adjust to life with a chronic disease. The lengthening survival time of cancer patients, which contributes to making cancer a chronic disease, as well as changes in the patient-caregiver relationship contribute to the development of therapeutic education in cancer. Pilot studies, conducted principally in the United States, evaluating the side effects of chemotherapy and the management of pain, have demonstrated that such educational programs could improve patient quality of life and decrease the side effects of treatments. The success of these programs depends on several parameters: taking into account patient's opinion in the elaboration and preparation of the programs; involving skilled multidisciplinary teams engaged in iterative educational actions; having recourse to methodological tools to evaluate the impact of implemented programs. Consistent with the World Health Organization guidelines, research should be conducted in France in order to elaborate and implement cancer-specific education programs and evaluate their potential benefit. Patient education programs on pain, fatigue, nutrition and treatment compliance are currently being developed at Saint-Etienne Regional Resource Centre for cancer information, prevention and education, within the framework of the Canceropole Lyon Auvergne Rhône-Alpes.

  19. Iron addiction: a novel therapeutic target in ovarian cancer

    Basuli, D.

    2017-01-01

    Ovarian cancer is a lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), the iron efflux pump, is decreased, and transferrin receptor (TFR1), the iron importer, is increased in tumor tissue from patients with high grade but not low grade serous ovarian cancer. A similar profile of decreased FPN and increased TFR1 is observed in a genetic model of ovarian cancer tumor-initiating cells (TICs). The net result of these changes is an accumulation of excess intracellular iron and an augmented dependence on iron for proliferation. A forced reduction in intracellular iron reduces the proliferation of ovarian cancer TICs in vitro, and inhibits both tumor growth and intraperitoneal dissemination of tumor cells in vivo. Some mechanistic studies demonstrate that iron increases metastatic spread by facilitating invasion through expression of matrix metalloproteases and synthesis of interleukin 6 (IL-6). Here, we show that the iron dependence of ovarian cancer TICs renders them exquisitely sensitive in vivo to agents that induce iron-dependent cell death (ferroptosis) as well as iron chelators, and thus creates a metabolic vulnerability that can be exploited therapeutically.

  20. EVALUATION OF THE THERAPEUTIC EFFICACY OF HIGH-INTENSITY PULSED-PERIODIC LASER RADIATION (CLINICAL AND EXPERIMENTAL OBSERVATIONS

    V. V. Sokolov

    2016-01-01

    Full Text Available From the experience of clinical observations, we have shown a high therapeutic effectiveness of the medical laser KULON-MED in: cosmetics, non-cancer inflammatory diseases of the gastrointestinal tract and cancer (cancer of the stomach and colon as at different wavelengths, and with different types of photosensitizers. In the area of anti-tumor photodynamic therapy (PDT, based on experimental studies, we have showed the high antitumor (sarcoma S‑37 effectiveness of the laser (with the inhibition of tumor growth of up to 100% for repetitively pulsed irradiation mode, and for mode fractionation doses laser radiation. In addition, significant differences are shown in the effectiveness of anticancer PDT methods in the application of high-intensity lasers, continuous and pulsed caused fundamental properties of laser radiation characteristics – time structure of the radiation pulses. Thus, for the first time we have shown that the time of high-intensity laser pulses structure significantly affects therapeutic efficacy laser system, and hence on the mechanisms of interaction of laser radiation with biological tissue.

  1. THERAPEUTIC ANTISENSE OLIGONUCLEOTIDES AGAINST CANCER: HURDLING TO THE CLINIC

    Pedro Miguel Duarte Moreno

    2014-10-01

    Full Text Available Under clinical development since the early 90’s and with two successfully approved drugs (Fomivirsen and Mipomersen, oligonucleotide-based therapeutics have not yet delivered a clinical drug to the market in the cancer field. Whilst many pre-clinical data has been generated, a lack of understanding still exists on how to efficiently tackle all the different challenges presented for cancer targeting in a clinical setting. Namely, effective drug vectorization, careful choice of target gene or synergistic multi-gene targeting are surely decisive, while caution must be exerted to avoid potential toxic, often misleading off-target-effects. Here a brief overview will be given on the nucleic acid chemistry advances that established oligonucleotide technologies as a promising therapeutic alternative and ongoing cancer related clinical trials. Special attention will be given towards a perspective on the hurdles encountered specifically in the cancer field by this class of therapeutic oligonucleotides and a view on possible avenues for success is presented, with particular focus on the contribution from nanotechnology to the field.

  2. Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family

    Shepard, H. Michael; Brdlik, Cathleen M.; Schreiber, Hans

    2008-01-01

    The human EGFR (HER) family is essential for communication between many epithelial cancer cell types and the tumor microenvironment. Therapeutics targeting the HER family have demonstrated clinical success in the treatment of diverse epithelial cancers. Here we propose that the success of HER family–targeted monoclonal antibodies in cancer results from their ability to interfere with HER family consolidation of signals initiated by a multitude of other receptor systems. Ligand/receptor systems that initiate these signals include cytokine receptors, chemokine receptors, TLRs, GPCRs, and integrins. We further extrapolate that improvements in cancer therapeutics targeting the HER family are likely to incorporate mechanisms that block or reverse stromal support of malignant progression by isolating the HER family from autocrine and stromal influences. PMID:18982164

  3. Breast cancer stem cells, EMT and therapeutic targets

    Kotiyal, Srishti; Bhattacharya, Susinjan, E-mail: s.bhattacharya@jiit.ac.in

    2014-10-10

    Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.

  4. Breast cancer. Nuclear medicine in diagnosis and therapeutic options

    Bombardieri, E.; Bonadonna, G.; Gianni, L.

    2008-01-01

    Brings up-to-date nuclear medical knowledge in breast cancer. Includes vital information on advances in the field of diagnosis. Supplies data on the development of some new modalities. Offers a general overview of the available tools for breast cancer treatment. There can never be enough material in the public domain about cancers, and particularly breast cancer. This book adds much to the literature. It provides general information on breast cancer management and considers all new methods of diagnosis and therapy. It focuses on nuclear medicine modalities by comparing their results with other diagnostic and therapeutic approaches. The coverage provides readers with up-to-date knowledge on breast cancer as well as information on the advances in the field of diagnosis. It also details data on the development of some new modalities and provides a general overview of the available tools for breast cancer treatment. In sum, it is a hugely useful text that performs a dual function. Not only does it provide practitioners of all descriptions with a vital overview of the current state of play in breast cancer treatment, but it also lays out in a beautifully structured way the latest diagnostic methodologies. (orig.)

  5. Androgen receptor activation: a prospective therapeutic target for bladder cancer?

    Mizushima, Taichi; Tirador, Kathleen A; Miyamoto, Hiroshi

    2017-03-01

    Patients with non-muscle-invasive or muscle-invasive bladder cancer undergoing surgery and currently available conventional therapy remain having a high risk of tumor recurrence or progression, respectively. Novel targeted molecular therapy is therefore expected to improve patient outcomes. Meanwhile, substantially higher incidence of bladder cancer in men has prompted research on androgen-mediated androgen receptor (AR) signaling in this malignancy. Indeed, preclinical evidence has suggested that AR signaling plays an important role in urothelial carcinogenesis and tumor outgrowth as well as resistance to some of the currently available conventional non-surgical therapies. Areas covered: We summarize and discuss available data suggesting the involvement of AR and its potential downstream targets in the development and progression of bladder cancer. Associations between AR signaling and sensitivity to cisplatin/doxorubicin or bacillus Calmette-Guérin treatment are also reviewed. Expert opinion: AR activation is likely to correlate with the promotion of urothelial carcinogenesis and cancer outgrowth as well as resistance to conventional therapies. Molecular therapy targeting the AR may thus provide effective chemopreventive and therapeutic approaches for urothelial cancer. Accordingly, bladder cancer can now be considered as an endocrine-related neoplasm. Clinical application of various anti-AR therapies available for AR-dependent prostate cancer to bladder cancer patients is anticipated.

  6. Predictive Biomarkers in Colorectal Cancer: From the Single Therapeutic Target to a Plethora of Options

    Daniela Rodrigues

    2016-01-01

    Full Text Available Colorectal cancer (CRC is one of the most frequent cancers and is a leading cause of cancer death worldwide. Treatments used for CRC may include some combination of surgery, radiation therapy, chemotherapy, and targeted therapy. The current standard drugs used in chemotherapy are 5-fluorouracil and leucovorin in combination with irinotecan and/or oxaliplatin. Most recently, biologic agents have been proven to have therapeutic benefits in metastatic CRC alone or in association with standard chemotherapy. However, patients present different treatment responses, in terms of efficacy and toxicity; therefore, it is important to identify biological markers that can predict the response to therapy and help select patients that would benefit from specific regimens. In this paper, authors review CRC genetic markers that could be useful in predicting the sensitivity/resistance to chemotherapy.

  7. Cell mediated therapeutics for cancer treatment: Tumor homing cells as therapeutic delivery vehicles

    Balivada, Sivasai

    Many cell types were known to have migratory properties towards tumors and different research groups have shown reliable results regarding cells as delivery vehicles of therapeutics for targeted cancer treatment. Present report discusses proof of concept for 1. Cell mediated delivery of Magnetic nanoparticles (MNPs) and targeted Magnetic hyperthermia (MHT) as a cancer treatment by using in vivo mouse cancer models, 2. Cells surface engineering with chimeric proteins for targeted cancer treatment by using in vitro models. 1. Tumor homing cells can carry MNPs specifically to the tumor site and tumor burden will decrease after alternating magnetic field (AMF) exposure. To test this hypothesis, first we loaded Fe/Fe3O4 bi-magnetic NPs into neural progenitor cells (NPCs), which were previously shown to migrate towards melanoma tumors. We observed that NPCs loaded with MNPs travel to subcutaneous melanoma tumors. After alternating magnetic field (AMF) exposure, the targeted delivery of MNPs by the NPCs resulted in a mild decrease in tumor size (Chapter-2). Monocytes/macrophages (Mo/Ma) are known to infiltrate tumor sites, and also have phagocytic activity which can increase their uptake of MNPs. To test Mo/Ma-mediated MHT we transplanted Mo/Ma loaded with MNPs into a mouse model of pancreatic peritoneal carcinomatosis. We observed that MNP-loaded Mo/Ma infiltrated pancreatic tumors and, after AMF treatment, significantly prolonged the lives of mice bearing disseminated intraperitoneal pancreatic tumors (Chapter-3). 2. Targeted cancer treatment could be achieved by engineering tumor homing cell surfaces with tumor proteases cleavable, cancer cell specific recombinant therapeutic proteins. To test this, Urokinase and Calpain (tumor specific proteases) cleavable; prostate cancer cell (CaP) specific (CaP1 targeting peptide); apoptosis inducible (Caspase3 V266ED3)- rCasp3V266ED3 chimeric protein was designed in silico. Hypothesized membrane anchored chimeric protein (rCasp3V

  8. Therapeutic efficacy of cyclic home elemental enteral alimentation in Crohn's disease: Japanese cooperative Crohn's disease study.

    Matsueda, K; Shoda, R; Takazoe, M; Hiwatashi, N; Bamba, T; Kobayashi, K; Saito, T; Terano, A; Yao, T

    1995-11-01

    Crohn's disease (CD) often flares up and requires frequent hospitalization and/or surgery. Cyclic home elemental enteral alimentation (C-HEEA) was developed to prevent flare-up of CD and to minimize patient hospitalization. However, its therapeutic efficacy has not been studied in a large patient population. Therefore, questionnaires were sent to members of the Inflammatory Bowel Disease (IBD) Research Group of Japan to evaluate the therapeutic efficacy of C-HEEA and to define the factors that may affect the efficacy of the treatment. Data for 410 patients (C-HEEA-treated n = 322; drug-treated n = 88) were collected from 29 institutions and analysis showed the following results. The cumulative remission and non-hospitalization rates of the C-HEEA treated group were significantly higher than the rates of the drug-treated group in all patients and in those with ileitis and ileo-colitis (P < 0.0001, P < 0.001, and P < 0.01, respectively), but no significant difference was noted in patients with colitis. Cumulative remission and non-hospitalization rates were also influenced by the daily calorie content of the elemental diet (ED); more than 1200 kcal of the ED per day was found to be more effective than lower amounts to maintain remission and to prevent hospitalization. The therapeutic efficacy of C-HEEA was shown to be superior to that of drug treatment in patients with CD with ileal involvement, and it is suggested that more than 1200kcal per day should be supplied by the ED to enhance its therapeutic efficacy.

  9. Systemic Administration of Interleukin 2 Enhances the Therapeutic Efficacy of Dendritic Cell-Based Tumor Vaccines

    Shimizu, K.; Fields, R. C.; Giedlin, M.; Mule, J. J.

    1999-03-01

    We have reported previously that murine bone marrow-derived dendritic cells (DC) pulsed with whole tumor lysates can mediate potent antitumor immune responses both in vitro and in vivo. Because successful therapy was dependent on host immune T cells, we have now evaluated whether the systemic administration of the T cell stimulatory/growth promoting cytokine interleukin-2 (IL-2) could enhance tumor lysate-pulsed DC-based immunizations to further promote protective immunity toward, and therapeutic rejection of, syngeneic murine tumors. In three separate approaches using a weakly immunogenic sarcoma (MCA-207), the systemic administration of non-toxic doses of recombinant IL-2 (20,000 and 40,000 IU/dose) was capable of mediating significant increases in the potency of DC-based immunizations. IL-2 could augment the efficacy of tumor lysate-pulsed DC to induce protective immunity to lethal tumor challenge as well as enhance splenic cytotoxic T lymphocyte activity and interferon-γ production in these treated mice. Moreover, treatment with the combination of tumor lysate-pulsed DC and IL-2 could also mediate regressions of established pulmonary 3-day micrometastases and 7-day macrometastases as well as established 14- and 28-day s.c. tumors, leading to either significant cure rates or prolongation in overall survival. Collectively, these findings show that nontoxic doses of recombinant IL-2 can potentiate the antitumor effects of tumor lysate-pulsed DC in vivo and provide preclinical rationale for the use of IL-2 in DC-based vaccine strategies in patients with advanced cancer.

  10. CIMAvax-EGF®, new therapeutic alternative for lung cancer: its application in Cienfuegos

    Yoana Herrera Leiva

    2017-04-01

    Full Text Available In 2016, the EGF-Predictor Phase IV Clinical Trial Opening Workshop was held in Cienfuegos, sponsored by the Center for Molecular Immunology of Havana which coexist with other clinical trials. The overall objective of the study is to evaluate the safety and efficacy of the CIMAVAX-EGF therapeutic vaccine for the treatment of patients diagnosed with lung cancer in advanced stages of the disease and, within its specific objectives, to assess overall survival and the treated patients’ life quality.

  11. Telomere biology: Rationale for diagnostics and therapeutics in cancer.

    Rousseau, Philippe; Autexier, Chantal

    2015-01-01

    The key step of carcinogenesis is the malignant transformation which is fundamentally a telomere biology dysfunction permitting cells to bypass the Hayflick limit and to divide indefinitely and uncontrollably. Thus all partners and structures involved in normal and abnormal telomere maintenance, protection and lengthening can be considered as potential anti-cancer therapeutic targets. In this Point of View we discuss, highlight and provide new perspectives from the current knowledge and understanding to position the different aspects of telomere biology and dysfunction as diagnostic, preventive and curative tools in the field of cancer.

  12. Gynecologic cancer treatment: risk factors for therapeutically induced neoplasia

    Messerschmidt, G.L.; Hoover, R.; Young, R.C.

    1980-01-01

    Therapeutic intervention in a course of illness, while producing the desired result, also may have some adverse long-term effects on the patient. Second malignancies are one of the known complications of therapy. The treatments of gynecologic cancers by surgery, irradiation and chemotherapy have been associated with subsequent neoplasms. The use of normal skin from the thigh to fabricate an artificial vagina has resulted in more squamous cell carcinomas than expected. Alkylating agents used in the treatment of ovarian cancer and other diseases have been shown to lead to an increased risk of leukemia. The incidence of lymphoma and uterine, urinary bladder and colon carcinomas has been associated with prior irradiation for gynecologic disease. The literature regarding the therapeutically induced risk factors in gynecologic therapy is reviewed and areas of our knowledge that require more investigation are identified

  13. Frizzled Receptors as Potential Therapeutic Targets in Human Cancers

    Chui-Mian Zeng

    2018-05-01

    Full Text Available Frizzled receptors (FZDs are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs that serve as receptors for secreted Wingless-type (WNT ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell proliferation, formation of neural synapses, and many other processes in developing and adult organisms. In this review, we will introduce the basic structural features and review the biological function and mechanism of FZDs in the progression of human cancers, followed by an analysis of clinical relevance and therapeutic potential of FZDs. We will focus on the development of antibody-based and small molecule inhibitor-based therapeutic strategies by targeting FZDs for human cancers.

  14. Targeted Therapeutic Nanoparticles: An Immense Promise to Fight against Cancer

    Sheikh Tasnim Jahan

    2017-01-01

    Full Text Available In nanomedicine, targeted therapeutic nanoparticle (NP is a virtual outcome of nanotechnology taking the advantage of cancer propagation pattern. Tying up all elements such as therapeutic or imaging agent, targeting ligand, and cross-linking agent with the NPs is the key concept to deliver the payload selectively where it intends to reach. The microenvironment of tumor tissues in lymphatic vessels can also help targeted NPs to achieve their anticipated accumulation depending on the formulation objectives. This review accumulates the application of poly(lactic-co-glycolic acid (PLGA and polyethylene glycol (PEG based NP systems, with a specific perspective in cancer. Nowadays, PLGA, PEG, or their combinations are the mostly used polymers to serve the purpose of targeted therapeutic NPs. Their unique physicochemical properties along with their biological activities are also discussed. Depending on the biological effects from parameters associated with existing NPs, several advantages and limitations have been explored in teaming up all the essential facts to give birth to targeted therapeutic NPs. Therefore, the current article will provide a comprehensive review of various approaches to fabricate a targeted system to achieve appropriate physicochemical properties. Based on such findings, researchers can realize the benefits and challenges for the next generation of delivery systems.

  15. Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides

    José Manuel Calderón-Montaño

    2014-01-01

    Full Text Available Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na+/K+-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies.

  16. New Advances in Nanotechnology-Based Diagnosis and Therapeutics for Breast Cancer: An Assessment of Active-Targeting Inorganic Nanoplatforms.

    Falagan-Lotsch, Priscila; Grzincic, Elissa M; Murphy, Catherine J

    2017-01-18

    Breast cancer is a major cause of suffering and mortality among women. Limitations in the current diagnostic methods and treatment approaches have led to new strategies to positively impact the survival rates and quality of life of breast cancer patients. Nanotechnology offers a real possibility of mitigating breast cancer mortality by early-stage cancer detection and more precise diagnosis as well as more effective treatments with minimal side effects. The current nanoplatforms approved for breast cancer therapeutics are based on passive tumor targeting using organic nanoparticles and have not provided the expected significant improvements in the clinic. In this review, we present the emerging approaches in breast cancer nanomedicine based on active targeting using versatile inorganic nanoplatforms with biomedical relevance, such as gold, silica, and iron oxide nanoparticles, as well as their efficacy in breast cancer imaging, drug and gene delivery, thermal therapy, combinational therapy, and theranostics in preclinical studies. The main challenges for clinical translation and perspectives are discussed.

  17. Therapeutic efficacy and dosimetric aspects of Rhenium-188-HEDP in bone pain palliation

    Liepe, Knut

    2005-01-01

    Full text: Bone metastases are a frequent complication of cancer, occurring in up 70% of patients suffering from advanced breast or prostate cancer and often present with severe bone pain. In this purpose the radionuclide therapy is a useful option for cancer patients. Different radionuclides are described, such as 89 Sr, 32 P, 153 Sm-EDTMP, 186 Re-HEDP, 131 I-BDP3, 90 Y, 117mSn-DTPA, 188 Re-HEDP and 188 Re-DMSA. The most experiences are available for 89 Sr. An indication for the treatment are patients with osteoblastic metastases, bone pain, sufficient bone marrow function and at least of three bone metastases visualized in bone scan. A bisphosphonate therapy, a chemotherapy with lower bone marrow toxicity or a local field external beam radiotherapy represent no contraindications, especially because the reported synergistic effects to the systemic radionuclide therapy. In 33 treated patients (breast and prostate cancer) we investigated the effect of 188 Re-HEDP on pain relief, analgesic intake and impairment of bone marrow function. There were an improvement on the Karnofsky performance scale from 74 7% to 85 9% 12 weeks after therapy (p= 0.001). The pain score showed a maximum decrease from 44 ± 18% to 27 ± 20% in the 3rd to the 8th week after therapy (p = .009) and 76% had a pain relief (20% were pain free). The maximal differences between the values of platelets and leukocytes before and after therapy were not statistically significant (p = 0.021 and p = 0.094). In 105 investigated patients treated with different radionuclides ( 89 Sr, 153 Sm-EDTMP, 186 Re-HEDP, 188 Re-HEDP and 89 Sr in combination with chemotherapy) no different therapeutic efficacy of the treatments were observed. In dose calculation of 188 Re-HEDP a radiation dose of 3.83 ± 2.01 mGy/MBq (12.6 Gy for 3300 MBq) for bone metastases and 0.61 ± 0.21 mGy/MBq (2 Gy for 3300 MBq) were found. With the introducing of radionuclide treatments with chemotherapy and repeated treatments, the

  18. The redox biology network in cancer pathophysiology and therapeutics

    Gina Manda

    2015-08-01

    Full Text Available The review pinpoints operational concepts related to the redox biology network applied to the pathophysiology and therapeutics of solid tumors. A sophisticated network of intrinsic and extrinsic cues, integrated in the tumor niche, drives tumorigenesis and tumor progression. Critical mutations and distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation and efficient repair mechanisms. Additionally, the complex inter-cellular crosstalk within the tumor niche, mediated by cytokines, redox-sensitive danger signals (HMGB1 and exosomes, under the pressure of multiple stresses (oxidative, inflammatory, metabolic, greatly contributes to the malignant phenotype. The tumor-associated inflammatory stress and its suppressive action on the anti-tumor immune response are highlighted. We further emphasize that ROS may act either as supporter or enemy of cancer cells, depending on the context. Oxidative stress-based therapies, such as radiotherapy and photodynamic therapy, take advantage of the cytotoxic face of ROS for killing tumor cells by a non-physiologically sudden, localized and intense oxidative burst. The type of tumor cell death elicited by these therapies is discussed. Therapy outcome depends on the differential sensitivity to oxidative stress of particular tumor cells, such as cancer stem cells, and therefore co-therapies that transiently down-regulate their intrinsic antioxidant system hold great promise. We draw attention on the consequences of the damage signals delivered by oxidative stress-injured cells to neighboring and distant cells, and emphasize the benefits of therapeutically triggered immunologic cell death in metastatic cancer. An integrative approach should be applied when designing therapeutic strategies in cancer, taking into consideration the mutational, metabolic, inflammatory and oxidative status of tumor cells, cellular

  19. Gynecologic cancer treatment: risk factors for therapeutically induced neoplasia

    Messerschmidt, G.L.; Hoover, R.; Young, R.C.

    1981-01-01

    Therapeutic intervention in a course of illness, while producing the desired result, also may have some adverse long-term effects on the patient. Second malignancies are one of the known complications of therapy. The treatments of gynecologic cancers by surgery, irradiation and chemotherapy have been associated with subsequent neoplasms. Care must be exercised in associating previous therapy and a subsequent malignancy. Naturally occurring second cancers must be separated from those which are iatrogenic. Associations in the literature have been made involving malignancies as a sequelae of prior gynecologic therapy. The use of normal skin from the thigh to fabricate an artificial vagina has resulted in more squamous cell carcinomas than expected. Alkylating agents used in the treatment of ovarian cancer and other diseases have been shown to lead to an increased risk of leukemia. Irradiation therapy, however, has not yet been shown to be related to leukemia in cervical cancer patients. The incidence of lymphoma and uterine, urinary bladder and colon carcinomas has been associated with prior irradiation for gynecologic disease. The literature regarding the therapeutically induced risk factors in gynecologic therapy is reviewed and areas of our knowledge that require more investigation are identified

  20. Therapeutic Efficacy of Meropenem for Treatment of Experimental Penicillin-Resistant Pneumococcal Meningitis

    Kim, Shin-Woo; Jin, Joung Hwa; Kang, Soo Jung; Jung, Sook-In; Kim, Yeon-Sook; Kim, Choon-Kwan; Lee, Hyuck; Oh, Won Sup; Kim, Sungmin; Peck, Kyong Ran

    2004-01-01

    With the widespread emergence of antimicrobial resistance, combination regimens of ceftriaxone and vancomycin (C+V) or ceftriaxone and rifampin (C+R) are recommended for empirical treatment of pneumococcal meningitis. To evaluate the therapeutic efficacy of meropenem (M), we compared various treatment regimens in arabbit model of meningitis caused by penicillin-resistant Streptococcus pneumoniae (PRSP). Therapeutic efficacy was also evaluated by the final bacterial concentration in the cerebrospinal fluid (CSF) at 24 hr. Each group consisted of six rabbits. C+V cleared the CSF at 10 hr, but regrowth was noted in 3 rabbits at 24 hr. Meropenem monotherapy resulted in sterilization at 10 hr, but regrowth was observed in all 6 rabbits at 24 hr. M+V also resulted in sterilization at 10 hr, but regrowth was observed in 2 rabbits at 24 hr. M+V was superior to the meropenem monotherapy at 24 hr (reduction of 4.8 vs. 1.8 log10 cfu/mL, respectively; p=0.003). The therapeutic efficacy of M+V was comparable to that of C+V (reduction of 4.8 vs. 4.0 log10 cfu/mL, respectively; p=0.054). The meropenem monotherapy may not be a suitable choice for PRSP meningitis, while combination of meropenem and vancomycin could be a possible alternative in the treatment of PRSP meningitis. PMID:14966336

  1. Tyrosine Kinase Receptor Landscape in Lung Cancer: Therapeutical Implications

    A. Quintanal-Villalonga

    2016-01-01

    Full Text Available Lung cancer is a heterogeneous disease responsible for the most cases of cancer-related deaths. The majority of patients are clinically diagnosed at advanced stages, with a poor survival rate. For this reason, the identification of oncodrivers and novel biomarkers is decisive for the future clinical management of this pathology. The rise of high throughput technologies popularly referred to as “omics” has accelerated the discovery of new biomarkers and drivers for this pathology. Within them, tyrosine kinase receptors (TKRs have proven to be of importance as diagnostic, prognostic, and predictive tools and, due to their molecular nature, as therapeutic targets. Along this review, the role of TKRs in the different lung cancer histologies, research on improvement of anti-TKR therapy, and the current approaches to manage anti-TKR resistance will be discussed.

  2. [Cancer stem cells as the therapeutic target of tomorrow].

    Hatina, Jiří

    2017-02-01

    The concept of hierarchical organization of tumour cell population, with cancer stem cells positioned at the apex of the cell hierarchy, can explain at least some crucial aspects of biological and clinical behaviour of cancer, like its propensity to relapse as well as the development of therapeutic resistance. The underlying biological properties of cancer stem cells are crucially dependent on various signals, inhibition of which provides an attractive opportunity to attack pharmacologically cancer stem cells. Currently, a lot of such stemness-inhibitors undergo various phases of clinical testing. Interestingly, numerous old drugs that are in routine use in human and veterinary medicine for non-oncological indications appear to be able to specifically target cancer stem cells as well. As cancer stem cells, at least for most tumours, represent usually only a minor tumour cell fraction, it is quite probable that the main focus of the clinical use of the stemness inhibitors would consist in their rational combinations with traditional anticancer treatment modalities. A highly important goal for the future research is to identify reliable and clinically applicable predictive markers that would allow to apply these novel anticancer drugs on the individual basis within the context of personalized medicine.

  3. Oncogenic Human Papillomavirus: Application of CRISPR/Cas9 Therapeutic Strategies for Cervical Cancer

    Shuai Zhen

    2017-12-01

    Full Text Available Oncogenic human papillomaviruses (HPVs cause different types of cancer especially cervical cancer. HPV-associated carcinogenesis provides a classical model system for clustered regularly interspaced short palindromic repeats (CRISPR/Cas9 based cancer therapies since the viral oncogenes E6 and E7 are exclusively expressed in cancerous cells. Sequence-specific gene knockdown/knockout using CRISPR/Cas9 shows promise as a novel therapeutic approach for the treatment of a variety of diseases that currently lack effective treatments. However, CRISPR/Cas9-based targeting therapy requires further validation of its efficacy in vitro and in vivo to eliminate the potential off-target effects, necessitates verification of the delivery vehicles and the combinatory use of conventional therapies with CRISPR/Cas9 to ensure the feasibility and safety. In this review we discuss the potential of combining CRISPR/Cas9 with other treatment options as therapies for oncogenic HPVs-associated carcinogenesis. and present our assessment of the promising path to the development of CRISPR/Cas9 therapeutic strategies for clinical settings.

  4. Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target.

    Chen, C-H; Fong, L W R; Yu, E; Wu, R; Trott, J F; Weiss, R H

    2017-06-22

    Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high-grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably vascular endothelial growth factor-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multikinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS (MARCKS phosphorylation site domain) peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multikinase inhibitors.

  5. Nucleic acid aptamer-guided cancer therapeutics and diagnostics: the next generation of cancer medicine.

    Xiang, Dongxi; Shigdar, Sarah; Qiao, Greg; Wang, Tao; Kouzani, Abbas Z; Zhou, Shu-Feng; Kong, Lingxue; Li, Yong; Pu, Chunwen; Duan, Wei

    2015-01-01

    Conventional anticancer therapies, such as chemo- and/or radio-therapy are often unable to completely eradicate cancers due to abnormal tumor microenvironment, as well as increased drug/radiation resistance. More effective therapeutic strategies for overcoming these obstacles are urgently in demand. Aptamers, as chemical antibodies that bind to targets with high affinity and specificity, are a promising new and novel agent for both cancer diagnostic and therapeutic applications. Aptamer-based cancer cell targeting facilitates the development of active targeting in which aptamer-mediated drug delivery could provide promising anticancer outcomes. This review is to update the current progress of aptamer-based cancer diagnosis and aptamer-mediated active targeting for cancer therapy in vivo, exploring the potential of this novel form of targeted cancer therapy.

  6. Enzymatic Inactivation of Endogenous IgG by IdeS Enhances Therapeutic Antibody Efficacy.

    Järnum, Sofia; Runström, Anna; Bockermann, Robert; Winstedt, Lena; Crispin, Max; Kjellman, Christian

    2017-09-01

    Endogenous plasma IgG sets an immunologic threshold that dictates the activity of tumor-directed therapeutic antibodies. Saturation of cellular antibody receptors by endogenous antibody limits antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Here, we show how enzymatic cleavage of IgG using the bacterial enzyme IdeS can be utilized to empty both high and low affinity Fcγ-receptors and clear the entire endogenous antibody pool. Using in vitro models, tumor animal models as well as ex vivo analysis of sera collected during a previous clinical trial with IdeS, we show how clearing of competing plasma antibody levels with IdeS unblocks cellular antibody receptors. We show that therapeutic antibodies against breast cancer (trastuzumab), colon cancer (cetuximab), and lymphomas (rituximab and alemtuzumab) can be potentiated when endogenous IgG is removed. Overall, IdeS is shown to be a potent tool to reboot the human antibody repertoire and to generate a window to preferentially load therapeutic antibodies onto effector cells and thereby create an armada of dedicated tumor-seeking immune cells. Mol Cancer Ther; 16(9); 1887-97. ©2017 AACR . ©2017 American Association for Cancer Research.

  7. Efficacy of cardiovascular complications correction in patients with breast cancer

    Savchenko, A.S.

    2011-01-01

    The work was performed with the purpose to assess the efficacy of cardiovascular complications correction at combination treatment for breast cancer (BC). Timely diagnosis and correction of cardiovascular diseases in BC with the use of inhalation cardioactive drugs (nitrates and calcium antagonists) improved the efficacy of accompanying therapy, prevented progress of early and late RT complications, improved the quality of life.

  8. Therapeutic Mechanisms of Vernonia amygdalina Delile in the Treatment of Prostate Cancer

    William Johnson

    2017-09-01

    Full Text Available Prostate cancer patients have been suffering from limited treatment options due to late diagnosis, poor drug tolerance, and multi-drug resistance to almost all the current drug treatments. Therefore, it is important to seek a new alternative therapeutic medicine that can effectively prevent the disease and even eradicate the progression and metastasis of prostate cancer. Vernonia amygdalina Delile (VAD is a common edible vegetable in Cameroon that has been used as a traditional medicine for some human diseases. However, to the best of our knowledge, no previous reports have explored its therapeutic efficacy against human prostate cancer. The objective of the present study was to assess the anticancer activities of VAD methanolic extracts in the prevention and treatment of prostate cancer using human androgen-independent prostate cancer (PC-3 cells as a test model. To achieve our objective, PC-3 cells were treated with various doses of VAD for 48 h. Data generated from the trypan blue test and MTT assay demonstrated that VAD extracts exhibited significant growth-inhibitory effects on PC-3 cells. Collectively, we established for the first time the antiproliferative effects of VAD on PC-3 cells, with an IC50 value of about 196.6 µg/mL. Further experiments, including cell morphology, lipid peroxidation and comet assays, and apoptosis analysis showed that VAD caused growth-inhibitory effects on PC-3 cells through the induction of cell growth arrest, DNA damage, apoptosis, and necrosis in vitro and may provide protection from oxidative stress diseases as a result of its high antioxidant content. These results provide useful data on the anticancer activities of VAD for prostate cancer and demonstrate the novel possibilities of this medicinal plant for developing prostate cancer therapies.

  9. Folic acid tagged nanoceria as a novel therapeutic agent in ovarian cancer

    Hijaz, Miriana; Das, Soumen; Mert, Ismail; Gupta, Ankur; Al-Wahab, Zaid; Tebbe, Calvin; Dar, Sajad; Chhina, Jasdeep; Giri, Shailendra; Munkarah, Adnan; Seal, Sudipta; Rattan, Ramandeep

    2016-01-01

    Nanomedicine is a very promising field and nanomedical drugs have recently been used as therapeutic agents against cancer. In a previous study, we showed that Nanoceria (NCe), nanoparticles of cerium oxide, significantly inhibited production of reactive oxygen species, cell migration and invasion of ovarian cancer cells in vitro, without affecting cell proliferation and significantly reduced tumor growth in an ovarian cancer xenograft nude model. Increased expression of folate receptor-α, an isoform of membrane-bound folate receptors, has been described in ovarian cancer. To enable NCe to specifically target ovarian cancer cells, we conjugated nanoceria to folic acid (NCe-FA). Our aim was to investigate the pre-clinical efficacy of NCe-FA alone and in combination with Cisplatin. Ovarian cancer cell lines were treated with NCe or NCe-FA. Cell viability was assessed by MTT and colony forming units. In vivo studies were carried in A2780 generated mouse xenografts treated with 0.1 mg/Kg NCe, 0.1 mg/Kg; NCe-FA and cisplatinum, 4 mg/Kg by intra-peritoneal injections. Tumor weights and burden scores were determined. Immunohistochemistry and toxicity assays were used to evaluate treatment effects. We show that folic acid conjugation of NCe increased the cellular NCe internalization and inhibited cell proliferation. Mice treated with NCe-FA had a lower tumor burden compared to NCe, without any vital organ toxicity. Combination of NCe-FA with cisplatinum decreased the tumor burden more significantly. Moreover, NCe-FA was also effective in reducing proliferation and angiogenesis in the xenograft mouse model. Thus, specific targeting of ovarian cancer cells by NCe-FA holds great potential as an effective therapeutic alone or in combination with standard chemotherapy. The online version of this article (doi:10.1186/s12885-016-2206-4) contains supplementary material, which is available to authorized users

  10. Self-Efficacy for Coping with Cancer Enhances the Effect of Reiki Treatments During the Pre-Surgery Phase of Breast Cancer Patients.

    Chirico, Andrea; D'Aiuto, Giuseppe; Penon, Antonella; Mallia, Luca; DE Laurentiis, Michelino; Lucidi, Fabio; Botti, Gerardo; Giordano, Antonio

    2017-07-01

    Self-efficacy for coping with cancer plays a critical role in influencing psychological cancer-related outcomes, some studies suggested its role in enhancing or reducing the effects of psychological interventions in cancer patients. Reiki has recently been included among the efficacious complementary therapeutic intervention for cancer patients. The present study evaluated the role of self-efficacy for coping with cancer as buffer of the Reiki treatment effects on cancer-related symptoms in a randomized controlled trial (intervention versus control group) of breast cancer patients (N=110) during the pre-surgery phase. Results showed that self-efficacy for coping with cancer can influence the effect of a Reiki treatment. Higher efficacious patients showed a more powerful effect of the Reiki intervention on both anxiety and mood than the low efficacious patients. From a practical perspective, the study provides insightful results for healthcare professionals. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  11. Factors Associated with Therapeutic Efficacy of Intravesical OnabotulinumtoxinA Injection for Overactive Bladder Syndrome.

    Sheng-Mou Hsiao

    Full Text Available To analyze the predictors of therapeutic efficacy after intravesical botulinum toxin A injection for overactive bladder syndrome (OAB refractory to antimuscarinic therapy.All consecutively OAB patients, who visited the urologic outpatient clinics of a medical center and refractory to antimuscarinic treatment, were prospectively enrolled. All enrolled patients received intravesical injection of 100 U onabotulinumtoxinA (Botox. The Global Response Assessment (GRA score ≥ 2 at 3 months after Botox injection was defined as a successful treatment, otherwise failed.Overall, 89 patients received intravesical injection. Eighty patients, including 42 men and 38 women, had received follow-up at 3 months. The overall success rate was 63.8%. The global response assessment, urgency severity score, urgency, urgency urinary incontinence and frequency episodes, and functional bladder capacity improved after treatment. However, post-void residual volume (PVR increased, and voiding efficiency (VE decreased after treatment. Female gender (odds ratio = 3.75 was the only independent factor associated with the success. Female gender (coefficient = 0.74, low baseline overactive bladder symptoms score (coefficient = -0.12 and the presence of OAB-wet (coefficient = 0.79 were independent factors associated with therapeutic efficacy (i.e., GRA score. VE (odds ratio = 0.062 was the only predictor for a large PVR at 3 months. The optimum cutoff value of VE was <87% with the area under the ROC curve being 0.64 (sensitivity = 63.8%, specificity = 57.1%.The therapeutic effects of Botox can persist till 6 months after treatment. Female gender, low overactive bladder symptoms score and OAB-wet are associated better therapeutic efficacy, and low baseline VE is associated with large PVR. These findings can serve as an initial guide or assist in consultation regarding the treatment of OAB patients with Botox injection.ClinicalTrials.gov NCT01657409.

  12. PPARγ as a Novel Therapeutic Target in Lung Cancer

    Aravind T. Reddy

    2016-01-01

    Full Text Available Lung cancer is the leading cause of cancer-related death, with more than half the patients having advanced-stage disease at the time of initial diagnosis and thus facing a poor prognosis. This dire situation poses a need for new approaches in prevention and treatment. Peroxisome proliferator-activated receptor γ (PPARγ is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. Its involvement in adipocyte differentiation and glucose and lipid homeostasis is well-recognized, but accumulating evidence now suggests that PPARγ may also function as a tumor suppressor, inhibiting development of primary tumors and metastases in lung cancer and other malignancies. Besides having prodifferentiation, antiproliferative, and proapoptotic effects, PPARγ agonists have been shown to prevent cancer cells from acquiring the migratory and invasive capabilities essential for successful metastasis. Angiogenesis and secretion of certain matrix metalloproteinases and extracellular matrix proteins within the tumor microenvironment are also regulated by PPARγ. This review of the current literature highlights the potential of PPARγ agonists as novel therapeutic modalities in lung cancer, either as monotherapy or in combination with standard cytotoxic chemotherapy.

  13. Rectal cancer and Fournier's gangrene - current knowledge and therapeutic options.

    Bruketa, Tomislav; Majerovic, Matea; Augustin, Goran

    2015-08-14

    Fournier's gangrene (FG) is a rapid progressive bacterial infection that involves the subcutaneous fascia and part of the deep fascia but spares the muscle in the scrotal, perianal and perineal region. The incidence has increased dramatically, while the reported incidence of rectal cancer-induced FG is unknown but is extremely low. Pathophysiology and clinical presentation of rectal cancer-induced FG per se does not differ from the other causes. Only rectal cancer-specific symptoms before presentation can lead to the diagnosis. The diagnosis of rectal cancer-induced FG should be excluded in every patient with blood on digital rectal examination, when urogenital and dermatological causes are excluded and when fever or sepsis of unknown origin is present with perianal symptomatology. Therapeutic options are more complex than for other forms of FG. First, the causative rectal tumor should be removed. The survival of patients with rectal cancer resection is reported as 100%, while with colostomy it is 80%. The preferred method of rectal resection has not been defined. Second, oncological treatment should be administered but the timing should be adjusted to the resolution of the FG and sometimes for the healing of plastic reconstructive procedures that are commonly needed for the reconstruction of large perineal, scrotal and lower abdominal wall defects.

  14. Dependence of therapeutic gain factor on stage of oral cancer

    Velmurugan, J.; Solomon, J.G.R.; Koteshwer Rao, K.; Supe, S.S.; Prasad, G.N.S.

    1998-01-01

    To achieve therapeutic gain, unconventional dose per fraction has been employed in radiotherapy, in addition to the conventional dose per fraction of 2 Gy. Dose fractionation factor (DFF) and therapeutic gain factor (TGF) have been utilised to test the efficiency of such unconventional fractionation schedules. In this study, isoeffective dose for 100% tumour regression and mucosal and skin reactions were estimated. CRE, TDF and ERD values for tumour and normal tissue reactions were evaluated. DEF and TGF values have been determined on the basis of dose, CRE, TDF and ERD, in order to understand the influence of these bioeffect models and stage of cancer on TGF associated with differing fractionation schedules. There was a noticeable difference in TGF values determined on the basis of four criteria, which is in agreement with radiobiological phenomenon, that tissues with different α/β values differ in their responsiveness. (author)

  15. Medical Therapies for Stricturing Crohn's Disease: Efficacy and Cross-Sectional Imaging Predictors of Therapeutic Failure.

    Campos, Cécile; Perrey, Antoine; Lambert, Céline; Pereira, Bruno; Goutte, Marion; Dubois, Anne; Goutorbe, Felix; Dapoigny, Michel; Bommelaer, Gilles; Hordonneau, Constance; Buisson, Anthony

    2017-06-01

    Medical therapy efficacy remains controversial in stricturing Crohn's disease. Cross-sectional imaging, especially magnetic resonance imaging, has been suggested as very helpful to guide therapeutic decision making. To assess efficacy and predictors of therapeutic failure in patients receiving medical treatments for stricturing Crohn's disease. In this retrospective study, therapeutic failure was defined as symptomatic stricture leading to surgical or endoscopic therapeutics, hospitalization, treatment discontinuation or additional therapy and short-term clinical response as clinical improvement assessed by two physicians. The 55 cross-sectional imaging examinations (33 magnetic resonance imaging and 22 CT scan) before starting medical therapy were analyzed independently by two radiologists. Results were expressed as hazard ratio (HR) or odds ratio (OR) with 95% confidence intervals (95% CI). Among 84 patients, therapeutic failure rate within 60 months was 66.6%. In multivariate analysis, Crohn's disease diagnosis after 40 years old (HR 3.9, 95% CI [1.37-11.2], p = 0.011), small stricture luminal diameter (HR 1.34, 95% CI [1.01-1.80], p = 0.046), increased stricture wall thickness (HR 1.23, 95% CI [1.04-1.46], p = 0.013) and fistula with abscess (HR 5.63, 95% CI [1.64-19.35], p = 0.006) were associated with therapeutic failure, while anti-TNF combotherapy (HR 0.17, 95% CI [0.40-0.71], p = 0.015) prevented it. Considering 108 therapeutic sequences, the short-term clinical response rate was 65.7%. In multivariate analysis, male gender (OR 0.15, 95% CI [0.03-0.64], p = 0.011), fistula with abscess (OR 0.09, 95% CI [0.01-0.77], p = 0.028) and comb sign (OR 0.23, 95% CI [0.005-0.97], p = 0.047) were associated with short-term clinical failure. Anti-TNF combotherapy seemed to prevent therapeutic failure, and cross-sectional imaging should be systematically performed to help medical management in stricturing Crohn's disease.

  16. Predictive markers of efficacy for an angiopoietin-2 targeting therapeutic in xenograft models.

    Gallen Triana-Baltzer

    Full Text Available The clinical efficacy of anti-angiogenic therapies has been difficult to predict, and biomarkers that can predict responsiveness are sorely needed in this era of personalized medicine. CVX-060 is an angiopoietin-2 (Ang2 targeting therapeutic, consisting of two peptides that bind Ang2 with high affinity and specificity, covalently fused to a scaffold antibody. In order to optimize the use of this compound in the clinic the construction of a predictive model is described, based on the efficacy of CVX-060 in 13 cell line and 2 patient-derived xenograft models. Pretreatment size tumors from each of the models were profiled for the levels of 27 protein markers of angiogenesis, SNP haplotype in 5 angiogenesis genes, and somatic mutation status for 11 genes implicated in tumor growth and/or vascularization. CVX-060 efficacy was determined as tumor growth inhibition (TGI% at termination of each study. A predictive statistical model was constructed based on the correlation of these efficacy data with the marker profiles, and the model was subsequently tested by prospective analysis in 11 additional models. The results reveal a range of CVX-060 efficacy in xenograft models of diverse tissue types (0-64% TGI, median = 27% and define a subset of 3 proteins (Ang1, EGF, Emmprin, the levels of which may be predictive of TGI by Ang2 blockade. The direction of the associations is such that better efficacy correlates with high levels of target and low levels of compensatory/antagonizing molecules. This effort has revealed a set of candidate predictive markers for CVX-060 efficacy that will be further evaluated in ongoing clinical trials.

  17. Canonical and non-canonical barriers facing antimiR cancer therapeutics.

    Cheng, Christopher J; Saltzman, W Mark; Slack, Frank J

    2013-01-01

    Once considered genetic "oddities", microRNAs (miRNAs) are now recognized as key epigenetic regulators of numerous biological processes, including some with a causal link to the pathogenesis, maintenance, and treatment of cancer. The crux of small RNA-based therapeutics lies in the antagonism of potent cellular targets; the main shortcoming of the field in general, lies in ineffective delivery. Inhibition of oncogenic miRNAs is a relatively nascent therapeutic concept, but as with predecessor RNA-based therapies, success hinges on delivery efficacy. This review will describes the canonical (e.g. pharmacokinetics and clearance, cellular uptake, endosome escape, etc.) and non-canonical (e.g. spatial localization and accessibility of miRNA, technical limitations of miRNA inhibition, off-target impacts, etc.) challenges to the delivery of antisense-based anti-miRNA therapeutics (i.e. antimiRs) for the treatment of cancer. Emphasis will be placed on how the current leading antimiR platforms-ranging from naked chemically modified oligonucleotides to nanoscale delivery vehicles-are affected by and overcome these barriers. The perplexity of antimiR delivery presents both engineering and biological hurdles that must be overcome in order to capitalize on the extensive pharmacological benefits of antagonizing tumor-associated miRNAs.

  18. Solid lipid nanoparticle suspension enhanced the therapeutic efficacy of praziquantel against tapeworm

    Xie S

    2011-10-01

    Full Text Available Shuyu Xie1,*, Baoliang Pan1,*, Baoxin Shi2, Zhuangzhi Zhang2, Xu Zhang2, Ming Wang1, Wenzhong Zhou11Department of Preventive Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China; 2Veterinary Research Institute, Xinjiang Academy of Animal Science, Xinjiang, People’s Republic of China *These authors contributed equally to this study Abstract: Hydatid disease caused by tapeworm is an increasing public health and socioeconomic concern. In order to enhance the therapeutic efficacy of praziquantel (PZQ against tapeworm, PZQ-loaded hydrogenated castor oil solid lipid nanoparticle (PZQ-HCO-SLN suspension was prepared by a hot homogenization and ultrasonication method. The stability of the suspension at 4°C and room temperature was evaluated by the physicochemical characteristics of the nanoparticles and in-vitro release pattern of the suspension. Pharmacokinetics was studied after subcutaneous administration of the suspension in dogs. The therapeutic effect of the novel formulation was evaluated in dogs naturally infected with Echinococcus granulosus. The results showed that the drug recovery of the suspension was 97.59% ± 7.56%. Nanoparticle diameter, polydispersivity index, and zeta potential were 263.00 ± 11.15 nm, 0.34 ± 0.06, and -11.57 ± 1.12 mV, respectively and showed no significant changes after 4 months of storage at both 4°C and room temperature. The stored suspensions displayed similar in-vitro release patterns as that of the newly prepared one. SLNs increased the bioavailability of PZQ 5.67-fold and extended the mean residence time of the drug from 56.71 to 280.38 hours. Single subcutaneous administration of PZQ-HCO-SLN suspension obtained enhanced therapeutic efficacy against tapeworm in infected dogs. At the dose of 5 mg/kg, the stool-ova reduction and negative conversion rates and tapeworm removal rate of the suspension were 100%, while the native PZQ were 91

  19. Cancer-specific self-efficacy and psychosocial and functional adaptation to early stage breast cancer.

    Manne, Sharon L; Ostroff, Jamie S; Norton, Tina R; Fox, Kevin; Grana, Generosa; Goldstein, Lori

    2006-04-01

    Although self-efficacy is considered a key psychological resource in adapting to chronic physical illness, this construct has received less attention among individuals coping with cancer. To examine changes in cancer self-efficacy over time among women with early stage breast cancer and associations between task-specific domains of self-efficacy and specific psychological, relationship, and functional outcomes. Ninety-five women diagnosed with early stage breast cancer completed surveys postsurgery and 1 year later. Cancer-related self-efficacy was relatively stable over 1 year, with only 2 domains of efficacy-(a) Activity Management and (b) Self-Satisfaction-evidencing significant increases over the 1-year time period. Cross-sectional findings were relatively consistent with predictions and suggested that specific domains of self-efficacy were more strongly related to relevant domains of adaptation. Longitudinal findings were not as consistent with the domain-specificity hypothesis but did suggest several predictive associations between self-efficacy and outcomes. Personal Management self-efficacy was associated with higher relationship satisfaction, higher Communication Self-Efficacy was associated with less functional impairment, and higher Affective Management self-efficacy was associated with higher self-esteem 1 year later. Specific domains of cancer-related self-efficacy are most closely related to relevant areas of adaptation when considered cross-sectionally, but further study is needed to clarify the nature of these relationships over time.

  20. Therapeutic efficacy and mechanism of action of ethamsylate, a long-standing hemostatic agent.

    Garay, Ricardo P; Chiavaroli, Carlo; Hannaert, Patrick

    2006-01-01

    Ethamsylate (2,5-dihydroxy-benzene-sulfonate diethylammonium salt) is a synthetic hemostatic drug indicated in cases of capillary bleeding. This review covers more than 40 years of intensive clinical and fundamental research with ethamsylate. First, we summarize the large medical literature concerning its clinical efficacy. Of these, well-controlled clinical trials clearly showed the therapeutic efficacy of ethamsylate in dysfunctional uterine bleeding, with the magnitude of blood-loss reduction being directly proportional to the severity of the menorrhagia. Other well-controlled clinical trials showed therapeutic efficacy of ethamsylate in periventricular hemorrhage in very low birth weight babies and surgical or postsurgical capillary bleeding. Second, we review the numerous investigations performed to elucidate the mechanism of action of ethamsylate. Ethamsylate acts on the first step of hemostasis by improving platelet adhesiveness and restoring capillary resistance. Recent studies showed that ethamsylate promotes P-selectin-dependent, platelet adhesive mechanisms. Finally, we compare ethamsylate with other recent hemostatic agents. It is suggested that the place of ethamsylate as a hemostatic agent is that of a mild but well-tolerated drug, particularly useful in dysfunctional uterine bleeding when contraception is not needed.

  1. Immunogenomic Classification of Colorectal Cancer and Therapeutic Implications

    Jessica Roelands

    2017-10-01

    Full Text Available The immune system has a substantial effect on colorectal cancer (CRC progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies is influenced by the immune system. The molecular characterization of colorectal cancer (CRC has led to the identification of favorable and unfavorable immunological attributes linked to clinical outcome. With the definition of consensus molecular subtypes (CMSs based on transcriptomic profiles, multiple characteristics have been proposed to be responsible for the development of the tumor immune microenvironment and corresponding mechanisms of immune escape. In this review, a detailed description of proposed immune phenotypes as well as their interaction with different therapeutic modalities will be provided. Finally, possible strategies to shift the CRC immune phenotype towards a reactive, anti-tumor orientation are proposed per CMS.

  2. Harnessing the fruits of nature for the development of multi-targeted cancer therapeutics.

    Sarkar, Fazlul H; Li, Yiwei

    2009-11-01

    Cancer cells exhibit deregulation in multiple cellular signaling pathways. Therefore, treatments using specific agents that target only one pathway usually fail in cancer therapy. The combination treatments using chemotherapeutic agents with distinct molecular mechanisms are considered more promising for higher efficacy; however, using multiple agents contributes to added toxicity. Emerging evidence has shown that some "natural products" such as isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin among many others, have growth inhibitory and apoptosis inducing effects on human and animal cancer cells mediated by targeting multiple cellular signaling pathways in vitro without causing unwanted toxicity in normal cells. Therefore, these non-toxic "natural products" from natural resources could be useful in combination with conventional chemotherapeutic agents for the treatment of human malignancies with lower toxicity and higher efficacy. In fact, recently increasing evidence from pre-clinical in vivo studies and clinical trials have shown some success in support of the use of rational design of multi-targeted therapies for the treatment of cancers using conventional chemotherapeutic agents in combination with "natural products". These studies have provided promising results and further opened-up newer avenues for cancer therapy. In this review article, we have succinctly summarized the known effects of "natural products" especially by focusing on isoflavones, indole-3-carbinol (I3C) and its in vivo dimeric product 3,3'-diindolylmethane (DIM), and curcumin, and provided a comprehensive view on the molecular mechanisms underlying the principle of cancer therapy using combination of "natural products" with conventional therapeutics.

  3. Emerging therapeutic potential of graviola and its constituents in cancers.

    Qazi, Asif Khurshid; Siddiqui, Jawed A; Jahan, Rahat; Chaudhary, Sanjib; Walker, Larry A; Sayed, Zafar; Jones, Dwight T; Batra, Surinder K; Macha, Muzafar A

    2018-04-05

    Cancer remains a leading cause of death in the USA and around the world. Although the current synthetic inhibitors used in targeted therapies have improved patient prognosis, toxicity and development of resistance to these agents remain a challenge. Plant-derived natural products and their derivatives have historically been used to treat various diseases, including cancer. Several leading chemotherapeutic agents are directly or indirectly based on botanical natural products. Beyond these important drugs, however, a number of crude herbal or botanical preparations have also shown promising utility for cancer and other disorders. One such natural resource is derived from certain plants of the family Annonaceae, which are widely distributed in tropical and subtropical regions. Among the best known of these is Annona muricata, also known as soursop, graviola or guanabana. Extracts from the fruit, bark, seeds, roots and leaves of graviola, along with several other Annonaceous species, have been extensively investigated for anticancer, anti-inflammatory and antioxidant properties. Phytochemical studies have identified the acetogenins, a class of bioactive polyketide-derived constituents, from the extracts of Annonaceous species, and dozens of these compounds are present in different parts of graviola. This review summarizes current literature on the therapeutic potential and molecular mechanism of these constituents from A.muricata against cancer and many non-malignant diseases. Based on available data, there is good evidence that these long-used plants could have both chemopreventive and therapeutic potential. Appropriate attention to safety studies will be important to assess their effectiveness on various diseases caused or promoted by inflammation.

  4. Current therapeutic strategies of anti-HER2 treatment in advanced breast cancer patients

    Joanna Huszno

    2016-03-01

    Full Text Available The HER2/neu ( ERBB2 oncogene is amplified and/or overexpressed in approximately 20% of breast cancers, and is a strong prognostic factor for relapse and poor overall survival, particularly in node-positive patients. It is also an important predictor for response to trastuzumab, which has established efficacy against breast cancer with overexpression or amplification of the HER2 oncogene. Treatment with the anti-HER2 humanized monoclonal antibody – trastuzumab significantly improves progression-free and overall survival among patients with HER2-positive breast cancer. However, in most patients with HER2-positive metastatic breast cancer, the disease progresses occurred, what cause the need for new targeted therapies for advanced disease. In clinical trials, there are tested new drugs to improve the results of treatment for this group of patients. This paper presents new drugs introduced into clinical practice for treatment of advanced breast cancer, whose molecular target are receptors of the HER2 family. In addition, new therapeutic strategies and drugs that are currently in clinical researches are discussed.

  5. Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances

    Lech, Gustaw; Słotwiński, Robert; Słodkowski, Maciej; Krasnodębski, Ireneusz Wojciech

    2016-01-01

    Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments. PMID:26855534

  6. Perspective on Cancer Therapeutics Utilizing Analysis of Circulating Tumor Cells

    Keun-Yeong Jeong

    2018-04-01

    Full Text Available Various methods are available for cancer screening, and the methods are performed depending on the origin site of cancer. Among these methods, biopsy followed by medical imaging is the most common. After cancer progression is determined, an optimal treatment—such as surgery, chemotherapy, and/or radiation therapy—is selected. A new assay has been developed that detects circulating tumor cells (CTCs. Tracking changes in CTCs may reveal important tumoral sensitivity information or resistance patterns to specific regimens and prompt changes in therapy on a personalized basis. Characterization of CTCs at the DNA, RNA, and protein levels is important for gaining insight for clinical applications. A small number of CTCs can be analyzed to obtain genome information such as the progression of cancer including metastasis, even in a single cluster. Although many clinical studies, particularly CTC enumeration and detection of specific oncogene expression, have increased the success rate of diagnosis and predicting prognosis, there is no consensus regarding the technical approaches and various aspects of the methodology, making it difficult to standardize optimal methods for CTC analysis. However, ongoing technological advances are currently being achieved and large-scale clinical studies are being conducted. Applying CTC analysis in the clinic would be very useful for advancing diagnosis, prognosis prediction, and therapeutics.

  7. Colorectal cancer tumour markers and biomarkers: Recent therapeutic advances.

    Lech, Gustaw; Słotwiński, Robert; Słodkowski, Maciej; Krasnodębski, Ireneusz Wojciech

    2016-02-07

    Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.

  8. New class of monoclonal antibodies against severe influenza: prophylactic and therapeutic efficacy in ferrets.

    Robert H E Friesen

    2010-02-01

    Full Text Available The urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian H5N1 viruses, and indeed the evolving swine-origin H1N1 influenza pandemic. A recently discovered class of human monoclonal antibodies with the ability to neutralize a broad spectrum of influenza viruses (including H1, H2, H5, H6 and H9 subtypes has the potential to prevent and treat influenza in humans. Here we report the latest efficacy data for a representative antibody of this novel class.We evaluated the prophylactic and therapeutic efficacy of the human monoclonal antibody CR6261 against lethal challenge with the highly pathogenic avian H5N1 virus in ferrets, the optimal model of human influenza infection. Survival rates, clinically relevant disease signs such as changes in body weight and temperature, virus replication in lungs and upper respiratory tract, as well as macro- and microscopic pathology were investigated. Prophylactic administration of 30 and 10 mg/kg CR6261 prior to viral challenge completely prevented mortality, weight loss and reduced the amount of infectious virus in the lungs by more than 99.9%, abolished shedding of virus in pharyngeal secretions and largely prevented H5N1-induced lung pathology. When administered therapeutically 1 day after challenge, 30 mg/kg CR6261 prevented death in all animals and blunted disease, as evidenced by decreased weight loss and temperature rise, reduced lung viral loads and shedding, and less lung damage.These data demonstrate the prophylactic and therapeutic efficacy of this new class of human monoclonal antibodies in a highly stringent and clinically relevant animal model of influenza and justify clinical development of this approach as intervention for both seasonal and pandemic influenza.

  9. Shangri-La revisited: an exploration of therapeutic efficacy among intentional communities.

    Francis, T L

    1992-04-01

    Field and literature surveys were employed to explore the therapeutic efficacy of a reportedly common set of social structures found among some Intentional Communities (ICs). Substance misuse served as an example of social problems plausibly related to the examined social structures, which included: (1) meditative practices, (2) progressive education, (3) holistic health practices, (4) nutritional diet, (5) open policy making, (6) equally or equitably shared resources, (7) integrating membership processes, and (8) environmental concern. The field survey identified and examined 11 such ICs, and the literature exploration concerning the structures found that they appear to be therapeutic. Future research should focus on refining the study of structural and antecedent variables and on finding relationships between these variables to communities in the larger society.

  10. Polymer Therapeutics: Biomarkers and New Approaches for Personalized Cancer Treatment.

    Atkinson, Stuart P; Andreu, Zoraida; Vicent, María J

    2018-01-23

    Polymer therapeutics (PTs) provides a potentially exciting approach for the treatment of many diseases by enhancing aqueous solubility and altering drug pharmacokinetics at both the whole organism and subcellular level leading to improved therapeutic outcomes. However, the failure of many polymer-drug conjugates in clinical trials suggests that we may need to stratify patients in order to match each patient to the right PT. In this concise review, we hope to assess potential PT-specific biomarkers for cancer treatment, with a focus on new studies, detection methods, new models and the opportunities this knowledge will bring for the development of novel PT-based anti-cancer strategies. We discuss the various "hurdles" that a given PT faces on its passage from the syringe to the tumor (and beyond), including the passage through the bloodstream, tumor targeting, tumor uptake and the intracellular release of the active agent. However, we also discuss other relevant concepts and new considerations in the field, which we hope will provide new insight into the possible applications of PT-related biomarkers.

  11. Triple negative breast cancer: new therapeutic approaches and BRCA status.

    Guney Eskiler, Gamze; Cecener, Gulsah; Egeli, Unal; Tunca, Berrin

    2018-05-01

    Treatment of triple negative breast cancer (TNBC) is a clinically challenging problem due to intriguing clinical and pathologic features of TNBC and natural or induced resistance to existing therapies. However, a great understanding of features of TNBC particularly associated with BRCA mutations has led to the development of different therapeutic approaches. Besides, identification of TNBC subtypes contribute to investigation of the underlying molecular differences and development of new strategies for the treatment of TNBC patients. In this review, we discussed the definition and characteristic properties of TNBC. We summarized an up-to-date description of the reported clinical trials of novel targeted strategies especially PARP inhibitors (PARPi) due to novel and highly potent for the treatment of TNBC. Additionally, we reviewed published studies which investigated the prevalence and types of BRCA1/2 mutation in breast cancer patients to assess and draw attention of association of BRCA status with TNBC. Consequently, the definition subtype of TNBC has important predictive value for the development of new therapeutic agents in the treatment of TNBC. Additionally, the incidence and types of mutations in BRCA-related pathways may be affected by ethnic origin and contribute to the risk of developing TNBC. © 2018 APMIS. Published by John Wiley & Sons Ltd.

  12. The mid-to-long term therapeutic efficacy of Graves' disease after interventional embolization

    Li Weiduo; Yang Jianyong; Zhuang Wenquan; Chen Wei; Li Heping

    2002-01-01

    Objective: To explore the mid-to-long term therapeutic efficacy of Graves' disease after interventional embolization. Methods: Twenty-five patients of Graves' disease treated with interventional embolization were followed up for 24-57 months. T 3 and T 4 were monitored at pre-operation, six months, 12 months, 2, 3 and 4 years after operation, respectively. Other references included pulse, thyroid size, and vessel's murmur. Results: Twenty-two patients completely relieved from the hyperthyroidism during the follow-up. Only one patient suffered from recurrence. Other two patients were still on maintaining dosage of antithyroid drug therapy. No hypothyroidism or hypoparathyroidism was found during this term. Conclusion: Mid-to-long term follow-up showed satisfactory efficacy of interventional therapy, offering another alternative for treatment of refractory Graves' disease

  13. Adverse events and therapeutic efficacy associated with TACE for hepatocellular carcinoma with a miriplatin-lipiodol suspension in comparison with a cisplatin-lipiodol suspension

    Araki, Takuji; Okada, Taiki; Kimura, Kazufumi; Sawada, Eiichi; Sano, Katushiro; Araki, Tsutomu

    2012-01-01

    The aim of this study was to evaluate the short-term adverse events and therapeutic efficacy of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) with a miriplatin-lipiodol suspension in comparison with a cisplatin-lipiodol suspension. Of patients who underwent TACE for unresectable HCCs in 2009 and 2010, twenty-nine and twenty-seven patients underwent TACE using cisplatin-lipiodol suspension (C-LS) and miriplatin-lipiodol suspension (M-LS), respectively. Adverse events of fever, pain, nausea, anorexia, elevation of aspartate aminotransferase (AST), total bilirubin, creatinine and a decrease in platelet count were evaluated by the National Cancer Institute Common Toxicity Criteria Ver.4. to compare the C-LS and M-LS groups. The short-term therapeutic efficacy of both groups was evaluated by the treatment effect (TE) on the CT images three months after TACE according to the General Rules for the Clinical and Pathological Study of Primary Liver Cancer (the 5th edition, Revised Version). With regard to the adverse events, the M-LS group had significantly less fever and anorexia than the C-LS group. No critical adverse events were observed in either group. The therapeutic efficacy was not significantly different between the groups. TACE with M-LS had fewer adverse events than TACE with C-LS, but neither TACE led to any critical adverse events. The short-term therapeutic efficacy of TACE with M-LS was equivalent to that of TACE with C-LS. (author)

  14. Mechanisms of therapeutic resistance in cancer (stem cells with emphasis on thyroid cancer cells.

    Sabine eHombach-Klonisch

    2014-03-01

    Full Text Available Tissue invasion, metastasis and therapeutic resistance to anti-cancer treatments are common and main causes of death in cancer patients. Tumor cells mount complex and still poorly understood molecular defense mechanisms to counteract and evade oxygen deprivation, nutritional restrictions as well as radio- and chemotherapeutic treatment regimens aimed at destabilizing their genomes and important cellular processes. In thyroid cancer, as in other tumors, such defense strategies include the reactivation in cancer cells of early developmental programs normally active exclusively in stem cells, the stimulation of cancer stem-like cells resident within the tumor tissue and the recruitment of bone marrow-derived progenitors into the tumor (Thomas et al., 2008;Klonisch et al., 2009;Derwahl, 2011. Metastasis and therapeutic resistance in cancer (stem cells involves the epithelial-to-mesenchymal transition- (EMT- mediated enhancement in cellular plasticity, which includes coordinated dynamic biochemical and nuclear changes (Ahmed et al., 2010. The purpose of the present review is to provide an overview of the role of DNA repair mechanisms contributing to therapeutic resistance in thyroid cancer and highlight the emerging roles of autophagy and damage associated molecular pattern (DAMP responses in EMT and chemoresistance in tumor cells. Finally, we use the stem cell factor and nucleoprotein High Mobility Group A2 (HMGA2 as an example to demonstrate how factors intended to protect stem cells are wielded by cancer (stem cells to gain increased transformative cell plasticity which enhances metastasis, therapeutic resistance and cell survival. Wherever possible, we have included information on these cellular processes and associated factors as they relate to thyroid cancer cells.

  15. Impact of diffusion barriers to small cytotoxic molecules on the efficacy of immunotherapy in breast cancer.

    Hiranmoy Das

    Full Text Available Molecular-focused cancer therapies, e.g., molecularly targeted therapy and immunotherapy, so far demonstrate only limited efficacy in cancer patients. We hypothesize that underestimating the role of biophysical factors that impact the delivery of drugs or cytotoxic cells to the target sites (for associated preferential cytotoxicity or cell signaling modulation may be responsible for the poor clinical outcome. Therefore, instead of focusing exclusively on the investigation of molecular mechanisms in cancer cells, convection-diffusion of cytotoxic molecules and migration of cancer-killing cells within tumor tissue should be taken into account to improve therapeutic effectiveness. To test this hypothesis, we have developed a mathematical model of the interstitial diffusion and uptake of small cytotoxic molecules secreted by T-cells, which is capable of predicting breast cancer growth inhibition as measured both in vitro and in vivo. Our analysis shows that diffusion barriers of cytotoxic molecules conspire with γδ T-cell scarcity in tissue to limit the inhibitory effects of γδ T-cells on cancer cells. This may increase the necessary ratios of γδ T-cells to cancer cells within tissue to unrealistic values for having an intended therapeutic effect, and decrease the effectiveness of the immunotherapeutic treatment.

  16. Targeting lipid metabolism of cancer cells: A promising therapeutic strategy for cancer.

    Liu, Qiuping; Luo, Qing; Halim, Alexander; Song, Guanbin

    2017-08-10

    One of the most important metabolic hallmarks of cancer cells is deregulation of lipid metabolism. In addition, enhancing de novo fatty acid (FA) synthesis, increasing lipid uptake and lipolysis have also been considered as means of FA acquisition in cancer cells. FAs are involved in various aspects of tumourigenesis and tumour progression. Therefore, targeting lipid metabolism is a promising therapeutic strategy for human cancer. Recent studies have shown that reprogramming lipid metabolism plays important roles in providing energy, macromolecules for membrane synthesis, and lipid signals during cancer progression. Moreover, accumulation of lipid droplets in cancer cells acts as a pivotal adaptive response to harmful conditions. Here, we provide a brief review of the crucial roles of FA metabolism in cancer development, and place emphasis on FA origin, utilization and storage in cancer cells. Understanding the regulation of lipid metabolism in cancer cells has important implications for exploring a new therapeutic strategy for management and treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Efficacy of reovirus against breast cancer

    Zhu Jingzhi; Chen Jue; Dong Shengxiang; Yan Weili; Wu Zhiyong

    2011-01-01

    To investigate the role of oncolytic reovirus in breast cancer, a tumor xenograft model of NOD/SCID mice was established using a biopsy sample of a primary infiltrating ductal carcinoma obtained from a breast cancer patient. The result of HE and TUNEL was analyzed after injecting the reovirus peritoneally for 3 days. The results showed that estrogen supplementation was required to establish appropriate human breast cancer xenograft model of NOD/SCID mice. 29.6% of these transplanted tumors grew with supplementation of Estrogen. Otherwise none grew (P<0.01). ER of the xenograft model was positive.After treatment with reovirus for 3 days, breast cancer cells were disrupted and disappeared which induced tissue looseness. The rate of apoptosis increased double than before. The biological characteristics of tumor xenograft model confirm with the primary breast cancer. The oncolytic reovirus can kill breast cancer in short time. (authors)

  18. Target-oriented mechanisms of novel herbal therapeutics in the chemotherapy of gastrointestinal cancer and inflammation.

    Ko, Joshua K; Auyeung, Kathy K

    2013-01-01

    A prominent group of effective cancer chemopreventive drugs has been derived from natural products having low toxicity while possessing apparent benefit in the disease process. It is plausible that there are multiple target molecules critical to cancer cell survival. Herbal terpenoids have demonstrated excellent target-specific anti-neoplastic functions by suppression of cell proliferation and induction of apoptosis. Transcriptional molecules in the NF-κB, MEK/ERK and PI3K/Akt/mTOR pathways are important molecular targets of chemotherapy that play distinctive roles in modulating the apoptosis cascades. It is recently suggested that NSAID-activated gene (NAG-1), a novel proapoptotic protein, is the upstream anti-carcinogenic target of NSAIDs, PPAR ligands and herbal chemotherapeutic agents that triggers some of the events mentioned above. Besides, angiogenesis, oxidative stress as well as inflammation are important factors that contribute to the development and metastasis of cancer, which could be actively modulated by novel agents of plant origin. The aim of the present review is to discuss and summarize the contemporary use of herbal therapeutics and phytochemicals in the treatment of human cancers, in particular that of the colon. The major events and signaling pathways in the carcinogenesis process being potentially modulated by natural products and novel herbal compounds will be evaluated, with emphasis on some terpenoids. Advances in eliciting the precise cellular and molecular mechanisms during the anti-tumorigenic process of novel herbal therapeutics will be of imperative clinical significance to increase the efficacy and reduce prominent adverse drug effects in cancer patients through target-specific therapy.

  19. [Prostate cancer microenvironment: Its structure, functions and therapeutic applications].

    Lorion, R; Bladou, F; Spatz, A; van Kempen, L; Irani, J

    2016-06-01

    In the field of prostate cancer there is a growing tendency for more and more studies to emphasise the predominant role of the zone situated between the tumour and the host: the tumour microenvironment. The aim of this article is to describe the structure and the functions of the prostate cancer microenvironment as well as the principal treatments that are being applied to it. PubMed and ScienceDirect databases have been interrogated using the association of keywords "tumour microenvironment" and "neoplasm therapy" along with "microenvironnement tumoral" and "traitements". Of the 593 articles initially found, 50 were finally included. The tumour microenvironment principally includes host elements that are diverted from their primary functions and encourage the development of the tumour. In it we find immunity cells, support tissue as well as vascular and lymphatic neovascularization. Highlighting the major role played by this microenvironment has led to the development of specific treatments, notably antiangiogenic therapy and immunotherapy. The tumour microenvironment, the tumour and the host influence themselves mutually and create a variable situation over time. Improvement of the knowledge of the prostate cancer microenvironment gradually enables us to pass from an approach centred on the tumour to a broader approach to the whole tumoral ecosystem. This enabled the emergence of new treatments whose place in the therapeutic arsenal still need to be found. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  20. Cancer-associated fibroblasts as target and tool in cancer therapeutics and diagnostics.

    De Vlieghere, Elly; Verset, Laurine; Demetter, Pieter; Bracke, Marc; De Wever, Olivier

    2015-10-01

    Cancer-associated fibroblasts (CAFs) are drivers of tumour progression and are considered as a target and a tool in cancer diagnostic and therapeutic applications. An increased abundance of CAFs or CAF signatures are recognized as a bad prognostic marker in several cancer types. Tumour-environment biomimetics strongly improve our understanding of the communication between CAFs, cancer cells and other host cells. Several experimental drugs targeting CAFs are in clinical trials for multiple tumour entities; alternatively, CAFs can be exploited as a tool to characterize the functionality of circulating tumour cells or to capture them as a tool to prevent metastasis. The continuous interaction between tissue engineers, biomaterial experts and cancer researchers creates the possibility to biomimic the tumour-environment and provides new opportunities in cancer diagnostics and management.

  1. Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins

    Alison Smith

    2016-01-01

    Full Text Available Biologics have emerged as a powerful and diverse class of molecular and cell-based therapies that are capable of replacing enzymes, editing genomes, targeting tumors, and more. As this complex array of tools arises a distinct set of challenges is rarely encountered in the development of small molecule therapies. Biotherapeutics tend to be big, bulky, polar molecules comprised of protein and/or nucleic acids. Compared to their small molecule counterparts, they are fragile, labile, and heterogeneous. Their biodistribution is often limited by hydrophobic barriers which often restrict their administration to either intravenous or subcutaneous entry routes. Additionally, their potential for immunogenicity has proven to be a challenge to developing safe and reliably efficacious drugs. Our discussion will emphasize immunogenicity in the context of therapeutic proteins, a well-known class of biologics. We set out to describe what is known and unknown about the mechanisms underlying the interplay between antigenicity and immune response and their effect on the safety, efficacy, pharmacokinetics, and pharmacodynamics of these therapeutic agents.

  2. Therapeutic orientations, professional efficacy, and burnout among substance abuse social workers in Israel.

    Tartakovsky, Eugene; Kovardinsky, Slava

    2013-07-01

    This study investigates the therapeutic orientations of substance abuse social workers and the relationship between these orientations and burnout. Ninety-two social workers who provided outpatient treatment to people suffering from substance-related disorders in Israel participated in the study. The results obtained demonstrated that the substance abuse social workers adhere more to the psychodynamic and ecosystemic therapeutic orientations than to the cognitive-behavioral orientation. A greater adherence to the cognitive-behavioral orientation was associated with a higher sense of professional efficacy; a greater adherence to the psychodynamic orientation was associated with a higher level of exhaustion; and greater adherence to the ecosystemic orientation was associated with lower levels of exhaustion and cynicism. Female social workers reported lower levels of exhaustion and cynicism. The cognitive-behavioral orientation mediated the connection between the social workers' experience in the field of substance abuse and two dimensions of burnout-exhaustion and professional efficacy. Significance of the findings for improving the well-being of substance abuse social workers and for the advancement of psychosocial services is discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. The Integrin-Regulated Kinase PYK-2: A Therapeutic Target for Prostate Cancer

    Edlund, Magnus

    2001-01-01

    ...) . A number of promising therapeutic targets for androgen-independent and metastatic prostate cancers are contained within the signaling cascades downstream of the ECM-binding Integrin molecules...

  4. Tumor Radiation Therapy Creates Therapeutic Vaccine Responses to the Colorectal Cancer Antigen GUCY2C

    Witek, Matthew [Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Blomain, Erik S.; Magee, Michael S.; Xiang, Bo; Waldman, Scott A. [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Snook, Adam E., E-mail: adam.snook@jefferson.edu [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)

    2014-04-01

    Purpose: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. Methods and Materials: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses were assessed by tumor size and incidence. Results: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P<.05), tumor eradication was maximized (P<.01), and tumor volumes were minimized (P<.001) in mice whose tumors were irradiated before, compared with after, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. The antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT showed long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells. Conclusions: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance

  5. Dana-Farber Cancer Institute: Identification of Therapeutic Targets in KRAS Driven Lung Cancer | Office of Cancer Genomics

    The CTD2 Center at Dana Farber Cancer Institute focuses on the use of high-throughput genetic and bioinformatic approaches to identify and credential oncogenes and co-dependencies in cancers. This Center aims to provide the cancer research community with information that will facilitate the prioritization of targets based on both genomic and functional evidence, inform the most appropriate genetic context for downstream mechanistic and validation studies, and enable the translation of this information into therapeutics and diagnostics.

  6. Multiple roles and therapeutic implications of Akt signaling in cancer

    Emiliano Calvo

    2009-06-01

    Full Text Available Emiliano Calvo1, Victoria Bolós2, Enrique Grande21Centro Integral Oncológico Clara Campal (CiOCC, Madrid. Spain; 2Pfizer Oncology, Alcobendas-Madrid, SpainAbstract: The prominence of the PI3K-Akt signaling pathway in several tumors indicates a relationship with tumor grade and proliferation. Critical cellular processes are driven through this pathway. More detailed knowledge of the pathogenesis of tumors would enable us to design targeted drugs to block both membrane tyrosine kinase receptors and the intracellular kinases involved in the transmission of the signal. The newly approved molecular inhibitors sunitinib (an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and other tyrosine kinase receptors, sorafenib (a serine–threonine kinase inhibitor that acts against B-Raf and temsirolimus (an mTOR inhibitor shown clinical activity in advanced kidney cancer. Chronic myeloid leukemia has changed its natural history thanks to imatinib and dasatinib, both of which inhibit the intracellular bcr/abl protein derived from the alteration in the Philadelphia chromosome. Intracellular pathways are still important in cancer development and their blockade directly affects outcome. Cross-talk has been observed but is not well understood. Vertical and horizontal pathway blockade are promising anticancer strategies. Indeed, preclinical and early clinical data suggest that combining superficial and intracellular blocking agents can synergize and leverage single-agent activity. The implication of the Akt signaling pathway in cancer is well established and has led to the development of new anticancer agents that block its activation.Keywords: Akt, cancer, therapeutic target, Akt inhibitors

  7. Plant Proteinase Inhibitors in Therapeutics – Focus on Cancer Therapy

    Sandhya Srikanth

    2016-12-01

    Full Text Available Plants are known to have many secondary metabolites and phytochemical compounds which are highly explored at biochemical and molecular genetics level and exploited enormously in the human health care sector. However, there are other less explored small molecular weight proteins, which inhibit proteases/proteinases. Plants are good sources of protease inhibitors (PIs which protect them against diseases, insects, pests, and herbivores. In the past, proteinaceous PIs were considered primarily as protein-degrading enzymes. Nevertheless, this view has significantly changed and PIs are now treated as very important signaling molecules in many biological activities such as inflammation, apoptosis, blood clotting and hormone processing. In recent years, PIs have been examined extensively as therapeutic agents, primarily to deal with various human cancers. Interestingly, many plant-based PIs are also found to be effective against cardiovascular diseases, osteoporosis, inflammatory diseases and neurological disorders. Several plant PIs are under further evaluation in in vitro clinical trials. Among all types of PIs, Bowman-Birk inhibitors (BBI has been studied extensively in the treatment of many diseases, especially in the field of cancer prevention. So far, crops such as beans, potatoes, barley, squash, millet, wheat, buckwheat, groundnut, chickpea, pigeonpea, corn and pineapple have been identified as good sources of PIs. The PI content of such foods has a significant influence on human health disorders, particularly in the regions where people mostly depend on these kind of foods. These natural PIs vary in concentration, protease specificity, heat stability, and sometimes several PIs may be present in the same species or tissue. However, it is important to carry out individual studies to identify the potential effects of each PI on human health. PIs in plants make them incredible sources to determine novel PIs with specific pharmacological and

  8. Paradoxical Roles of Nanoparticles in Cancer Therapeutics and Carcinogenesis

    Despeaux, Emily

    Nanoparticles (NPs) are becoming increasingly common in consumer goods and are under investigation for a variety of industrial and biomedical applications. However, challenges in determining NP toxicity may prevent them from reaching their full potential. NPs cannot be treated as single class for toxicity evaluations. Even among particles made from the same material, particle-specific physical properties, including size, shape, surface charge, agglomeration state, and surface modifications have a strong effect on the toxicity. Even so, the obstacles to conclusively and reproducibly evaluating toxicity span all NP classes. NP literature is riddled with confusing and often contradictory reports regarding the biocompatibility of both engineered NPs, designed with biocompatibility as a priority, and NPs from occupational or environmental exposures. Incomplete NP characterization and sample inhomogeneity represent major confounding factors in disparate results from seemingly comparable study setups. Additionally, NPs can interfere with many conventional toxicity screening methods. Inappropriate doses, exposure routes, and toxicity endpoints further diminish the utility of many published studies. Given the burgeoning interest in NP-based therapeutic agents, consistent, reliable standards are needed to ensure the biocompatibility of new formulations. To those ends, the synthesis, characterization, and in vitro toxicity of a multi-functional NP therapeutic were investigated (Chapter 2). Specifically, superparamagnetic iron oxide nanoparticles (SPIONs) were coated with amphiphilic polymer and functionalized with antisense oligonucleotides targeting survivin, an anti-apoptotic protein that is highly overexpressed in cancer. SPION physical properties, including particle size and composition, were characterized at each step of synthesis. Our results showed that the SPION platform is biocompatible and capable of delivering functional antisense oligonucleotides to regulate

  9. Efficacy of radiotherapy in esophageal cancer patients with dysphagia

    Shimizu, Yuri; Niibe, Yuzuru; Terahara, Atsuro; Shimada, Hideaki; Yajima, Satoshi; Kikuchi, Yoshinori

    2016-01-01

    To retrospectively assess the efficacy of radiotherapy in esophageal cancer patients with dysphagia due to the primary lesion at our institute, by evaluating change of Mellow-Pinkas-dysphagia score and subjective symptom. We confarmed radiotherapy for esophageal cancer help improve dysphagia. Change of Mel-low-Pinkas-dysphagia score throughout radiotherapy did not match with change of subjective dysphagia, which have relevancy to patients' quality of life. New evaluation criterion is required. (author)

  10. Efficacy of c-Met inhibitor for advanced prostate cancer

    Tu, William H; Zhu, Chunfang; Clark, Curtis; Christensen, James G; Sun, Zijie

    2010-01-01

    Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer. We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression. We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration. The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer

  11. Assessing the efficacy of cancer screening

    Gemma Jacklyn

    2017-07-01

    Full Text Available Background: Population-based cancer screening has been established for several types of cancer in Australia and internationally. Screening may perform differently in practice from randomised controlled trials, which makes evaluating programs complex. Materials and methods: We discuss how to assess the evidence of benefits and harms of cancer screening, including the main biases that can mislead clinicians and policy makers (such as volunteer, lead-time, length-time and overdiagnosis bias. We also discuss ways in which communication of risks can inform or mislead the community. Results: The evaluation of cancer screening programs should involve balancing the benefits and harms. When considering the overall worth of an intervention and allocation of scarce health resources, decisions should focus on the net benefits and be informed by systematic reviews. Communication of screening outcomes can be misleading. Many messages highlight the benefits while downplaying the harms, and often use relative risks and 5-year survival to persuade people to screen rather than support informed choice. Lessons learned: An evidence based approach is essential when evaluating and communicating the benefits and harms of cancer screening, to minimise misleading biases and the reliance on intuition.

  12. Oxidative Stress and Liver Cancer: Etiology and Therapeutic Targets

    Zhanpeng Wang

    2016-01-01

    Full Text Available Accumulating evidence has indicated that oxidative stress (OS is associated with the development of hepatocellular carcinoma (HCC. However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal—from either an internal or external source—and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV and hepatitis C virus (HCV infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD. The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC.

  13. Molecular pathology and prostate cancer therapeutics: from biology to bedside.

    Rodrigues, Daniel Nava; Butler, Lisa M; Estelles, David Lorente; de Bono, Johann S

    2014-01-01

    Prostate cancer (PCa) is the second most commonly diagnosed malignancy in men and has an extremely heterogeneous clinical behaviour. The vast majority of PCas are hormonally driven diseases in which androgen signalling plays a central role. The realization that castration-resistant prostate cancer (CRPC) continues to rely on androgen signalling prompted the development of new, effective androgen blocking agents. As the understanding of the molecular biology of PCas evolves, it is hoped that stratification of prostate tumours into distinct molecular entities, each with its own set of vulnerabilities, will be a feasible goal. Around half of PCas harbour rearrangements involving a member of the ETS transcription factor family. Tumours without this rearrangement include SPOP mutant as well as SPINK1-over-expressing subtypes. As the number of targeted therapy agents increases, it is crucial to determine which patients will benefit from these interventions and molecular pathology will be key in this respect. In addition to directly targeting cells, therapies that modify the tumour microenvironment have also been successful in prolonging the lives of PCa patients. Understanding the molecular aspects of PCa therapeutics will allow pathologists to provide core recommendations for patient management. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  14. Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258 and its Therapeutic Implications

    Shalini S. Yadav

    2017-06-01

    Full Text Available Prostate cancer (PCa remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT; however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC. With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258 is a pan receptor tyrosine kinase (RTK inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.

  15. Prophylactic and therapeutic efficacy of human monoclonal antibodies against H5N1 influenza.

    Cameron P Simmons

    2007-05-01

    Full Text Available New prophylactic and therapeutic strategies to combat human infections with highly pathogenic avian influenza (HPAI H5N1 viruses are needed. We generated neutralizing anti-H5N1 human monoclonal antibodies (mAbs and tested their efficacy for prophylaxis and therapy in a murine model of infection.Using Epstein-Barr virus we immortalized memory B cells from Vietnamese adults who had recovered from infections with HPAI H5N1 viruses. Supernatants from B cell lines were screened in a virus neutralization assay. B cell lines secreting neutralizing antibodies were cloned and the mAbs purified. The cross-reactivity of these antibodies for different strains of H5N1 was tested in vitro by neutralization assays, and their prophylactic and therapeutic efficacy in vivo was tested in mice. In vitro, mAbs FLA3.14 and FLD20.19 neutralized both Clade I and Clade II H5N1 viruses, whilst FLA5.10 and FLD21.140 neutralized Clade I viruses only. In vivo, FLA3.14 and FLA5.10 conferred protection from lethality in mice challenged with A/Vietnam/1203/04 (H5N1 in a dose-dependent manner. mAb prophylaxis provided a statistically significant reduction in pulmonary virus titer, reduced associated inflammation in the lungs, and restricted extrapulmonary dissemination of the virus. Therapeutic doses of FLA3.14, FLA5.10, FLD20.19, and FLD21.140 provided robust protection from lethality at least up to 72 h postinfection with A/Vietnam/1203/04 (H5N1. mAbs FLA3.14, FLD21.140 and FLD20.19, but not FLA5.10, were also therapeutically active in vivo against the Clade II virus A/Indonesia/5/2005 (H5N1.These studies provide proof of concept that fully human mAbs with neutralizing activity can be rapidly generated from the peripheral blood of convalescent patients and that these mAbs are effective for the prevention and treatment of H5N1 infection in a mouse model. A panel of neutralizing, cross-reactive mAbs might be useful for prophylaxis or adjunctive treatment of human cases of H5N1

  16. Threat and efficacy in Malaysia’s cancer news coverage

    Collin Jerome

    2017-12-01

    Full Text Available Background: The news media plays important roles not only in creating and disseminating health messages, but also in influencing people’s perceptions of health and their health behaviours. However, much more needs to be known about the creation process, particularly how health messages are created with the goal of raising awareness and knowledge, and changing people’s attitudes and behaviours. This paper presents a study aimed at examining cancer risk messages in Malaysia’s leading newspapers. Methods: Our search identified count the total 73 articles related to cancer which were published in three leading Malaysian English dailies in 2012 – September 2017. Of these, 10 were selected for a content analysis using the Extended Parallel Process (EPPM Model. The analysis focused on the presence and the levels of two important components required for designing effective health risk message: threat (severity and susceptibility and efficacy (responses efficacy and self-efficacy. The language used in the news articles was also analysed to see whether it helped enhance the threat-efficacy levels which are crucial for increasing message acceptance and yielding behaviour change. Results: Present study shows that the varying presence of threat and efficacy in the articles as evidenced by messages that focused on threat alone with no efficacy and messages that highlighted both threat and efficacy. Results also show contrasting levels of threat and efficacy as evidenced by messages that possessed high levels of threat and efficacy and messages that revealed a high level of threat and a low level of efficacy. Furthermore, the contents were composed differently in terms of language use: some articles used neutral language while others used vivid and descriptive language in addressing the topic and target audience. These have implication on message acceptance and behaviour change where high levels of threat and efficacy, and the ways in which vivid

  17. Chemoradiation therapy efficacy in patients with local cervical cancer

    Nemal'tsova, O.A.

    2007-01-01

    To analyze the efficacy of the original chronomodulation chemoradiation for local cervical cancer (CC) comparing it with the results of the standard treatment protocol and Hydrea administration as a radiomodifier. The use of the original protocol reduced the number of long-term metastases 6.3 times when compared with Hydrea use and 4.5 times when compared with the traditional treatment

  18. Inhibition of DNA2 nuclease as a therapeutic strategy targeting replication stress in cancer cells.

    Kumar, S; Peng, X; Daley, J; Yang, L; Shen, J; Nguyen, N; Bae, G; Niu, H; Peng, Y; Hsieh, H-J; Wang, L; Rao, C; Stephan, C C; Sung, P; Ira, G; Peng, G

    2017-04-17

    Replication stress is a characteristic feature of cancer cells, which is resulted from sustained proliferative signaling induced by activation of oncogenes or loss of tumor suppressors. In cancer cells, oncogene-induced replication stress manifests as replication-associated lesions, predominantly double-strand DNA breaks (DSBs). An essential mechanism utilized by cells to repair replication-associated DSBs is homologous recombination (HR). In order to overcome replication stress and survive, cancer cells often require enhanced HR repair capacity. Therefore, the key link between HR repair and cellular tolerance to replication-associated DSBs provides us with a mechanistic rationale for exploiting synthetic lethality between HR repair inhibition and replication stress. DNA2 nuclease is an evolutionarily conserved essential enzyme in replication and HR repair. Here we demonstrate that DNA2 is overexpressed in pancreatic cancers, one of the deadliest and more aggressive forms of human cancers, where mutations in the KRAS are present in 90-95% of cases. In addition, depletion of DNA2 significantly reduces pancreatic cancer cell survival and xenograft tumor growth, suggesting the therapeutic potential of DNA2 inhibition. Finally, we develop a robust high-throughput biochemistry assay to screen for inhibitors of the DNA2 nuclease activity. The top inhibitors were shown to be efficacious against both yeast Dna2 and human DNA2. Treatment of cancer cells with DNA2 inhibitors recapitulates phenotypes observed upon DNA2 depletion, including decreased DNA double strand break end resection and attenuation of HR repair. Similar to genetic ablation of DNA2, chemical inhibition of DNA2 selectively attenuates the growth of various cancer cells with oncogene-induced replication stress. Taken together, our findings open a new avenue to develop a new class of anticancer drugs by targeting druggable nuclease DNA2. We propose DNA2 inhibition as new strategy in cancer therapy by targeting

  19. Percutaneous Radiofrequency Ablation for the Hepatocellular Carcinoma Abutting the Diaphragm: Assessment of Safety and Therapeutic Efficacy

    Kang, Tae Wook; Rhim, Hyun Chul; Kim, Eun Young; Kim, Young Sun; Choi, Dong Il; Lee, Won Jae; Lim, Hyo K.

    2009-01-01

    To assess the safety and therapeutic efficacy of a percutaneous radiofrequency (RF) ablation for the hepatocellular carcinoma (HCC) abutting the diaphragm. We retrospectively assessed 80 patients who underwent a percutaneous RF ablation for a single nodular (< 4 cm) HCC over the last four years. Each patient underwent an ultrasound-guided RF ablation using internally cooled electrodes for the first-line treatment. We divided patients into two subgroups based on whether the index tumor was abutting (less than 5 mm) the diaphragm or not: group A (abutting; n = 31) versus group B (non-abutting; n = 49). We compared the two subgroups for complications and therapeutic efficacy using image and the review of medical records. The statistical assessment included an independent t-test, Fisher's exact test, and chi-square test. The assessment of the diaphragmatic swelling at CT immediately following the procedure was more severe in group A than group B (mean thickness change:1.44 vs. 0.46 mm, p = 0.00). Further, right shoulder pain was more common in group A than B (p = 0.01). Although minor complications (hemothorax 1 case, pleural effusion 1 case) were noted only in group A, no major thoracic complication occurred in either group. The technical success rate was lower in group A than group B (84% vs. 98%, p = 0.03). As well, the primary and secondary technique effectiveness rates in group A and group B were 90% versus 98% (p = 0.29) and 79% versus 91% (p = 0.25), respectively. The local tumor progression rate was higher in group A than in group B (29% vs. 6%, p = 0.02). We found that the percutaneous RF ablation for the HCC abutting the diaphragm is a safe procedure without major complications. However, it is less effective with regard to technical success and local tumor control

  20. Efficacy of bowel cancer appeals for promoting physical activity.

    Jalleh, Geoffrey; Donovan, Robert J; Slevin, Terry; Dixon, Helen

    2005-08-01

    To investigate the potential efficacy of bowel cancer prevention messages in increasing intentions to be more physically active. A convenience sample of 281 physically inactive persons aged 30-60 years was recruited in the Perth city centre and randomly assigned to a bowel cancer and physical activity message or a heart disease and physical activity message. After reading a booklet containing information about physical activity and its link either to bowel cancer (n = 141) or cardiovascular disease (n = 140), respondents filled in a self-completion questionnaire. The main response measures were impact on intentions to be more physically active, and perceived believability and relevance of the message. Perceived believability of the message was high in both conditions. Perceived personal relevance of the message was substantially lower in the bowel cancer than the cardiovascular disease condition. Overall, the cardiovascular disease condition achieved somewhat higher behavioural intentions than the bowel cancer condition. The finding that two in three respondents in the bowel cancer condition had increased intention to increase their level of physical activity provides support for the potential efficacy of promoting physical activity in reducing the risk of bowel cancer.

  1. Newly engineered magnetic erythrocytes for sustained and targeted delivery of anti-cancer therapeutic compounds.

    Caterina Cinti

    Full Text Available Cytotoxic chemotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can they be selectively improved? Alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. These formulations are associated with problems like severe toxic side effects on healthy organs, drug resistance and limited access of the drug to the tumor sites suggested the need to focus on site-specific controlled drug delivery systems. In response to these concerns, we have developed a new drug delivery system based on magnetic erythrocytes engineered with a viral spike fusion protein. This new erythrocyte-based drug delivery system has the potential for magnetic-controlled site-specific localization and highly efficient fusion capability with the targeted cells. Here we show that the erythro-magneto-HA virosomes drug delivery system is able to attach and fuse with the target cells and to efficiently release therapeutic compounds inside the cells. The efficacy of the anti-cancer drug employed is increased and the dose required is 10 time less than that needed with conventional therapy.

  2. Newly Engineered Magnetic Erythrocytes for Sustained and Targeted Delivery of Anti-Cancer Therapeutic Compounds

    Taranta, Monia; Naldi, Ilaria

    2011-01-01

    Cytotoxic chemotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can they be selectively improved? Alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. These formulations are associated with problems like severe toxic side effects on healthy organs, drug resistance and limited access of the drug to the tumor sites suggested the need to focus on site-specific controlled drug delivery systems. In response to these concerns, we have developed a new drug delivery system based on magnetic erythrocytes engineered with a viral spike fusion protein. This new erythrocyte-based drug delivery system has the potential for magnetic-controlled site-specific localization and highly efficient fusion capability with the targeted cells. Here we show that the erythro-magneto-HA virosomes drug delivery system is able to attach and fuse with the target cells and to efficiently release therapeutic compounds inside the cells. The efficacy of the anti-cancer drug employed is increased and the dose required is 10 time less than that needed with conventional therapy. PMID:21373641

  3. Acacetin enhances the therapeutic efficacy of doxorubicin in non-small-cell lung carcinoma cells.

    Reenu Punia

    Full Text Available Anthracyclines are efficient and potent agents to treat broad range of cancers but cytotoxicity induced by them limits their use in therapeutics. Use of plant-derived agents help to prevent or delay the process of cancer progression and their combination increases the anti-cancer potential of mainstream compound. However, multidrug resistance is major cause of treatment failure in cancer patients.In this study, combination treatments of fisetin or acacetin with doxorubicin were explored for their potential synergistic effect on non-small-cell lung carcinoma (NSCLC cells.During this study, NSCLC model cell lines A549 and H1299 were used to determine the combinatorial effect of phytochemicals namly acacetin and fisetin with doxorubicin.The effects of individual compounds and their combination on cell viability, clonogenic potential and cell cycle progression were studied. Efflux of doxorubicin was measured by spectrofluorophotometer, whereas accumulation inside the cells was analyzed by flow cytometry and confocal microscopy. Expression of MDR1 was checked by semi-quantitative PCR.The results showed that the cell viability of A549 and H1299 cells were significantly decreased in time- and dose-dependent manner, although A549 cells showed more sensitivity toward doxorubicin than H1299 cells. Mostly, combination of doxorubicin showed good synergy with acacetin in both the cell lines whereas, fisetin exerted synergistic effect only at 72 h of treatment in H1299 cells. Acacetin with doxorubicin caused G2/M arrest by downregulating CDK-cyclin complex in A549 cells. Acacetin-doxorubicin combination decreased the clonogenic potential of A549 and H1299 cells upto 82% and 59%, respectively, as compared to control. Acacetin also decreased efflux of doxorubicin by 59% after 30 mins of exposure to A549 cells and further increased accumulation of doxorubicin inside the cells upto 55% in 2 h. The modulatory effect of acacetin-doxorubicin combination on

  4. Therapeutic efficacy of rose oil: A comprehensive review of clinical evidence

    Safieh Mohebitabar

    2017-04-01

    Full Text Available Objective: Rose oil is obtained from the petals of difference Rosa species especially Rosa centifolia L. and Rosa damascena Mill. Various pharmacological properties have been attributed to rose oil. The aim of the present study was to review the rose oil therapeutic effects which had been clinically evaluated in trial studies. Materials and Methods: Google scholar, PubMed, Cochrane Library, and Scopus were searched for human studies which have evaluated the therapeutic effects of rose oil and published in English language until August 2015. Results: Thirteen clinical trials (772 participants were included in this review. Rose oil was administered via inhalation or used topically. Most of the studies (five trials evaluated the analgesic effect of rose oil. Five studies evaluated the physiological relaxation effect of rose oil. Anti-depressant, psychological relaxation, improving sexual dysfunction, and anti-anxiety effects were the other clinical properties reported for rose oil. Conclusion: Numerous studies on the pharmacological properties of rose oil have been done in animals, but studies in humans are few.  In this study, it was observed that rose oil had physiological and psychological relaxation, analgesic and anti-anxiety effects. To obtain conclusive results on the efficacy and safety of rose oil, further clinical trials with larger sample size and better designation are required.

  5. Therapeutic efficacy of natural prostaglandin in the treatment of pyometra in bitches

    Basanti Jena

    2013-12-01

    Full Text Available Aim: The current study was done to study the therapeutic effect of natural prostaglandin in treatment of canine pyometra. Materials and Methods: Seven bitches were treated with natural PGF2 á i.e. dinoprost tromethamine at the dose rate of 100 μg/kg body weight subcutaneously once daily for 7 days with supportive therapies. The physiological, haematological and biochemical parameters were studied before (0th day and after treatment (8th day. Therapeutic efficacy was assessed in terms of return of abnormal parameters to either normal or near normal value as compared to the untreated control group, intensity of side effects and post treatment reproductive status. Results: All physiological, haematological and biochemical parameters in the seven treated bitches returned to normal range at the end of treatment. The intensity of side effects was quite severe in the treatment group. Six bitches came to estrus within 2 months of treatment and out of them four conceived on subsequent mating. In rest three bitches there was recurrence of pyometra within 4 months of treatment. Conclusion: Though conception rate of recovered bitches is decreased when compared with that of normal healthy bitches still this treatment protocol can be used successfully in treatment of canine pyometra to conserve the breeding capability of bitches. [Vet World 2013; 6(6.000: 295-299

  6. Therapeutic Targeting of AXL Receptor Tyrosine Kinase Inhibits Tumor Growth and Intraperitoneal Metastasis in Ovarian Cancer Models

    Pinar Kanlikilicer

    2017-12-01

    Full Text Available Despite substantial improvements in the treatment strategies, ovarian cancer is still the most lethal gynecological malignancy. Identification of drug treatable therapeutic targets and their safe and effective targeting is critical to improve patient survival in ovarian cancer. AXL receptor tyrosine kinase (RTK has been proposed to be an important therapeutic target for metastatic and advanced-stage human ovarian cancer. We found that AXL-RTK expression is associated with significantly shorter patient survival based on the The Cancer Genome Atlas patient database. To target AXL-RTK, we developed a chemically modified serum nuclease-stable AXL aptamer (AXL-APTAMER, and we evaluated its in vitro and in vivo antitumor activity using in vitro assays as well as two intraperitoneal animal models. AXL-aptamer treatment inhibited the phosphorylation and the activity of AXL, impaired the migration and invasion ability of ovarian cancer cells, and led to the inhibition of tumor growth and number of intraperitoneal metastatic nodules, which was associated with the inhibition of AXL activity and angiogenesis in tumors. When combined with paclitaxel, in vivo systemic (intravenous [i.v.] administration of AXL-aptamer treatment markedly enhanced the antitumor efficacy of paclitaxel in mice. Taken together, our data indicate that AXL-aptamers successfully target in vivo AXL-RTK and inhibit its AXL activity and tumor growth and progression, representing a promising strategy for the treatment of ovarian cancer.

  7. Therapeutic Drug Monitoring of Lacosamide in Norway: Focus on Pharmacokinetic Variability, Efficacy and Tolerability.

    Svendsen, Torleiv; Brodtkorb, Eylert; Baftiu, Arton; Burns, Margrete Larsen; Johannessen, Svein I; Johannessen Landmark, Cecilie

    2017-07-01

    Lacosamide (LCM) is a new antiepileptic drug (AED). Experience from therapeutic drug monitoring (TDM) in clinical practice is limited. The purpose of this study is to evaluate the pharmacokinetic variability of LCM in relation to efficacy and tolerability in patients with refractory epilepsy in a real-life setting. Variables included age, gender, daily doses and serum concentrations of LCM and other AEDs from the TDM-database at the National Center for Epilepsy in Norway. Clinical data regarding efficacy and tolerability were collected from medical records. The Norwegian Prescription Database (NorPD) was used to include population-based numbers of users. TDM-data from 344 patients were included. The median dose, serum concentration, and concentration/dose (C/D)-ratio of LCM was 350 (range 25-700) mg/day, 19.7 (range 8.1-56.2) µmol/L, and 0.06 (0.02-0.82) µmol/L/mg, respectively. Serum concentrations were reduced by 28% by concomitant use of enzyme inducers and increased by 30% in patients aged >65 years. Efficacy and tolerability were assessed in 227 patients: 29% had >50% seizure reduction (eight seizure free), 30% had no effect, and 44% reported adverse effects. In Norway, there were on average 500 patients per year using LCM in this period based on NorPD. The study demonstrated pharmacokinetic variability and use of TDM of LCM in Norway. Data were collected from multiple sources for improved pharmacovigilance. Serum concentrations were influenced by enzyme inducers and ageing, indicating the usefulness of TDM. Effect and tolerability were favorable within a suggested reference range of 10-40 µmol/L given drug-fasting conditions.

  8. Overlapping activities of TGF-β and Hedgehog signaling in cancer: therapeutic targets for cancer treatment.

    Perrot, Carole Y; Javelaud, Delphine; Mauviel, Alain

    2013-02-01

    Recent advances in the field of cancer therapeutics come from the development of drugs that specifically recognize validated oncogenic or pro-metastatic targets. The latter may be mutated proteins with altered function, such as kinases that become constitutively active, or critical components of growth factor signaling pathways, whose deregulation leads to aberrant malignant cell proliferation and dissemination to metastatic sites. We herein focus on the description of the overlapping activities of two important developmental pathways often exacerbated in cancer, namely Transforming Growth Factor-β (TGF-β) and Hedgehog (HH) signaling, with a special emphasis on the unifying oncogenic role played by GLI1/2 transcription factors. The latter are the main effectors of the canonical HH pathway, yet are direct target genes of TGF-β/SMAD signal transduction. While tumor-suppressor in healthy and pre-malignant tissues, TGF-β is often expressed at high levels in tumors and contributes to tumor growth, escape from immune surveillance, invasion and metastasis. HH signaling regulates cell proliferation, differentiation and apoptosis, and aberrant HH signaling is found in a variety of cancers. We discuss the current knowledge on HH and TGF-β implication in cancer including cancer stem cell biology, as well as the current state, both successes and failures, of targeted therapeutics aimed at blocking either of these pathways in the pre-clinical and clinical settings. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Synthetic Lethal Therapeutic Approaches for ARID1A-Mutated Ovarian Cancer

    2017-10-01

    Award Number: W81XWH-16-1-0496 TITLE: Synthetic lethal therapeutic approaches for ARID1A-mutated ovarian cancer PRINCIPAL INVESTIGATOR: Rugang...AND SUBTITLE Synthetic lethal therapeutic approaches for ARID1A-mutated ovarian cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0496 5c...Release; Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological

  10. Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-Resistant Prostate Cancer

    2017-12-01

    AWARD NUMBER: W81XWH-13-1-0163 TITLE: Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer ...Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Feng Yang, Ph.D. 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: fyang@bcm.edu...W81XWH-13-1-0163 " Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer " Introduction AR signaling

  11. TNK2 Tyrosine Kinase as a Novel Therapeutic Target in Triple-Negative Breast Cancer

    2017-10-01

    Award Number: W81XWH-15-1-0311 TITLE: TNK2 Tyrosine Kinase as a Novel Therapeutic Target in Triple- Negative Breast Cancer PRINCIPAL...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Triple-negative breast cancers (TNBCs) represent only 10%-15% of all breast cancers ; however... cancers (TNBC) represent 10-15% of all breast cancers . While significant advances have been made for targeted therapy of ER and HER2-positive breast

  12. Therapeutic efficacy and toxicity of a single and double application of boron neutron capture therapy (BNCT) in a hamster cheek pouch oral precancer model

    Monti Hughes, A; Pozzi, E C C; Thorp, S; Garabalino, M A; Farias, R O; Gonzalez, S J; Heber, E M; Itoiz, M E; Aromando, R F; Molinari, A J; Miller, M; Nigg, D W; Curotto, P; Trivillin, V A; Schwint, A E

    2012-01-01

    Tumor development from tissue with potentially malignant disorders (PMD) gives rise to second primary tumors. We previously demonstrated the partial inhibitory effect on tumor development of Boron Neutron Capture Therapy (BNCT) mediated by the boron compounds BPA (boronophenylalanine) and decahydrodecaborate (GB-10) in a hamster pouch oral precancer model. Seeking to optimize BNCT, the aim of the present study was to contribute to the knowledge of BNCT radiobiology for oral precancer and assess new BNCT protocols in terms of inhibition of tumor development and radiotoxicity. Groups of cancerized hamsters were locally exposed to single or double applications (2 weeks apart) of BPA-BNCT or (GB-10 + BPA)-BNCT at a total dose of 8Gy to tissue with PMD; to a single application of BPA-BNCT at 6Gy and to a double application (4 weeks apart) of BPA-BNCT or (BPA + GB-10)-BNCT at a total dose of 10Gy. Cancerized, sham-irradiated hamsters served as controls. Clinical status, tumor development from tissue with PMD and mucositis were followed for 8 months. The marked therapeutic efficacy of single applications of BNCT at 6 and 8Gy were associated to severe radiotoxicity. Dose fractionation into 2 applications reduced mucositis but also reduced therapeutic efficacy, depending on dose and interval between applications. A double application (4 weeks apart) of (GB-10 + BPA)-BNCT at a total dose of 10Gy rendered the best therapeutic advantage, i.e. 63% - 100% inhibition of tumor development with only slight mucositis in 67% of cases. The data reported herein show that issues such as dose levels and dose fractionation, interval between applications, and choice of boron compounds are pivotal to therapeutic advantage and must be tailored for a particular pathology and anatomic site. The present study determined treatment conditions that would contribute to optimize BNCT for precancer and that would warrant cautious assessment in a clinical scenario (author)

  13. A theranostic prodrug delivery system based on Pt(IV) conjugated nano-graphene oxide with synergistic effect to enhance the therapeutic efficacy of Pt drug.

    Li, Jingwen; Lyv, Zhonglin; Li, Yanli; Liu, Huan; Wang, Jinkui; Zhan, Wenjun; Chen, Hong; Chen, Huabing; Li, Xinming

    2015-05-01

    Due to their high NIR-optical absorption and high specific surface area, graphene oxide and graphene oxide-based nanocomposites have great potential in both drug delivery and photothermal therapy. In the work reported herein we successfully integrate a Pt(IV) complex (c,c,t-[Pt(NH3)2Cl2(OH)2]), PEGylated nano-graphene oxide (PEG-NGO), and a cell apoptosis sensor into a single platform to generate a multifunctional nanocomposite (PEG-NGO-Pt) which shows potential for targeted drug delivery and combined photothermal-chemotherapy under near infrared laser irradiation (NIR), and real-time monitoring of its therapeutic efficacy. Non-invasive imaging using a fluorescent probe immobilized on the GO shows an enhanced therapeutic effect of PEG-NGO-Pt in cancer treatment via apoptosis and cell death. Due to the enhanced cytotoxicity of cisplatin and the highly specific tumor targeting of PEG-NGO-Pt at elevated temperatures, this nanocomposite displays a synergistic effect in improving the therapeutic efficacy of the Pt drug with complete destruction of tumors, no tumor recurrence and minimal systemic toxicity in comparison with chemotherapy or photothermal treatment alone, highlighting the advantageous effects of integrating Pt(IV) with GO for anticancer treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Therapeutic immunization strategies against cervical cancer : induction of cell-mediated immunity in murine models

    Bungener, Laura Barbara

    2004-01-01

    The aim of the study described in this thesis is the development of a therapeutic immunization strategy against cervical cancer and pre-malignant precursor lesions of cervical cancer (CIN lesions). Cervical cancer is caused by high risk human papillomavirus (HPV). Two of the early proteins of high

  15. Therapeutic Efficacy of Allyl Isothiocyanate Evaluated on N-Nitrosodiethylamine/Phenobarbitol induced Hepatocarcinogenesis in Wistar Rats

    G. Thiyagarajan

    2010-07-01

    Full Text Available N-nitrosodiethylamine (NDEA is a potential carcinogenic agent that induces liver cancer. To evaluate the chemotherapeutic effect of Allyl isothiocyanate in the experimental model, Wistar male rats were administered single dose of intraperitoneal (IP injection of NDEA. Two weeks after administration of NDEA, Phenobarbital at the concentration of 0.05% was incorporated in rat chow for up to 14 successive weeks to promote liver cancer. Allyl isothiocyanate (AITC (2mg/kg body weight in addition with 0.5ml of corn oil was given orally on a daily basis. At the end of this experimental period, the rats were sacrificed and the blood samples were taken for biochemical studies. The levels of the marker enzymes for liver function were measured in serum. The results of the biochemical studies showed that NDEA administration followed by phenobarbital induces macro and microscopic liver tumors that increase the levels of marker enzymes and decreases the level of antioxidant in the serum in addition to loss of body weight. Conclusively, the administration of AITC as therapeutic treatment for hepatocarcinoma has significantly reduced the tumor development and counteracted all the biochemical effects induced by NDEA.

  16. Plasma microRNAs serve as biomarkers of therapeutic efficacy and disease progression in hypertension-induced heart failure

    Dickinson, Brent A; Semus, Hillary M; Montgomery, Rusty L; Stack, Christianna; Latimer, Paul A; Lewton, Steven M; Lynch, Joshua M; Hullinger, Thomas G; Seto, Anita G; van Rooij, Eva

    AIMS: Recent studies have shown that microRNAs (miRNAs), besides being potent regulators of gene expression, can additionally serve as circulating biomarkers of disease. The aim of this study is to determine if plasma miRNAs can be used as indicators of disease progression or therapeutic efficacy in

  17. Therapeutic efficacy and safety evaluation of erythrocyte concentrate used in dogs

    Ildiko Barabasi

    2016-11-01

    Full Text Available Therapeutic efficacy and safety evaluation of erythrocyte concentrate used in dogs 1Ildikó BARABÁSI, 1Cristina ȘTEFǍNUȚ, 1Laurenţ OGNEAN 1University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca, 400037, Manastur street, no.3-5, Cluj-Napoca, Romania *Corresponding author: lognean@yahoo.com   Keywords: dogs, erythrocyte concentrate, hematocrit, immune-mediated hemolytic anemia, transfusion therapy Introduction: The minimum dose of whole blood products as well as erythrocyte concentrate has been under a lot of debate, new equations for calculating the optimal dose being made up from a large variety of hematologists (Kisielewicz et al 2014; Helm and Knottenbelt, 2010; Gibson, 2007. Aim: The therapeutical efficacy of erythrocyte concentrates in dogs with different types of anemia by measuring the hematocrit level 6 hours after the transfusion and a complete blood count 5 days post-transfusion therapy. Materials and methods: Blood tests were performed with ADIVA hematological analyzer; the 6 hour post-transfusion hematocrit was determined by a micro hematocrit. On admission every patient received a routine blood test that included 40 hematological parameters and 21 biochemical parameters. In addition, a detailed examination of the blood smears was also performed by the ADIVA hematological analyzer with 26 parameters that mostly referred to red blood cell and white blood cell morphology. Blood typing was done using the RapidVet quick test kit. Patients received only type specific blood and to limit transfusion reaction occurrences, in addition, a crossmatch test was performed before every transfusion. Statistical analysis was accomplished with GraphPadInStat 3.0 and the graphical depiction of the obtained results was made using the Origin 8.5. graphics program. Results: Statistical analysis reveal that the total red blood cell count underwent very significant changes (p=0.0052 as well as the hemoglobin (p=0.0085. The hematocrit

  18. Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model.

    Xiujuan Zhang

    Full Text Available Multiple sclerosis (MS, characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE, a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression.

  19. Efficacy of a therapeutic vaccine using mutated β-amyloid sensitized dendritic cells in Alzheimer's mice.

    Luo, Zhongqiu; Li, Jialin; Nabar, Neel R; Lin, Xiaoyang; Bai, Ge; Cai, Jianfeng; Zhou, Shu-Feng; Cao, Chuanhai; Wang, Jinhuan

    2012-09-01

    Despite FDA suspension of Elan's AN-1792 amyloid beta (Aβ) vaccine in phase IIb clinical trials, the implications of this study are the guiding principles for contemporary anti-Aβ immunotherapy against Alzheimer's disease (AD). AN-1792 showed promising results with regards to Aβ clearance and cognitive function improvement, but also exhibited an increased risk of Th1 mediated meningoencephalitis. As such, vaccine development has continued with an emphasis on eliciting a notable anti-Aβ antibody titer, while avoiding the unwanted Th1 pro-inflammatory response. Previously, we published the first report of an Aβ sensitized dendritic cell vaccine as a therapeutic treatment for AD in BALB/c mice. Our vaccine elicited an anti-Aβ titer, with indications that a Th1 response was not present. This study is the first to investigate the efficacy and safety of our dendritic cell vaccine for the prevention of AD in transgenic mouse models (PDAPP) for AD. We also used Immunohistochemistry to characterize the involvement of LXR, ABCA1, and CD45 in order to gain insight into the potential mechanisms through which this vaccine may provide benefit. The results indicate that (1) the use of mutant Aβ1-42 sensitized dendritic cell vaccine results in durable antibody production, (2) the vaccine provides significant benefits with regards to cognitive function without the global (Th1) inflammation seen in prior Aβ vaccines, (3) histological studies showed an overall decrease in Aβ burden, with an increase in LXR, ABCA1, and CD45, and (4) the beneficial results of our DC vaccine may be due to the LXR/ABCA1 pathway. In the future, mutant Aβ sensitized dendritic cell vaccines could be an efficacious and safe method for the prevention or treatment of AD that circumvents problems associated with traditional anti-Aβ vaccines.

  20. Design of dendrimer-based drug delivery nanodevices with enhanced therapeutic efficacies

    Kannan, Rangaramanujam

    2007-03-01

    Dendrimers and hyperbranched polymers possess highly branched architectures, with a large number of controllable, tailorable, `peripheral' functionalities. Since the surface chemistry of these materials can be modified with relative ease, these materials have tremendous potential in targeted drug delivery. They have significant potential compared to liposomes and nanoparticles, because of the reduced macrophage update, increased cellular transport, and the ability to modulate the local environment through functional groups. We are developing nanodevices based on dendritic systems for drug delivery, that contain a high drug payload, ligands, and imaging agents, resulting in `smart' drug delivery devices that can target, deliver, and signal. In collaboration with the Children's Hospital of Michigan, Karmanos Cancer Institute, and College of Pharmacy, we are testing the in vitro and in vivo response of these nanodevices, by adapting the chemistry for specific clinical applications such as asthma and cancer. These materials are characterized by UV/Vis spectroscopy, flow cytometry, fluorescence/confocal microscopy, and appropriate animal models. Our results suggest that: (1) We can prepare drug-dendrimer conjugates with drug payloads of greater than 50%, for a variety of drugs; (2) The dendritic polymers are capable of transporting and delivering drugs into cells faster than free drugs, with superior therapeutic efficiency. This can be modulated by the surface functionality of the dendrimer; (3) For chemotherapy drugs, the conjugates are a factor of 6-20 times more effective even in drug-resistant cell lines; (4) For corticosteroidal drugs, the dendritic polymers provide higher drug residence times in the lung, allowing for passive targeting. The ability of the drug-dendrimer-ligand conjugates to target specific asthma and cancer cells is currently being explored using in vitro and in vivo animal models.

  1. Guanylyl cyclase C in colorectal cancer: susceptibility gene and potential therapeutic target.

    Lin, Jieru E; Li, Peng; Pitari, Giovanni M; Schulz, Stephanie; Waldman, Scott A

    2009-05-01

    Colorectal cancer is one of the leading causes of tumor-related morbidity and mortality worldwide. While mechanisms underlying this disease have been elucidated over the past two decades, these molecular insights have failed to translate into efficacious therapy. The oncogenomic view of cancer suggests that terminal transformation reflects the sequential corruption of signal transduction circuits regulating key homeostatic mechanisms, whose multiplicity underlies the therapeutic resistance of most tumors to interventions targeting individual pathways. Conversely, the paucity of mechanistic insights into proximal pathophysiological processes that initiate and amplify oncogenic circuits preceding accumulation of mutations and transformation impedes development of effective prevention and therapy. In that context, guanylyl cyclase C (GCC), the intestinal receptor for the paracrine hormones guanylin and uroguanylin, whose early loss characterizes colorectal transformation, has emerged as a component of lineage-specific homeostatic programs organizing spatiotemporal patterning along the crypt-surface axis. Dysregulation of GCC signaling, reflecting hormone loss, promotes tumorigenesis through reprogramming of replicative and bioenergetic circuits and genomic instability. Compensatory upregulation of GCC in response to hormone loss provides a unique translational opportunity for prevention and treatment of colorectal tumors by hormone-replacement therapy.

  2. New Epigenetic Therapeutic Intervention for Metastatic Breast Cancer

    2017-04-01

    Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China...Foundation 2016 NIH - New Innovator Award 2017 NIH - “ Cancer Drug Development & Therapeutics” (CDDT) 2017 NIH/NIAID - Special Emphasis Panel...Chemistry 2011 - Editor, Cancer Reports, Pancreatic Disorders & Therapy 2015 - Associate Editor, Molecular and Cellular Oncology (sections of

  3. Development of novel miR-129 mimics with enhanced efficacy to eliminate chemoresistant colon cancer stem cells

    Ju, Jingfang

    2018-01-01

    Background Resistance to 5-Fluorouracil (5-FU) based chemotherapy is the major reason for failure of treating patients with advanced colorectal cancer. Materials and methods In this study, we developed a novel miR-129 mimic with potent efficacy in eliminating resistant colon cancer stem cells both in vitro and in vivo. We integrated 5-FU into miR-129 by replacing Uracil (U) to generate 5-FU-miR-129 mimics (Mimic-1). Results Mimic-1 is a strong therapeutic candidate with a number of unique features. Mimic-1 can be delivered to cancer cells without any transfection reagents (e.g. lipids, viral vector, nanoparticles). Mimic-1 is more potent at inhibiting cell proliferation and inducing cell cycle arrest at G1 phase than native miR-129 and the other mimics tested, while retaining target specificity. Mimic-1 prevents colon cancer metastasis in vivo without toxicity. Conclusion This represents a significant advancement in the development of a nontoxic and highly potent miRNA based cancer therapeutics and establishes a foundation for further developing Mimic-1 as a novel anti-cancer therapeutic for treating colorectal cancer. PMID:29507661

  4. MicroRNAs and liver cancer associated with iron overload: Therapeutic targets unravelled

    Greene, Catherine M; Varley, Robert B; Lawless, Matthew W

    2013-01-01

    Primary liver cancer is a global disease that is on the increase. Hepatocellular carcinoma (HCC) accounts for most primary liver cancers and has a notably low survival rate, largely attributable to late diagnosis, resistance to treatment, tumour recurrence and metastasis. MicroRNAs (miRNAs/miRs) are regulatory RNAs that modulate protein synthesis. miRNAs are involved in several biological and pathological processes including the development and progression of HCC. Given the poor outcomes with current HCC treatments, miRNAs represent an important new target for therapeutic intervention. Several studies have demonstrated their role in HCC development and progression. While many risk factors underlie the development of HCC, one process commonly altered is iron homeostasis. Iron overload occurs in several liver diseases associated with the development of HCC including Hepatitis C infection and the importance of miRNAs in iron homeostasis and hepatic iron overload is well characterised. Aberrant miRNA expression in hepatic fibrosis and injury response have been reported, as have dysregulated miRNA expression patterns affecting cell cycle progression, evasion of apoptosis, invasion and metastasis. In 2009, miR-26a delivery was shown to prevent HCC progression, highlighting its therapeutic potential. Several studies have since investigated the clinical potential of other miRNAs with one drug, Miravirsen, currently in phase II clinical trials. miRNAs also have potential as biomarkers for the diagnosis of HCC and to evaluate treatment efficacy. Ongoing studies and clinical trials suggest miRNA-based treatments and diagnostic methods will have novel clinical applications for HCC in the coming years, yielding improved HCC survival rates and patient outcomes. PMID:23983424

  5. A Novel Therapeutic Modality for Advanced Stage Prostate Cancer Treatment

    2017-10-01

    Androgen Receptor Signaling Inhibitors Repress Prostate Cancer Growth by Downregulating Androgen Receptor Splice Variants, EZH2, and Src. Cancer ...research 2015;75(24):5309-17. 18. Wadosky KM, Koochekpour S. Androgen receptor splice variants and prostate cancer : From bench to bedside. Oncotarget...2017;8(11):18550-76. 19. Cao S, Zhan Y, Dong Y. Emerging data on androgen receptor splice variants in prostate cancer . Endocrine-related cancer

  6. Anti-EGFR Therapy: Mechanism and Advances in Clinical Efficacy in Breast Cancer

    John F. Flynn

    2009-01-01

    Full Text Available This review will focus on recent advances in the application of antiepidermal growth factor receptor (anti-EGFR for the treatment of breast cancer. The choice of EGFR, a member of the ErbB tyrosine kinase receptor family, stems from evidence pinpointing its role in various anti-EGFR therapies. Therefore, an increase in our understanding of EGFR mechanism and signaling might reveal novel targets amenable to intervention in the clinic. This knowledge base might also improve existing medical treatment options and identify research gaps in the design of new therapeutic agents. While the approved use of drugs like the dual kinase inhibitor Lapatinib represents significant advances in the clinical management of breast cancer, confirmatory studies must be considered to foster the use of anti-EGFR therapies including safety, pharmacokinetics, and clinical efficacy.

  7. Diagnostic efficacy and therapeutic impact of computed tomography in the evaluation of clinically suspected otosclerosis

    Dudau, Cristina; Salim, Fakhruddin; Jiang, Dan; Connor, Steve E.J.

    2017-01-01

    To assess the diagnostic efficacy and therapeutic impact of CT in evaluating patients with clinically suspected otosclerosis. CT scans performed over a 5-year period for clinically suspected otosclerosis were retrospectively reviewed. CT diagnoses were correlated with subsequent surgical management. For otosclerosis positive cases, clinically significant extensions of otosclerosis were correlated with audiometry and the diagnosis was correlated with surgical findings. Of 259 CT studies, 46 % of patients were positive, 49 % negative and 5 % equivocal for otosclerosis. A relevant alternative CT diagnosis was evident in 33 % of the negative studies. One targeted surgery was performed for every four CT studies. CT outcome influenced the decision to perform stapedectomy in 41 % CT-positive versus 4 % CT-negative patients. CT-positive ears for otosclerosis could not be predicted from baseline clinical or audiometric criteria. Those with endosteal extension demonstrated lower bone conduction thresholds presurgically. The positive predictive value of CT diagnosis of otosclerosis was 100 %. CT demonstrated a high rate of clinically relevant diagnoses in both CT-positive and -negative for otosclerosis patients, and this frequently influenced surgical management. CT also added value by demonstrating relevant extensions of the otosclerotic foci, some of which were predictive of audiometric parameters. (orig.)

  8. Do ABO blood group antigens hamper the therapeutic efficacy of mesenchymal stromal cells?

    Moll, Guido; Hult, Annika; von Bahr, Lena; Alm, Jessica J; Heldring, Nina; Hamad, Osama A; Stenbeck-Funke, Lillemor; Larsson, Stella; Teramura, Yuji; Roelofs, Helene; Nilsson, Bo; Fibbe, Willem E; Olsson, Martin L; Le Blanc, Katarina

    2014-01-01

    Investigation into predictors for treatment outcome is essential to improve the clinical efficacy of therapeutic multipotent mesenchymal stromal cells (MSCs). We therefore studied the possible harmful impact of immunogenic ABO blood groups antigens - genetically governed antigenic determinants - at all given steps of MSC-therapy, from cell isolation and preparation for clinical use, to final recipient outcome. We found that clinical MSCs do not inherently express or upregulate ABO blood group antigens after inflammatory challenge or in vitro differentiation. Although antigen adsorption from standard culture supplements was minimal, MSCs adsorbed small quantities of ABO antigen from fresh human AB plasma (ABP), dependent on antigen concentration and adsorption time. Compared to cells washed in non-immunogenic human serum albumin (HSA), MSCs washed with ABP elicited stronger blood responses after exposure to blood from healthy O donors in vitro, containing high titers of ABO antibodies. Clinical evaluation of hematopoietic stem cell transplant (HSCT) recipients found only very low titers of anti-A/B agglutination in these strongly immunocompromised patients at the time of MSC treatment. Patient analysis revealed a trend for lower clinical response in blood group O recipients treated with ABP-exposed MSC products, but not with HSA-exposed products. We conclude, that clinical grade MSCs are ABO-neutral, but the ABP used for washing and infusion of MSCs can contaminate the cells with immunogenic ABO substance and should therefore be substituted by non-immunogenic HSA, particularly when cells are given to immunocompentent individuals.

  9. Diagnostic efficacy and therapeutic impact of computed tomography in the evaluation of clinically suspected otosclerosis

    Dudau, Cristina [King' s College Hospital NHS Foundation Trust, Department of Neuroradiology, London (United Kingdom); Salim, Fakhruddin; Jiang, Dan [Department of Otolaryngology, Head and Neck Surgery, Auditory Implantation Centre, London (United Kingdom); Connor, Steve E.J. [Department of Radiology, Guy' s and St Thomas' NHS Foundation Trust, London (United Kingdom)

    2017-03-15

    To assess the diagnostic efficacy and therapeutic impact of CT in evaluating patients with clinically suspected otosclerosis. CT scans performed over a 5-year period for clinically suspected otosclerosis were retrospectively reviewed. CT diagnoses were correlated with subsequent surgical management. For otosclerosis positive cases, clinically significant extensions of otosclerosis were correlated with audiometry and the diagnosis was correlated with surgical findings. Of 259 CT studies, 46 % of patients were positive, 49 % negative and 5 % equivocal for otosclerosis. A relevant alternative CT diagnosis was evident in 33 % of the negative studies. One targeted surgery was performed for every four CT studies. CT outcome influenced the decision to perform stapedectomy in 41 % CT-positive versus 4 % CT-negative patients. CT-positive ears for otosclerosis could not be predicted from baseline clinical or audiometric criteria. Those with endosteal extension demonstrated lower bone conduction thresholds presurgically. The positive predictive value of CT diagnosis of otosclerosis was 100 %. CT demonstrated a high rate of clinically relevant diagnoses in both CT-positive and -negative for otosclerosis patients, and this frequently influenced surgical management. CT also added value by demonstrating relevant extensions of the otosclerotic foci, some of which were predictive of audiometric parameters. (orig.)

  10. Biomarkers for disease progression and AAV therapeutic efficacy in feline Sandhoff disease

    Bradbury, Allison M; Gray-Edwards, Heather L; Shirley, Jamie L; McCurdy, Victoria J; Colaco, Alexandria N; Randle, Ashley N; Christopherson, Pete W; Bird, Allison C; Johnson, Aime K; Wilson, Diane U; Hudson, Judith A; De Pompa, Nicholas L; Sorjonen, Donald C; Brunson, Brandon L; Jeyakumar, Mylvaganam; Platt, Frances M; Baker, Henry J; Cox, Nancy R; Sena-Esteves, Miguel; Martin, Douglas R

    2014-01-01

    The GM2 gangliosidoses, Tay-Sachs disease (TSD) and Sandhoff disease (SD), are progressive neurodegenerative disorders that are caused by a mutation in the enzyme β-N-acetylhexosaminidase (Hex). Due to the recent emergence of novel experimental treatments, biomarker development has become particularly relevant in GM2 gangliosidosis as an objective means to measure therapeutic efficacy. Here we describe blood, cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), and electrodiagnostic methods for evaluating disease progression in the feline SD model and application of these approaches to assess AAV-mediated gene therapy. SD cats were treated by intracranial injections of the thalami combined with either the deep cerebellar nuclei or a single lateral ventricle using AAVrh8 vectors encoding feline Hex. Significantly altered in untreated SD cats, blood and CSF based biomarkers were normalized after AAV gene therapy. Also reduced after treatment were expansion of the lysosomal compartment in peripheral blood mononuclear cells and elevated activity of secondary lysosomal enzymes. MRI changes characteristic of the gangliosidoses were documented in SD cats and normalized after AAV gene therapy. The minimally invasive biomarkers reported herein should be useful to assess disease progression of untreated GM2 patients and those in future clinical trials. PMID:25284324

  11. Therapeutic efficacy of chemotherapy with ACNU and radiation therapy for malignant glioma in the cerebral hemisphere

    Miyagami, Mitsusuke; Katayama, Yoichi; Nakamura, Saburo [Nihon Univ., Tokyo (Japan). School of Medicine

    2000-10-01

    Seventy-two patients with malignant gliomas (57 with glioblastoma and 15 with anaplastic astrocytoma) in the cerebral hemisphere were studied retrospectively to evaluate the therapeutic efficacy of chemotherapy with nimustine and radiation after surgery. Survival was analyzed with the Kaplan-Meier method in 21 patients treated with radiotherapy after surgery and 51 patients treated with nimustine and radiotherapy after surgery. Histological classification age, and the extent of resection of the tumors were significantly correlated with survival. The median survival time was 8 months in patients treated with radiotherapy and 15 months in patients treated with nimustine and radiotherapy. The 2- and 5-year survival rates were 12% and 0% in patients treated with radiotherapy and 33% and 22% in patients treated with nimustine and radiotherapy. Thus, a significant difference in survival was recognized, and chemotherapy with nimustine was found to be useful as an adjuvant therapy for glioblastoma after surgery. However, survival time did not differ between intravenous and intra-arterial infusion of nimustine. (author)

  12. Efficacy of Morin as a Potential Therapeutic Phytocomponent: Insights into the Mechanism of Action

    Amarendranath Choudhury

    2017-11-01

    Full Text Available Morin (3,5,7,29,49-pentahydroxyflavone is a yellow colour natural bioflavonoid abundantly available in different species of Moraceae family. Besides this, Morin is also harvested from several other sources like tea, coffee, cereals, fruits and red wine. Anti-oxidant, anti-inflammatory, and antiproliferative potency of Morin is well established in both in vivo and in vitro experiments. Among all major sources of Morin, Almond (Prunus dulcis, Fig (Chlorophora tinctoria, and Indian guava (Psidium guajava contains high quantity of it. Easy availability, less side effects and robust functional properties have encouraged the use of these plants in the traditional herbal medicine. In last few decades, the studies on Morin have opened up a whole new era in the therapeutic medicine. Besides anti-oxidant, anti-inflammatory, and antiproliferative activity, Morin has also been reported as a potential neuroprotective agent against many neurological diseases including Alzheimer’s disease, Parkinson’s disease, and cerebral ischemia. According to published reports, the underlying neuroprotective mechanism of Morin is focused mainly on its capacity to inhibit oxidative stress in brain. However, recent data also supports its efficacy in neuroprotection by effectively interacting in the β‒amyloid pathways, inflammatory pathways, and apoptotic pathways. In the present review, we have accumulated all the protective contributions of Morin and intended to drag a mechanistic pathway containing the molecular events leading to the protection against various anomalies.

  13. Therapeutic efficacy and safety of propylthiouracil in psoriasis: An open-label study

    Pushpa Gnanaraj

    2011-01-01

    Full Text Available Background: Psoriasis is a common hyperproliferative disorder of the skin associated with significant morbidity. Most of the drugs used in psoriasis provide only a temporary relief, whereas they are riddled with potential toxicities and cost concerns. Hence, there is a constant need to explore newer, effective, orally administered, and cost-effective drugs with minimal adverse effects. In this scenario, propylthiouracil (PTU, an antithyroid thioureylene has been shown to be effective in psoriasis which satisfies the above criteria. Aim: The objective of our study is to assess the clinical efficacy of PTU in psoriasis. Methods: A total of 25 patients with plaque psoriasis were treated with oral PTU for 12 weeks. Clinical response was assessed using the "Psoriasis Area and Severity Index" (PASI score. Routine blood analyses and thyroid function tests were carried out periodically during the study. Results: Oral PTU produced significant clearing of lesions at 6 weeks and 12 weeks of the study period in all patients, as demonstrated by the reduction in PASI scores (33.9% in 6 weeks and 74.1% reduction in 12 weeks. Four patients experienced near complete clearing of the lesions. One patient developed mild elevation of liver enzymes which reversed on withdrawal of PTU. None of the patients had hypothyroidism or cytopenias. Conclusion: PTU significantly clears the lesions in psoriasis with minimal adverse effects. Hence, it can be considered as a therapeutic option in psoriasis, especially when the standard drugs cannot be used due to their toxicities or forbidding cost.

  14. Development and Evaluation of Mouth Dissolving Films of Amlodipine Besylate for Enhanced Therapeutic Efficacy

    K. M. Maheswari

    2014-01-01

    Full Text Available The present investigation was undertaken with an objective of formulating mouth dissolving films (MDFs of Amlodipine Besylate (AMLO to enhance convenience and compliance of the elderly and pediatric patients for better therapeutic efficacy. Film formers like hydroxy propyl methyl cellulose (HPMC and methyl cellulose (MC along with film modifiers like poly vinyl pyrrolidone K30 (PVP K30, and sodium lauryl sulphate (SLS as solubilizing agents were evaluated. The prepared MDFs were evaluated for in vitro dissolution characteristics, in vitro disintegration time, and their physicomechanical properties. All the prepared MDFs showed good mechanical properties like tensile strength, folding endurance, and % elongation. MDFs were evaluated by means of FTIR, SEM, and X-RD studies. MDFs with 7.5% (w/w of HPMC E3 gave better dissolution properties when compared to HPMC E5, HPMC E15, and MC. MDFs with PVP K30 and SLS gave superior dissolution properties when compared to MDFs without PVP K30 and SLS. The dissolution properties of MDFs with PVP K30 were superior when compared to MDFs with SLS. In the case of F3 containing 7.5% of HPMC E3 and 0.04% of PVP K30, complete and faster release was observed within 60 sec when compared to other formulations. Release kinetics data reveals diffusion is the release mechanism.

  15. Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations.

    Kourie, Hampig Raphael; Chaix, Marie; Gombos, Andrea; Aftimos, Phillippe; Awada, Ahmad

    2016-08-01

    Despite the availability of several potent HER2-directed targeted agents, primary and acquired resistance continues to influence patient outcomes in HER2-positive breast cancer. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor in late-phase clinical development. This review article focuses on neratinib in the treatment of HER2-positive breast cancer - early and metastatic stage - and HER2-mutant breast cancer, with particular emphasis on the pharmacokinetics and pharmacodynamics of the drug. The phase III ExteNET trial shows that neratinib improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in early-stage HER2-positive breast cancer, and in particular HER2+/HR+ tumors. Survival data are awaited. The investigational role of neratinib in high-risk patients or conversely in de-escalation dual regimens with other anti-HER2 therapies and without chemotherapy are of interest. Phase II trials show that neratinib has efficacy, either as monotherapy or in combination with other chemotherapeutic or endocrine agents, in patients with HER2-positive metastatic breast cancer and in tumors harboring HER2 mutations. The role of neratinib in therapeutic algorithms of HER2-positive patients, as well as delaying CNS events, awaits the results of ongoing trials such as NALA. Diarrhea, the main toxicity of neratinib, can be effectively managed with early loperamide prophylaxis.

  16. AKT2 siRNA delivery with amphiphilic-based polymeric micelles show efficacy against cancer stem cells.

    Rafael, Diana; Gener, Petra; Andrade, Fernanda; Seras-Franzoso, Joaquin; Montero, Sara; Fernández, Yolanda; Hidalgo, Manuel; Arango, Diego; Sayós, Joan; Florindo, Helena F; Abasolo, Ibane; Schwartz, Simó; Videira, Mafalda

    2018-11-01

    Development of RNA interference-based therapies with appropriate therapeutic window remains a challenge for advanced cancers. Because cancer stem cells (CSC) are responsible of sustaining the metastatic spread of the disease to distal organs and the progressive gain of resistance of advanced cancers, new anticancer therapies should be validated specifically for this subpopulation of cells. A new amphihilic-based gene delivery system that combines Pluronic ® F127 micelles with polyplexes spontaneously formed by electrostatic interaction between anionic siRNA and cationic polyethylenimine (PEI) 10K, was designed (PM). Resultant PM gather the requirements for an efficient and safe transport of siRNA in terms of its physicochemical characteristics, internalization capacity, toxicity profile and silencing efficacy. PM were loaded with a siRNA against AKT2, an important oncogene involved in breast cancer tumorigenesis, with a special role in CSC malignancy. Efficacy of siAKT2-PM was validated in CSC isolated from two breast cancer cell lines: MCF-7 and Triple Negative MDA-MB-231 corresponding to an aggressive subtype of breast cancer. In both cases, we observed significant reduction on cell invasion capacity and strong inhibition of mammosphere formation after treatment. These results prompt AKT2 inhibition as a powerful therapeutic target against CSC and pave the way to the appearance of more effective nanomedicine-based gene therapies aimed to prevent CSC-related tumor recurrence.

  17. CCR 20th Anniversary Commentary: Prospects and Challenges of Therapeutic Nanoparticles in Cancer.

    Rahman, Mohammad Aminur; Shin, Dong M

    2015-10-15

    In their review article published in the March 1, 2008, issue of Clinical Cancer Research, Cho and colleagues presented the strong potential of nanotechnology in cancer. This commentary discusses the latest advances in nanotechnology, which provide novel approaches for cancer diagnosis, imaging, drug delivery, and personalized therapy; highlights the perspectives for therapeutic nanoparticles; and describes the advantages and challenges of their multifunctionalities. ©2015 American Association for Cancer Research.

  18. Low-dose radiation potentiates the therapeutic efficacy of folate receptor-targeted hapten therapy.

    Sega, Emanuela I; Lu, Yingjuan; Ringor, Michael; Leamon, Christopher P; Low, Philip S

    2008-06-01

    Human cancers frequently overexpress a high-affinity cell-surface receptor for the vitamin folic acid. Highly immunogenic haptens can be targeted to folate receptor-expressing cell surfaces by administration of folate-hapten conjugates, rendering the decorated tumor cell surfaces more recognizable by the immune system. Treatment of antihapten-immunized mice with folate-hapten constructs results in elimination of moderately sized tumors by the immune system. However, when subcutaneous tumors exceed 300 mm(3) before initiation of therapy, antitumor activity is significantly decreased. In an effort to enhance the efficacy of folate-targeted hapten immunotherapy (FTHI) against large tumors, we explored the combination of targeted hapten immunotherapy with low-dose radiotherapy. Mice bearing 300-mm(3) subcutaneous tumors were treated concurrently with FTHI (500 nmol/kg of folate conjugated to fluorescein isothiocyanate, 20,000 U/dose of interleukin 2, and 25,000 U/dose of interferon alpha) and low-dose radiotherapy (3 Gy/dose focused directly on the desired tumor mass). The efficacy of therapy was evaluated by measuring tumor volume. Tumor growth analyses show that radiotherapy synergizes with FTHI in antihapten-immunized mice, thereby allowing for cures of animals bearing tumors greater than 300 mm(3). More importantly, nonirradiated distal tumor masses in animals containing locally irradiated tumors also showed improved response to hapten immunotherapy, suggesting that not all tumor lesions must be identified and irradiated to benefit from the combination therapy. These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice.

  19. Low-Dose Radiation Potentiates the Therapeutic Efficacy of Folate Receptor-Targeted Hapten Therapy

    Sega, Emanuela I.; Lu Yingjuan; Ringor, Michael; Leamon, Christopher P.; Low, Philip S.

    2008-01-01

    Purpose: Human cancers frequently overexpress a high-affinity cell-surface receptor for the vitamin folic acid. Highly immunogenic haptens can be targeted to folate receptor-expressing cell surfaces by administration of folate-hapten conjugates, rendering the decorated tumor cell surfaces more recognizable by the immune system. Treatment of antihapten-immunized mice with folate-hapten constructs results in elimination of moderately sized tumors by the immune system. However, when subcutaneous tumors exceed 300 mm 3 before initiation of therapy, antitumor activity is significantly decreased. In an effort to enhance the efficacy of folate-targeted hapten immunotherapy (FTHI) against large tumors, we explored the combination of targeted hapten immunotherapy with low-dose radiotherapy. Methods and Materials: Mice bearing 300-mm 3 subcutaneous tumors were treated concurrently with FTHI (500 nmol/kg of folate conjugated to fluorescein isothiocyanate, 20,000 U/dose of interleukin 2, and 25,000 U/dose of interferon α) and low-dose radiotherapy (3 Gy/dose focused directly on the desired tumor mass). The efficacy of therapy was evaluated by measuring tumor volume. Results: Tumor growth analyses show that radiotherapy synergizes with FTHI in antihapten-immunized mice, thereby allowing for cures of animals bearing tumors greater than 300 mm 3 . More importantly, nonirradiated distal tumor masses in animals containing locally irradiated tumors also showed improved response to hapten immunotherapy, suggesting that not all tumor lesions must be identified and irradiated to benefit from the combination therapy. Conclusions: These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice

  20. Development of new therapeutic methods of lung cancer through team approach study

    Park, Jong Ho; Zo, Jae Ill; Baek, Hee Jong; Jung, Jin Haeng; Lee, Jae Cheol; Ryoo, Baek Yeol; Kim, Mi Sook; Choi, Du Hwan; Park, Sun Young; Lee, Hae Young

    2000-12-01

    The aims of this study were to make the lung cancer clinics in Korea Cancer Center Hospital, and to establish new therapeutic methods of lung cancer for increasing the cure rate and survival rate of patients. Also another purpose of this study was to establish a common treatment method in our hospital. All patients who were operated in Korea Cancer Center Hospital from 1987 due to lung cancer were followed up and evaluated. And we have been studied the effect of postoperative adjuvant therapy in stage I, II, IIIA non-small cell lung cancer patients from 1989 with the phase three study form. Follow-up examinations were scheduled in these patients and interim analysis was made. Also we have been studied the effect of chemo-therapeutic agents in small cell lung cancer patients from 1997 with the phase two study form. We evaluated the results of this study. Some important results of this study were as follows. 1. The new therapeutic method (surgery + MVP chemotherapy) was superior to the standard therapeutic one in stage I Non-small cell lung cancer patients. So, we have to change the standard method of treatment in stage I NSCLC. 2. Also, this new therapeutic method made a good result in stage II NSCLC patients. And this result was reported in The Annals of Thoracic Surgery. 3. However, this new therapeutic method was not superior to the standard treatment method (surgery only) in stage IIIA NSCLC patients. So, we must develop new chemo-therapeutic agents in the future for advanced NSCLC patients. 4. In the results of the randomized phase II studies about small cell lung cancer, there was no difference in survival between Etoposide + Carboplatin + Ifosfamide + Cisplatin group and Etoposide + Carboplatin + Ifosfamide + Cisplatin + Tamoxifen group in both the limited and extended types of small cell lung cancer patients

  1. S14 as a Therapeutic Target in Breast Cancer

    Kinlaw, William

    2004-01-01

    .... Our aims are first to develop a model of anti-S14 breast cancer therapy in mice. Intratumoral adenoviral delivery of an S14-antisense gene into human breast cancer cell xenografts caused a significant inhibition of tumor growth...

  2. CDK5 as a Therapeutic Target in Prostate Cancer Metastasis

    Nelkin, Barry D

    2008-01-01

    We have recently found that CDK5 is active in prostate cancer cell lines and in almost all human metastatic prostate cancers, and inhibition of CDK5 activity resulted in reduction of spontaneous metastases by 79...

  3. CDK5 as a Therapeutic Target in Prostate Cancer Metastasis

    Nelkin, Barry

    2007-01-01

    We have recently found that CDK5 is active in prostate cancer cell lines and in almost all human metastatic prostate cancers, and inhibition of CDK5 activity resulted in reduction of spontaneous metastases by 79...

  4. A short synthetic peptide fragment of human C2ORF40 has therapeutic potential in breast cancer

    Lin, Chaoyang [Shandong Univ., Jinan (China); Zhang, Pengju [Shandong Univ., Jinan (China); Jiang, Anli [Shandong Univ., Jinan (China); Mao, Jian-Hua [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Wei, Guangwei [Shandong Univ. School of Medicine, Jinan (China)

    2017-03-30

    C2ORF40 encodes a secreted protein which is cleaved to generate soluble peptides by proteolytic processing and this process is believed to be necessary for C2ORF40 to exert cell type specific biological activity. Here, we reported a short mimic peptide of human C2ORF40 acts potential therapeutic efficacy in human cancer cells in vitro and in vivo. We synthesized a short peptide of human C2ORF40, named C2ORF40 mimic peptide fragment and assessed its biological function on cancer cell growth, migration and tumorigenesis. Cell growth assay showed that C2ORF40 mimic peptide fragment significantly suppressed cell proliferation of breast and lung cancer cells. Moreover, C2ORF40 mimic peptide fragment significantly inhibited the migration and invasion of breast cancer cells. Furthermore, we showed that this peptide suppressed tumorigenesis in breast tumor xenograft model. Cell cycle assay indicated that the C2ORF40 mimic peptide fragment suppressed the growth of tumor cells through inducing mitotic phase arrest. In conclusion, our results firstly suggested that this short synthetic peptide of human C2ORF40 may be a candidate tumor therapeutic agent.

  5. Nutraceuticals as potential therapeutic agents for colon cancer: a review

    Kuppusamy, Palaniselvam; Yusoff, Mashitah M.; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj

    2014-01-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment o...

  6. Drosophila as a Screening Platform for Novel Lung Cancer Therapeutics

    2016-09-01

    Distinct roles for two receptor tyrosine kinases in epithelial branching morphogenesis in Drosophila. Dev. Cell 9, 831–842. Cancer Genome Atlas Research...Ras isoprenylation and pAkt inhibition by zole- dronic acid and fluvastatin enhances paclitaxel activity in T24 bladder cancer cells. Cancers (Basel...PKB signaling via P2X7 receptor in pancreatic cancer cells. Biochem. Pharmacol. 78, 1115–1126. Mo, H., and Elson, C.E. (2004). Studies of the

  7. The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients.

    El-Najjar, Nahed; Jantsch, Jonathan; Gessner, André

    2017-08-28

    Cancer remains a leading cause of mortality and morbidity worldwide. In addition to organ failure, the most frequent reasons for admission of cancer patients to intensive care units (ICU) are: infections and sepsis. As critically ill, the complexity of the health situation of cancer patients renders the standard antimicrobial regimen more complex and even inadequate which results in increased mortality rates. This is due to pathophysiological changes in the volume of distribution, increased clearance, as well as to organ dysfunction. While in the former cases a decrease in drug efficacy is observed, the hallmark of the latter one is overdosing leading to increased toxicity at the expense of efficacy. Furthermore, an additional risk factor is the potential drug-drug interaction between antibiotics and antineoplastic agents. Therefore, therapeutic drug monitoring (TDM) is a necessity to improve the clinical outcome of antimicrobial therapy in cancer patients. To be applied in routine analysis the method used for TDM should be cheap, fast and highly accurate/sensitive. Furthermore, as ICU patients are treated with a cocktail of antibiotics the method has to cover the simultaneous analysis of antibiotics used as a first/second line of treatment. The aim of the current review is to briefly survey the pitfalls in the current antimicrobial therapy and the central role of TDM in dose adjustment and drug-drug interaction's evaluation. A major section is dedicated to summarize the currently published analytical methods and to shed light on the difficulties and potential problems that can be encountered during method development.

  8. Tumor P-Glycoprotein Correlates with Efficacy of PF-3758309 in in vitro and in vivo Models of Colorectal Cancer

    Bradshaw-Pierce, Erica Lynn; Pitts, Todd M.; Tan, Aik-Choon; McPhillips, Kelly; West, Mark; Gustafson, Daniel L.; Halsey, Charles; Nguyen, Leslie; Lee, Nathan V.; Kan, Julie L. C.; Murray, Brion William; Eckhardt, S. Gail

    2013-01-01

    P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, is overexpressed in a number of different cancers and some studies show that P-gp overexpression can be correlated to poor prognosis or therapeutic resistance. Here we sought to elucidate if PF-3758309 (PF-309), a novel p-21 activated kinase inhibitor, efficacy was influenced by tumor P-gp. Based on in vitro proliferation data, a panel of colorectal cancer cell lines were ranked as sensitive or resistant and ABCB1...

  9. Tumor p-glycoprotein correlates with efficacy of PF-3758309 in in vitro and in vivo models of colorectal cancer.

    Erica Lynn Bradshaw-Pierce; Erica Lynn Bradshaw-Pierce; Todd M Pitts; Aik-Choon eTan; Kelly eMcPhillips; Mark eWest; Daniel L Gustafson; Charles eHalsey; Leslie eNguyen; Nathan V Lee; Julie LC Kan; Brion William Murray; S. Gail eEckhardt

    2013-01-01

    P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, is overexpressed in a number of different cancers and some studies show that P-gp overexpression can be correlated to poor prognosis or therapeutic resistance. Here we sought to elucidate if PF-3758309 (PF-309), a novel p-21 activated kinase inhibitor, efficacy was influenced by tumor P-gp. Based on in vitro proliferation data, a panel of colorectal cancer cell lines were ranked as sensitive or resistant and ABCB...

  10. Identifying therapeutic targets in gastric cancer: the current status and future direction

    Yu, Beiqin; Xie, Jingwu

    2016-01-01

    Gastric cancer is the third leading cause of cancer-related death worldwide. Our basic understanding of gastric cancer biology falls behind that of many other cancer types. Current standard treatment options for gastric cancer have not changed for the last 20 years. Thus, there is an urgent need to establish novel strategies to treat this deadly cancer. Successful clinical trials with Gleevec in CML and gastrointestinal stromal tumors have set up an example for targeted therapy of cancer. In this review, we will summarize major progress in classification, therapeutic options of gastric cancer. We will also discuss molecular mechanisms for drug resistance in gastric cancer. In addition, we will attempt to propose potential future directions in gastric cancer biology and drug targets. PMID:26373844

  11. Periostin: a promising target of therapeutical intervention for prostate cancer

    Ding Weihong

    2011-06-01

    Full Text Available Abstract Background In our recent study, Periostin was up-regulated in prostate cancer(PCa compared with benign prostate hyperplasia (BPH by proteomics analysis of prostate biopsies. We investigated the effect of sliencing Periostin by RNA interference (RNAi on the proliferation and migration of PCa LNCap cell line. Methods All the prostate biopsies from PCa, BPH and BPH with local prostatic intraepithelial neoplasm(PIN were analyzed by iTRAQ(Isobaric tags for relative and absolute quantification technology. Western blotting and immunohistochemical staining were used to verify Periostin expression in the tissues of PCa. Periostin expression in different PCa cell lines was determined by immunofluorescence staining, western blotting and reverse transcription PCR(RT-PCR. The LNCap cells with Periostin expression were used for transfecting shRNA-Periostin lentiviral particles. The efficancy of transfecting shRNA lentiviral particles was evaluated by immunofluorescence, western blotting and Real-time PCR. The effect of silencing Periostin expression by RNAi on proliferation of LNCap cells was determined by MTT assay and tumor xenografts. The tissue slices from theses xenografts were analyzed by hematoxylin and eosin(HE staining. The expression of Periostin in the xenografts was deteminned by Immunohistochemical staining and western blotting. The migration of LNCap cells after silencing Periostin gene expression were analyzed in vitro. Results Periostin as the protein of interest was shown 9.12 fold up-regulation in PCa compared with BPH. The overexpression of Periostin in the stroma of PCa was confirmed by western blotting and immunohistochemical staining. Periostin was only expressed in PCa LNCap cell line. Our results indicated that the transfection ratio was more than 90%. As was expected, both the protein level and mRNA level of Periostin in the stably expressing shRNA-Periostin LNCap cells were significantly reduced. The stably expressing sh

  12. Therapeutic targeting of the p53 pathway in cancer stem cells

    Prabhu, Varun V.; Allen, Joshua E.; Hong, Bo; Zhang, Shengliang; Cheng, Hairong; El-Deiry, Wafik S.

    2013-01-01

    Introduction Cancer stem cells are a high profile drug target for cancer therapeutics due to their indispensable role in cancer progression, maintenance, and therapeutic resistance. Restoring wild-type p53 function is an attractive new therapeutic approach for the treatment of cancer due to the well-described powerful tumor suppressor function of p53. As emerging evidence intimately links p53 and stem cell biology, this approach also provides an opportunity to target cancer stem cells. Areas covered Therapeutic approaches to restore the function of wild-type p53, cancer and normal stem cell biology in relation to p53, and the downstream effects of p53 on cancer stem cells. Expert opinion The restoration of wild-type p53 function by targeting p53 directly, its interacting proteins, or its family members holds promise as a new class of cancer therapies. This review examines the impact that such therapies may have on normal and cancer stem cells based on the current evidence linking p53 signaling with these populations. PMID:22998602

  13. Nutraceuticals as potential therapeutic agents for colon cancer: a review.

    Kuppusamy, Palaniselvam; Yusoff, Mashitah M; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj

    2014-06-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis.

  14. Molecular pathways and therapeutic targets in lung cancer

    Shtivelman, Emma; Hensing, Thomas; Simon, George R.; Dennis, Phillip A.; Otterson, Gregory A.; Bueno, Raphael; Salgia, Ravi

    2014-01-01

    Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review. PMID:24722523

  15. Nutraceuticals as potential therapeutic agents for colon cancer: a review

    Palaniselvam Kuppusamy

    2014-06-01

    Full Text Available Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis.

  16. Skp2 is a Promising Therapeutic Target in Breast Cancer

    Wang, Zhiwei; Fukushima, Hidefumi; Inuzuka, Hiroyuki; Wan, Lixin; Liu, Pengda; Gao, Daming [Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (United States); Sarkar, Fazlul H. [Department of Pathology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI (United States); Wei, Wenyi, E-mail: wwei2@bidmc.harvard.edu [Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA (United States)

    2012-01-04

    Breast cancer is the most common type of cancer among American women, and remains the second leading cause of cancer-related death for female in the United States. It has been known that several signaling pathways and various factors play critical roles in the development and progression of breast cancer, such as estrogen receptor, Notch, PTEN, human epidermal growth factor receptor 2, PI3K/Akt, BRCA1, and BRCA2. Emerging evidence has shown that the F-box protein S-phase kinase associated protein 2 (Skp2) also plays an important role in the pathogenesis of breast cancer. Therefore, in this brief review, we summarize the novel functions of Skp2 in the pathogenesis of breast cancer. Moreover, we provide further evidence regarding the state of our knowledge toward the development of novel Skp2 inhibitors especially natural “chemopreventive agents” as targeted approach for the prevention and/or treatment of breast cancer.

  17. Glyco-engineering strategies for the development of therapeutic enzymes with improved efficacy for the treatment of lysosomal storage diseases.

    Oh, Doo-Byoung

    2015-08-01

    Lysosomal storage diseases (LSDs) are a group of inherent diseases characterized by massive accumulation of undigested compounds in lysosomes, which is caused by genetic defects resulting in the deficiency of a lysosomal hydrolase. Currently, enzyme replacement therapy has been successfully used for treatment of 7 LSDs with 10 approved therapeutic enzymes whereas new approaches such as pharmacological chaperones and gene therapy still await evaluation in clinical trials. While therapeutic enzymes for Gaucher disease have N-glycans with terminal mannose residues for targeting to macrophages, the others require N-glycans containing mannose-6-phosphates that are recognized by mannose-6-phosphate receptors on the plasma membrane for cellular uptake and targeting to lysosomes. Due to the fact that efficient lysosomal delivery of therapeutic enzymes is essential for the clearance of accumulated compounds, the suitable glycan structure and its high content are key factors for efficient therapeutic efficacy. Therefore, glycan remodeling strategies to improve lysosomal targeting and tissue distribution have been highlighted. This review describes the glycan structures that are important for lysosomal targeting and provides information on recent glyco-engineering technologies for the development of therapeutic enzymes with improved efficacy.

  18. [Therapeutic efficacy of compound Xuanju capsule on autoimmune prostatitis in rats: an experimental study].

    Li, Tian-Fu; Wu, Qiu-Yue; Li, Wei-Wei; Zhang, Cui; Li, Na; Shang, Xue-Jun; Xia, Xin-Yi; Xu, Hao-Qin; Huang, Yu-Feng

    2014-05-01

    To evaluate the therapeutic effect of Compound Xuanju Capsule (CXC) on autoimmune prostatitis in rat models. Sixty healthy male Wistar rats were randomly divided into five groups of equal number: blank control, low-concentration purified prostate protein (low-conc PPP), low-conc PPP + CXC treatment, high-concentration PPP (hi-con PPP), and hi-conc PPP + CXC treatment. Autoimmune prostatitis models were established by intragastric administration of PPP solution at 15 mg/ml (low concentration) and 80 mg/ml, respectively. At 30 days after modeling, the rats in the blank control and low-conc and hi-conc PPP model groups were treated with normal saline, and those in the other two groups with CXC at a daily dose of 0.068 g/ml. At 30, 45, and 60 days, all the animals were sacrificed for observation of pathological changes in the prostate tissue and determination of the levels of IL-8, IL-10, and TNF-alpha in the serum. Compared with the PPP models, the hi-conc PPP + CXC group showed significantly reduced levels of IL-8 and TNF-alpha in the serum at 45 days ([148.54 +/- 17.23] and [62.14 +/- 5.59] pg/ml vs [100.77 +/- 11.08] and [32.63 +/- 2.91] pg/ml, P microscope. Compound Xuanju Capsule is efficacious on autoimmune prostatis in rats by reducing inflammatory changes in the prostate tissue and improving the expression of inflammatory factors.

  19. Therapeutic efficacy of autologous platelet-rich plasma and polydeoxyribonucleotide on female pattern hair loss.

    Lee, Si-Hyung; Zheng, Zhenlong; Kang, Jin-Soo; Kim, Do-Young; Oh, Sang Ho; Cho, Sung Bin

    2015-01-01

    Autologous platelet-rich plasma (PRP) exerts positive therapeutic effects on hair thickness and density in patients with pattern hair loss. The aim of our study was to evaluate the efficacy of intra-perifollicular autologous PRP and polydeoxyribonucleotide (PDRN) injections in treating female pattern hair loss (FPHL). Twenty FPHL patients were treated with a single session of PRP injection, followed by 12 sessions of PDRN intra-perifollicular injection, along the scalp at weekly intervals. Additionally, another 20 FPHL patients were treated with 12 sessions of PDRN injection only. Meanwhile, one half of the backs of two rabbits was injected with the PRP preparation, while the other half was injected with phosphate buffered saline as a control. Tissue samples from the rabbits were analyzed by real-time polymerase chain reaction and Western blotting. Compared with baseline values, patients treated with PRP and PDRN injections exhibited clinical improvement in mean hair counts (23.2 ± 15.5%; p hair thickness (16.8 ± 10.8%; p hair counts (17.9 ± 13.2%; p hair thickness (13.5 ± 10.7%; p hair thickness than treatment with PDRN therapy alone (p = 0.031), but not in hair counts (p > 0.05). The pilot animal study revealed significant up-regulation of WNT, platelet-derived growth factor, and fibroblast growth factor expression in rabbit skin treated with the PRP preparation, compared with control skin. In conclusion, intra-perifollicular injections of autologous PRP and/or PDRN generate improvements in hair thickness and density in FPHL patients. © 2014 by the Wound Healing Society.

  20. Neuroprotective efficacy and therapeutic window of curcuma oil: in rat embolic stroke model

    Dohare, Preeti; Garg, Puja; sharma, Uma; Jagannathan, NR; Ray, Madhur

    2008-01-01

    Background Among the naturally occurring compounds, turmeric from the dried rhizome of the plant Curcuma longa has long been used extensively as a condiment and a household remedy all over Southeast Asia. Turmeric contains essential oil, yellow pigments (curcuminoids), starch and oleoresin. The present study was designed for investigating the neuroprotective efficacy and the time window for effective therapeutic use of Curcuma oil (C. oil). Method In the present study, the effect of post ischemic treatment of C.oil after ischemia induced by occlusion of the middle cerebral artery in the rat was observed. C.oil (500 mg/kg body wt) was given 4 hrs post ischemia. The significant effect on lesion size as visualized by using diffusion-weighted magnetic resonance imaging and neuroscore was still evident when treatment was started 4 hours after insult. Animals were assessed for behavioral deficit scores after 5 and 24 hours of ischemia. Subsequently, the rats were sacrificed for evaluation of infarct and edema volumes and other parameters. Results C.oil ameliorated the ischemia induced neurological functional deficits and the infarct and edema volumes measured after 5 and 24 hrs of ischemia. After 24 hrs, immunohistochemical and Western blot analysis demonstrated that the expression of iNOS, cytochrome c and Bax/Bcl-2 were altered after the insult, and antagonized by treatment with C.oil. C.oil significantly reduced nitrosative stress, tended to correct the decreased mitochondrial membrane potential, and also affected caspase-3 activation finally apoptosis. Conclusion Here we demonstrated that iNOS-derived NO produced during ischemic injury was crucial for the up-regulation of ischemic injury targets. C.oil down-regulates these targets this coincided with an increased survival rate of neurons. PMID:18826584

  1. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys.

    Warren, Travis K; Jordan, Robert; Lo, Michael K; Ray, Adrian S; Mackman, Richard L; Soloveva, Veronica; Siegel, Dustin; Perron, Michel; Bannister, Roy; Hui, Hon C; Larson, Nate; Strickley, Robert; Wells, Jay; Stuthman, Kelly S; Van Tongeren, Sean A; Garza, Nicole L; Donnelly, Ginger; Shurtleff, Amy C; Retterer, Cary J; Gharaibeh, Dima; Zamani, Rouzbeh; Kenny, Tara; Eaton, Brett P; Grimes, Elizabeth; Welch, Lisa S; Gomba, Laura; Wilhelmsen, Catherine L; Nichols, Donald K; Nuss, Jonathan E; Nagle, Elyse R; Kugelman, Jeffrey R; Palacios, Gustavo; Doerffler, Edward; Neville, Sean; Carra, Ernest; Clarke, Michael O; Zhang, Lijun; Lew, Willard; Ross, Bruce; Wang, Queenie; Chun, Kwon; Wolfe, Lydia; Babusis, Darius; Park, Yeojin; Stray, Kirsten M; Trancheva, Iva; Feng, Joy Y; Barauskas, Ona; Xu, Yili; Wong, Pamela; Braun, Molly R; Flint, Mike; McMullan, Laura K; Chen, Shan-Shan; Fearns, Rachel; Swaminathan, Swami; Mayers, Douglas L; Spiropoulou, Christina F; Lee, William A; Nichol, Stuart T; Cihlar, Tomas; Bavari, Sina

    2016-03-17

    The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the

  2. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats.

    Jan B W J Cornelissen

    Full Text Available High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10, and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application.

  3. Therapeutic efficacy and microSPECT/CT imaging of {sup 188}Re-DXR-liposome in a C26 murine colon carcinoma solid tumor model

    Chang, Y.-J.; Chang, C.-H.; Yu, C.-Y.; Chang, T.-J.; Chen, L.-C. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Chen, M.-H. [National Health Research Institutes, Miaoli, Taiwan (China); Lee, T.-W. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Ting Gann [National Health Research Institutes, Miaoli, Taiwan (China)], E-mail: gann.ting@msa.hinet.net

    2010-01-15

    Nanocarriers can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness and reducing toxicity. The objective of this study was to investigate the therapeutic efficacy of a new co-delivery radiochemotherapeutics of {sup 188}Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin (DXR) ({sup 188}Re-DXR-liposome) in a C26 murine colon carcinoma solid tumor model. To evaluate the targeting and localization of {sup 188}Re-DXR-liposome in C26 murine tumor-bearing mice, biodistribution, microSPECT/CT imaging and pharmacokinetic studies were performed. The antitumor effect of {sup 188}Re-DXR-liposome was assessed by tumor growth inhibition, survival ratio and histopathological hematoxylin-eosin staining. The tumor target and localization of the nanoliposome delivery radiochemotherapeutics of {sup 188}Re-DXR-liposome were demonstrated in the biodistribution, pharmacokinetics and in vivo nuclear imaging studies. In the study on therapeutic efficacy, the tumor-bearing mice treated with bimodality radiochemotherapeutics of {sup 188}Re-DXR-liposome showed better mean tumor growth inhibition rate (MGI) and longer median survival time (MGI=0.048; 74 days) than those treated with radiotherapeutics of {sup 188}Re-liposome (MGI=0.134; 60 days) and chemotherapeutics of Lipo-Dox (MGI=0.413; 38 days). The synergistic tumor regression effect was observed with the combination index (CI) exceeding 1 (CI=1.145) for co-delivery radiochemotherapeutics of {sup 188}Re-DXR-liposome. Two (25%) of the mice treated with radiochemotherapeutics were completely cured after 120 days. The therapeutic efficacy of radiotherapeutics of {sup 188}Re-liposome and the synergistic effect of the combination radiochemotherapeutics of {sup 188}Re-DXR-liposome have been demonstrated in a C26 murine solid tumor animal model, which pointed to the potential benefit and promise of the co-delivery of

  4. Anti-Angiogenic Therapeutic Indictors in Breast Cancer

    Su, Min-Ying

    2003-01-01

    This project studies the therapeutic indicators in ant-angiogenic therapy. Every animal with mammary tumor was scheduled to receive a baseline MRI, core biopsy, then followed by 4 treatments with weekly MRI follow...

  5. MicroRNAs in cancer therapeutics: "from the bench to the bedside".

    Monroig-Bosque, Paloma del C; Rivera, Carlos A; Calin, George A

    2015-01-01

    MicroRNAs (miRNAs) are non-coding RNA transcripts that regulate physiological processes by targeting proteins directly. Their involvement in research has been robust, and evidence of their regulative functions has granted them the title: master regulators of the human genome. In cancer, they are considered important therapeutic agents, due to the fact that their aberrant expression contributes to disease development, progression, metastasis, therapeutic response and patient overall survival. This has endeavored fields of biomedical sciences to invest in developing and exploiting miRNA-based therapeutics thoroughly. Herein we highlight relevant ongoing/open clinical trials involving miRNAs and cancer.

  6. A dynamical systems model for combinatorial cancer therapy enhances oncolytic adenovirus efficacy by MEK-inhibition.

    Bagheri, Neda; Shiina, Marisa; Lauffenburger, Douglas A; Korn, W Michael

    2011-02-01

    Oncolytic adenoviruses, such as ONYX-015, have been tested in clinical trials for currently untreatable tumors, but have yet to demonstrate adequate therapeutic efficacy. The extent to which viruses infect targeted cells determines the efficacy of this approach but many tumors down-regulate the Coxsackievirus and Adenovirus Receptor (CAR), rendering them less susceptible to infection. Disrupting MAPK pathway signaling by pharmacological inhibition of MEK up-regulates CAR expression, offering possible enhanced adenovirus infection. MEK inhibition, however, interferes with adenovirus replication due to resulting G1-phase cell cycle arrest. Therefore, enhanced efficacy will depend on treatment protocols that productively balance these competing effects. Predictive understanding of how to attain and enhance therapeutic efficacy of combinatorial treatment is difficult since the effects of MEK inhibitors, in conjunction with adenovirus/cell interactions, are complex nonlinear dynamic processes. We investigated combinatorial treatment strategies using a mathematical model that predicts the impact of MEK inhibition on tumor cell proliferation, ONYX-015 infection, and oncolysis. Specifically, we fit a nonlinear differential equation system to dedicated experimental data and analyzed the resulting simulations for favorable treatment strategies. Simulations predicted enhanced combinatorial therapy when both treatments were applied simultaneously; we successfully validated these predictions in an ensuing explicit test study. Further analysis revealed that a CAR-independent mechanism may be responsible for amplified virus production and cell death. We conclude that integrated computational and experimental analysis of combinatorial therapy provides a useful means to identify treatment/infection protocols that yield clinically significant oncolysis. Enhanced oncolytic therapy has the potential to dramatically improve non-surgical cancer treatment, especially in locally advanced

  7. Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice.

    Judge, Adam D; Robbins, Marjorie; Tavakoli, Iran; Levi, Jasna; Hu, Lina; Fronda, Anna; Ambegia, Ellen; McClintock, Kevin; MacLachlan, Ian

    2009-03-01

    siRNAs that specifically silence the expression of cancer-related genes offer a therapeutic approach in oncology. However, it remains critical to determine the true mechanism of their therapeutic effects. Here, we describe the preclinical development of chemically modified siRNA targeting the essential cell-cycle proteins polo-like kinase 1 (PLK1) and kinesin spindle protein (KSP) in mice. siRNA formulated in stable nucleic acid lipid particles (SNALP) displayed potent antitumor efficacy in both hepatic and subcutaneous tumor models. This was correlated with target gene silencing following a single intravenous administration that was sufficient to cause extensive mitotic disruption and tumor cell apoptosis. Our siRNA formulations induced no measurable immune response, minimizing the potential for nonspecific effects. Additionally, RNAi-specific mRNA cleavage products were found in tumor cells, and their presence correlated with the duration of target mRNA silencing. Histological biomarkers confirmed that RNAi-mediated gene silencing effectively inhibited the target's biological activity. This report supports an RNAi-mediated mechanism of action for siRNA antitumor effects, suggesting a new methodology for targeting other key genes in cancer development with siRNA-based therapeutics.

  8. Therapeutic Efficacy of Bipolar Radiofrequency Thermotherapy for Patients with Chronic Prostatitis: A Retrospective Analysis of 26 Cases

    Lim, Ju Young; Shim, Seung Bum; Yoo, Dong Hoon; Park, Young Woong; Kim, Jong Yeon; Noh, Joon Hwa

    2012-01-01

    Purpose Chronic prostatitis (CP) does not yet have a universally successful therapy. Alternative treatments including thermotherapy have been adopted in the multimodal management of pain and voiding dysfunction. We retrospectively analyzed the therapeutic efficacy of bipolar radiofrequency thermotherapy for patients who were unsatisfied with conventional medication for CP. Materials and Methods A retrospective study between October 2009 and September 2010 of 26 patients who were under 50 year...

  9. Radiotherapy-induced anti-tumor immunity contributes to the therapeutic efficacy of irradiation and can be augmented by CTLA-4 blockade in a mouse model.

    Yuya Yoshimoto

    Full Text Available PURPOSE: There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL activity. METHODS AND MATERIALS: C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD was defined as the time (in days for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. RESULTS: In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days and prolonged median survival time (MST to 59 days (versus 28 days in the non-irradiated group. CD8(+ cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days. Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days, while anti-FR4 and anti-GITR antibodies did not affect efficacy. CONCLUSIONS: Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4

  10. Radiotherapy-Induced Anti-Tumor Immunity Contributes to the Therapeutic Efficacy of Irradiation and Can Be Augmented by CTLA-4 Blockade in a Mouse Model

    Yoshimoto, Yuya; Suzuki, Yoshiyuki; Mimura, Kousaku; Ando, Ken; Oike, Takahiro; Sato, Hiro; Okonogi, Noriyuki; Maruyama, Takanori; Izawa, Shinichiro; Noda, Shin-ei; Fujii, Hideki; Kono, Koji; Nakano, Takashi

    2014-01-01

    Purpose There is growing evidence that tumor-specific immune responses play an important role in anti-cancer therapy, including radiotherapy. Using mouse tumor models we demonstrate that irradiation-induced anti-tumor immunity is essential for the therapeutic efficacy of irradiation and can be augmented by modulation of cytotoxic T lymphocyte (CTL) activity. Methods and Materials C57BL/6 mice, syngeneic EL4 lymphoma cells, and Lewis lung carcinoma (LL/C) cells were used. Cells were injected into the right femurs of mice. Ten days after inoculation, tumors were treated with 30 Gy of local X-ray irradiation and their growth was subsequently measured. The effect of irradiation on tumor growth delay (TGD) was defined as the time (in days) for tumors to grow to 500 mm3 in the treated group minus that of the untreated group. Cytokine production and serum antibodies were measured by ELISA and flow cytometry. Results In the EL4 tumor model, tumors were locally controlled by X-ray irradiation and re-introduced EL4 cells were completely rejected. Mouse EL4-specific systemic immunity was confirmed by splenocyte cytokine production and detection of tumor-specific IgG1 antibodies. In the LL/C tumor model, X-ray irradiation also significantly delayed tumor growth (TGD: 15.4 days) and prolonged median survival time (MST) to 59 days (versus 28 days in the non-irradiated group). CD8(+) cell depletion using an anti-CD8 antibody significantly decreased the therapeutic efficacy of irradiation (TGD, 8.7 days; MST, 49 days). Next, we examined whether T cell modulation affected the efficacy of radiotherapy. An anti-CTLA-4 antibody significantly increased the anti-tumor activity of radiotherapy (TGD was prolonged from 13.1 to 19.5 days), while anti-FR4 and anti-GITR antibodies did not affect efficacy. Conclusions Our results indicate that tumor-specific immune responses play an important role in the therapeutic efficacy of irradiation. Immunomodulation, including CTLA-4 blockade, may be a

  11. New cancer diagnostics and therapeutics from a ninth 'hallmark of cancer': symmetric self-renewal by mutated distributed stem cells.

    Sherley, James L

    2013-11-01

    A total of eight cellular alterations associated with human carcinogenesis have been framed as the 'hallmarks of cancer'. This representation overlooks a ninth hallmark of cancer: the requirement for tumor-originating distributed stem cells to shift sufficiently from asymmetric to symmetric self-renewal kinetics for attainment of the high cell production rate necessary to form clinically significant tumors within a human lifespan. Overlooking this ninth hallmark costs opportunities for discovery of more selective molecular targets for development of improved cancer therapeutics and missing cancer stem cell biomarkers of greater specificity. Here, the biological basis for the ninth hallmark of cancer is considered toward highlighting its importance in human carcinogenesis and, as such, its potential for revealing unique molecules for targeting cancer diagnostics and therapeutics.

  12. Disrupting the Scaffold to Improve Focal Adhesion Kinase–Targeted Cancer Therapeutics

    Cance, William G.; Kurenova, Elena; Marlowe, Timothy; Golubovskaya, Vita

    2013-01-01

    Focal adhesion kinase (FAK) is emerging as a promising cancer target because it is highly expressed at both the transcriptional and translational level in cancer and is involved in many aspects of tumor growth, invasion, and metastasis. Existing FAK-based therapeutics focus on inhibiting the kinase's catalytic function and not the large scaffold it creates that includes many oncogenic receptor tyrosine kinases and tumor suppressor proteins. Targeting the FAK scaffold is a feasible and promising approach for developing highly specific therapeutics that disrupt FAK signaling pathways in cancer. PMID:23532331

  13. Disrupting the scaffold to improve focal adhesion kinase-targeted cancer therapeutics.

    Cance, William G; Kurenova, Elena; Marlowe, Timothy; Golubovskaya, Vita

    2013-03-26

    Focal adhesion kinase (FAK) is emerging as a promising cancer target because it is highly expressed at both the transcriptional and translational level in cancer and is involved in many aspects of tumor growth, invasion, and metastasis. Existing FAK-based therapeutics focus on inhibiting the kinase's catalytic function and not the large scaffold it creates that includes many oncogenic receptor tyrosine kinases and tumor suppressor proteins. Targeting the FAK scaffold is a feasible and promising approach for developing highly specific therapeutics that disrupt FAK signaling pathways in cancer.

  14. Neoadjuvant therapy for esophageal cancer. Indication and efficacy

    Kato, Ken; Hamaguchi, Tetsuya; Yamada, Yasuhide; Shirao, Kuniaki; Shimada, Yasuhiro

    2007-01-01

    Some approaches such as adjuvant chemotherapy, neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy have been tried to improve the efficacy of treatment for resectable esophageal cancer patients. The usefullness of neoadjuvant chemotherapy, has remained a matter of controversy. However, there is a report from JCOG9907 in Japan that two courses of neoadjuvant 5-fluorouracil/cisplatin (5-FU/CDDP) improved the survival of esophageal squamous cell cancer patients. Neoadjuvant chemoradiotherapy has not had a consistent evaluation because of the varying results of each trial. But from the results of meta-analysis and CALGB9781, the neoadjuvant chemoradiotherapy called ''trimodality therapy'' has been a standard treatment in the United States. We should evaluate whether there would be similar effectiveness in Japan, where the histology and operative approach are different. Some approaches such as DNA microarray and proteomics, which can predict the treatment effect, are being tried. (author)

  15. [Neoadjuvant therapy for esophageal cancer - indication and efficacy].

    Kato, Ken; Hamaguchi, Tetsuya; Yamada, Yasuhide; Shirao, Kuniaki; Shimada, Yasuhiro

    2007-10-01

    Some approaches such as adjuvant chemotherapy, neoadjuvant chemotherapy and neoadjuvant chemoradiotherapy have been tried to improve the efficacy of treatment for resectable esophageal cancer patients. The usefullness of neoadjuvant chemotherapy, has remained a matter of controversy. However, there is a report from JCOG9907 in Japan that two courses of neoadjuvant 5-FU/CDDP improved the survival of esophageal squamous cell cancer patients. Neoadjuvant chemoradiotherapy has not had a consistent evaluation because of the varying results of each trial. But from the results of meta-analysis and CALGB9781, the neoadjuvant chemoradiotherapy called "trimodality therapy" has been a standard treatment in the United States. We should evaluate whether there would be similar effectiveness in Japan, where the histology and operative approach are different. Some approaches such as DNA microarray and proteomics, which can predict the treatment effect, are being tried.

  16. Dual-therapeutic reporter genes fusion for enhanced cancer gene therapy and imaging.

    Sekar, T V; Foygel, K; Willmann, J K; Paulmurugan, R

    2013-05-01

    Two of the successful gene-directed enzyme prodrug therapies include herpes simplex virus-thymidine kinase (HSV1-TK) enzyme-ganciclovir prodrug and the Escherichia coli nitroreductase (NTR) enzyme-CB1954 prodrug strategies; these enzyme-prodrug combinations produce activated cytotoxic metabolites of the prodrugs capable of tumor cell death by inhibiting DNA synthesis and killing quiescent cells, respectively. Both these strategies also affect significant bystander cell killing of neighboring tumor cells that do not express these enzymes. We have developed a dual-combination gene strategy, where we identified HSV1-TK and NTR fused in a particular orientation can effectively kill tumor cells when the tumor cells are treated with a fusion HSV1-TK-NTR gene- along with a prodrug combination of GCV and CB1954. In order to determine whether the dual-system demonstrate superior therapeutic efficacy than either HSV1-TK or NTR systems alone, we conducted both in vitro and in vivo tumor xenograft studies using triple negative SUM159 breast cancer cells, by evaluating the efficacy of cell death by apoptosis and necrosis upon treatment with the dual HSV1-TK genes-GCV-CB1954 prodrugs system, and compared the efficiency to HSV1-TK-GCV and NTR-CB1954. Our cell-based studies, tumor regression studies in xenograft mice, histological analyses of treated tumors and bystander studies indicate that the dual HSV1-TK-NTR-prodrug system is two times more efficient even with half the doses of both prodrugs than the respective single gene-prodrug system, as evidenced by enhanced apoptosis and necrosis of tumor cells in vitro in culture and xenograft of tumor tissues in animals.

  17. Next-Gen Therapeutics for Skin Cancer: Nutraceuticals.

    Sreedhar, Annapoorna; Li, Jun; Zhao, Yunfeng

    2018-05-15

    Growing modernization and lifestyle changes with limited physical activity have impacted diet and health, leading to an increased cancer mortality rate worldwide. As a result, there is a greater need than before to develop safe and novel anticancer drugs. Current treatment options such as chemotherapy, radiotherapy and surgery, induce unintended side effects, compromising patient's quality of life, and physical well-being. Therefore, there has been an increased global interest in the use of dietary supplements and traditional herbal medicines for treatment of cancer. Recently, nutraceuticals or "natural" substances isolated from food have attracted considerable attention in the cancer field. Emerging research suggests that nutraceuticals may indeed prevent and protect against cancer. The intent of this article is to review some of the current spice-derived nutraceuticals in the treatment of melanoma and skin cancer.

  18. BMI-1, a promising therapeutic target for human cancer

    WANG, MIN-CONG; LI, CHUN-LI; CUI, JIE; JIAO, MIN; WU, TAO; JING, LI; NAN, KE-JUN

    2015-01-01

    BMI-1 oncogene is a member of the polycomb-group gene family and a transcriptional repressor. Overexpression of BMI-1 has been identified in various human cancer tissues and is known to be involved in cancer cell proliferation, cell invasion, distant metastasis, chemosensitivity and patient survival. Accumulating evidence has revealed that BMI-1 is also involved in the regulation of self-renewal, differentiation and tumor initiation of cancer stem cells (CSCs). However, the molecular mechanisms underlying these biological processes remain unclear. The present review summarized the function of BMI-1 in different human cancer types and CSCs, and discussed the signaling pathways in which BMI-1 is potentially involved. In conclusion, BMI-1 may represent a promising target for the prevention and therapy of various cancer types. PMID:26622537

  19. Therapeutic Targeting of Lipid Droplets as Disease Markers in Ovarian Cancer

    2016-03-01

    Defective Autophagy and Increased Lipid Droplet Biogenesis in vitro and in vivo in Ovarian Cancer. American Association of Cancer Research , May 18-22...AWARD NUMBER: W81XWH-13-1-0119 TITLE: Therapeutic Targeting of Lipid Droplets as Disease Markers in Ovarian Cancer PRINCIPAL INVESTIGATOR...FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: Approved for Public Release

  20. Enhancing the efficacy of cisplatin in ovarian cancer treatment – could arsenic have a role

    Helm C William

    2009-01-01

    Full Text Available Abstract Ovarian cancer affects more than 200,000 women each year around the world. Most women are not diagnosed until the disease has already metastasized from the ovaries with a resultant poor prognosis. Ovarian cancer is associated with an overall 5 year survival of little more than 50%. The mainstay of front-line therapy is cytoreductive surgery followed by chemotherapy. Traditionally, this has been by the intravenous route only but there is more interest in the delivery of intraperitoneal chemotherapy utilizing the pharmaco-therapeutic advantage of the peritoneal barrier. Despite three large, randomized clinical trials comparing intravenous with intraperitoneal chemotherapy showing improved outcomes for those receiving at least part of their chemotherapy by the intraperitoneal route. Cisplatin has been the most active drug for the treatment of ovarian cancer for the last 4 decades and the prognosis for women with ovarian cancer can be defined by the tumor response to cisplatin. Those whose tumors are innately platinum-resistant at the time of initial treatment have a very poor prognosis. Although the majority of patients with ovarian cancer respond to front-line platinum combination chemotherapy the majority will develop disease that becomes resistant to cisplatin and will ultimately succumb to the disease. Improving the efficacy of cisplatin could have a major impact in the fight against this disease. Arsenite is an exciting agent that not only has inherent single-agent tumoricidal activity against ovarian cancer cell lines but also multiple biochemical interactions that may enhance the cytotoxicity of cisplatin including inhibition of deoxyribose nucleic acid (DNA repair. In vitro studies suggest that arsenite may enhance the activity of cisplatin in other cell types. Arsenic trioxide is already used clinically to treat acute promyelocytic leukemia demonstrating its safety profile. Further research in ovarian cancer is warranted to define

  1. Clinical efficacy of CT-guided 125I seed implantation therapy for advanced pancreatic cancer

    Wang Zhongmin; Lu Jian; Gong Ju; Zheng Yunfeng; Zhang Liyun; Huang Gang; Chen Kemin

    2009-01-01

    Objective: To discuss the clinical efficacy of CT-guided radioactive 125 I seed implantation treatment for unresectable pancreatic cancer. Methods: Forty patients with inoperable pancreatic cancer were enrolled in this study, including 25 males and 15 females with an median age of 69 years (38-89 years). Treatment planning system (TPS) was used to reconstruct 3-dimensional images of pancreatic tumor and to define the quantity and distribution of 125 I seeds. The radioactivity of 125 I seeds was 0.5 - 0.8 mCi / seed. The seeds were implanted into pancreatic tumor under CT guidance at intervals of 1 cm and were kept away from vessels, pancreatic duct and other adjacent important organs. The tumor matched peripheral dose (MPD) was 60-140 Gy. The median amount of implanted 125 I seeds was 36 (18-68) in number. CT scan was performed immediately after the procedure to check the quality of the seeds. In addition, 10 patients received concurrent chemotherapy with arterial infusion of gemcitabin and 5-fluororacil (5-Fu) for 3 to 4 therapeutic courses. Results: The median diameter of the tumors was 4.9 cm. The follow-up period was 2 to 28 months. After the treatment the refractory pain was significantly relieved (P 125 I seed implantation is a safe, effective and minimally-invasive brachytherapy for unresectable pancreatic cancer with reliable short-term efficacy. It has an excellent anti-pain effect. The curative results can be further improved when chemotherapy is employed together. However, its long-term efficacy needs to be observed. (authors)

  2. Neuropilin 2: Novel Biomarker and Therapeutic Target for Aggressive Prostate Cancer

    2016-11-01

    Expression and significance of vascular endothelial growth factor receptor 2 in bladder cancer . J. Urol. 175, 1245–1252 (2006). 130. Sato, K. et al...Expression of vascular endothelial growth factor gene and its receptor (flt-1) gene in urinary bladder cancer . Tohoku J. Exp. Med. 185, 173–184 (1998). R...inhibition should improve the efficacy of these therapies significantly. 15. SUBJECT TERMS Prostate cancer , VEGF, Neuropilin, IGF-1 receptor , PTEN, stem

  3. Therapeutic efficacy of different brands of albendazole against soil transmitted helminths among students of Mendera Elementary School, Jimma, Southwest Ethiopia.

    Tefera, Ephrem; Belay, Tariku; Mekonnen, Seleshi Kebede; Zeynudin, Ahmed; Belachew, Tefera

    2015-01-01

    Different brands Albendazole are commercially available and the efficacious brand/s is/are required for effective control of STHs infection. Thus, this study is aimed at determining the therapeutic efficacy of different brands of albendazole against soil transmitted helminths among school children of Jimma town. A cross sectional survey for prevalence of geohelminths and a randomized trial for efficacy study of different brands of albendazole was conducted among students Mendera Elementary School from March 29 to April 29, 2010. Positive subjects were randomized into three treatment arms using lottery method. The collected stool samples were examined by the McMaster method. CRs were calculated using SPSS windows version 16 and ERRs were calculated using appropriate formula. Of the 715 school children who had their stools examined, 326 were positive for STHs with a prevalence rate of 45.6%. The cure rates (CR) for A. lumbricoides, T. trichiura and Hookworm were 99.4, 59.9 and 93.7%, respectively. Similarly, the egg reduction rates (ERR) were 97, 99.9 and 99.9% respectively. A statistical significant mean STH egg count difference were observed between pre and post-intervention study (p 0.05). All the three brands of Albendazole tested regardless of the brand type were therapeutically efficacious for Ascariasis, Trichuriasis and Hookworm infections irrespective of the infection status whether it was single or multiple.

  4. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma

    2011-01-01

    Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent. PMID:21299897

  5. Autophagy Therapeutic Potential of Garlic in Human Cancer Therapy

    Yung-Lin Chu

    2013-07-01

    Full Text Available Cancer is one of the deadliest diseases against humans. To tackle this menace, humans have developed several high-technology therapies, such as chemotherapy, tomotherapy, targeted therapy, and antibody therapy. However, all these therapies have their own adverse side effects. Therefore, recent years have seen increased attention being given to the natural food for complementary therapy, which have less side effects. Garlic 大 蒜 Dà Suàn; Allium sativum, is one of most powerful food used in many of the civilizations for both culinary and medicinal purpose. In general, these foods induce cancer cell death by apoptosis, autophagy, or necrosis. Studies have discussed how natural food factors regulate cell survival or death by autophagy in cancer cells. From many literature reviews, garlic could not only induce apoptosis but also autophagy in cancer cells. Autophagy, which is called type-II programmed cell death, provides new strategy in cancer therapy. In conclusion, we wish that garlic could be the pioneer food of complementary therapy in clinical cancer treatment and increase the life quality of cancer patients.

  6. Flavonoids as Chemopreventive and Therapeutic Agents Against Lung Cancer

    Albert Cabrera

    2014-05-01

    Full Text Available The objective of the present review is to study the relationship between flavonoids and lung cancer, proposing that their regular consumption in Western diets could be beneficial for protecting patients against lung cancer. An extensive search of the scientific literature was performed in the following electronic specialized databases (PubMed central (PMC-NBCI, Elsevier Journal, SciELO Spain, Scirus, Science Direct, including studies in animals, cells, and humans, in order to establish the effect of flavonoids in the prevention and development of lung cancer. Although in vitro and animal studies show the potential ability of flavonoids to act against different types of cancers, especially against lung cancers, the diverse results reported within epidemiological studies, together with the lack of experiments in humans, are the major factors in limiting making dietary recommendations based on scientific evidence for the management of patients with lung cancer. Therefore, the authors of the present study recommend following the dietary health practice guidelines which promotes the consumption of food enriched in flavonoids and reflects the current state of knowledge of an effective and appropriate diet in lung cancer patients.Erratum in: Rev Esp Nutr Hum Diet. 2013;17(2:91-92Link: http://www.renhyd.org/index.php/renhyd/article/view/6/17

  7. Cancer risks following diagnostic and therapeutic radiation exposure in children

    Kleinerman, Ruth A. [National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, EPS 7044, Rockville, MD (United States)

    2006-09-15

    The growing use of interventional and fluoroscopic imaging in children represents a tremendous benefit for the diagnosis and treatment of benign conditions. Along with the increasing use and complexity of these procedures comes concern about the cancer risk associated with ionizing radiation exposure to children. Children are considerably more sensitive to the carcinogenic effects of ionizing radiation than adults, and children have a longer life expectancy in which to express risk. Numerous epidemiologic cohort studies of childhood exposure to radiation for treatment of benign diseases have demonstrated radiation-related risks of cancer of the thyroid, breast, brain and skin, as well as leukemia. Many fewer studies have evaluated cancer risk following diagnostic radiation exposure in children. Although radiation dose for a single procedure might be low, pediatric patients often receive repeated examinations over time to evaluate their conditions, which could result in relatively high cumulative doses. Several cohort studies of girls and young women subjected to multiple diagnostic radiation exposures have been informative about increased mortality from breast cancer with increasing radiation dose, and case-control studies of childhood leukemia and postnatal diagnostic radiation exposure have suggested increased risks with an increasing number of examinations. Only two long-term follow-up studies of cancer following cardiac catheterization in childhood have been conducted, and neither reported an overall increased risk of cancer. Most cancers can be induced by radiation, and a linear dose-response has been noted for most solid cancers. Risks of radiation-related cancer are greatest for those exposed early in life, and these risks appear to persist throughout life. (orig.)

  8. Cancer risks following diagnostic and therapeutic radiation exposure in children

    Kleinerman, Ruth A.

    2006-01-01

    The growing use of interventional and fluoroscopic imaging in children represents a tremendous benefit for the diagnosis and treatment of benign conditions. Along with the increasing use and complexity of these procedures comes concern about the cancer risk associated with ionizing radiation exposure to children. Children are considerably more sensitive to the carcinogenic effects of ionizing radiation than adults, and children have a longer life expectancy in which to express risk. Numerous epidemiologic cohort studies of childhood exposure to radiation for treatment of benign diseases have demonstrated radiation-related risks of cancer of the thyroid, breast, brain and skin, as well as leukemia. Many fewer studies have evaluated cancer risk following diagnostic radiation exposure in children. Although radiation dose for a single procedure might be low, pediatric patients often receive repeated examinations over time to evaluate their conditions, which could result in relatively high cumulative doses. Several cohort studies of girls and young women subjected to multiple diagnostic radiation exposures have been informative about increased mortality from breast cancer with increasing radiation dose, and case-control studies of childhood leukemia and postnatal diagnostic radiation exposure have suggested increased risks with an increasing number of examinations. Only two long-term follow-up studies of cancer following cardiac catheterization in childhood have been conducted, and neither reported an overall increased risk of cancer. Most cancers can be induced by radiation, and a linear dose-response has been noted for most solid cancers. Risks of radiation-related cancer are greatest for those exposed early in life, and these risks appear to persist throughout life. (orig.)

  9. Therapeutic efficacy of percutaneous radiofrequency ablation versus microwave ablation for hepatocellular carcinoma.

    Lei Zhang

    Full Text Available The aim of this study was to investigate the therapeutic efficacy of percutaneous radiofrequency (RF ablation versus microwave (MW ablation for hepatocellular carcinoma (HCC measuring ≤ 5 cm in greatest diameter. From January 2006 to December 2006, 78 patients had undergone RF ablation whereas 77 had undergone MW ablation. Complete ablation (CA, local tumour progression (LTP and distant recurrence (DR were compared. The overall survival curves were calculated with the Kaplan-Meier technique and compared with the log-rank test. The CA rate was 83.4% (78/93 for RF ablation and 86.7%(91/105 for MW ablation. The LTP rate was 11.8% (11/93 for RF ablation and 10.5% (11/105 for MW ablation. DR was found in 51 (65.4% in the RF ablation and 62 (80.5% in the MW ablation. There was no significant difference in the 1-, 3-, and 5-year overall survival rates (P = 0.780 and the 1-, 3-, and 5-year disease-free survival rates (P = 0.123 between RF and MW ablation. At subgroup analyses, for patients with tumors ≤ 3.0 cm, there was no significant difference in the 1-, 3-, and 5-year overall survival rates (P = 0.067 and the corresponding disease-free survival rates(P = 0.849. For patients with tumor diameters of 3.1-5.0 cm, the 1-, 3-, and 5-year overall survival rates were 87.1%, 61.3%, and 40.1% for RF ablation and 85.4%, 36.6%, and 22% for MW ablation, with no significant difference (P = 0.068. The corresponding disease-free survival rates were 74.2%, 54.8%, and 45.2% for the RF ablation group and 53.3%, 26.8%, and 17.1% for the MW ablation group. The disease-free survival curve for the RF ablation group was significantly better than that for the MW ablation group (P = 0.018. RF ablation and MW ablation are both effective methods in treating hepatocellular carcinomas, with no significant differences in CA, LTP, DR, and overall survival.

  10. Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression.

    Roseman, Leor; Nutt, David J; Carhart-Harris, Robin L

    2017-01-01

    < 0.05). Discussion: This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. Future therapeutic work with psychedelics should recognize the essential importance of quality of experience in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety. Trial Registration: ISRCTN, number ISRCTN14426797, http://www.isrctn.com/ISRCTN14426797.

  11. Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression

    Leor Roseman

    2018-01-01

    ASC (p < 0.05.Discussion: This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. Future therapeutic work with psychedelics should recognize the essential importance of quality of experience in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety.Trial Registration: ISRCTN, number ISRCTN14426797, http://www.isrctn.com/ISRCTN14426797

  12. Therapeutic Efficacy of Endometrial Scratching in Repeated Controlled Ovarian Stimulation (COS) Failure Cycles

    Wadhwa, Leena; Mishra, Mona

    2018-01-01

    Objective: The objective of the study was (1) “to evaluate the therapeutic efficacy of endometrial scratching in repeated controlled ovarian stimulation (COS) failure cycles.” And (2) “to compare differences in pregnancy outcome by endometrial scratching in early (D2–D4) and late follicular phases (D7–D9) of the same stimulation cycle.” Materials and Methods: Women attending infertility clinic in a tertiary care center and who have two or more repeated COS failure cycles and planned for COS with intrauterine insemination (IUI) were included in the study which is a prospective parallel, interventional, single-blinded, randomized control study, in 1:1 allocation ratio. A total of 165 patients were recruited and randomly allocated into three groups: Group A (n = 55) underwent endometrial scratching on D2–D4 of the same COS cycle, Group B (n = 55) on D7–D9, and Group C (n = 55) no intervention done. All the patients underwent COS according to standard protocol followed by IUI. Results: Clinical pregnancy rate was 12.73% (odds ratio [OR] =0.87 95% confidence interval [CI] =0.288–2.55, P = 1), 16.36% (OR = 1.15; 95% CI = 0.40–3.23, P = 1), and 14.54%, respectively, in Group A, B, and C, respectively (P = 0.86), as per intention to treat analysis. Using Chi-square test, P value between Group A and B was 0.787, between Group A and C was 1.000, and between Group B and C was 1.000. As per protocol analysis, clinical pregnancy rate was 13.46% (OR = 0.83; 95% CI = 0.27–2.5, P = 0.74), 19.57% (OR = 1.3 95%; CI = 0.45–3.73, P = 0.41), and 15.69%. Using Chi-square test, Pvalue between Group A and B was 0.588, between Group A and C was 0.967, and between Group B and C was 0.815. No abortions and multiple pregnancies occurred in either of the groups. Conclusion: The effect found was of good quantum in Group B as per protocol analysis which could be of clinical relevance if larger sample size would have been taken. Endometrial scratching is a cost

  13. Therapeutic efficacy of fibroblast growth factor 10 in a rabbit model of dry eye.

    Zheng, Wenjing; Ma, Mingming; Du, Ergang; Zhang, Zhengwei; Jiang, Kelimu; Gu, Qing; Ke, Bilian

    2015-11-01

    The aim of the present study was to investigate the therapeutic efficacy of fibroblast growth factor 10 (FGF10) in the promotion of healing, survival and expression of mucin in corneal epithelial cells in a rabbit dry eye model. A total of 12 healthy female New Zealand white rabbits were divided randomly into three groups. The lacrimal glands were injected with saline either alone (normal control group) or with concanavalin A (Con A), with either topical phosphate‑buffered saline (PBS; PBS control group) or 25 µg/ml FGF10 (FGF10 treatment group). Lacrimal gland inflammation, tear function, corneal epithelial cell integrity, cell apoptosis and mucin expression were subsequently assessed. Lacrimal gland tissue biopsies were performed in conjunction with histology and electron microscopy observations. Tear meniscus height (TMH) and tear meniscus area (TMA) were measured using Fourier domain‑optical coherence tomography. Tear membrane break‑up time (TBUT) was also assessed and corneal fluorescein staining was performed. The percentages of apoptotic corneal and conjunctival (Cj) epithelial cells (ECs) were counted using a terminal deoxynucleotidyl transferase‑mediated dUTP nick end labeling method. The mRNA expression levels of Muc1 were determined using reverse transcription‑quantitative polymerase chain reaction analyses. The TMH and TMA values of the PBS and treatment groups were found to be significantly reduced, compared with those of the normal control group 3 days after Con A injection. However, the TMH and TMA of the FGF10 treatment group were higher, compared with those of the PBS group 3 and 7 days after treatment, respectively. Furthermore, the FGF10 treatment group exhibited prolonged TBUT, reduced corneal fluorescein staining and repaired epithelial cell ultrastructure7 days after treatment. The percentages of apoptotic corneal‑ and Cj‑ECs in the FGF10 treatment group were significantly reduced, compared with those in the PBS group. FGF10

  14. Efficacy of Early Diagnosis and Treatment in Women with a Family History of Breast Cancer

    Pål Møller

    1999-01-01

    Full Text Available BACKGROUND: Surveillance programmes for women at increased genetic risk of breast cancer are being established worldwide but little is known of their efficacy in early detection of cancers and hence reduction in mortality.

  15. Praziquantel synergistically enhances paclitaxel efficacy to inhibit cancer cell growth.

    Zhen Hua Wu

    Full Text Available The major challenges we are facing in cancer therapy with paclitaxel (PTX are the drug resistance and severe side effects. Massive efforts have been made to overcome these clinical challenges by combining PTX with other drugs. In this study, we reported the first preclinical data that praziquantel (PZQ, an anti-parasite agent, could greatly enhance the anticancer efficacy of PTX in various cancer cell lines, including PTX-resistant cell lines. Based on the combination index value, we demonstrated that PZQ synergistically enhanced PTX-induced cell growth inhibition. The co-treatment of PZQ and PTX also induced significant mitotic arrest and activated the apoptotic cascade. Moreover, PZQ combined with PTX resulted in a more pronounced inhibition of tumor growth compared with either drug alone in a mouse xenograft model. We tried to investigate the possible mechanisms of this synergistic efficacy induced by PZQ and PTX, and we found that the co-treatment of the two drugs could markedly decrease expression of X-linked inhibitor of apoptosis protein (XIAP, an anti-apoptotic protein. Our data further demonstrated that down-regulation of XIAP was required for the synergistic interaction between PZQ and PTX. Together, this study suggested that the combination of PZQ and PTX may represent a novel and effective anticancer strategy for optimizing PTX therapy.

  16. Immunogenomic Classification of Colorectal Cancer and Therapeutic Implications

    Roelands, Jessica; Kuppen, Peter J. K.; Vermeulen, Louis; Maccalli, Cristina; Decock, Julie; Wang, Ena; Marincola, Francesco M.; Bedognetti, Davide; Hendrickx, Wouter

    2017-01-01

    The immune system has a substantial effect on colorectal cancer (CRC) progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies) is influenced by the immune system. The molecular characterization of

  17. VITAL: Vanguard Investigations of Therapeutic Approaches to Lung Cancer

    Hong, Waun K; Lotan, Reuben; Stewart, David

    2006-01-01

    .... In addition, the clinical trials that will be conducted in the VITAL Research Program will demonstrate the true rate of lung cancer recurrence and second primary tumor incidence in patients at high...

  18. Therapeutic potential of snake venom in cancer therapy: current perspectives

    Vyas, Vivek Kumar; Brahmbhatt, Keyur; Bhatt, Hardik; Parmar, Utsav

    2013-01-01

    Many active secretions produced by animals have been employed in the development of new drugs to treat diseases such as hypertension and cancer. Snake venom toxins contributed significantly to the treatment of many medical conditions. There are many published studies describing and elucidating the anti-cancer potential of snake venom. Cancer therapy is one of the main areas for the use of protein peptides and enzymes originating from animals of different species. Some of these proteins or peptides and enzymes from snake venom when isolated and evaluated may bind specifically to cancer cell membranes, affecting the migration and proliferation of these cells. Some of substances found in the snake venom present a great potential as anti-tumor agent. In this review, we presented the main results of recent years of research involving the active compounds of snake venom that have anticancer activity. PMID:23593597

  19. The epigenome as a therapeutic target in prostate cancer.

    Perry, Antoinette S; Watson, R William G; Lawler, Mark; Hollywood, Donal

    2010-12-01

    During cancer development and progression, tumor cells undergo abnormal epigenetic modifications, including DNA methylation, histone deacetylation and nucleosome remodeling. Collectively, these aberrations promote genomic instability and lead to silencing of tumor-suppressor genes and reactivation of oncogenic retroviruses. Epigenetic modifications, therefore, provide exciting new avenues for prostate cancer research. Promoter hypermethylation is widespread during neoplastic transformation of prostate cells, which suggests that restoration of a 'normal' epigenome through treatment with inhibitors of the enzymes involved could be clinically beneficial. Global patterns of histone modifications are also being defined and have been associated with clinical and pathologic predictors of prostate cancer outcome. Although treatment for localized prostate cancer can be curative, the development of successful therapies for the management of castration-resistant metastatic disease is urgently needed. Reactivation of tumor-suppressor genes by demethylating agents and histone deacetylase inhibitors could be a potential treatment option for patients with advanced disease.

  20. Development of a Multifaceted Ovarian Cancer Therapeutic and Imaging Agent

    Markland, Francis S

    2008-01-01

    ...%. This project outlines the development of a recombinant version of a member of a class of proteins known as disintegrins as an innovative imaging and diagnostic agent for ovarian cancer (OC). Vicrostatin (VN...

  1. CDK5 as a Therapeutic Target in Prostate Cancer Metastasis

    Nelkin, Barry

    2007-01-01

    .... We also proposed to examine the role of CDK5 activity in growth of prostate cancer metastatic to bone, using PC3 based bioluminescent cell clones, and to explore the potential for CDK5 inhibition...

  2. Epidemiological, clinical and therapeutic profile of cervical cancer in ...

    MJP

    2015-08-21

    Aug 21, 2015 ... Results: The incidence of cervical cancer in Butembo was 0.97% with a peak in 2011 .... bleeding, vaginal discharge, pelvic pain, Schiller. Test, clinical ..... female students and staff in a tertiary institution in the Niger Delta.

  3. Therapeutic vaccines for cancer: an overview of clinical trials

    Melero, I.; Gaudernack, G.; Gerritsen, W.R.; Huber, C.; Parmiani, G.; Scholl, S.; Thatcher, N.; Wagstaff, J.; Zielinski, C.; Faulkner, I.; Mellstedt, H.

    2014-01-01

    The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the

  4. Therapeutic Strategies Against Cyclin E1 Amplified Ovarian Cancers

    2017-10-01

    13-14 ( References ) 1. INTRODUCTION: Approximately 20% of high grade serous ovarian cancers harbor Cyclin E1 (CCNE1) amplification and are associated... Harvard Medical School and was named Director of Translational Research in the Gynecologic Oncology Program at Dana-Farber Cancer Institute. How...on HDAC6 activity. Nat Cell Biol 19:962-973. PMID: 28737768. PMC5541905. Books or other non-periodical, one-time publications. “Nothing to Report

  5. New Diagnostic and Therapeutic Approaches to Eradicating Recurrent Breast Cancer

    2015-09-01

    barcode vectors, which allows for PCR amplification of barcodes from genomic DNA . To identify and quantify relative abundance of each clonal population...Define tumor cell hallmarks that predict risk of breast cancer recurrence a. Identify human breast cancer barcoded DTCs that convert to malignancy in...xenograft mouse models of metastasis – 100% complete in one model; 40% complete for bone metastasis model b. Identify mouse Her2+ barcoded DTCs that

  6. Myeloid-Derived Suppressor Cells and Therapeutic Strategies in Cancer

    Hiroshi Katoh

    2015-01-01

    Full Text Available Development of solid cancer depends on escape from host immunosurveillance. Various types of immune cells contribute to tumor-induced immune suppression, including tumor associated macrophages, regulatory T cells, type 2 NKT cells, and myeloid-derived suppressor cells (MDSCs. Growing body of evidences shows that MDSCs play pivotal roles among these immunosuppressive cells in multiple steps of cancer progression. MDSCs are immature myeloid cells that arise from myeloid progenitor cells and comprise a heterogeneous immune cell population. MDSCs are characterized by the ability to suppress both adaptive and innate immunities mainly through direct inhibition of the cytotoxic functions of T cells and NK cells. In clinical settings, the number of circulating MDSCs is associated with clinical stages and response to treatment in several cancers. Moreover, MDSCs are reported to contribute to chemoresistant phenotype. Collectively, targeting MDSCs could potentially provide a rationale for novel treatment strategies in cancer. This review summarizes recent understandings of MDSCs in cancer and discusses promissing clinical approaches in cancer patients.

  7. Animal models and therapeutic molecular targets of cancer: utility and limitations

    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

  8. New strategies to improve the efficacy of colorectal cancer vaccines: from bench to bedside.

    Mocellin, Simone

    2006-12-01

    By exploiting a naturally occurring defense system, anticancer vaccination embodies an ideal non-toxic treatment capable of evoking tumor-specific immune responses that can ultimately recognize and kill colorectal cancer (CRC) cells. Despite the enormous theoretical potential of active specific immunotherapy, no vaccination regimen has achieved sufficient therapeutic efficacy necessary for clinical implementation. Nevertheless, several immunological advances have opened new avenues of research to decipher the biological code governing tumor immune responsiveness, and this is leading to the design of potentially more effective immunotherapeutic protocols. This review briefly summarizes the principles behind anti-CRC vaccination and describes the most promising immunological strategies that have been developed, which are expected to renew interest in this molecularly targeted anticancer approach.

  9. Characterization of KIF11 as a novel prognostic biomarker and therapeutic target for oral cancer.

    Daigo, Kayo; Takano, Atsushi; Thang, Phung Manh; Yoshitake, Yoshihiro; Shinohara, Masanori; Tohnai, Iwau; Murakami, Yoshinori; Maegawa, Jiro; Daigo, Yataro

    2018-01-01

    Oral cancer has a high mortality rate, and its incidence is increasing gradually worldwide. As the effectiveness of standard treatments is still limited, the development of new therapeutic strategies is eagerly awaited. Kinesin family member 11 (KIF11) is a motor protein required for establishing a bipolar spindle in cell division. The role of KIF11 in oral cancer is unclear. Therefore, the present study aimed to assess the role of KIF11 in oral cancer and evaluate its role as a prognostic biomarker and therapeutic target for treating oral cancer. Immunohistochemical analysis demonstrated that KIF11 was expressed in 64 of 99 (64.6%) oral cancer tissues but not in healthy oral epithelia. Strong KIF11 expression was significantly associated with poor prognosis among oral cancer patients (P=0.034), and multivariate analysis confirmed its independent prognostic value. In addition, inhibition of KIF11 expression by transfection of siRNAs into oral cancer cells or treatment of cells with a KIF11 inhibitor significantly suppressed cell proliferation, probably through G2/M arrest and subsequent induction of apoptosis. These results suggest that KIF11 could be a potential prognostic biomarker and therapeutic target for oral cancer.

  10. Small molecule inhibitor screening identifified HSP90 inhibitor 17-AAG as potential therapeutic agent for gallbladder cancer.

    Weber, Helga; Valbuena, José R; Barbhuiya, Mustafa A; Stein, Stefan; Kunkel, Hana; García, Patricia; Bizama, Carolina; Riquelme, Ismael; Espinoza, Jaime A; Kurtz, Stephen E; Tyner, Jeffrey W; Calderon, Juan Francisco; Corvalán, Alejandro H; Grez, Manuel; Pandey, Akhilesh; Leal-Rojas, Pamela; Roa, Juan C

    2017-04-18

    Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.

  11. Maximizing the Therapeutic Efficacy of Imatinib Mesylate-Loaded Niosomes on Human Colon Adenocarcinoma Using Box-Behnken Design.

    Kassem, Mohammed A; El-Sawy, Hossam S; Abd-Allah, Fathy I; Abdelghany, Tamer M; El-Say, Khalid M

    2017-01-01

    This research purposed to formulate an optimized imatinib mesylate (IM)-loaded niosomes to improve its chemotherapeutic efficacy. The influence of 3 formulation factors on niosomal vesicular size (Y 1 ), zeta potential (Y 2 ), entrapment capacity percentage (Y 3 ), the percentage of initial drug release after 2 h (Y 4 ), and the percentage of cumulative drug release after 24 h (Y 5 ) were studied and optimized using Box-Behnken design. Optimum desirability was specified and the optimized formula was prepared, stability tested, morphologically examined, checked for vesicular bilayer formation and evaluated for its in vitro cytotoxicity on 3 different cancer cell lines namely MCF-7, HCT-116, and HepG-2 in addition to 1 normal cell line to ensure its selectivity against cancer cells. The actual responses of the optimized IM formulation were 425.36 nm, -62.4 mV, 82.96%, 18.93%, and 89.45% for Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 , respectively. The optimized IM-loaded niosomes confirmed the spherical vesicular shape imaged by both light and electron microscopes and further proven by differential scanning calorimetry. Moreover, the optimized formula exhibited improved stability on storage at 4 ± 2°C and superior efficacy on MCF7, HCT-116, and HepG2 as IC 50 values were 6.7, 16.4, and 7.3 folds less than those of free drug, respectively. Interestingly, IC 50 of the optimized formula against normal cell line was ranged from 3 to 11 folds higher than in different cancer cells indicating a higher selectivity of the optimized formula to cancer cells. In conclusion, the incorporation of IM in niosomes enhanced its efficacy and selectivity toward cancer cells, presenting a promising tool to fight cancer using this approach. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  12. Inhibition of miR-155, a therapeutic target for breast cancer, prevented in cancer stem cell formation.

    Zuo, Jiangcheng; Yu, Yalan; Zhu, Man; Jing, Wei; Yu, Mingxia; Chai, Hongyan; Liang, Chunzi; Tu, Jiancheng

    2018-02-06

    Breast cancer is a common cancer in women of worldwide. Cancer cells with stem-like properties played important roles in breast cancer, such as relapse, metastasis and treatment resistance. Micro-RNA-155 (miR-155) is a well-known oncogenic miRNA overexpressed in many human cancers. The expression levels of miR-155 in 38 pairs of cancer tissues and adjacent normal tissues from breast cancer patients were detected using quantitative real-time PCR. The invasive cell line MDA-MB-231 was used to quantify the expression of miR-155 by tumor-sphere forming experiment. Soft agar colony formation assay and tumor xenografts was used to explore whether the inhibition of miR-155 could reduce proliferation of cancer cells in vivo and vitro. In the study, we found miR-155 was upregulated in BC. Soft agar colony formation assay and tumor xenografts showed inhibition of miR-155 could significantly reduce proliferation of cancer cells in vivo and vitro, which confirmed that miR-155 is an effective therapeutic target of breast cancer. Sphere-forming experiment showed that overexpression of miR-155 significantly correlated with stem-like properties. Expressions of ABCG2, CD44 and CD90 were repressed by inhibition of miR-155, but CD24 was promoted. Interestingly, inhibition of miR-155 rendered MDA-MB-231 cells more sensitive to Doxorubicinol, which resulted in an increase of inhibition rate from 20.23% to 68.72%. Expression of miR-155 not only was a therapeutic target but also was associated with cancer stem cell formation and Doxorubicinol sensitivity. Our results underscore the importance of miR-155 as a therapeutic target and combination of Doxorubicinol and miR-155-silencing would be a potential way to cure breast cancer.

  13. Therapeutic ratio and fractionation in cancer of the lung

    Cox, J.D.; Bauer, M.

    1988-01-01

    Bronchopulmonary carcinomas have long been considered among the most frustrating problems in radiation oncology. In spite of the reasonably favorable results reported over 30 years ago with conventional X-irradiation of patients with operable carcinoma of the lung, the patients usually referred for radiation therapy with unresectable tumors permit few opportunities for successful treatment and thus lead to a general nihilism about this disease. The potential damage that can occur from radiation therapy to the normal lung can be life-threatening. Such damage was thought, erroneously, to be increased dramatically with even moderately high doses, e.g.; more than 50 Gy in 5 weeks. Therefore, few attempts were made to deliver the same high doses of radiations that would be considered mandatory for epithelial tumors of other locations such as the upper respiratory and digestive tract or the female genital tract. The therapeutic ratio was altered in an unfavorable direction with the use of small numbers of large fractions. Based on the earliest RTOG studies of carcinoma of the lung, the therapeutic ratio is at an acceptable level with 60 Gy in 30 fractions of 2.0 Gy in 6 weeks. It is encouraging that there is no evidence of an increased rate of morbidity in the hyperfractionation trials of the RTOG. The data are too preliminary with regard to therapeutic effect to know if there will truly be an increase in therapeutic ratio. It was evident that 12-24 months of follow-up are necessary before definitive answers are available

  14. Alternative splicing in cancers: From aberrant regulation to new therapeutics.

    Song, Xiaowei; Zeng, Zhenyu; Wei, Huanhuan; Wang, Zefeng

    2018-03-01

    Alternative splicing is one of the most common mechanisms for gene regulation in humans, and plays a vital role to increase the complexity of functional proteins. In this article, we seek to provide a general review on the relationships between alternative splicing and tumorigenesis. We briefly introduce the basic rules for regulation of alternative splicing, and discuss recent advances on dynamic regulation of alternative splicing in cancers by highlighting the roles of a variety of RNA splicing factors in tumorigenesis. We further discuss several important questions regarding the splicing of long noncoding RNAs and back-splicing of circular RNAs in cancers. Finally, we discuss the current technologies that can be used to manipulate alternative splicing and serve as potential cancer treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Targeting the Prostate Cancer Microenvironment to Improve Therapeutic Outcomes

    2013-06-01

    Hutchinson Cancer Research Center, respectively. B. Torok-Strorb, Fred Hutchinson Cancer Research Center, provided HS5 and HS27A HPV E6 / E7 immortalized...BCR-ABLþ, Arf-null lymphoblastic leukemia. Genes Dev 2007;21:2283–7. 13. Yamamoto-SugitaniM, Kuroda J, Ashihara E,Nagoshi H, Kobayashi T, Matsumoto Y ...xenografts compring PCa cells (PC3/VCaP) with PSC27 fibroblasts and examine tumor responses to single agent or combination therapy. ( y 1/m 1-6) 1

  16. The Therapeutic Potential of CRISPR/Cas9 Systems in Oncogene-Addicted Cancer Types: Virally Driven Cancers as a Model System

    Luqman Jubair

    2017-09-01

    Full Text Available The field of gene editing is undergoing unprecedented growth. The first ex vivo human clinical trial in China started in 2016, more than 1000 US patents have been filed, and there is exponential growth in publications. The ability to edit genes with high fidelity is promising for the development of new treatments for a range of diseases, particularly inherited conditions, infectious diseases, and cancers. For cancer, a major issue is the identification of driver mutations and oncogenes to target for therapeutic effect, and this requires the development of robust models with which to prove their efficacy. The challenge is that there is rarely a single critical gene. However, virally driven cancers, in which cells are addicted to the expression of a single viral oncogene in some cases, may serve as model systems for CRISPR/Cas therapies, as they did for RNAi. These models and systems offer an excellent opportunity to test both preclinical models and clinical conditions to examine the effectiveness of gene editing, and here we review the options and offer a way forward. Keywords: CRISPR/Cas9, virally-driven cancers, cervical cancer, oncogene-addiction

  17. Development of new therapeutic methods of lung cancer through team approach study (II)

    Zo, Jae Ill; Park, Jong Ho; Baek, Hee Jong

    1999-12-01

    The aims of this study were to make the lung cancer clinics in Korea Cancer Center Hospital, and to establish new therapeutic methods of lung cancer for increasing the cure rate and survival rate of patients. Also another purpose of this study was to establish a common treatment method in our hospital. All patients who were operated in Korea Cancer Center Hospital from 1987 due to lung cancer were followed up and evaluated. And we have been studied the effect of postoperative adjuvant therapy in stage 1, 2, 3A non-small cell lung cancer patients from 1989 with the phase three study form. Follow-up examinations were scheduled in these patients and interim analysis was made. Also we have been studied the effect of chemotherapeutic agents in small cell lung cancer patients from 1997 with the phase two study form. We evaluated the results of this study

  18. RhoC a new target for therapeutic vaccination against metastatic cancer

    Wenandy, L.; Sorensen, R.B.; Straten, P.T.

    2008-01-01

    Most cancer deaths are due to the development of metastases. Increased expression of RhoC is linked to enhanced metastatic potential in multiple cancers. Consequently, the RhoC protein is an attractive target for drug design. The clinical application of immunotherapy against cancer is rapidly...... of cancer makes RhoC a very attractive target for anti-cancer immunotherapy. Herein, we describe an HLA-A3 restricted epitope from RhoC, which is recognized by cytotoxic T cells. Moreover, RhoC-specific T cells show cytotoxic potential against HLA-matched cancer cells of different origin. Thus, RhoC may...... moving forward in multiple areas, including the adoptive transfer of anti-tumor-reactive T cells and the use of "therapeutic" vaccines. The over-expression of RhoC in cancer and the fact that immune escape by down regulation or loss of expression of this protein would reduce the morbidity and mortality...

  19. Caffeic Acid Phenethyl Ester Is a Potential Therapeutic Agent for Oral Cancer

    Ying-Yu Kuo

    2015-05-01

    Full Text Available Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% of oral cancers are oral and oropharyngeal squamous cell carcinoma (OSCC. The overall five-year survival rate of OSCC patients is approximately 63%, which is due to the low response rate to current therapeutic drugs. In this review we discuss the possibility of using caffeic acid phenethyl ester (CAPE as an alternative treatment for oral cancer. CAPE is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment can effectively suppress the proliferation, survival, and metastasis of oral cancer cells. CAPE treatment inhibits Akt signaling, cell cycle regulatory proteins, NF-κB function, as well as activity of matrix metalloproteinase (MMPs, epidermal growth factor receptor (EGFR, and Cyclooxygenase-2 (COX-2. Therefore, CAPE treatment induces cell cycle arrest and apoptosis in oral cancer cells. According to the evidence that aberrations in the EGFR/phosphoinositide 3-kinase (PI3K/protein kinase B (Akt signaling, NF-κB function, COX-2 activity, and MMPs activity are frequently found in oral cancers, and that the phosphorylation of Akt, EGFR, and COX-2 correlates to oral cancer patient survival and clinical progression, we believe that CAPE treatment will be useful for treatment of advanced oral cancer patients.

  20. Strategy to prime the host and cells to augment therapeutic efficacy of progenitor cells for patients with myocardial infarction

    Jeehoon Kang

    2016-11-01

    Full Text Available Cell therapy in myocardial infarction (MI is an innovative strategy that is regarded as a rescue therapy to repair the damaged myocardium and to promote neovascularization for the ischemic border zone. Among several stem cell sources for this purpose, autologous progenitors from bone marrow or peripheral blood would be the most feasible and safest cell-source. Despite the theoretical benefit of cell therapy, this method is not widely adopted in the actual clinical practice due to its low therapeutic efficacy. Various methods have been used to augment the efficacy of cell therapy in MI, such as using different source of progenitors, genetic manipulation of cells, or priming of the cells or hosts (patients with agents. Among these methods, the strategy to augment the therapeutic efficacy of the autologous peripheral blood mononuclear cells by priming agents may be the most feasible and the safest method that can be applied directly to the clinic. In this review, we will discuss the current status and future directions of priming peripheral blood mononuclear cells or patients, as for cell therapy of MI.

  1. Optimal Therapeutic Strategy for Non-small Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor

    Zhong SHI

    2015-02-01

    Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.

  2. A Novel Approach to Detect Therapeutic Resistance in Breast Cancer

    2008-09-01

    Resistance in Breast Cancer PRINCIPAL INVESTIGATOR: Kamila Czene, Ph.D. CONTRACTING ORGANIZATION: Karolinska Institutet ...ORGANIZATION REPORT NUMBER Karolinska Institutet Stockholm, Sweden 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10...analysis. The digital image analysis algorithms and software that have been developed at Karolinska Institutet consists of an optimized combination of

  3. Targeting the Prostate Cancer Microenvironment to Improve Therapeutic Outcomes

    2015-08-01

    rapamycin pre-treatment of the latter. 22 (Chiang and Abraham, 2005; Copp et al., 2009; Criollo et al., 2010) but suppressed by rapamycin in the...mTOR Signaling Complex 2. Cancer Res. 69: 1821-1827. Criollo , A., Senovilla, L., Authier, H., Maiuri, M. C., Morselli, E. et al. 2010. The IKK complex

  4. Treatment/Comparative therapeutics: cancer of the larynx and hypopharynx.

    McMullen, Caitlin P; Smith, Richard V

    2015-07-01

    This article reviews the management of laryngeal and hypopharyngeal squamous cell carcinoma. Available therapies for early and late stage cancers are discussed, and the literature is reviewed. The indications and outcomes of surgical and nonsurgical modalities are discussed and compared. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. The therapeutic potential of MicroRNAs in cancer

    Thorsen, Stine Buch; Obad, Susanna; Jensen, Niels Frank

    2012-01-01

    MicroRNAs (miRNAs) have been uncovered as important posttranscriptional regulators of nearly every biological process in the cell. Furthermore, mounting evidence implies that miRNAs play key roles in the pathogenesis of cancer and that many miRNAs can function either as oncogenes or tumor...

  6. Epigenetics modifications and therapeutic prospects in human thyroid cancer

    Maria Graziella eCatalano

    2012-03-01

    Full Text Available At present no successful treatment is available for advanced thyroid cancer, which comprises poorly differentiated, anaplastic, and metastatic or recurrent differentiated thyroid cancer not responding to radioiodine. In the last few years, biologically targeted therapies for advanced thyroid carcinomas have been proposed on the basis of the recognition of key oncogenic mutations. Although the results of several phase II trials look promising, none of the patients treated had a complete response, and only a minority of them had a partial response, suggesting that the treatment is, at best, effective in stabilizing patients with progressive disease. Epigenetic refers to the study of heritable changes in gene expression that occur without any alteration in the primary DNA sequence. The epigenetic processes establish and maintain the global and local chroma¬tin states that determine gene expression. Epigenetic abnormalities are present in almost all cancers and, together with genetic changes, drive tumour progression. Various genes involved in the control of cell proliferation and invasion (p16INK4A, RASSF1A,PTEN, Rap1GAP, TIMP3, DAPK, RARβ2, E-cadherin, and CITED1 as well as genes specific of thyroid differentiation (Na+/I- symport, TSH receptor, pendrin, SL5A8, and TTF-1 present aberrant methylation in thyroid cancer.This review deals with the most frequent epigenetic alterations in thyroid cancer and focuses on epigenetic therapy, whose goal is to target the chromatin in rapidly dividing tumour cells and potentially restore normal cell functions. Experimental data and clinical trials, especially using deacetylase inhibitors and demethylating agents, are discussed.

  7. Rapid arc in cancer treatment - a therapeutic perspective

    Rao, Suresh

    2013-01-01

    Recently, volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time compared to conventional intensity-modulated fixed-field treatment (IMRT). We applied the hypothesis of VMAT technique at our hospital to determine the superior dose coverage for planning target volume (PTV) with adequate sparing of organs-at-risk (OARs). The delivery time and monitor units (MUs) is reduced in comparison with conventional fixed-field IMRT. Rapid Arc (RA) plans had a pre-treatment quality assurance and results were summarised in terms of the Gamma Agreement Index (GAI) scoring criteria of 3% and 3 mm thresholds. A total of 771 patients were treated between July 2011 and August 2013 of which head and neck cancer were 385, prostate cancer 53, brain tumours 112, cervical and endometrial cancer 77, breast cancer 38, rectal and bladder cancer 56, special technique using SBRT 45 (Liver and Lung) and Cranio-spinal irradiation 5 patients using RA single (177 control points) and double arcs (354 control points). The Average treatment time was 4.8 ±0.2 minutes (220 seconds of beam-on). The number of MU per fraction of 2.0 Gy was 522.5 ± 133.62. VMAT can be a valuable clinical tool that can deliver the prescribed dose efficiently in 1.5-3 minutes (single or double arcs) with high target homogeneity and adequate sparing of organs at risk. It would allow to reduce patient lying time on couch and over all beam on time from 4 hours to one hour. The toxicity (Tracheal fistula) observed in two patients of Carcinoma Lung receiving SRT high lights the need for peer review. (author)

  8. Alternative Splicing in Breast Cancer and the Potential Development of Therapeutic Tools.

    Martínez-Montiel, Nancy; Anaya-Ruiz, Maricruz; Pérez-Santos, Martín; Martínez-Contreras, Rebeca D

    2017-10-05

    Alternative splicing is a key molecular mechanism now considered as a hallmark of cancer that has been associated with the expression of distinct isoforms during the onset and progression of the disease. The leading cause of cancer-related deaths in women worldwide is breast cancer, and even when the role of alternative splicing in this type of cancer has been established, the function of this mechanism in breast cancer biology is not completely decoded. In order to gain a comprehensive view of the role of alternative splicing in breast cancer biology and development, we summarize here recent findings regarding alternative splicing events that have been well documented for breast cancer evolution, considering its prognostic and therapeutic value. Moreover, we analyze how the response to endocrine and chemical therapies could be affected due to alternative splicing and differential expression of variant isoforms. With all this knowledge, it becomes clear that targeting alternative splicing represents an innovative approach for breast cancer therapeutics and the information derived from current studies could guide clinical decisions with a direct impact in the clinical advances for breast cancer patients nowadays.

  9. Annexin A9 (ANXA9) biomarker and therapeutic target in epithelial cancer

    Hu, Zhi [El Cerrito, CA; Kuo, Wen-Lin [San Ramon, CA; Neve, Richard M [San Mateo, CA; Gray, Joe W [San Francisco, CA

    2012-06-12

    Amplification of the ANXA9 gene in human chromosomal region 1q21 in epithelial cancers indicates a likelihood of both in vivo drug resistance and metastasis, and serves as a biomarker indicating these aspects of the disease. ANXA9 can also serve as a therapeutic target. Interfering RNAs (iRNAs) (such as siRNA and miRNA) and shRNA adapted to inhibit ANXA9 expression, when formulated in a therapeutic composition, and delivered to cells of the tumor, function to treat the epithelial cancer.

  10. Gene therapy of cancer and development of therapeutic target gene

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene.

  11. Gene therapy of cancer and development of therapeutic target gene

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene

  12. Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles

    Jingga Morry

    2017-04-01

    Full Text Available Oxidative stress, mainly contributed by reactive oxygen species (ROS, has been implicated in pathogenesis of several diseases. We review two primary examples; fibrosis and cancer. In fibrosis, ROS promote activation and proliferation of fibroblasts and myofibroblasts, activating TGF-β pathway in an autocrine manner. In cancer, ROS account for its genomic instability, resistance to apoptosis, proliferation, and angiogenesis. Importantly, ROS trigger cancer cell invasion through invadopodia formation as well as extravasation into a distant metastasis site. Use of antioxidant supplements, enzymes, and inhibitors for ROS-generating NADPH oxidases (NOX is a logical therapeutic intervention for fibrosis and cancer. We review such attempts, progress, and challenges. Lastly, we review how nanoparticles with inherent antioxidant activity can also be a promising therapeutic option, considering their additional feature as a delivery platform for drugs, genes, and imaging agents.

  13. MicroRNA-196a is a putative diagnostic biomarker and therapeutic target for laryngeal cancer.

    Koichiro Saito

    Full Text Available BACKGROUND: MicroRNA (miRNA is an emerging subclass of small non-coding RNAs that regulates gene expression and has a pivotal role for many physiological processes including cancer development. Recent reports revealed the role of miRNAs as ideal biomarkers and therapeutic targets due to their tissue- or disease-specific nature. Head and neck cancer (HNC is a major cause of cancer-related mortality and morbidity, and laryngeal cancer has the highest incidence in it. However, the molecular mechanisms involved in laryngeal cancer development remain to be known and highly sensitive biomarkers and novel promising therapy is necessary. METHODOLOGY/PRINCIPAL FINDINGS: To explore laryngeal cancer-specific miRNAs, RNA from 5 laryngeal surgical specimens including cancer and non-cancer tissues were hybridized to microarray carrying 723 human miRNAs. The resultant differentially expressed miRNAs were further tested by using quantitative real time PCR (qRT-PCR on 43 laryngeal tissue samples including cancers, noncancerous counterparts, benign diseases and precancerous dysplasias. Significant expressional differences between matched pairs were reproduced in miR-133b, miR-455-5p, and miR-196a, among which miR-196a being the most promising cancer biomarker as validated by qRT-PCR analyses on additional 84 tissue samples. Deep sequencing analysis revealed both quantitative and qualitative deviation of miR-196a isomiR expression in laryngeal cancer. In situ hybridization confirmed laryngeal cancer-specific expression of miR-196a in both cancer and cancer stroma cells. Finally, inhibition of miR-196a counteracted cancer cell proliferation in both laryngeal cancer-derived cells and mouse xenograft model. CONCLUSIONS/SIGNIFICANCE: Our study provided the possibilities that miR-196a might be very useful in diagnosing and treating laryngeal cancer.

  14. Therapeutic Strategies against Cyclin E1-Amplified Ovarian Cancers

    2016-10-01

    Philadelphia, Pennsylva- nia . 4Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 5Center for RNAi and Non...exonuclease domain mutations. Mod Pathol. 2015; 28: 505 –514. 7. Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of...types. Nature. 2014; 505 :495–501. 33. Wagle N, Berger MF, Davis MJ, Blumenstiel B, Defelice M, Pochanard P, Ducar M, Van Hummelen P, Macconaill LE

  15. Vital: Vanguard Investigations of Therapeutic Approaches to Lung Cancer

    2007-01-01

    immunohistochemistry (IHC) laboratory with manual and automated immunohistochemical techniques and in situ tissue-based methodologies, such as FISH and...Multiple-Drug Dose-Effect Analyzer and Manual uniform measures. Statistics in Medicine 22, 2091-2100. Cambridge, U.K.: Biosoft. Venables, W. N. and Ripley...Supplementary data for this article are available at Cancer Research Online tirsnsfection reagent (Roche Diagnos~tics Corp., Indianapolis, INI) following ( htp

  16. Tubulins as therapeutic targets in cancer: from bench to bedside

    Katsetos, C.D.; Dráber, Pavel

    2012-01-01

    Roč. 18, č. 19 (2012), s. 2778-2792 ISSN 1381-6128 R&D Projects: GA ČR GA204/09/1777; GA AV ČR KAN200520701; GA MŠk 1M0506 Institutional research plan: CEZ:AV0Z50520514 Keywords : microtubules * tubulin * cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.311, year: 2012

  17. Preventive and therapeutic potential of peptides from cereals against cancer.

    Ortiz-Martinez, Margarita; Winkler, Robert; García-Lara, Silverio

    2014-12-05

    Epidemiological studies have shown that regular consumption of food based on whole-grain cereals and their products is associated with reduced risks of various types of degenerative chronic diseases. Food proteins are considered an important source of nutraceutical peptides and amino acids that can exert biological functions to promote health and prevent disease, including cancer. There have been several reports on peptides with anti-tumour activity in recent years. Plant-derived peptides, such as rapeseed, amaranth and soybean lunasin have received main attention. In this review, we extend this vision to analyse the evidence of current advances in peptides in cereals such as wheat, maize, rice, barley, rye and pseudocereals compared with soybean. We also show evidence of several mechanisms through which bioactive peptide exerts anti-tumour activity. Finally, we report the current status of major strategies for the fractionation, isolation and characterisation of bioactive peptides in cereals. In recent reports, it has been shown that peptides are an interesting alternative in the search for new treatments for cancer. One of the most studied sources of these peptides is food proteins; however, a review that includes more recent findings for cereals as a potential source of bioactive peptides in the treatment of cancer, the techniques for their isolation and characterisation and the assays used to prove their bioactivity is not available. This review can be used as a tool in the search for new sources of anti-cancer peptides. The authors have no conflicts of interest, financial or otherwise. Copyright © 2014 Elsevier B.V. All rights reserved.

  18. Therapeutic efficacy of Artemether/Lumefantrine (Coartem® against Plasmodium falciparum in Kersa, South West Ethiopia

    Animut Abebe

    2010-01-01

    Full Text Available Abstract Background Artemether/Lumefantrine (Coartem® has been used as a first-line treatment for uncomplicated Plasmodium falciparum infection since 2004 in Ethiopia. In the present study the therapeutic efficacy of artemether/lumefantrine for the treatment of uncomplicated P. falciparum infection at Kersa, Jima zone, South-west Ethiopia, has been assessed. Methods A 28 day therapeutic efficacy study was conducted between November 2007 and January 2008, in accordance with the 2003 WHO guidelines. Outcomes were classified as early treatment failure (ETF, late clinical failure (LCF, late parasitological failure (LPF and adequate clinical and parasitological response (ACPR. Results 90 patients were enrolled and completed the 28 day follow-up period after treatment with artemether/lumefantrine. Cure rate was very high, 96.3%, with 95% CI of 0.897-0.992 (PCR uncorrected. Age-stratified data showed adequate clinical and parasitological response (ACPR to be 100% for children under 5 and 97.4% and 87.3% for children aged 5-14, and adults, respectively. There was no early treatment failure (ETF in all age groups. Fever was significantly cleared on day 3 (P 0.05. No major side effect was observed in the study except the occurrence of mouth ulcers in 7% of the patients. Conclusions The current study proved the excellent therapeutic efficacy of artemether/lumefantrine in the study area and the value of using it. However, the proper dispensing and absorption of the drug need to be emphasized in order to utilize the drug for a longer period of time. This study recommends further study on the toxicity of the drug with particular emphasis on the development of oral ulcers in children.

  19. Carbon nanotubes as cancer therapeutic carriers and mediators

    Son, Kuk Hui; Hong, Jeong Hee; Lee, Jin Woo

    2016-01-01

    Carbon nanotubes (CNTs) have received increasing attention in biomedical fields because of their unique structures and properties, including high aspect ratios, large surface areas, rich surface chemical functionalities, and size stability on the nanoscale. Particularly, they are attractive as carriers and mediators for cancer therapy. Through appropriate functionalization, CNTs have been used as nanocarriers for anticancer drugs including doxorubicin, camptothecin, carboplatin, cisplatin, paclitaxel, Pt(II), and Pt(IV), and genes including plasmid DNA, small-interfering RNA, oligonucleotides, and RNA/DNA aptamers. CNTs can also deliver proteins and immunotherapy components. Using combinations of light energy, they have also been applied as mediators for photothermal therapy and photodynamic therapy to directly destroy cancer cells without severely damaging normal tissue. If limitations such as a long-term cytotoxicity in the body, lack of size uniformity during the synthetic process, loading deviations for drug–CNT complexes, and release controllability at the target point are overcome, CNTs will become one of the strongest tools that are available for various other biomedical fields as well as for cancer therapy. PMID:27785021

  20. Nab-paclitaxel for the treatment of breast cancer: efficacy, safety, and approval

    Iwase H

    2011-07-01

    Full Text Available Yutaka Yamamoto1, Ichiro Kawano2, Hirotaka Iwase11Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Surgery, Asahino General Hospital, Kumamoto, JapanAbstract: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel is a novel formulation of paclitaxel that does not require solvents such as polyoxyethylated castor oil and ethanol. Use of these solvents has been associated with toxic response, including hypersensitivity reactions and prolonged sensory neuropathy, as well as a negative impact in relation to the therapeutic index of paclitaxel. nab-paclitaxel displays greater antitumor activity and less toxicity than solvent-base paclitaxel. In a phase I trial of single nab-paclitaxel, the maximum tolerated dose was 300 mg/m2 with the dose limiting toxicities being sensory neuropathy, stomatitis, and superficial keratopathy. In the metastatic setting, a pivotal comparative randomized phase III study demonstrated that nab-paclitaxel (at 260 mg/m2 over 30 minutes infusion without premedication every 3 weeks mediated a superior objective response rate and prolonged time to progression compared with solvent-based paclitaxel (at 175 mg/m2 over a 3-hour injection with standard premedication. The nab-paclitaxel-treated group showed a higher incidence of sensory neuropathy than the solvent-based paclitaxel group. However, these adverse side effects rapidly resolved after interruption of treatment and dose reduction. Weekly administration of nab-paclitaxel was also more active and displayed less toxicity compared with 100 mg/m2 docetaxel given triweekly. Nab-paclitaxel has already been approved in 42 countries for the treatment of metastatic breast cancer previously treated with anthracycline, based on confirmation of the efficacy and manageable toxicity in the metastatic setting. This review summarizes the most relevant knowledge on nab-paclitaxel for treating breast cancer

  1. Effects of the application of therapeutic massage in children with cancer: a systematic review

    Rodríguez-Mansilla, Juan; González-Sánchez, Blanca; Torres-Piles, Silvia; Martín, Jorge Guerrero; Jiménez-Palomares, María; Bellino, Macarena Núñez

    2017-01-01

    ABSTRACT Objective: to learn about the effects of the use of therapeutic massage in children with cancer. Method: systematic review of controlled clinical trials The search was conducted in November 2014 in the following databases: Pubmed, CSIC, Dialnet, Scopus, Cochrane and PEDro. Inclusion criteria were: clinical trials, published in English or Spanish, analyzing the effects of massage on the different stages and types of childhood cancer (between 1 and 18 years old). Results: of 1007...

  2. A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution

    Grace R. Anderson; Peter S. Winter; Kevin H. Lin; Daniel P. Nussbaum; Merve Cakir; Elizabeth M. Stein; Ryan S. Soderquist; Lorin Crawford; Jim C. Leeds; Rachel Newcomb; Priya Stepp; Catherine Yip; Suzanne E. Wardell; Jennifer P. Tingley; Moiez Ali

    2017-01-01

    Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tiss...

  3. Administration of BMSCs with muscone in rats with gentamicin-induced AKI improves their therapeutic efficacy.

    Pengfei Liu

    Full Text Available The therapeutic action of bone marrow-derived mesenchymal stem cells (BMSCs in acute kidney injury (AKI has been reported by several groups. However, recent studies indicated that BMSCs homed to kidney tissues at very low levels after transplantation. The lack of specific homing of exogenously infused cells limited the effective implementation of BMSC-based therapies. In this study, we provided evidence that the administration of BMSCs combined with muscone in rats with gentamicin-induced AKI intravenously, was a feasible strategy to drive BMSCs to damaged tissues and improve the BMSC-based therapeutic effect. The effect of muscone on BMSC bioactivity was analyzed in vitro and in vivo. The results indicated that muscone could promote BMSC migration and proliferation. Some secretory capacity of BMSC still could be improved in some degree. The BMSC-based therapeutic action was ameliorated by promoting the recovery of biochemical variables in urine or blood, as well as the inhibition of cell apoptosis and inflammation. In addition, the up-regulation of CXCR4 and CXCR7 expression in BMSCs could be the possible mechanism of muscone amelioration. Thus, our study indicated that enhancement of BMSCs bioactivities with muscone could increase the BMSC therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI.

  4. VITAL (Vanguard Investigations of Therapeutic Approaches to Lung Cancer)

    2009-01-01

    expression are important for driving tumorigenesis. k1 k2 k3 k3 -ab k4-ab k7 k8 k9 k10 k11 k12 k13 k14 k15 Figure 1...normal” area, except cases k3 and k4, which are from LIFE-abnormal while white-light normal area. Nevertheless, there is no obvious disparity among these... vitamin E and β caro- tene on the incidence of lung cancer and other can- cers in male smokers. N Engl J Med 1994;330: 1029–35. 6. Omenn GS, Goodman GE

  5. New Epigenetic Therapeutic Intervention for Metastatic Breast Cancer

    2017-04-01

    Metastasis” 04/20/2017 Distinguished Scientist Speaker, University of Southern Alabama Mitchell Cancer Institute, Mobile , AL, “Role and Regulation...tracks for Il21 andRock2, two important genes in Th17 cell differentiation (Figure 3G ). Further, the functional dif- ferences of Brd2 and Brd4 in gene...terminal Dub3 (Fig. 2f). Consistent with this, Dub3 only stabilized the N-terminal but not the C-terminal fragments of Snail1 (Fig. 2g ). The interaction

  6. Nordic Walking, a therapeutic modality against cancer related fatigue

    González Castro, Cristina

    2014-01-01

    Existe evidencia de que el ejercicio físico puede mejorar los síntomas de los pacientes y supervivientes de cáncer y en especial la fatiga relativa al cáncer (FRC). El Nordic Walking (NW) es una novedosa forma de ejercicio físico que presenta ventajas fisiológicas y psicológicas significativas respecto de la marcha normal. Este artículo propone el NW como tratamiento terapéutico alternativo contra la FRC. There is evidence that physical exercise can improve symptoms in cancer patients and ...

  7. Clinical investigation of TROP-2 as an independent biomarker and potential therapeutic target in colon cancer.

    Zhao, Peng; Yu, Hai-Zheng; Cai, Jian-Hui

    2015-09-01

    Colon cancer is associated with a severe demographic and economic burden worldwide. The pathogenesis of colon cancer is highly complex and involves sequential genetic and epigenetic mechanisms. Despite extensive investigation, the pathogenesis of colon cancer remains to be elucidated. As the third most common type of cancer worldwide, the treatment options for colon cancer are currently limited. Human trophoblast cell‑surface marker (TROP‑2), is a cell‑surface transmembrane glycoprotein overexpressed by several types of epithelial carcinoma. In addition, TROP‑2 has been demonstrated to be associated with tumorigenesis and invasiveness in solid types of tumor. The aim of the present study was to investigate the protein expression of TROP‑2 in colon cancer tissues, and further explore the association between the expression of TROP‑2 and clinicopathological features of patients with colon cancer. The expression and localization of the TROP‑2 protein was examined using western blot analysis and immunofluorescence staining. Finally, the expression of TROP‑2 expression was correlated to conventional clinicopathological features of colon cancer using a χ2 test. The results revealed that TROP‑2 protein was expressed at high levels in the colon cancer tissues, which was associated with the development and pathological process of colon cancer. Therefore, TROP‑2 may be used as a biomarker to determine the clinical prognosis, and as a potential therapeutic target in colon cancer.

  8. Therapeutic Potential, Challenges and Future Perspective of Cancer Stem Cells in Translational Oncology: A Critical Review.

    Shukla, Gaurav; Khera, Harvinder Kour; Srivastava, Amit Kumar; Khare, Piush; Patidar, Rahul; Saxena, Rajiv

    2017-01-01

    Stem cell research is a rapidly developing field that offers effective treatment for a variety of malignant and non-malignant diseases. Stem cell is a regenerative medicine associated with the replacement, repair, and restoration of injured tissue. Stem cell research is a promising field having maximum therapeutic potential. Cancer stem cells (CSCs) are the cells within the tumor that posses capacity of selfrenewal and have a root cause for the failure of traditional therapies leading to re-occurrence of cancer. CSCs have been identified in blood, breast, brain, and colon cancer. Traditional therapies target only fast growing tumor mass, but not slow-dividing cancer stem cells. It has been shown that embryonic pathways such as Wnt, Hedgehog and Notch, control self-renewal capacity and involved in cancer stem cell maintenance. Targeting of these pathways may be effective in eradicating cancer stem cells and preventing chemotherapy and radiotherapy resistance. Targeting CSCs has become one of the most effective approaches to improve the cancer survival by eradicating the main root cause of cancer. The present review will address, in brief, the importance of cancer stem cells in targeting cancer as better and effective treatment along with a concluding outlook on the scope and challenges in the implication of cancer stem cells in translational oncology. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu® disables cancer cell survival in human pancreatic cancer with acquired chemoresistance

    O’Shea LK

    2014-01-01

    Full Text Available Leah K O'Shea,1 Samar Abdulkhalek,1 Stephanie Allison,2 Ronald J Neufeld,2 Myron R Szewczuk11Department of Biomedical and Molecular Sciences, 2Department of Chemical Engineering, Queen's University, Kingston, ON, CanadaBackground: Resistance to drug therapy, along with high rates of metastasis, contributes to the low survival rate in patients diagnosed with pancreatic cancer. An alternate treatment for human pancreatic cancer involving targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu® was investigated in human pancreatic cancer (PANC1 cells with acquired resistance to cisplatin and gemcitabine. Its efficacy in overcoming the intrinsic resistance of the cell to chemotherapeutics and metastasis was evaluated.Methods: Microscopic imaging, immunocytochemistry, immunohistochemistry, and WST-1 cell viability assays were used to evaluate cell survival, morphologic changes, and expression levels of E-cadherin, N-cadherin, and VE-cadherin before and after treatment with oseltamivir phosphate in PANC1 cells with established resistance to cisplatin, gemcitabine, or a combination of the two agents, and in archived paraffin-embedded PANC1 tumors grown in RAGxCγ double mutant mice.Results: Oseltamivir phosphate overcame the chemoresistance of PANC1 to cisplatin and gemcitabine alone or in combination in a dose-dependent manner, and disabled the cancer cell survival mechanism(s. Oseltamivir phosphate also reversed the epithelial-mesenchymal transition characteristic of the phenotypic E-cadherin to N-cadherin changes associated with resistance to drug therapy. Low-dose oseltamivir phosphate alone or in combination with gemcitabine in heterotopic xenografts of PANC1 tumors growing in RAGxCγ double mutant mice did not prevent metastatic spread to the liver and lung.Conclusion: Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate at the growth factor receptor level disables the intrinsic signaling platform for cancer cell survival

  10. Human cervical cancer: therapeutic response assessment by innovative molecular strategies

    Nagarajan, Bala

    2016-01-01

    In Asia-Pacific region, the incidence of cancer of uterine cervix is high. Cancer is a multiple disease of multiple etiologies that has bearing on gene alteration that end result in abnormal cell dysfunction. We address the process interfacing infection, inflammation and oxidative damage that would lead to identify markers - to help improve patient management and bench to bedside. Radiation causes cell damage through production of reactive oxygen species. Radiation-induced DNA strand break is the primary mode of cell death. However, a secondary form of damage includes base modification or DNA adducts that are lethal on accumulation at higher levels. We analyzed polar and lipophilic adducts and found that the levels of adducts formed were independent of severity of disease status. 8 oxodG could be used as a marker to reflect patients potential to fix the lesion and response to radiation therapy. There was an increase in adduct levels in post treatment samples when compared to pre-RT, indicating radiation-induced DNA damage. Patients divided into two groups, high and low adduct formers, tend to show interindividual differences to fix the lesion that could be used to delineate radio-resistant or non-responding tumors. We have also looked at inflammatory cytokines, both by immunocytochemistry and m-RNA by RT-PCR through therapy, and generated definitive data that augur well with treatment response. The bottom line approach is prognostication and stratification. (author)

  11. In Vitro Evaluation of Biofilm Dispersal as a Therapeutic Strategy To Restore Antimicrobial Efficacy

    Roizman, Dan; Vidaillac, Celine; Givskov, Michael

    2017-01-01

    As a proof-of-concept study, the direct impact of biofilm dispersal on the in vitro efficacy of imipenem and tobramycin was evaluated against 3-day-old biofilms of Pseudomonas aeruginosa. Arabinose induction of biofilm dispersal via activation of the phosphodiesterase YhjH in the P. aeruginosa en...

  12. An experimental Toxoplasma gondii dose response challenge model to study therapeutic or vaccine efficacy in cats

    Cornelissen, J.B.W.J.; Giessen, van der J.W.B.; Takumi, K.; Teunis, P.F.M.; Wisselink, H.J.

    2014-01-01

    High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment.

  13. Novel inhibitor of DNA ligase IV with a promising cancer therapeutic ...

    Home; Journals; Journal of Biosciences; Volume 39; Issue 3. Novel inhibitor of DNA ligase IV with a promising cancer therapeutic potential. Ashwin Kotnis Rita Mulherkar. Clipboards Volume 39 Issue 3 June 2014 pp 339-340. Fulltext. Click here to view fulltext PDF. Permanent link:

  14. Protective and therapeutic effects of cannabis plant extract on liver cancer induced by dimethylnitrosamine in mice

    Neveen Abd El Moneim Hussein

    2014-09-01

    Conclusion: The protective effect of cannabis extract is more pronounced in group taking cannabis before DMNA. Cannabinoids might exert their anti-tumor effects by the direct induction of apoptosis and can decrease telomerase activity by inhibiting the expression of the TERT gene. Coordination between inhibition of telomerase activity and induction of apoptosis might be a potential therapeutic agent for cancer treatment.

  15. The psychological impact of breast reconstruction after prophylactic or therapeutic mastectomy for breast cancer

    Gopie, Jessica Premdee

    2013-01-01

    In this thesis the psychological impact of two types of breast reconstruction after prophylactic or therapeutic mastectomy for breast cancer was investigated with a prospective study including 202 patients from different hospitals in the South-West of the Netherlands between 2007-2012. With

  16. Intuition, subjectivity, and Le bricoleur: cancer patients' accounts of negotiating a plurality of therapeutic options.

    Broom, Alex

    2009-08-01

    Cancer patients are now combining complementary and alternative medicine (CAM) with biomedical cancer treatments, reflecting an increasingly pluralistic health care environment. However, there has been little research done on the ways in which cancer patients juggle multiplicity in claims to expertise, models of disease, and therapeutic practice. Drawing on the accounts of cancer patients who use CAM, in this article I develop a conceptualization of therapeutic decision making, utilizing the notion of bricolage as a key point of departure. The patient accounts illustrate the "piecing together" (or bricolage) of therapeutic trajectories, drawing on intuitive, embodied knowledge, as well as formalized "objective" scientific expertise. Le bricoleur, as characterized here, actively mediates, rather than accepts or rejects CAM or biomedicine, and utilizes a combination of scientific expertise, embodied physicality, and social knowledge to make decisions and assess therapeutic effectiveness. Although these "border crossings" are potentially subversive of established biomedical expertise, the analysis also illustrates the structural constraints (and penalties) associated with bricolage, and furthermore, the interplay of a repositioning of responsibility with neoliberal forms of self-governance.

  17. Combination therapy of potential gene to enhance oral cancer therapeutic effect

    Yeh, Chia-Hsien; Hsu, Yih-Chih

    2015-03-01

    The epidermal growth factor receptor (EGFR) over-regulation related to uncontrolled cell division and promotes progression in tumor. Over-expression of human epidermal growth factor receptor (EGFR) has been detected in oral cancer cells. EGFR-targeting agents are potential therapeutic modalities for treating oral cancer based on our in vitro study. Liposome nanotechnology is used to encapsulate siRNA and were modified with target ligand to receptors on the surface of tumor cells. We used EGFR siRNA to treat oral cancer in vitro.

  18. Development of Therapeutic Modality of Esophageal Cancer Using Ho-166 Stent

    Lee, Jong Doo; Park, Kwang Kyun; Lee, Min Geol [Yonsei University Medical College, Seoul (Korea, Republic of); Park, Kyung Bae [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1997-09-01

    The prognosis of esophageal cancer is poor due absence of serosa which prevent local invasion to the surrounding organs such as aorta, mediastinum, trachea, and bronchi. We developed a Ho-166 Coated Radioactive Self-Expandable Metallic Stent which is a new herapeutic device in the treatment of esophageal cancer and underwent an animal experiment in mongrel dogs. We observed mucosal destruction by 4-6 mCi of Ho-166 without serious complications such as perforation of esophageal wall. Therefore, Ho-166 coated self-expandable stent appears to be an effective therapeutic device in the palliative treatment of esophageal cancer. 17 refs., 4 figs. (author)

  19. Punica granatum fabricated platinum nanoparticles: A therapeutic pill for breast cancer

    Jha, Babita; Rao, Mugdha; Chattopadhyay, A.; Bandyopadhyay, A.; Prasad, K.; Jha, Anal K.

    2018-05-01

    The current research highlights the fabrication of biocompatible platinum nanoparticles (Pt NPs) in first hand from arils of Punica granatum by using green chemistry approach. Formation of Pt NPs was determined by UV-visible, X-ray diffraction, and FTIR techniques. The anti-cancer potential of fabricated Pt NPs was evaluated by MTT assay on MCF7 and MDA-MB-231 breast cancer cell lines. This work is foreshadowing the prospect of Pt NPs application as a therapeutic drug for cancer treatment.

  20. Therapeutic peptides for cancer therapy. Part I - peptide inhibitors of signal transduction cascades.

    Bidwell, Gene L; Raucher, Drazen

    2009-10-01

    Therapeutic peptides have great potential as anticancer agents owing to their ease of rational design and target specificity. However, their utility in vivo is limited by low stability and poor tumor penetration. The authors review the development of peptide inhibitors with potential for cancer therapy. Peptides that inhibit signal transduction cascades are discussed. The authors searched Medline for articles concerning the development of therapeutic peptides and their delivery. Given our current knowledge of protein sequences, structures and interaction interfaces, therapeutic peptides that inhibit interactions of interest are easily designed. These peptides are advantageous because they are highly specific for the interaction of interest, and they are much more easily developed than small molecule inhibitors of the same interactions. The main hurdle to application of peptides for cancer therapy is their poor pharmacokinetic and biodistribution parameters. Therefore, successful development of peptide delivery vectors could potentially make possible the use of this new and very promising class of anticancer agents.

  1. Undifferentiated nasopharyngeal cancer (UCNT): current diagnostic and therapeutic aspects

    Altun, M.; Fandi, A.; Dupuis, O.; Cvitkovic, E.; Krajina, Z.; Eschwege, F.

    1995-01-01

    Undifferentiated carcinoma of the nasopharynx (UCNT) is a particular head and neck epidermoid lineage tumor related to the Epstein Barr Virus (EBV). It has geographically selective endemic epidemiologic features, without relation to external carcinogens. Its systemic aggressiveness is the source of most disease-related demises, because radiotherapy achieves excellent local control and a significant percentage of cure in patients with exclusive locoregional disease. Differences in the staging systems currently in use, the recent changes in imaging and radiotherapy technology, and the lack of distinction between UCNT and squamous cell carcinoma (SCC) of the nasopharynx in Western literature reports make for some difficulty in therapeutic results evaluation when analyzing available literature. Its chemosensitivity is a relatively recent acknowledged fact, and its use in metastatic patients results in a high percentage of objective responses, many of long duration. Neoadjuvant cisplatin-based chemotherapy seems to be of benefit, but outstanding controversies in this regard will be soon answered through ongoing phase III trials. After a review of the current literature of all the above-mentioned aspects of this fascinating nosologic entity, our own experience, both in metastatic and locoregional disease patients is analyzed

  2. Curcumin and 5-Fluorouracil-loaded, folate- and transferrin-decorated polymeric magnetic nanoformulation: a synergistic cancer therapeutic approach, accelerated by magnetic hyperthermia

    Balasubramanian S

    2014-01-01

    Full Text Available Sivakumar Balasubramanian,1 Aswathy Ravindran Girija,1 Yutaka Nagaoka,1 Seiki Iwai,1 Masashi Suzuki,1 Venugopal Kizhikkilot,2 Yasuhiko Yoshida,1 Toru Maekawa,1 Sakthikumar Dasappan Nair1 1Bio Nano Electronics Research Center, Graduate School of Interdisciplinary New Science, Toyo University, Kawagoe, Japan; 2Department of Respiratory Medicine, Sooriya Hospital, Chennai, India Abstract: The efficient targeting and therapeutic efficacy of a combination of drugs (curcumin and 5-Fluorouracil [5FU] and magnetic nanoparticles encapsulated poly(D,L-lactic-co-glycolic acid nanoparticles, functionalized with two cancer-specific ligands are discussed in our work. This multifunctional, highly specific nanoconjugate resulted in the superior uptake of nanoparticles by cancer cells. Upon magnetic hyperthermia, we could harness the advantages of incorporating magnetic nanoparticles that synergistically acted with the drugs to destroy cancer cells within a very short period of time. The remarkable multimodal efficacy attained by this therapeutic nanoformulation offers the potential for targeting, imaging, and treatment of cancer within a short period of time (120 minutes by initiating early and late apoptosis. Keywords: nanotechnology, curcumin, 5FU, folate, transferrin, PLGA nanoparticle, magnetic hyperthermia

  3. Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery

    Tian, Xi; Lara, Haydee; Wagner, Kyle T.; Saripalli, Srinivas; Hyder, Syed Nabeel; Foote, Michael; Sethi, Manish; Wang, Edina; Caster, Joseph M.; Zhang, Longzhen; Wang, Andrew Z.

    2015-11-01

    Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment.

  4. Cancer stem cells in hepatocellular carcinoma: Therapeutic implications based on stem cell biology.

    Chiba, Tetsuhiro; Iwama, Atsushi; Yokosuka, Osamu

    2016-01-01

    Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer-related death worldwide. Despite advances in its diagnosis and treatment, the prognosis of patients with advanced HCC remains unfavorable. Recent advances in stem cell biology and associated technologies have enabled the identification of minor components of tumorigenic cells, termed cancer stem cells (CSC) or tumor-initiating cells, in cancers such as HCC. Furthermore, because CSC play a central role in tumor development, metastasis and recurrence, they are considered to be a therapeutic target in cancer treatment. Hepatic CSC have been successfully identified using functional and cell surface markers. The analysis of purified hepatic CSC has revealed the molecular machinery and signaling pathways involved in their maintenance. In addition, epigenetic transcriptional regulation has been shown to be important in the development and maintenance of CSC. Although inhibitors of CSC show promise as CSC-targeting drugs, novel therapeutic approaches for the eradication of CSC are yet to be established. In this review, we describe recent progress in hepatic CSC research and provide a perspective on the available therapeutic approaches based on stem cell biology. © 2015 The Japan Society of Hepatology.

  5. BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations.

    Markowski, Mark C; De Marzo, Angelo M; Antonarakis, Emmanuel S

    2017-12-01

    The bromodomain and extra-terminal (BET) family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer (mCRPC), particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor (AR). Areas covered: We speculate that a combination approach using inhibitors of BET proteins (BETi) with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BETi together with other agents in prostate cancer. A literature search using Pubmed was performed for this review. Expert opinion: Use of BETi in the treatment of mCRPC patients may require the addition of a second novel agent.

  6. Advances in the proteomic discovery of novel therapeutic targets in cancer

    Guo S

    2013-10-01

    Full Text Available Shanchun Guo,1 Jin Zou,2 Guangdi Wang3 1Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, 2Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA, USA; 3Research Centers in Minority Institutions Cancer Research Program, Xavier University of Louisiana, New Orleans, LA, USA Abstract: Proteomic approaches are continuing to make headways in cancer research by helping to elucidate complex signaling networks that underlie tumorigenesis and disease progression. This review describes recent advances made in the proteomic discovery of drug targets for therapeutic development. A variety of technical and methodological advances are overviewed with a critical assessment of challenges and potentials. A number of potential drug targets, such as baculoviral inhibitor of apoptosis protein repeat-containing protein 6, macrophage inhibitory cytokine 1, phosphoglycerate mutase 1, prohibitin 1, fascin, and pyruvate kinase isozyme 2 were identified in the proteomic analysis of drug-resistant cancer cells, drug action, and differential disease state tissues. Future directions for proteomics-based target identification and validation to be more translation efficient are also discussed. Keywords: proteomics, cancer, therapeutic target, signaling network, tumorigenesis

  7. Neoadjuvant Therapy in Patients with Pancreatic Cancer: A Disappointing Therapeutic Approach?

    Zimmermann, Carolin; Folprecht, Gunnar; Zips, Daniel; Pilarsky, Christian; Saeger, Hans Detlev; Grutzmann, Robert

    2011-01-01

    Pancreatic cancer is a devastating disease. It is the fourth leading cause of cancer-related death in Germany. The incidence in 2003/2004 was 16 cases per 100.000 inhabitants. Of all carcinomas, pancreatic cancer has the highest mortality rate, with one- and five-year survival rates of 25% and less than 5%, respectively, regardless of the stage at diagnosis. These low survival rates demonstrate the poor prognosis of this carcinoma. Previous therapeutic approaches including surgical resection combined with adjuvant therapy or palliative chemoradiation have not achieved satisfactory results with respect to overall survival. Therefore, it is necessary to evaluate new therapeutic approaches. Neoadjuvant therapy is an interesting therapeutic option for patients with pancreatic cancer. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging, increasing the probability of a margin-negative resection and decreasing the occurrence of lymph node metastasis. Currently, there is no universally accepted approach for treating patients with pancreatic cancer in the neoadjuvant setting. In this review, the most common neoadjuvant strategies will be described, compared and discussed

  8. Targeting c-Met in Cancer by MicroRNAs: Potential Therapeutic Applications in Hepatocellular Carcinoma.

    Karagonlar, Zeynep F; Korhan, Peyda; Atabey, Neşe

    2015-11-01

    Preclinical Research Cancer is one of the world's deadliest diseases, with very low survival rates and increased occurrence in the future. Successfully developed target-based therapies have significantly changed cancer treatment. However, primary and/or acquired resistance in the tumor is a major challenge in current therapies and novel combinational therapies are required. RNA interference-mediated gene inactivation, alone or in combination with other current therapies, provides novel promising therapeutics that can improve cure rate and overcome resistance mechanisms to conventional therapeutics. Hepatocyte Growth Factor/c-Met signaling is one of the most frequently dysregulated pathways in human cancers and abnormal c-Met activation is correlated with poor clinical outcomes and drug resistance in hepatocellular carcinoma (HCC). In recent years, a growing number of studies have identified several inhibitors and microRNAs (miRNAs), specifically targeting c-Met in various cancers, including HCC. In this review, we discuss current knowledge regarding miRNAs, focusing on their involvement in cancer and their potential as research tools and therapeutics. Then, we focus on the potential use of c-Met targeting miRNAs for suppressing aberrant c-Met signaling in HCC treatment. © 2015 Wiley Periodicals, Inc.

  9. The Course of Self-Efficacy for Therapeutic Use of Self in Norwegian Occupational Therapy Students: A 10-Month Follow-Up Study

    Kathrin Schwank

    2018-01-01

    Full Text Available Background. Occupational therapy students need to develop self-efficacy for managing the therapeutic relationship in practice. This study examined the 10-month trajectories of Norwegian students’ self-efficacy for use of self. Methods. Eighty-nine students completed self-efficacy questionnaires related to the use of self after a workshop and at 3- and 10-month follow-up. Changes on the three outcome measures (self-efficacy for therapeutic mode use, for recognizing clients’ interpersonal characteristics, and for managing interpersonal events were analyzed with repeated measures ANOVA. Results. Across the follow-up period, the students improved their self-efficacy for therapeutic mode use (partial η2 = 0.44, p<0.001, for recognizing clients’ interpersonal characteristics (partial η2 = 0.81, p<0.001, and for managing interpersonal events (partial η2=0.32, p<0.001. Conclusion. The increased self-efficacy for use of self that was found at 3-month follow-up was maintained at 10-month follow-up. The results indicate that students may experience a boost in self-efficacy for therapeutic use of self after a brief workshop and that these changes can be sustained over time.

  10. Effects of the application of therapeutic massage in children with cancer: a systematic review

    Juan Rodríguez-Mansilla

    Full Text Available ABSTRACT Objective: to learn about the effects of the use of therapeutic massage in children with cancer. Method: systematic review of controlled clinical trials The search was conducted in November 2014 in the following databases: Pubmed, CSIC, Dialnet, Scopus, Cochrane and PEDro. Inclusion criteria were: clinical trials, published in English or Spanish, analyzing the effects of massage on the different stages and types of childhood cancer (between 1 and 18 years old. Results: of 1007 articles found, 7 met the inclusion criteria. Their authors use different massage techniques (Swedish massage, effleurage, petrissage, frictions, pressures, obtaining benefits in the symptoms present during the illness (decrease of pain, nausea, stress, anxiety and increase of white blood cells and neutrophils. Conclusion: therapeutic massage improves the symptoms of children with cancer, but there is a need for more research that may support the effects attributed to it.

  11. Engineered magnetic core shell nanoprobes: Synthesis and applications to cancer imaging and therapeutics.

    Mandal, Samir; Chaudhuri, Keya

    2016-02-26

    Magnetic core shell nanoparticles are composed of a highly magnetic core material surrounded by a thin shell of desired drug, polymer or metal oxide. These magnetic core shell nanoparticles have a wide range of applications in biomedical research, more specifically in tissue imaging, drug delivery and therapeutics. The present review discusses the up-to-date knowledge on the various procedures for synthesis of magnetic core shell nanoparticles along with their applications in cancer imaging, drug delivery and hyperthermia or cancer therapeutics. Literature in this area shows that magnetic core shell nanoparticle-based imaging, drug targeting and therapy through hyperthermia can potentially be a powerful tool for the advanced diagnosis and treatment of various cancers.

  12. Quantifying the importance of pMHC valency, total pMHC dose and frequency on nanoparticle therapeutic efficacy.

    Sugarman, Jordan; Tsai, Sue; Santamaria, Pere; Khadra, Anmar

    2013-05-01

    Nanoparticles (NPs) coated with β-cell-specific peptide major histocompatibility complex (pMHC) class I molecules can effectively restore normoglycemia in spontaneously diabetic nonobese diabetic mice. They do so by expanding pools of cognate memory autoreactive regulatory CD8+ T cells that arise from naive low-avidity T-cell precursors to therapeutic levels. Here we develop our previously constructed mathematical model to explore the effects of compound design parameters (NP dose and pMHC valency) on therapeutic efficacy with the underlying hypothesis that the functional correlates of the therapeutic response (expansion of autoregulatory T cells and deletion of autoantigen-loaded antigen-presenting cells by these T cells) are biphasic. We show, using bifurcation analysis, that the model exhibits a 'resonance'-like behavior for a given range of NP dose in which bistability between the healthy state (possessing zero level of effector T-cell population) and autoimmune state (possessing elevated level of the same population) disappears. A heterogeneous population of model mice subjected to several treatment protocols under these new conditions is conducted to quantify both the average percentage of autoregulatory T cells in responsive and nonresponsive model mice, and the average valency-dependent minimal optimal dose needed for effective therapy. Our results reveal that a moderate increase (≥1.6-fold) in the NP-dependent expansion rate of autoregulatory T-cell population leads to a significant increase in the efficacy and the area corresponding to the effective treatment regimen, provided that NP dose ≥8 μg. We expect the model developed here to generalize to other autoimmune diseases and serve as a computational tool to understand and optimize pMHC-NP-based therapies.

  13. Bladder Cancer Stem-Like Cells: Their Origin and Therapeutic Perspectives

    Tomokazu Ohishi

    2015-12-01

    Full Text Available Bladder cancer (BC, the most common cancer arising from the human urinary tract, consists of two major clinicopathological phenotypes: muscle-invasive bladder cancer (MIBC and non-muscle-invasive bladder cancer (NMIBC. MIBC frequently metastasizes and is associated with an unfavorable prognosis. A certain proportion of patients with metastatic BC can achieve a remission with systemic chemotherapy; however, the disease relapses in most cases. Evidence suggests that MIBC comprises a small population of cancer stem cells (CSCs, which may be resistant to these treatments and may be able to form new tumors in the bladder or other organs. Therefore, the unambiguous identification of bladder CSCs and the development of targeted therapies are urgently needed. Nevertheless, it remains unclear where bladder CSCs originate and how they are generated. We review recent studies on bladder CSCs, specifically focusing on their proposed origin and the possible therapeutic options based on the CSC theory.

  14. Albumin nanoparticles with synergistic antitumor efficacy against metastatic lung cancers.

    Kim, Bomi; Seo, Bohyung; Park, Sanghyun; Lee, Changkyu; Kim, Jong Oh; Oh, Kyung Taek; Lee, Eun Seong; Choi, Han-Gon; Youn, Yu Seok

    2017-10-01

    Albumin nanoparticles are well-known as effective drug carriers used to deliver hydrophobic chemotherapeutic agents. Albumin nanoparticles encapsulating curcumin and doxorubicin were fabricated using slightly modified nanoparticle albumin-bound (nab™) technology, and the synergistic effects of these two drugs were examined. Albumin nanoparticles encapsulating curcumin, doxorubicin, and both curcumin and doxorubicin were prepared using a high pressure homogenizer. The sizes of albumin nanoparticles were ∼130nm, which was considered to be suitable for the EPR (enhanced permeability and retention) effect. Albumin nanoparticles gradually released drugs over a period of 24h without burst effect. To confirm the synergistic effect of two drugs, in vitro cytotoxicity assay was performed using B16F10 melanoma cells. The cytotoxic effect on B16F10 melanoma cells was highest when co-treated with both curcumin and doxorubicin compared to single treatment of either curcumin and doxorubicin. The combined index calculated by medium-effect equation was 0.6069, indicating a synergistic effect. Results of confocal laser scanning microscopy and fluorescence-activated cell sorting corresponded to results from an in vitro cytotoxicity assay, indicating synergistic cytotoxicity induced by both drugs. A C57BL/6 mouse model induced by B16F10 lung metastasis was used to study in vivo therapeutic effects. When curcumin and doxorubicin were simultaneously treated, the metastatic melanoma mass in the lungs macroscopically decreased compared to curcumin or doxorubicin alone. Albumin nanoparticles encapsulating two anticancer drugs were shown to have an effective therapeutic result and would be an excellent way to treat resistant lung cancers. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Drug-releasing nano-engineered titanium implants: therapeutic efficacy in 3D cell culture model, controlled release and stability

    Gulati, Karan [School of Chemical Engineering, The University of Adelaide, SA 5005 (Australia); Kogawa, Masakazu; Prideaux, Matthew; Findlay, David M. [Discipline of Orthopaedics and Trauma, The University of Adelaide, SA 5005 (Australia); Atkins, Gerald J., E-mail: gerald.atkins@adelaide.edu.au [Discipline of Orthopaedics and Trauma, The University of Adelaide, SA 5005 (Australia); Losic, Dusan, E-mail: dusan.losic@adelaide.edu.au [School of Chemical Engineering, The University of Adelaide, SA 5005 (Australia)

    2016-12-01

    There is an ongoing demand for new approaches for treating localized bone pathologies. Here we propose a new strategy for treatment of such conditions, via local delivery of hormones/drugs to the trauma site using drug releasing nano-engineered implants. The proposed implants were prepared in the form of small Ti wires/needles with a nano-engineered oxide layer composed of array of titania nanotubes (TNTs). TNTs implants were inserted into a 3D collagen gel matrix containing human osteoblast-like, and the results confirmed cell migration onto the implants and their attachment and spread. To investigate therapeutic efficacy, TNTs/Ti wires loaded with parathyroid hormone (PTH), an approved anabolic therapeutic for the treatment of severe bone fractures, were inserted into 3D gels containing osteoblast-like cells. Gene expression studies revealed a suppression of SOST (sclerostin) and an increase in RANKL (receptor activator of nuclear factor kappa-B ligand) mRNA expression, confirming the release of PTH from TNTs at concentrations sufficient to alter cell function. The performance of the TNTs wire implants using an example of a drug needed at relatively higher concentrations, the anti-inflammatory drug indomethacin, is also demonstrated. Finally, the mechanical stability of the prepared implants was tested by their insertion into bovine trabecular bone cores ex vivo followed by retrieval, which confirmed the robustness of the TNT structures. This study provides proof of principle for the suitability of the TNT/Ti wire implants for localized bone therapy, which can be customized to cater for specific therapeutic requirements. - Highlights: • Ti wire with titania nanotubes (TNTs) are proposed as ‘in-bone’ therapeutic implants. • 3D cell culture model is used to confirm therapeutic efficacy of drug releasing implants. Osteoblasts migrated and firmly attached to the TNTs and the micro-scale cracks. • Tailorable drug loading from few nanograms to several hundred

  16. Therapeutic efficacy of monthly subcutaneous injection of daclizumab in relapsing multiple sclerosis

    Cohan, Stanley

    2016-01-01

    Despite the availability of multiple disease-modifying therapies for relapsing multiple sclerosis (MS), there remains a need for highly efficacious targeted therapy with a favorable benefit–risk profile and attributes that encourage a high level of treatment adherence. Daclizumab is a humanized monoclonal antibody directed against CD25, the α subunit of the high-affinity interleukin 2 (IL-2) receptor, that reversibly modulates IL-2 signaling. Daclizumab treatment leads to antagonism of proinflammatory, activated T lymphocyte function and expansion of immunoregulatory CD56bright natural killer cells, and has the potential to, at least in part, rectify the imbalance between immune tolerance and autoimmunity in relapsing MS. The clinical pharmacology, efficacy, and safety of subcutaneous daclizumab have been evaluated extensively in a large clinical study program. In pivotal studies, daclizumab demonstrated superior efficacy in reducing clinical and radiologic measures of MS disease activity compared with placebo or intramuscular interferon beta-1a, a standard-of-care therapy for relapsing MS. The risk of hepatic disorders, cutaneous events, and infections was modestly increased. The monthly subcutaneous self-injection dosing regimen of daclizumab may be advantageous in maintaining patient adherence to treatment, which is important for optimal outcomes with MS disease-modifying therapy. Daclizumab has been approved in the US and in the European Union and represents an effective new treatment option for patients with relapsing forms of MS, and is currently under review by other regulatory agencies. PMID:27672308

  17. The therapeutic efficacy of sacroiliac joint blocks with triamcinolone acetonide in the treatment of sacroiliac joint dysfunction without spondyloarthropathy.

    Liliang, Po-Chou; Lu, Kang; Weng, Hui-Ching; Liang, Cheng-Loong; Tsai, Yu-Duan; Chen, Han-Jung

    2009-04-20

    Prospective case series. The study aimed to investigate the therapeutic efficacy of sacroiliac joint (SIJ) blocks with triamcinolone acetonide in patients with SIJ pain without spondyloarthropathy. Numerous studies have demonstrated that SIJ blocks with corticosteroid/anesthetic provide long-term pain relief in seronegative spondyloarthropathy. However, only one report on SIJ dysfunction patients without spondyloarthropathy shows promising results. We conducted a prospective observational study of patients at a University Spine Center from March 2005 to May 2006. The above mentioned SIJ blocks were performed in 150 patients, and dual SIJ blocks confirmed SIJ pain in 39 patients (26%). Twenty-six patients (66.7%) experienced significant pain reduction for more than 6 weeks; the overall mean duration of pain reduction in these responders was 36.8 +/- 9.9 weeks. SIJ blocks were ineffective in 13 patients (33.3%); the mean duration of pain reduction in these patients was 4.4 +/- 1.8 weeks. Univariate analysis revealed that treatment failure was significantly associated with a history of lumbar/lumbosacral fusion (P = 0.03). SIJ blocks with triamcinolone acetonide are beneficial for some patients with SIJ pain without spondyloarthropathy. The SIJ blocks showed a long-lasting efficacy in two-thirds of the patients; however, the duration of its efficacy was shorter in patients with a history of lumbar/lumbosacral fusion. These findings suggest the need for further studies.

  18. Curcumin's Neuroprotective Efficacy in Drosophila Model of Idiopathic Parkinson's Disease Is Phase Specific: Implication of its Therapeutic Effectiveness

    Phom, Limamanen; Achumi, Bovito; Alone, Debasmita P.; Muralidhara

    2014-01-01

    Abstract Selective degeneration of dopaminergic neurons in the substantia nigra underlies the basic motor impairments of Parkinson's disease (PD). Curcumin has been used for centuries in traditional medicines in India. Our aim is to understand the efficacy of genotropic drug curcumin as a neuroprotective agent in PD. Analysis of different developmental stages in model organisms revealed that they are characterized by different patterns of gene expression which is similar to that of developmental stages of human. Genotropic drugs would be effective only during those life cycle stages for which their target molecules are available. Hence there exists a possibility that targets of genotropic compounds such as curcumin may not be present in all life stages. However, no reports are available in PD models illustrating the efficacy of curcumin in later phases of adult life. This is important because this is the period during which late-onset disorders such as idiopathic PD set in. To understand this paradigm, we tested the protective efficacy of curcumin in different growth stages (early, late health stage, and transition phase) in adult Drosophila flies. Results showed that it can rescue the motor defects during early stages of life but is ineffective at later phases. This observation was substantiated with the finding that curcumin treatment could replenish depleted brain dopamine levels in the PD model only during early stages of life cycle, clearly suggesting its limitation as a therapeutic agent in late-onset neurodegenerative disorders such as PD. PMID:25238331

  19. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis

    Dorlo, Thomas P. C.; Balasegaram, Manica; Beijnen, Jos H.; de Vries, Peter J.

    2012-01-01

    Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells as well as some pathogenic bacteria and fungi. For 10 years it has been licensed in India for the treatment of visceral leishmaniasis (VL), a fatal neglected parasitic disease. It

  20. The therapeutic implications of plasticity of the cancer stem cell phenotype.

    Kevin Leder

    2010-12-01

    Full Text Available The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra- or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer.

  1. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study.

    Kitchener, H; Swart, A M C; Qian, Q; Amos, C; Parmar, M K B

    2009-01-10

    Hysterectomy and bilateral salpingo-oophorectomy (BSO) is the standard surgery for stage I endometrial cancer. Systematic pelvic lymphadenectomy has been used to establish whether there is extra-uterine disease and as a therapeutic procedure; however, randomised trials need to be done to assess therapeutic efficacy. The ASTEC surgical trial investigated whether pelvic lymphadenectomy could improve survival of women with endometrial cancer. From 85 centres in four countries, 1408 women with histologically proven endometrial carcinoma thought preoperatively to be confined to the corpus were randomly allocated by a minimisation method to standard surgery (hysterectomy and BSO, peritoneal washings, and palpation of para-aortic nodes; n=704) or standard surgery plus lymphadenectomy (n=704). The primary outcome measure was overall survival. To control for postsurgical treatment, women with early-stage disease at intermediate or high risk of recurrence were randomised (independent of lymph-node status) into the ASTEC radiotherapy trial. Analysis was by intention to treat. This study is registered, number ISRCTN 16571884. After a median follow-up of 37 months (IQR 24-58), 191 women (88 standard surgery group, 103 lymphadenectomy group) had died, with a hazard ratio (HR) of 1.16 (95% CI 0.87-1.54; p=0.31) in favour of standard surgery and an absolute difference in 5-year overall survival of 1% (95% CI -4 to 6). 251 women died or had recurrent disease (107 standard surgery group, 144 lymphadenectomy group), with an HR of 1.35 (1.06-1.73; p=0.017) in favour of standard surgery and an absolute difference in 5-year recurrence-free survival of 6% (1-12). With adjustment for baseline characteristics and pathology details, the HR for overall survival was 1.04 (0.74-1.45; p=0.83) and for recurrence-free survival was 1.25 (0.93-1.66; p=0.14). Our results show no evidence of benefit in terms of overall or recurrence-free survival for pelvic lymphadenectomy in women with early

  2. Graphene- gold based nanocomposites applications in cancer diseases; Efficient detection and therapeutic tools.

    Al-Ani, Lina A; AlSaadi, Mohammed A; Kadir, Farkaad A; Hashim, Najihah M; Julkapli, Nurhidayatullaili M; Yehye, Wageeh A

    2017-10-20

    Early detection and efficient treatment of cancer disease remains a drastic challenge in 21st century. Throughout the bulk of funds, studies, and current therapeutics, cancer seems to aggressively advance with drug resistance strains and recurrence rates. Nevertheless, nanotechnologies have indeed given hope to be the next generation for oncology applications. According to US National cancer institute, it is anticipated to revolutionize the perspectives of cancer diagnosis and therapy. With such success, nano-hybrid strategy creates a marvelous preference. Herein, graphene-gold based composites are being increasingly studied in the field of oncology, for their outstanding performance as robust vehicle of therapeutic agents, built-in optical diagnostic features, and functionality as theranostic system. Additional modes of treatments are also applicable including photothermal, photodynamic, as well as combined therapy. This review aims to demonstrate the various cancer-related applications of graphene-gold based hybrids in terms of detection and therapy, highlighting the major attributes that led to designate such system as a promising ally in the war against cancer. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: a novel therapeutic approach for cancer

    Yuan YG

    2017-09-01

    Full Text Available Yu-Guo Yuan,1 Qiu-Ling Peng,2 Sangiliyandi Gurunathan3 1College of Veterinary Medicine/Animal Science and Technology/Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, 2College of Chemistry and Bioengineering, Yichun University, Yichun, People’s Republic of China; 3Department of Stem cell and Regenerative Biotechnology, Konkuk University, Seoul, Republic of Korea Background: Breast cancer is the most common malignant disease that occurs in women. Histone deacetylase (HDAC inhibition has recently emerged as an effective and attractive target for the treatment of cancer. The aim of this study was to investigate the efficacy of a combined treatment of tubastatin A (TUB-A and palladium nanoparticles (PdNPs against MDA-MB-231 human breast cancer cells using two different cytotoxic agents that work by two different mechanisms, thereby decreasing the probability of chemoresistance in cancer cells and increasing the efficacy of toxicity, to provide efficient therapy for advanced stage of cancer without any undesired side effects. Methods: PdNPs were synthesized using a novel biomolecule called R-phycoerythrin and characterized using various analytical techniques. The combinatorial effect of TUB-A and PdNPs was assessed by various cellular and biochemical assays and also by gene expression analysis. Results: The biologically synthesized PdNPs had an average size of 25 nm and were spherical in shape. Treatment of MDA-MB-231 human breast cancer cells with TUB-A or PdNPs showed a dose-dependent effect on cell viability. The combination of 4 µM TUB-A and 4 µM PdNPs had a significant inhibitory effect on cell viability compared with either TUB-A or PdNPs alone. The combinatorial treatment also had a more pronounced effect on the inhibition of HDAC activity and enhanced apoptosis by regulating various cellular and biochemical changes. Conclusion: Our results suggest

  4. An acute exercise session increases self-efficacy in sedentary endometrial cancer survivors and controls.

    Hughes, Daniel; Baum, George; Jovanovic, Jennifer; Carmack, Cindy; Greisinger, Anthony; Basen-Engquist, Karen

    2010-11-01

    Self-efficacy can be affected by mastery experiences and somatic sensations. A novel exercise experience and associated sensations may impact self-efficacy and subsequent behaviors. We investigated the effect of a single exercise session on self-efficacy for sedentary endometrial cancer survivors compared with sedentary women of a similar age, but with no cancer history. Twenty survivors and 19 controls completed an exercise session performed as a submaximal cycle ergometry test. Sensations and efficacy were measured before and after exercise. Repeated measures analysis of variance (ANOVA) was performed. Regression models were used to determine predictors of self-efficacy and subsequent exercise. Self-efficacy increased for both survivors and controls, but survivors had a higher rate of increase, and the change predicted subsequent exercise. The association between exercise-related somatic sensations and self-efficacy differed between the 2 groups. A novel exercise experience had a larger effect on self-efficacy and subsequent exercise activity for endometrial cancer survivors than controls. Somatic sensations experienced during exercise may differ for survivors, which may be related to the experience of having cancer. Understanding factors affecting confidence in novel exercise experiences for populations with specific cancer histories is of the utmost importance in the adoption of exercise behaviors.

  5. A Therapeutic Communication Study of Families with Children Suffering from Cancer

    Devie Rahmawati

    2017-12-01

    Full Text Available Therapeutic communication is a relatively new area of research in Indonesia. It is widely known that the success of therapeutic communication is largely influenced by the medical providers’ communication effectiveness when dealing with their clients. This paper reports on research that aimed to explore the connection between therapeutic communication and satisfaction and dissatisfaction as experienced by families of child cancer patients. It used a quantitative approach with a cross-sectional design. The sample was the families of child cancer patients who were acccompanying the patients during hospital stay treatment at an Indonesian public hospital in Jakarta over the period December of   2014 – March 2015. There were 23 respondents for the research. The statistical test used was chi-square with an 0.05 level of significance. The result indicated that 56.5% of the respondents were satisfied with the therapeutic communication provided by nursing staff and that those who praticed therapeutic communication well, were 22 times more likely to provide a satisfactory level to the families  of   child  cancer  patients  compared  with  those who  did not  apply good therapeutic communication  (the value of p=0.003 and Odds ratio= 22. Thus, the research indicated that the medical providers’ communication effectiveness was associated with the patients’ satisfaction. We suggest that medical providers be given workshops on how to improve their communication skills to make their clients more satisfied with the medical services.

  6. CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer

    Yoshida, Kazumichi; Tsujimoto, Hironori; Matsumura, Kouji; Kinoshita, Manabu; Takahata, Risa; Matsumoto, Yusuke; Hiraki, Shuichi; Ono, Satoshi; Seki, Shuhji; Yamamoto, Junji; Hase, Kazuo

    2015-01-01

    CD47 is an antiphagocytic molecule that acts via ligation to signal regulatory protein alpha on phagocytes; its enhanced expression and therapeutic targeting have recently been reported for several malignancies. However, CD47 expression in gastric cancer is not well documented. Immunohistochemical expression of CD47 in surgical specimens was investigated. Expression of CD47 and CD44, a known gastric cancer stem cell marker, were investigated in gastric cancer cell lines by flow cytometry. MKN45 and MKN74 gastric cancer cells were sorted by fluorescence-activated cell sorting according to CD44 and CD47 expression levels, and their in vitro proliferation, spheroid-forming capacity, and in vivo tumorigenicity were studied. In vitro phagocytosis of cancer cells by human macrophages in the presence of a CD47 blocking monoclonal antibody (B6H12) and the survival of immunodeficient mice intraperitoneally engrafted with MKN45 cells and B6H12 were compared to experiments using control antibodies. Immunohistochemistry of the clinical specimens indicated that CD47 was positive in 57 out of 115 cases, and its positivity was an independent adverse prognostic factor. Approximately 90% of the MKN45 and MKN74 cells expressed CD47 and CD44. CD47 hi gastric cancer cells showed significantly higher proliferation and spheroid colony formation than CD47 lo , and CD44 hi CD47 hi cells showed the highest proliferation in vitro and tumorigenicity in vivo. B6H12 significantly enhanced in vitro phagocytosis of cancer cells by human macrophages and prolonged the survival of intraperitoneal cancer dissemination in mice compared to control antibodies. In conclusion, CD47 is an adverse prognostic factor and promising therapeutic target in gastric cancer

  7. Effects of ABCB1, ABCC2, UGT2B7 and HNF4α genetic polymorphisms on oxcarbazepine concentrations and therapeutic efficacy in patients with epilepsy.

    Shen, Chunhong; Zhang, Bijun; Liu, Zhirong; Tang, Yelei; Zhang, Yinxi; Wang, Shan; Guo, Yi; Ding, Yao; Wang, Shuang; Ding, Meiping

    2017-10-01

    The aim of the study is to investigate the effects of ABCB1, ABCC2, UGT2B7 and HNF4α genetic polymorphisms on plasma oxcarbazepine (OXC) concentrations and therapeutic efficacy in Han Chinese patients with epilepsy. We recruited 116 Han Chinese patients with epilepsy who were receiving OXC monotherapy. Blood samples were taken and OXC levels were measured. The polymorphisms of ABCB1 rs1045642, ABCC2 rs2273697, UGT2B7 rs7439366, and HNF4α rs2071197 were determined. The therapeutic efficacy of OXC at the 1-year time-point was assessed. Data analysis was performed using IBM SPSS Statistics 22.0. The genetic polymorphism of ABCB1 rs1045642 was found to be associated with normalized OXC concentration and therapeutic efficacy in patients with epilepsy (P<0.05). As for UGT2B7 rs7439366, the allele polymorphism exhibited a correlation with treatment outcome, but not OXC concentration. The polymorphisms of ABCC2 rs2273697 and HNF4α rs2071197 was not associated with OXC concentrations and therapeutic efficacy. These results suggested that ABCB1 rs1045642 and UGT2B7 rs7439366 may affect OXC pharmacokinetics and therapeutic efficacy in Han Chinese patients with epilepsy. However, further studies in larger populations and other ethnic groups are required. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  8. Novel nitric oxide generating compound glycidyl nitrate enhances the therapeutic efficacy of chemotherapy and radiotherapy.

    Ning, Shoucheng; Bednarski, Mark; Oronsky, Bryan; Scicinski, Jan; Knox, Susan J

    2014-05-09

    Selective release of nitric oxide (NO) in tumors could improve the tumor blood flow and drug delivery for chemotherapeutic agents and radiotherapy, thereby increasing the therapeutic index. Glycidyl nitrate (GLYN) is a NO generating small molecule, and has ability to release NO on bioactivation in SCC VII tumor cells. GLYN-induced intracellular NO generation was significantly attenuated by NO scavenger carboxy-PTIO (cPTIO) and NAC. GLYN significantly increases tumor blood flow, but has no effect on the blood flow of normal tissues in tumor-bearing mice. When used with cisplatin, GLYN significantly increased the tumor growth inhibition effect of cisplatin. GLYN also had a modest radiosensitizing effect in vitro and in vivo. GLYN was well tolerated and there were no acute toxicities found at its effective therapeutic doses in preclinical studies. These results suggest that GLYN is a promising new drug for use with chemotherapy and radiotherapy, and provide a compelling rationale for future studies of GLYN and related compounds. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Network Meta-Analysis Comparing the Efficacy of Therapeutic Treatments for Bronchiolitis in Children.

    Guo, Caili; Sun, Xiaomin; Wang, Xiaowen; Guo, Qing; Chen, Dan

    2018-01-01

    This study aims to compare placebo (PBO) and 7 therapeutic regimens-namely, bronchodilator agents (BAs), hypertonic saline (HS), BA ± HS, corticosteroids (CS), epinephrine (EP), EP ± CS, and EP ± HS-to determine the optimal bronchiolitis treatment. We plotted networks using the curative outcome of several studies and specified the relations among the experiments by using mean difference, standardized mean difference, and corresponding 95% credible interval. The surface under the cumulative ranking curve (SUCRA) was used to separately rank each therapy on clinical severity score (CSS) and length of hospital stay (LHS). This network meta-analysis included 40 articles from 1995 to 2016 concerning the treatment of bronchiolitis in children. All 7 therapeutic regimens displayed no significant difference to PBO with regard to CSS in our study. Among the 7 therapies, BA performed better than CS. As for LHS, EP and EP ± HS had an advantage over PBO. Moreover, EP and EP ± HS were also more efficient than BA. The SUCRA results showed that EP ± CS is most effective, and EP ± HS is second most effective with regard to CSS. With regard to LHS, EP ± HS ranked first, EP ± CS ranked second, and EP ranked third. We recommend EP ± CS and EP ± HS as the first choice for bronchiolitis treatment in children because of their outstanding performance with regard to CSS and LHS. © 2017 American Society for Parenteral and Enteral Nutrition.

  10. [Therapeutic efficacy of nootropil different doses in attention deficit hyperactivity disorder].

    Zavadenko, N N; Suvorinova, S Iu

    2004-01-01

    Attention Deficit Hyperactivity Disorder (ADHD) is the most common cause of behavioral and learning problems in childhood. Therapeutic efficiency of nootropil (piracetam) in two different doses has been evaluated in the open control study of 80 children with ADHD, 70 boys and 10 girls, aged 6-11 years, being divided into 3 groups. Two groups received nootropil, as a monotherapy, for a month: 1st group (30 patients)--in the dosage of 70 mg/kg daily and 2nd group (30 patients)--40 mg/kg daily orally. The control group of 20 patients did not receive any treatment. All children were examined twice with one month interval. A procedure of assessment included of structured questionnaire to parents, neurological examination with scored evaluation of subtle signs and psychological testing. Nootropil therapy in ADHD children resulted in the improvement of behavioral characteristics, motor coordination as well as continuous, selective and divided attention. A response rate was 60% in patients received 70 mg/kg of nootropil and 43% for nootropil dosage of 40 mg/kg. The results of the study suggest more considerable positive therapeutic effects of nootropil higher dose on behavioral, motor and attention characteristics in children with ADHD.

  11. CIMAvax-EGF®: Therapeutic Vaccine Against Non-small Cell Lung Cancer in Advanced Stages

    Diana Rosa Fernández Ruiz

    2017-02-01

    Full Text Available Biotechnology is one of the scientific activities deployed by the Cuban State, which shows greater results and impact on the of the Cuban population health. It has increased the therapeutic repertoire in dealing with oncological diseases with products such as CIMAvax-EGF®, the first therapeutic vaccine of its kind, from the Molecular Immunology Center, against non-small cell lung cancer in advanced stages IIIB IV. The application of this product already extends to Primary Health Care with encouraging results, by prolonging the survival of patients with higher quality of life.

  12. Enhanced antitumor efficacy and reduced systemic toxicity of sulfatide-containing nanoliposomal doxorubicin in a xenograft model of colorectal cancer.

    Jia Lin

    Full Text Available Sulfatide is a glycosphingolipid known to interact with several extracellular matrix proteins, such as tenascin-C which is overexpressed in many types of cancer including that of the colon. In view of the limited success of chemotherapy in colorectal cancer and high toxicity of doxorubicin (DOX, a sulfatide-containing liposome (SCL encapsulation approach was taken to overcome these barriers. This study assessed the in vitro cytotoxicity, biodistribution, therapeutic efficacy and systemic toxicity in vivo of sulfatide-containing liposomal doxorubicin (SCL-DOX using human colonic adenocarcinoma HT-29 xenograft as the experimental model. In vitro, SCL-DOX was shown to be delivered into the nuclei and displayed prolonged retention compared with the free DOX. The use of this nanodrug delivery system to deliver DOX for treatment of tumor-bearing mice produced a much improved therapeutic efficacy in terms of tumor growth suppression and extended survival in contrast to the free drug. Furthermore, treatment of tumor-bearing mice with SCL-DOX resulted in a lower DOX uptake in the principal sites of toxicity of the free drug, namely the heart and skin, as well as reduced myelosuppression and diminished cardiotoxicity. Such natural lipid-guided nanodrug delivery systems may represent a new strategy for the development of effective anticancer chemotherapeutics targeting the tumor microenvironment for both primary tumor and micrometastases.

  13. Therapeutic efficacy and toxicity of {sup 225}Ac-labelled vs. {sup 213}Bi-labelled tumour-homing peptides in a preclinical mouse model of peritoneal carcinomatosis

    Essler, Markus; Gaertner, Florian C.; Blechert, Birgit; Senekowitsch-Schmidtke, Reingard; Seidl, Christof [Technische Universitaet Muenchen, Department of Nuclear Medicine, Munich (Germany); Neff, Frauke [Helmholtz Zentrum Muenchen, Institute of Pathology, Neuherberg (Germany); Bruchertseifer, Frank; Morgenstern, Alfred [Institute for Transuranium Elements, European Commission, Joint Research Centre, Karlsruhe (Germany)

    2012-04-15

    Targeted delivery of alpha-particle-emitting radionuclides is a promising novel option in cancer therapy. We generated stable conjugates of the vascular tumour-homing peptide F3 both with {sup 225}Ac and {sup 213}Bi that specifically bind to nucleolin on the surface of proliferating tumour cells. The aim of our study was to determine the therapeutic efficacy of {sup 225}Ac-DOTA-F3 in comparison with that of {sup 213}Bi-DTPA-F3. ID{sub 50} values of {sup 213}Bi-DTPA-F3 and {sup 225}Ac-DOTA-F3 were determined via clonogenic assays. The therapeutic efficacy of both constructs was assayed by repeated treatment of mice bearing intraperitoneal MDA-MB-435 xenograft tumours. Therapy was monitored by bioluminescence imaging. Nephrotoxic effects were analysed by histology. ID{sub 50} values of {sup 213}Bi-DTPA-F3 and {sup 225}Ac-DOTA-F3 were 53 kBq/ml and 67 Bq/ml, respectively. The median survival of control mice treated with phosphate-buffered saline was 60 days after intraperitoneal inoculation of 1 x 10{sup 7} MDA-MB-435 cells. Therapy with 6 x 1.85 kBq of {sup 225}Ac-DOTA-F3 or 6 x 1.85 MBq of {sup 213}Bi-DTPA-F3 prolonged median survival to 95 days and 97 days, respectively. While F3 labelled with short-lived {sup 213}Bi (t{sub 1/2} 46 min) reduced the tumour mass at early time-points up to 30 days after treatment, the antitumour effect of {sup 225}Ac-DOTA-F3 (t{sub 1/2} 10 days) increased at later time-points. The difference in the fraction of necrotic cells after treatment with {sup 225}Ac-DOTA-F3 (43%) and with {sup 213}Bi-DTPA-F3 (36%) was not significant. Though histological analysis of kidney samples revealed acute tubular necrosis and tubular oedema in 10-30% of animals after treatment with {sup 225}Ac-DOTA-F3 or {sup 213}Bi-DTPA-F3, protein casts were negligible (2%), indicating only minor damage to the kidney. Therapy with both {sup 225}Ac-DOTA-F3 and {sup 213}Bi-DTPA-F3 increased survival of mice with peritoneal carcinomatosis. Mild renal toxicity of both

  14. Clinical efficacy and safety of T-DM1 for patients with HER2-positive breast cancer

    Ma B

    2016-02-01

    Full Text Available Bo Ma,1 Qianqian Ma,2 Hongqiang Wang,3 Guolei Zhang,1 Huiying Zhang,1 Xiaohong Wang1 1Affiliated Central Hospital of Huzhou Teachers College, Huzhou, Zhejiang, People’s Republic of China; 2University Hospital of Tuebingen, Tuebingen, Germany; 3Department of Oncology, Hospital of Zhoushan, Zhoushan, Zhejiang, People’s Republic of China Purpose: The aim of this study was to evaluate the therapeutic efficacy and safety of trastuzumab emtansine (T-DM1 for the treatment of patients with human epidermal growth factor receptor 2-positive breast cancer.  Methods: We performed a systemic review and meta-analysis of the relevant published clinical studies. A computerized search was performed for controlled clinical trials of T-DM1 in targeted treatment. Overall survival, progression-free survival, objective response rate, symptom progression free, and adverse events (AEs were evaluated.  Results: Eight eligible trials with a total of 2,016 patients with breast cancer were included in the present meta-analysis. The treatment of patients with breast cancer with T-DM1 was associated with significantly increased overall and progression-free survival when compared with controls (P<0.0001. An analysis of the objective response rate and symptom progression free also demonstrated favorable results for T-DM1 treatment (P≤0.0001. There was no significant difference between the T-DM1 and control groups with respect to nonhematologic or hematologic AEs (P=0.99 and P=0.30, respectively.  Conclusion: Overall, T-DM1 is efficacious in the treatment of patients with human epidermal growth factor receptor 2-positive breast cancer and low rates of AEs compared with controls. Keywords: breast cancer, meta-analysis, HER2, T-DM1, efficacy

  15. A meta-analytic review of the relationship of cancer coping self-efficacy with distress and quality of life.

    Chirico, Andrea; Lucidi, Fabio; Merluzzi, Thomas; Alivernini, Fabio; Laurentiis, Michelino De; Botti, Gerardo; Giordano, Antonio

    2017-05-30

    Self-efficacy for coping with cancer is a specific construct that refers to behaviors that occur in the course of dealing with a cancer diagnosis, cancer treatments, and transitioning to survivorship. One of the more widely used measures of self-efficacy for coping strategies with cancer is the Cancer Behavior Inventory. The following general questions provide a framework for this research: 1. Is self-efficacy for coping with cancer related to distress and quality of life of a cancer patient?. 2. Do self-efficacy for coping with cancer and the target psychological outcomes (i.e., distress and quality of life) change in longitudinal studies, with or without intervention? One-hundred eighty studies cited the different versions of the Cancer Behavior Inventory and 47 used the scale. Result showed an inverse relationship between self-efficacy for coping with cancer and distress, and a positive relationship between self-efficacy for coping with cancer and Quality of Life, both with a large effect size. The strong relationship of self-efficacy and outcomes, resulted of the specificity of the instrument, which targets specific coping strategies that are closely aligned with positive outcomes in adjusting to cancer. However, the results are consistent with the theory, which states that compared to those with low efficacy, highly efficacious people demonstrate less anxiety and better adjustment in stressful situations and consistent with prior results in which self-efficacy is positively related to quality of life.

  16. Breast Cancer Gene Therapy: Development of Novel Non-Invasive Magnetic Resonance Assay to Optimize Efficacy

    Mason, Ralph P

    2007-01-01

    Gene therapy holds great promise for treatment of breast cancer. In particular clinical trials are underway to apply therapeutic genes related to pro-drug activation or to modulate the activity of oncogenes by blocking promoter sites...

  17. Efficacy of post-operative radiotherapy in the treatment of breast cancer

    Api, P; Corcione, S; Magnoni, G

    1985-01-01

    A clinical evaluation regarding the efficacy of post-operative radiotherapy in 294 patients with breast cancer is presented. In the author's opinion post-operative radiotherapy is fundamental in the treatment of this tumor. 21 refs.

  18. Loss of CHD1 causes DNA repair defects and enhances prostate cancer therapeutic responsiveness

    Kari, Vijayalakshmi; Mansour, Wael Yassin; Raul, Sanjay Kumar

    2016-01-01

    The CHD1 gene, encoding the chromo-domain helicase DNA-binding protein-1, is one of the most frequently deleted genes in prostate cancer. Here, we examined the role of CHD1 in DNA double-strand break (DSB) repair in prostate cancer cells. We show that CHD1 is required for the recruitment of Ct......-homologous end joining. Together, we provide evidence for a previously unknown role of CHD1 in DNA DSB repair via HR and show that CHD1 depletion sensitizes cells to PARP inhibitors, which has potential therapeutic relevance. Our findings suggest that CHD1 deletion, like BRCA1/2 mutation in ovarian cancer, may...... serve as a marker for prostate cancer patient stratification and the utilization of targeted therapies such as PARP inhibitors, which specifically target tumors with HR defects....

  19. Survivin - an inhibitor of apoptosis and a new therapeutic target in cancer

    Pizem, J.; Coer, A.

    2003-01-01

    Survivin is a unique member of the inhibitor of apoptosis (IAP) protein family. It inhibits apoptosis by interfering with post-mitochondrial events during apoptosis, thus blocking activation of caspases. The expression of survivin is among the most tumour specific of all human genes. It is overexpressed in most human cancers but is not detected in most normal tissues. Some molecular mechanisms of survivin upregulation in cancer have been elucidated, including loss of the wild-type p53. Tumours that overexpress survivin generally bear a worse prognosis and are associated with resistance to therapy. Its differential expression in cancer versus normal tissues makes survivin detection a useful tool in cancer diagnostics and a promising therapeutic target. Survivin targeting has resulted in increased spontaneous and induced apoptosis and inhibition of tumour growth. Some anticancer drugs currently introduced into clinical practice might well act by inactivating survivin. (author)

  20. Serum protein profile at remission can accurately assess therapeutic outcomes and survival for serous ovarian cancer.

    Jinhua Wang

    Full Text Available BACKGROUND: Biomarkers play critical roles in early detection, diagnosis and monitoring of therapeutic outcome and recurrence of cancer. Previous biomarker research on ovarian cancer (OC has mostly focused on the discovery and validation of diagnostic biomarkers. The primary purpose of this study is to identify serum biomarkers for prognosis and therapeutic outcomes of ovarian cancer. EXPERIMENTAL DESIGN: Forty serum proteins were analyzed in 70 serum samples from healthy controls (HC and 101 serum samples from serous OC patients at three different disease phases: post diagnosis (PD, remission (RM and recurrence (RC. The utility of serum proteins as OC biomarkers was evaluated using a variety of statistical methods including survival analysis. RESULTS: Ten serum proteins (PDGF-AB/BB, PDGF-AA, CRP, sFas, CA125, SAA, sTNFRII, sIL-6R, IGFBP6 and MDC have individually good area-under-the-curve (AUC values (AUC = 0.69-0.86 and more than 10 three-marker combinations have excellent AUC values (0.91-0.93 in distinguishing active cancer samples (PD & RC from HC. The mean serum protein levels for RM samples are usually intermediate between HC and OC patients with active cancer (PD & RC. Most importantly, five proteins (sICAM1, RANTES, sgp130, sTNFR-II and sVCAM1 measured at remission can classify, individually and in combination, serous OC patients into two subsets with significantly different overall survival (best HR = 17, p<10(-3. CONCLUSION: We identified five serum proteins which, when measured at remission, can accurately predict the overall survival of serous OC patients, suggesting that they may be useful for monitoring the therapeutic outcomes for ovarian cancer.

  1. Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis.

    Suzuki, Hideo; Kaneko, Tsuyoshi; Mizokami, Yuji; Narasaka, Toshiaki; Endo, Shinji; Matsui, Hirofumi; Yanaka, Akinori; Hirayama, Aki; Hyodo, Ichinosuke

    2013-05-07

    Ulcerative colitis (UC) is a chronic inflammatory bowel disease that may become intractable when treated with conventional medications such as aminosalicylates, corticosteroids, and azathioprine. The herbal medicine Qing Dai has traditionally been used in Chinese medicine to treat UC patients, but there is a lack of published data on the efficacy of Qing Dai in UC treatment. We report several cases of patients with intractable UC who take Qing Dai in a retrospective observational study. Furthermore, we explore the mechanisms of action of Qing Dai. Nine patients with active UC who received conventional medications but wished to receive Qing Dai as an alternative medication were included in our analysis. The UC severity level was determined based on the clinical activity index (CAI). Additionally, 5 of the 9 patients were endoscopically evaluated according to the Matts grading system. Each patient received 2 g/d of Qing Dai orally and continued taking other medications for UC as prescribed. Electron spin resonance was applied to explore the mechanisms of action of Qing Dai. After 4 mo of treatment with Qing Dai, the CAI score decreased from 8.3 ± 2.4 to 2.4 ± 3.4 (mean ± SD; P Qing Dai possesses strong hydroxyl radical scavenging activity. Qing Dai showed significant clinical and endoscopic efficacy in patients who failed to respond to conventional medications. Scavenging of hydroxyl radicals appears to be a potential mechanism through which Qing Dai acts, but the significance of the scavenging ability of Qing Dai with respect to the anti-inflammatory effect in UC patients warrants further investigation.

  2. Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma.

    Marrero, Luis; Wyczechowska, Dorota; Musto, Alberto E; Wilk, Anna; Vashistha, Himanshu; Zapata, Adriana; Walker, Chelsey; Velasco-Gonzalez, Cruz; Parsons, Christopher; Wieland, Scott; Levitt, Daniel; Reiss, Krzysztof; Prakash, Om

    2014-10-01

    Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo), aldoxorubicin (Aldoxo), which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc) was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents-3/4 maximum tolerated dose (MTD)], Doxo [6 mg/kg (3/4 MTD)], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67) and abundant intratumoral programmed cell death (cleaved caspase-3). Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

  3. Therapeutic Efficacy of Aldoxorubicin in an Intracranial Xenograft Mouse Model of Human Glioblastoma

    Luis Marrero

    2014-10-01

    Full Text Available Glioblastoma multiforme (GBM is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo, aldoxorubicin (Aldoxo, which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents—3/4 maximum tolerated dose (MTD], Doxo [6 mg/kg (3/4 MTD], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67 and abundant intratumoral programmed cell death (cleaved caspase-3. Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

  4. [Epidemiologic and therapeutic study on gonococcal infections--clinical efficacy of cefetamet pivoxil].

    Nishimura, M; Kumamoto, Y; Hirose, T; Hayashi, K; Tsukamoto, T; Gohro, T; Ikegaki, S; Kamito, H; Inoke, T; Henmi, I

    1990-07-01

    We studied the epidemiology of 109 cases of gonococcal infections (105 males with urethritis and 4 females with cervicitis), together with the basic and clinical effects of cefetamet pivoxil in the cases. The peak of age distribution of the male patients was in the younger half of their twenties, and all of the 4 female cases were between 20 and 39 years old. The major source of infections in the males younger than 25 years old was their girl friends or so-called pick-up friends, and that of the males older than 25 years old workers serving at an amusement center, for example, bars and so-called special massage parlor, which accounted for about three fourths of the male cases between 35 and 44 years old. The distribution of the MIC (inoculum size; 10(6) CFU/ml) of Cefetamet against beta-lactamase non penicillinase producing Neisseria gonorrhoeae (non-PPNG) ranged from 0.025 to 0.1 microgram/ml and that against beta-lactamase producing Neisseria gonorrhoeae ranged from 0.025 to 0.05 microgram/ml. The isolation rate of PPNG was 10.2% (9/88). In male patients with gonococcal urethritis, the efficacy rate was 100% on days 3 and 7 for 1,000 mg single dose and 7-day treatment and 500 mg single dose treatment. One of the cases treated with 250 mg single dose therapy was unchanged at 3, but the efficacy rate of the remaining cases was 100% at day 7. Complicated urethritis with C. trachomatis was noticed in 25.7% (5/105) of the male urethritis and in 25.0% (1/4) of the female cervicitis cases. The only side effect was diarrhea observed in 1 of the 124 case (0.8%).

  5. Preclinical therapeutic potential of a nitrosylating agent in the treatment of ovarian cancer.

    Shailendra Giri

    Full Text Available This study examines the role of s-nitrosylation in the growth of ovarian cancer using cell culture based and in vivo approaches. Using the nitrosylating agent, S-nitrosoglutathione (GSNO, a physiological nitric oxide molecule, we show that GSNO treatment inhibited proliferation of chemoresponsive and chemoresistant ovarian cancer cell lines (A2780, C200, SKVO3, ID8, OVCAR3, OVCAR4, OVCAR5, OVCAR7, OVCAR8, OVCAR10, PE01 and PE04 in a dose dependent manner. GSNO treatment abrogated growth factor (HB-EGF induced signal transduction including phosphorylation of Akt, p42/44 and STAT3, which are known to play critical roles in ovarian cancer growth and progression. To examine the therapeutic potential of GSNO in vivo, nude mice bearing intra-peritoneal xenografts of human A2780 ovarian carcinoma cell line (2 × 10(6 were orally administered GSNO at the dose of 1 mg/kg body weight. Daily oral administration of GSNO significantly attenuated tumor mass (p<0.001 in the peritoneal cavity compared to vehicle (phosphate buffered saline treated group at 4 weeks. GSNO also potentiated cisplatin mediated tumor toxicity in an A2780 ovarian carcinoma nude mouse model. GSNO's nitrosylating ability was reflected in the induced nitrosylation of various known proteins including NFκB p65, Akt and EGFR. As a novel finding, we observed that GSNO also induced nitrosylation with inverse relationship at tyrosine 705 phosphorylation of STAT3, an established player in chemoresistance and cell proliferation in ovarian cancer and in cancer in general. Overall, our study underlines the significance of S-nitrosylation of key cancer promoting proteins in modulating ovarian cancer and proposes the therapeutic potential of nitrosylating agents (like GSNO for the treatment of ovarian cancer alone or in combination with chemotherapeutic drugs.

  6. Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

    Wairagu, Peninah M.; Park, Kwang Hwa; Kim, Jihye; Choi, Jong-Whan; Kim, Hyun-Won; Yeh, Byung-Il; Jung, Soon-Hee; Yong, Suk-Joong; Jeong, Yangsik

    2014-01-01

    Highlights: • The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. • Growth inhibition by NR ligands or TKIs is target receptor level-dependent. • T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs

  7. In Vitro and In Vivo Synergistic Therapeutic Effect of Cisplatin with Human Papillomavirus16 E6/E7 CRISPR/Cas9 on Cervical Cancer Cell Line

    Shuai Zhen

    2016-12-01

    Full Text Available PURPOSE: Human papillomavirus (HPV type 16 is one of the major etiologic factors of cervical cancer. Our study aims to investigate the potentiality of the antiviral clustered regularly interspaced short palindromic repeat (CRISPR/CRISPR-associated Cas9 system (CRISPR/Cas9 targeting the E6 and E7 oncogenes of HPV16 as a potential chemosensitizer of cisplatin (cis-diaminedichloroplatinum II; CDDP for cervical cancer. METHODS: Specifically, the therapeutic efficacy of combination of CDDP and HPV16 E6 + E7-CRISPR/Cas9 was assessed in cervical cancer cells and cervical cancer xenograft models. RESULTS: In vitro experiments showed that long-term exposure of SiHa cells to the HPV16 E6 + E7-CRISPR/Cas9 induced apoptosis, and its pro-apoptosis effect became more obvious when combined with CDDP. In vivo study found the efficacy of the combination of HPV16 E6 + E7-CRISPR/Cas9 and CDDP were superior to either of the treatments in term of apoptosis induction and metastasis inhibition. CONCLUSION: Collectively, our results suggested that HPV16 E6 + E7-CRISPR/Cas9 could be an effective sensitizer of CDDP chemotherapy in cervical cancer.

  8. Therapeutic efficacy of narrow band imaging-assisted transurethral electrocoagulation for ulcer-type interstitial cystitis/painful bladder syndrome.

    Kajiwara, Mitsuru; Inoue, Shougo; Kobayashi, Kanao; Ohara, Shinya; Teishima, Jun; Matsubara, Akio

    2014-04-01

    Narrow band imaging cystoscopy can increase the visualization and detection of Hunner's lesions. A single-center, prospective clinical trial was carried out aiming to show the effectiveness of narrow band imaging-assisted transurethral electrocoagulation for ulcer-type interstitial cystitis/painful bladder syndrome. A total of 23 patients (19 women and 4 men) diagnosed as having ulcer-type interstitial cystitis/painful bladder syndrome were included. All typical Hunner's lesions and suspected areas identified by narrow band imaging were electrocoagulated endoscopically after the biopsy of those lesions. Therapeutic efficacy was assessed prospectively by using visual analog scale score of pain, O'Leary-Sant's symptom index, O'Leary-Sant's problem index and overactive bladder symptom score. The mean follow-up period was 22 months. All patients (100%) experienced a substantial improvement in pain. The average visual analog scale pain scores significantly decreased from 7.3 preoperatively to 1.2 1 month postoperatively. A total of 21 patients (91.3%) who reported improvement had at least a 50% reduction in bladder pain, and five reported complete resolution. Daytime frequency was significantly decreased postoperatively. O'Leary-Sant's symptom index, O'Leary-Sant's problem index and overactive bladder symptom score were significantly decreased postoperatively. However, during the follow-up period, a total of six patients had recurrence, and repeat narrow band imaging-assisted transurethral electrocoagulation of the recurrent lesions was carried out for five of the six patients, with good response in relieving bladder pain. Our results showed that narrow band imaging-assisted transurethral electrocoagulation could be a valuable therapeutic alternative in patients with ulcer-type interstitial cystitis/painful bladder syndrome, with good efficacy and reduction of recurrence rate. © 2014 The Japanese Urological Association.

  9. THERAPEUTIC EFFECT OF SOLASODINE RHAMNOSYL GLYCOSIDES FOR LARGE SKIN CANCERS: TWO CLINICAL CASES

    Bill E. Cham

    2012-01-01

    Full Text Available Solasodine rhamnosyl glycosides (BEC are a new class of antineoplastics, the efficiency of which administered via intravenous, intraperitoneal, and intratumoral routes is higher than that of many other antitumor agents. Early investigations have established the efficiency of topical BEC applications as a treatment option for non-melanoma skin cancers. There have recently been two clinical cases that count in favor of the fact that the cream formulation Curaderm containing BEC has a very high efficacy in the treatment of large non-melanoma skin cancers that are incurable by other existing methods. Also, Curaderm treatment shows a splendid cosmetic effect. 

  10. Childhood cancer: feelings expressed by children in chemotherapy during therapeutic toy sessions

    Luís Paulo Souza e Souza

    2012-09-01

    Full Text Available This study aimed at understanding the feelings experienced by the child with cancer manifested during Therapeutic Toy sessions. This qualitative research was performed with five children aged between three and twelve years, of both sexes. Data collection was carried out through a participatory and systematic observation, coupled with interviews intermediated by Therapeutic Toy Sessions. The data was worked using discourse analysis. The child with cancer was shown as a being full of feelings. The fear of death, pain, sadness on the limitations imposed by the disease, the withdrawal and rebellion with the procedures, the anguish in the face of uncertainties were negative feelings expressed by the children in the dramatizations. However, the development of treatment, the manifestation of a good prognosis and outcome of cure were emerging feelings of hope and happiness before the treatment, optimism in return to usual activities and overcoming amidst the difficulties experienced.

  11. Functionalized bioengineered spider silk spheres improve nuclease resistance and activity of oligonucleotide therapeutics providing a strategy for cancer treatment.

    Kozlowska, Anna Karolina; Florczak, Anna; Smialek, Maciej; Dondajewska, Ewelina; Mackiewicz, Andrzej; Kortylewski, Marcin; Dams-Kozlowska, Hanna

    2017-09-01

    oligonucleotide delivery system that can be utilized to improve pharmacokinetics of RNA-based therapeutics. Although, the siRNA constructs have already given very promising results in the cancer therapy, the in vivo application of RNA-based oligonucleotide therapeutics still is limited due to their sensitivity to serum nucleases and some toxicity. We propose a carrier for RNA-based therapeutics that is made of bioengineered spider silk. We showed that functionalized bioengineered spider silk spheres not only protected RNA-based therapeutics from degradation by serum nucleases, but what is more important the embedding of siRNA into silk spheres delayed and extended target gene silencing compared with naked oligonucleotides. Moreover, we showed that plain silk spheres did not have unspecific effect on target gene levels proving not only to be non-cytotoxic but also very neutral vehicles in terms of TLR9/STAT3 activation in macrophages. We demonstrated advantages of novel delivery technology in safety and efficacy comparing with delivery of naked CpG-STAT3siRNA therapeutics. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  12. Targeting Cancer Stem Cells and Their Niche: Current Therapeutic Implications and Challenges in Pancreatic Cancer

    Jiangang Zhao

    2017-01-01

    Full Text Available Cancer stem cells (CSCs have been identified as a subpopulation of stem-like cancer cells with the ability of self-renewal and differentiation in hematological malignancies and solid tumors. Pancreatic cancer is one of the most lethal cancers worldwide. CSCs are thought to be responsible for cancer initiation, progression, metastasis, chemoresistance, and recurrence in pancreatic cancer. In this review, we summarize the characteristics of pancreatic CSCs and discuss the mechanisms involved in resistance to chemotherapy, the interactions with the niche, and the potential role in cancer immunoediting. We propose that immunotherapy targeting pancreatic CSCs, in combination with targeting the niche components, may provide a novel treatment strategy to eradicate pancreatic CSCs and hence improve outcomes in pancreatic cancer.

  13. The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity.

    Anne Kleijn

    Full Text Available The oncolytic adenovirus Delta24-RGD represents a new promising therapeutic agent for patients with a malignant glioma and is currently under investigation in clinical phase I/II trials. Earlier preclinical studies showed that Delta24-RGD is able to effectively lyse tumor cells, yielding promising results in various immune-deficient glioma models. However, the role of the immune response in oncolytic adenovirus therapy for glioma has never been explored. To this end, we assessed Delta24-RGD treatment in an immune-competent orthotopic mouse model for glioma and evaluated immune responses against tumor and virus. Delta24-RGD treatment led to long-term survival in 50% of mice and this effect was completely lost upon administration of the immunosuppressive agent dexamethasone. Delta24-RGD enhanced intra-tumoral infiltration of F4/80+ macrophages, CD4+ and CD8+ T-cells, and increased the local production of pro-inflammatory cytokines and chemokines. In treated mice, T cell responses were directed to the virus as well as to the tumor cells, which was reflected in the presence of protective immunological memory in mice that underwent tumor rechallenge. Together, these data provide evidence that the immune system plays a vital role in the therapeutic efficacy of oncolytic adenovirus therapy of glioma, and may provide angles to future improvements on Delta24-RGD therapy.

  14. EFFICACY OF SOFT TISSUE APPLICATION, MANUALLY-THERAPEUTICAL TECHNIQUES FOR KNEE ARTHROKINEMATICS RECOVERY COMPLEX IN PATIENTS AFTER ARTHROSCOPIC MENISCECTOMY

    Kostov Rostislav V

    2015-07-01

    Full Text Available Introduction: In this article we present the final effect of the application of complex soft tissue manually-treatment system for recovery of joint kinematics in patients with moderate and minimal protective period of rehabilitation after arthroscopic meniscectomy. Material and Methods: The study was conducted in 2005-2012 into three medical centers in Bulgaria: Blagoevgrad, Sofia and Pleven. The study included a total of 110 patients divided into three groups (Control and Experimental I and Experimental Group II who studied the effect of topical application of the manual therapeutic techniques compared to traditional rehabilitation methods applied. For testing the efficacy of a treatment approach in the three groups of patients, the results have processed by the method of variational analysis. Results: After analysis of results we find significantly more fully and without residual short violations recovery for all controlled parameters in patients who have implemented comprehensive manually-therapeutic treatment compared with control group patients. Conclusion: Application of adequate physiological and pedagogically grounded complex rehabilitation is required in patients after arthroscopic meniscectomy model with motor deficits in tractable routine rehabilitation. Observations allow us to offer a methodology for implementation in general practice rehabilitation in patients after meniscal ruptures treated by arthroscopic meniscectomy and motor deficits, intractable routine rehabilitation.

  15. Necrosis avid near infrared fluorescent cyanines for imaging cell death and their use to monitor therapeutic efficacy in mouse tumor models

    Xie, Bangwen; Stammes, Marieke A.; van Driel, Pieter B. A. A.; Cruz, Luis J.; Knol-Blankevoort, Vicky T.; Löwik, Martijn A. M.; Mezzanotte, Laura; Que, Ivo; Chan, Alan; van den Wijngaard, Jeroen P. H. M.; Siebes, Maria; Gottschalk, Sven; Razansky, Daniel; Ntziachristos, Vasilis; Keereweer, Stijn; Horobin, Richard W.; Hoehn, Mathias; Kaijzel, Eric L.; van Beek, Ermond R.; Snoeks, Thomas J. A.; Löwik, Clemens W. G. M.

    2015-01-01

    Quantification of tumor necrosis in cancer patients is of diagnostic value as the amount of necrosis is correlated with disease prognosis and it could also be used to predict early efficacy of anti-cancer treatments. In the present study, we identified two near infrared fluorescent (NIRF)

  16. Does the addition of Serenoa repens to tamsulosin improve its therapeutical efficacy in benign prostatic hyperplasia?

    Argirović Aleksandar

    2013-01-01

    Full Text Available Background/Aim. It has been observed that a large number of patients with low urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH has been treated with a combination of tamsulosin (TAM + Serenoa repens (SR (TAM + SR. The aim of this study was to compare a combination TAM + SR with TAM and SR alone, to see if there was any difference in efficacy and tolerance of each in patients with LUTS/BPH. Methods. In this prospective study patients had to have prostate volume (PV 3, a maximal flow rate (Qmax of 5-15 mL/s, with post voiding residual volume (PVR < 150 mL and serum prostatic antigen (PSA < 4 ng/mL. TAM (0.4 mg was administered once a day, SR (320 mg daily or SR (320 mg + TAM (0.4 mg daily for a median period of 6 months. Results. A total of 297 patients were recruited, whereas 265 patients were fully available: 87 into the group TAM, 97 into the group SR and 81 into the group TAM + SR. There was no statistically significant difference between the treatment groups in the sense of demographic and other baseline parameters. No difference was found among the 3 treatment groups, neither in the major endpoint of the study in the sense of a change between baseline and final evaluation in total IPSS, obstructive and irritative subscores, improvement of QoLs, increase in Qmax, nor for the second endpoint including diminution of PV, PSA and PVR. During the treatment period 20 (23% of the patients managed with TAM and 17 (21% with TAM + SR had drug-treated with related adverse reactions. No adverse effect was detected in the group SR. Conclusion. Treatment of BPH by both SR and TAM seems to be efficacious alone. None of them had superiority over another and, additionally, a combined therapy (TAM + SR does not provide extra benefits. Furthermore, SR is a well-tolerated agent that can be used alternatively in the treatment of LUTS/BPH.

  17. Therapeutic Efficacy of Vectored PGT121 Gene Delivery in HIV-1-Infected Humanized Mice.

    Badamchi-Zadeh, Alexander; Tartaglia, Lawrence J; Abbink, Peter; Bricault, Christine A; Liu, Po-Ting; Boyd, Michael; Kirilova, Marinela; Mercado, Noe B; Nanayakkara, Ovini S; Vrbanac, Vladimir D; Tager, Andrew M; Larocca, Rafael A; Seaman, Michael S; Barouch, Dan H

    2018-04-01

    Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies. However, administration of purified bNAbs poses challenges in resource-poor settings, where the HIV-1 disease burden is greatest. In vivo vector-based production of bNAbs represents an alternative strategy. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1-specific bNAb PGT121 in wild-type and immunocompromised C57BL/6 mice as well as in HIV-1-infected bone marrow-liver-thymus (BLT) humanized mice. Ad5.PGT121 and AAV1.PGT121 produced functional antibody in vivo Ad5.PGT121 produced PGT121 rapidly within 6 h, whereas AAV1.PGT121 produced detectable PGT121 in serum by 72 h. Serum PGT121 levels were rapidly reduced by the generation of anti-PGT121 antibodies in immunocompetent mice but were durably maintained in immunocompromised mice. In HIV-1-infected BLT humanized mice, Ad5.PGT121 resulted in a greater reduction of viral loads than did AAV1.PGT121. Ad5.PGT121 also led to more-sustained virologic control than purified PGT121 IgG. Ad5.PGT121 afforded more rapid, robust, and durable antiviral efficacy than AAV1.PGT121 and purified PGT121 IgG in HIV-1-infected humanized mice. Further evaluation of vector delivery of HIV-1 bNAbs is warranted, although approaches to prevent the generation of antiantibody responses may also be required. IMPORTANCE Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies, but delivery of purified antibodies may prove challenging. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1-specific bNAb PGT121. Ad5.PGT121 afforded more rapid, robust, and durable antiviral efficacy than AAV1.PGT121 and purified PGT121 IgG in HIV-1-infected humanized mice. Copyright © 2018 Badamchi-Zadeh et al.

  18. Crosstalk between Apoptosis and Autophagy: Molecular Mechanisms and Therapeutic Strategies in Cancer

    Abdelouahid El-Khattouti

    2013-01-01

    Full Text Available Both apoptosis and autophagy are highly conserved processes that besides their role in the maintenance of the organismal and cellular homeostasis serve as a main target of tumor therapeutics. Although their important roles in the modulation of tumor therapeutic strategies have been widely reported, the molecular actions of both apoptosis and autophagy are counteracted by cancer protective mechanisms. While apoptosis is a tightly regulated process that is implicated in the removal of damaged or unwanted cells, autophagy is a cellular catabolic pathway that is involved in lysosomal degradation and recycling of proteins and organelles, and thereby is considered an important survival/protective mechanism for cancer cells in response to metabolic stress or chemotherapy. Although the relationship between autophagy and cell death is very complicated and has not been characterized in detail, the molecular mechanisms that control this relationship are considered to be a relevant target for the development of a therapeutic strategy for tumor treatment. In this review, we focus on the molecular mechanisms of apoptosis, autophagy, and those of the crosstalk between apoptosis and autophagy in order to provide insight into the molecular mechanisms that may be essential for the balance between cell survival and death as well as their role as targets for the development of novel therapeutic approaches.

  19. Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

    Brito, Ana Filipa; Ribeiro, Marina; Abrantes, Ana Margarida; Pires, Ana Salomé; Teixo, Ricardo Jorge; Tralhão, José Guilherme; Botelho, Maria Filomena

    2015-01-01

    Cancer is a problem of global importance, since the incidence is increasing worldwide and therapeutic options are generally limited. Thus, it becomes imperative to find new therapeutic targets as well as new molecules with therapeutic potential for tumors. Flavonoids are polyphenolic compounds that may be potential therapeutic agents. Several studies have shown that these compounds have a higher anticancer potential. Among the flavonoids in the human diet, quercetin is one of the most important. In the last decades, several anticancer properties of quercetin have been described, such as cell signaling, pro-apoptotic, anti-proliferative and anti-oxidant effects, growth suppression. In fact, it is now well known that quercetin has diverse biological effects, inhibiting multiple enzymes involved in cell proliferation, as well as, in signal transduction pathways. On the other hand, there are also studies reporting potential synergistic effects when combined quercetin with chemotherapeutic agents or radiotherapy. In fact, several studies which aim to explore the anticancer potential of these combined treatments have already been published, the majority with promising results. Actually it is well known that quercetin can act on the chemosensitization and radiosensitization but also as chemoprotective and radioprotective, protecting normal cells of the side effects that results from chemotherapy and radiotherapy, which obviously provides notable advantages in their use in anticancer treatment. Thus, all these data indicate that quercetin may have a key role in anticancer treatment. In this context, this review is focused on the relationship between flavonoids and cancer, with special emphasis on the role of quercetin.

  20. Anti-tumour therapeutic efficacy of OX40L in murine tumour model.

    Ali, Selman A; Ahmad, Murrium; Lynam, June; McLean, Cornelia S; Entwisle, Claire; Loudon, Peter; Choolun, Esther; McArdle, Stephanie E B; Li, Geng; Mian, Shahid; Rees, Robert C

    2004-09-09

    OX40 ligand (OX40L), a member of TNF superfamily, is a co-stimulatory molecule involved in T cell activation. Systemic administration of mOX40L fusion protein significantly inhibited the growth of experimental lung metastasis and subcutaneous (s.c.) established colon (CT26) and breast (4T1) carcinomas. Vaccination with OX40L was significantly enhanced by combination treatment with intra-tumour injection of a disabled infectious single cycle-herpes simplex virus (DISC-HSV) vector encoding murine granulocyte macrophage-colony stimulating factor (mGM-CSF). Tumour rejection in response to OX40L therapy required functional CD4+ and CD8+ T cells and correlated with splenocyte cytotoxic T lymphocytes (CTLs) activity against the AH-1 gp70 peptide of the tumour associated antigen expressed by CT26 cells. These results demonstrate the potential role of the OX40L in cancer immunotherapy.

  1. RNAi therapeutics and applications of microRNAs in cancer treatment.

    Uchino, Keita; Ochiya, Takahiro; Takeshita, Fumitaka

    2013-06-01

    RNA interference-based therapies are proving to be powerful tools for combating various diseases, including cancer. Scientists are researching the development of safe and efficient systems for the delivery of small RNA molecules, which are extremely fragile in serum, to target organs and cells in the human body. A dozen pre-clinical and clinical trials have been under way over the past few years involving biodegradable nanoparticles, lipids, chemical modification and conjugation. On the other hand, microRNAs, which control the balance of cellular biological processes, have been studied as attractive therapeutic targets in cancer treatment. In this review, we provide an overview of RNA interference-based therapeutics in clinical trials and discuss the latest technology for the systemic delivery of nucleic acid drugs. Furthermore, we focus on dysregulated microRNAs in human cancer, which have progressed in pre-clinical trials as therapeutic targets, and describe a wide range of strategies to control the expression levels of endogenous microRNAs. Further development of RNA interference technologies and progression of clinical trials will contribute to the achievement of practical applications of nucleic acid drugs.

  2. Therapeutic Efficacy of the Combined Extract of Herbal Medicine Against Infectious Bursal Disease in Chickens

    Changbo Ou, Ningning Shi1, Qing Pan, Deyu Tian, Wenshu Zeng and Cheng He*

    2013-07-01

    Full Text Available Currently, infectious bursal disease (IBD is a highly contagious disease leading to huge economic losses in poultry industry. Our objective was to investigate potential therapeutic effects of the combined extracts of Rhizoma Dryopteridis crassirhizomatis and Fructus mume (RDCFM against IBDV infection. Seventy-two 4-week-old SPF chickens were randomly divided into six groups and inoculated intranasally with 0.2 ml of 102.5 EID50 of IBDV strain CJ801. Twenty-four hours post infection, the birds were orally administered with 400, 200 and 100 mg/kg BW of RDCFM, respectively, 125 mg/kg Astragalus polysaccharide (ASP and saline water, respectively for 5 days and then monitored daily for 10 days. Finally, the remaining birds were euthanized to collect the sera for detecting antibodies and immune organs for determining the immune organs index as well as virus loads. The herbal extracts improved survival rate and relative body gain rate. Virus loads in bursa of Fabricius in herbal treated groups decreased significantly while higher antibody levels were detected in the three RDCFM groups as compared to those of ASP and infection group. These results implied that chickens administered with 100-200 mg/kg of RDCFM for 5 days could improve protection against IBDV infection and RDCFM may be a promising alternative to ASP and egg yolk antibody.

  3. Therapeutic efficacy of neuromuscular electrical stimulation and electromyographic biofeedback on Alzheimer's disease patients with dysphagia.

    Tang, Yi; Lin, Xiang; Lin, Xiao-Juan; Zheng, Wei; Zheng, Zhi-Kai; Lin, Zhao-Min; Chen, Jian-Hao

    2017-09-01

    To study the therapeutic effect of neuromuscular electrical stimulation and electromyographic biofeedback (EMG-biofeedback) therapy in improving swallowing function of Alzheimer's disease patients with dysphagia.A series of 103 Alzheimer's disease patients with dysphagia were divided into 2 groups, among which the control group (n = 50) received swallowing function training and the treatment group (n = 53) received neuromuscular electrical stimulation plus EMG-biofeedback therapy. The mini-mental state scale score was performed in all patients along the treatment period. Twelve weeks after the treatment, the swallowing function was assessed by the water swallow test. The nutritional status was evaluated by Mini Nutritional Assessment (MNA) as well as the levels of hemoglobin and serum albumin. The frequency and course of aspiration pneumonia were also recorded.No significant difference on mini-mental state scale score was noted between 2 groups. More improvement of swallowing function, better nutritional status, and less frequency and shorter course of aspiration pneumonia were presented in treatment group when compared with the control group.Neuromuscular electrical stimulation and EMG-biofeedback treatment can improve swallowing function in patients with Alzheimer's disease and significantly reduce the incidence of adverse outcomes. Thus, they should be promoted in clinical practice.

  4. Economic demand predicts addiction-like behavior and therapeutic efficacy of oxytocin in the rat

    Bentzley, Brandon S.; Jhou, Thomas C.; Aston-Jones, Gary

    2014-01-01

    Development of new treatments for drug addiction will depend on high-throughput screening in animal models. However, an addiction biomarker fit for rapid testing, and useful in both humans and animals, is not currently available. Economic models are promising candidates. They offer a structured quantitative approach to modeling behavior that is mathematically identical across species, and accruing evidence indicates economic-based descriptors of human behavior may be particularly useful biomarkers of addiction severity. However, economic demand has not yet been established as a biomarker of addiction-like behavior in animals, an essential final step in linking animal and human studies of addiction through economic models. We recently developed a mathematical approach for rapidly modeling economic demand in rats trained to self-administer cocaine. We show here that economic demand, as both a spontaneous trait and induced state, predicts addiction-like behavior, including relapse propensity, drug seeking in abstinence, and compulsive (punished) drug taking. These findings confirm economic demand as a biomarker of addiction-like behavior in rats. They also support the view that excessive motivation plays an important role in addiction while extending the idea that drug dependence represents a shift from initially recreational to compulsive drug use. Finally, we found that economic demand for cocaine predicted the efficacy of a promising pharmacotherapy (oxytocin) in attenuating cocaine-seeking behaviors across individuals, demonstrating that economic measures may be used to rapidly identify the clinical utility of prospective addiction treatments. PMID:25071176

  5. Therapeutic efficacy of AS2077715 against experimental tinea pedis in guinea pigs in comparison with terbinafine.

    Ohsumi, Keisuke; Murai, Hidetsugu; Nakamura, Ikko; Watanabe, Masato; Fujie, Akihiko

    2014-10-01

    AS2077715 is a novel antifungal metabolite produced by the newly isolated fungal strain Capnodium sp. 339855. This compound has potent inhibitory activity against Trichophyton mentagrophytes mitochondrial cytochrome bc1 complex (complex III) and potent fungicidal activity against T. mentagrophytes, as measured in vitro. Here, we compared the effects of AS2077715 and terbinafine in a guinea pig model of tinea pedis. In a treatment regimen started from the day 7 after infection, 10 daily oral doses of 10 and 20 mg kg(-1) AS2077715 and 20 mg kg(-1) of terbinafine significantly decreased fungal colony-forming units (CFUs) in foot pad skin. In a treatment regimen started from the day 11 after infection, 20 mg kg(-1) AS2077715 significantly reduced fungal CFUs in foot pad skin after 7 daily doses in comparison with 20 mg kg(-1) terbinafine-treated guinea pigs. Our findings suggest that in vivo potency and efficacy of AS2077715 are equal to or greater than that of terbinafine, positioning AS2077715 as a good candidate for use in treating trichophytosis.

  6. Activated mammalian target of rapamycin is a potential therapeutic target in gastric cancer

    Xu, Da-zhi; Sun, Xiao-wei; Guan, Yuan-xiang; Li, Yuan-fang; Lin, Tong-yu; Geng, Qi-rong; Tian, Ying; Cai, Mu-yan; Fang, Xin-juan; Zhan, You-qing; Zhou, Zhi-wei; Li, Wei; Chen, Ying-bo

    2010-01-01

    The mammalian target of rapamycin (mTOR) plays a key role in cellular growth and homeostasis. The purpose of our present study is to investigate the expression of activated mTOR (p-mTOR) in gastric cancer patients, their prognostic significance and the inhibition effect of RAD001 on tumor growth and to determine whether targeted inhibition of mTOR could be a potential therapeutic strategy for gastric cancer. The expression of p-mTOR was detected in specimens of 181 gastric cancers who underwent radical resection (R0) by immunohistochemistry. The correlation of p-mTOR expression to clinicopathologic features and survival of gastric cancer was studied. We also determined the inhibition effect of RAD001 on tumor growth using BGC823 and AGS human gastric cancer cell lines. Immunostaining for p-mTOR was positive in 93 of 181 (51.4%) gastric cancers, closely correlated with lymph node status and pTNM stage. Patients with p-mTOR positive showed significantly shorter disease-free survival (DFS) and overall survival (OS) rates than those with p-mTOR-negative tumors in univariable analyses, and there was a trend toward a correlation between p-mTOR expression and survival in multivariable analyses. RAD001 markedly inhibited dose-dependently proliferation of human gastric carcinoma cells by down-regulating expression of p70s6k, p-p70s6k, C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53. In gastric cancer, p-mTOR is a potential therapeutic target and RAD001 was a promising treatment agent with inducing cell cycle arrest and apoptosis by down-regulating expression of C-myc, CyclinD1 and Bcl-2, up-regulating expression of P53

  7. Cancer-specific Therapeutic Potential of Resveratrol: Metabolic Approach against Hallmarks of Cancer

    Dong Hoon Suh

    2013-08-01

    Full Text Available ABSTRACTCancer hallmarks include evading apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis. Cancer cells undergo metabolic reprogramming and inevitably take advantage of glycolysis to meet the increased metabolic demand: rapid energy generation and macromolecular synthesis. Resveratrol, a polyphenolic phytoalexin, is known to exhibit pleiotropic anti-cancer effects most of which are linked to metabolic reprogramming in cancer cells. This review summarizes various anti-cancer effects of resveratrol in the context of cancer hallmarks in relation to metabolic reprogramming.

  8. Engineering Multi-Walled Carbon Nanotube Therapeutic Bionanofluids to Selectively Target Papillary Thyroid Cancer Cells.

    Idit Dotan

    Full Text Available The incidence of papillary thyroid carcinoma (PTC has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches.Thyroid Stimulating Hormone Receptor (TSHR was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining.TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls.A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam radiation or chemotherapy, with

  9. Therapeutic efficacy of intralesional 131I-labelled hyaluronectin in grafted human glioblastoma

    Girard, N.; Courel, M.N.; Vera, P.; Delpech, B. [Centre Henri-Becquerel, Rouen (France). Laboratoire d' Oncologie Moleculaire

    2000-07-01

    The grafted human glioblastoma cell CB109 was used as a model for intralesional therapy with 131I-labelled hyaluronectin glycoprotein (131I-HN). 131I-HN bound specifically to in situ hyaluronic acid (HA), a main component of the extracellular matrix which is involved in tumour invasion. Labelling experimental conditions were determined and, finally, 25 {mu}Ci/{mu}gHN, 1 {mu}g chloramine-T/{mu}gHN and a 60-s stirring period provided a 131I-HN preparation with an optimal affinity for HA (64% compared to unlabelled HN). Following intratumoral injection, 131I-HN was retained with a limited diffusion outside the tumour. On day 4 the radioactivity concentrated in the tumour was still 25 times greater than that in the liver, spleen and kidneys combined. For therapeutic assays, 65 {mu}Ci 131I-HN was injected into the tumour, resulting in a delivery of 6.8 Gy over a 7-day period. Controls received unlabelled HN, heat-inactivated HN, a mixture of inactivated HN plus free 131I or no treatment (six animals per group). Tumour volumes were evaluated every second day from treatment day and the rate of tumour growth was expressed as a ratio of tumour size at time intervals to the tumour size at the time of injection. Growth curves were compared: heat-inactivated with or without free 131I had no anti-tumour effect. Unlabelled HN-injected tumours had a slightly slower growth rate than untreated tumours (p < 0.02) and growth rate of 131I-HN-injected tumours was much lower (p < 0.00002). A pronounced inhibitory effect with intralesional 131I-labelled HN injection resulted from a combination of a) blockage of HA, a proliferation facilitating factor, and b) local irradiation of tumoral tissue, while uptake in normal tissues was minimized.

  10. Therapeutic efficacy of intralesional 131I-labelled hyaluronectin in grafted human glioblastoma

    Girard, N.; Courel, M.N.; Vera, P.; Delpech, B.

    2000-01-01

    The grafted human glioblastoma cell CB109 was used as a model for intralesional therapy with 131I-labelled hyaluronectin glycoprotein (131I-HN). 131I-HN bound specifically to in situ hyaluronic acid (HA), a main component of the extracellular matrix which is involved in tumour invasion. Labelling experimental conditions were determined and, finally, 25 μCi/μgHN, 1 μg chloramine-T/μgHN and a 60-s stirring period provided a 131I-HN preparation with an optimal affinity for HA (64% compared to unlabelled HN). Following intratumoral injection, 131I-HN was retained with a limited diffusion outside the tumour. On day 4 the radioactivity concentrated in the tumour was still 25 times greater than that in the liver, spleen and kidneys combined. For therapeutic assays, 65 μCi 131I-HN was injected into the tumour, resulting in a delivery of 6.8 Gy over a 7-day period. Controls received unlabelled HN, heat-inactivated HN, a mixture of inactivated HN plus free 131I or no treatment (six animals per group). Tumour volumes were evaluated every second day from treatment day and the rate of tumour growth was expressed as a ratio of tumour size at time intervals to the tumour size at the time of injection. Growth curves were compared: heat-inactivated with or without free 131I had no anti-tumour effect. Unlabelled HN-injected tumours had a slightly slower growth rate than untreated tumours (p < 0.02) and growth rate of 131I-HN-injected tumours was much lower (p < 0.00002). A pronounced inhibitory effect with intralesional 131I-labelled HN injection resulted from a combination of a) blockage of HA, a proliferation facilitating factor, and b) local irradiation of tumoral tissue, while uptake in normal tissues was minimized

  11. Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma

    Adrian Biddle

    2016-02-01

    Full Text Available Cancer stem cells (CSCs drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT and mesenchymal-to-epithelial transition (MET to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC, we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/−CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.

  12. Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma.

    Biddle, Adrian; Gammon, Luke; Liang, Xiao; Costea, Daniela Elena; Mackenzie, Ian C

    2016-02-01

    Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44(high)EpCAM(low/-) CD24(+) cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.

  13. The use of nanoparticles as a promising therapeutic approach in cancer immunotherapy.

    Hosseini, Maryam; Haji-Fatahaliha, Mostafa; Jadidi-Niaragh, Farhad; Majidi, Jafar; Yousefi, Mehdi

    2016-06-01

    Cancer is one of the most important causes of death all over the world, which has not yet been treated efficiently. Although several therapeutic approaches have been used, some side effects such as toxicity and drug resistance have been observed in patients, particularly with chemotherapy. The nanoparticle-mediated drug delivery systems (DDS) have a great potential to improve cancer treatment by transferring therapeutic factors directly to the tumor site. Such a treatment significantly decreases the adverse effects associated with cancer therapy on healthy tissues. Two main strategies, including passive and active methods, have been considered to be effective techniques which can target the drugs to the tumor sites. The current review sheds some light on the place of nanotechnology in cancer drug delivery, and introduces nanomaterials and their specific characteristics that can be used in tumor therapy. Moreover, passive and active targeting approaches focus on antibodies, particularly single chain variable fragments (scFv), as a novel and important ligand in a drug delivery system.

  14. The approach of cancer related fatigue in rehabilitation medicine: Part II – Therapeutic interventions

    Salca Amalia

    2015-09-01

    Full Text Available Starting with patient’ diagnose and continuing throughout the treatment and thereafter, cancer-related fatigue (CRF is a distressing and disabling symptom, highly prevalent across the cancer continuum2. This is a review article mainly focusing on the rehabilitation objectives and interventions in CRF, and implementation issues, according to the report of an NCCN member institution4. Implementation is the most problematic, considering the large number of patients to whom it is addressed to and the variety of pathologies within this group of patients. The onset of CRF is difficult to establish, because of the limitations of reporting this symptom4, but it is a valuable predictor in prognosis. The main interventions in rehabilitation applicable to these patients are discussed in correlation to the objectives of each phase of therapeutic management in cancer: pre-operatory, before, during or after radio and/or chemotherapy Conclusion: Rehabilitation interventions should be applied to all patients diagnosed with cancer, according to their phase of oncologic treatment and the objectives. This should be practiced as preventive measure, but as a therapeutic one to, considering the high incidence of CFR before diagnose.

  15. Regulation of matriptase and HAI-1 system, a novel therapeutic target in human endometrial cancer cells.

    Sun, Pengming; Xue, Lifang; Song, Yiyi; Mao, Xiaodan; Chen, Lili; Dong, Binhua; Braicu, Elena Loana; Sehouli, Jalid

    2018-02-27

    The effects of specific and non-specific regulation of matriptase on endometrial cancer cells in vitro were investigated. Messenger ribonucleic acid (mRNA) and protein expression of matriptase and hepatocyte growth factor activator inhibitor-1 (HAI-1) in RL-952, HEC-1A, and HEC-1B endometrial cancer cells were detected by real-time quantitative PCR (RT-qPCR) and western blot. The cells were infected with lentivirus-mediated small-interfering RNA (siRNA) targeted on matriptase (MA-siRNA) or treated with different cisplatin (DDP) concentrations. After treatment, invasion, migration, and cellular apoptosis were analyzed. Matriptase mRNA and protein expression significantly decreased to 80% after infection with MA-siRNA ( P scratch and trans-well chamber assays showed significant inhibition of invasiveness and metastasis. Upon incubation with cisplatin at concentrations higher than the therapeutic dose for 24 h, the expressions of matriptase and HAI-1 significantly decreased ( P endometrial cancer cells were significantly decreased ( P endometrial cancer cells showed promising therapeutic features.

  16. Specific RSK kinase inhibition by dibenzyl trisulfide and implication for therapeutic treatment of cancer.

    Lowe, Henry I C; Facey, Caroline O B; Toyang, Ngeh J; Bryant, Joseph L

    2014-04-01

    The Jamaican "Guinea Hen Weed" (Petiveria alliacea L.) plant has been traditionally used in folklore medicine to treat a variety of diseases including cancer. In the present study we investigated on the therapeutic feasibility of dibenzyl trisulfide (DTS) (isolated from the Jamaican Guinea Hen Weed) as a potent small-molecule kinase inhibitor to treat cancer. We investigated the inhibitory effects of DTS against a large panel of kinases using a well-established competitive binding assay. Cell proliferation data were obtained using the WST-1 colorimetric assay. DTS inhibited the activity of the C-terminal kinase domain of RSK1 (80% compared to control) with a Kd of 1.3 μM. Anti-proliferative effects of DTS were observed in small lung, pancreatic, breast, and prostate cancer cells with IC50 values ranging from 0.34-0.84 μM. We have identified DTS as a highly selective and isoform-specific RSK1 kinase inhibitor with broad cancer therapeutic potential.

  17. Association between self-efficacy and quality of life in women with breast cancer undergoing chemotherapy

    MZ. Kiaei

    2016-06-01

    Full Text Available Background: Self-efficacy is known as a factor which influences health behaviors, chronic diseases management and quality of life in patients with cancer. Objective: The aim of this study was to investigate the association of self-efficacy and quality of life in women with breast cancer undergoing chemotherapy. Methods: This cross sectional study was conducted in 100 women with breast cancer referred to Seyed Al-Shohada Hospital, Isfahan in 2015. The study subjects were selected by simple random sampling method. The measurement tools were the Sherer self-efficacy scale and the World Health Organization WHOQOL-BREF quality of life assessment. Data were analyzed using one-way ANOVA and Pearson’s correlation coefficient. Findings: Mean age was 48.25±11.93 years. The mean self-efficacy score and quality of life score were 55.78± 11 and 75.91±15.28, respectively and both of them were average. There was positive significant correlation between self-efficacy and quality of life. There was also significant association between self-efficacy and quality of life domains including physical health, mental health, social relationships and environment. Conclusion: With regards to the results, it seems that activities such as workshops for patients, presence of a psychologist in department of chemotherapy, and providing health facilities can be effective for increasing self-efficacy and quality of life in patients with cancer.

  18. Implications of microRNAs in Colorectal Cancer Development, Diagnosis, Prognosis and Therapeutics

    Haiyan eZhai

    2011-11-01

    Full Text Available MicroRNAs (miRNAs are a class of non-coding small RNAs with critical regulatory functions as post-transcriptional regulators. Due to the fundamental importance and broad impact of miRNAs on multiple genes and pathways, dysregulated miRNAs have been associated with human diseases, including cancer. Colorectal cancer (CRC is among the most deadly diseases, and miRNAs offer a new frontier for target discovery and novel biomarkers for both diagnosis and prognosis. In this review, we summarize the recent advancement of miRNA research in CRC, in particular, the roles of miRNAs in colorectal cancer stem cells, EMT, chemoresistance, therapeutics, diagnosis and prognosis.

  19. Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment.

    Kintzing, James R; Filsinger Interrante, Maria V; Cochran, Jennifer R

    2016-12-01

    Protein-based therapeutics have been revolutionizing the oncology space since they first appeared in the clinic two decades ago. Unlike traditional small-molecule chemotherapeutics, protein biologics promote active targeting of cancer cells by binding to cell-surface receptors and other markers specifically associated with or overexpressed on tumors versus healthy tissue. While the first approved cancer biologics were monoclonal antibodies, the burgeoning field of protein engineering is spawning research on an expanded range of protein formats and modifications that allow tuning of properties such as target-binding affinity, serum half-life, stability, and immunogenicity. In this review we highlight some of these strategies and provide examples of modified and engineered proteins under development as preclinical and clinical-stage drug candidates for the treatment of cancer. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Therapeutic effect of angiogenesis inhibitor combined with radiotherapy on liver metastasis model of colon cancer

    Jin Liugen; Zhou Shifu

    2005-01-01

    Objective: To observe the therapeutic effect of angiogenesis inhibitor combined with radiotherapy on liver metastasis model of colon cancer. Methods: Nude mice liver metastasis model of colon cancer was established with human colon cancer cells line (LS174T) inoculated into mice' spleen and followed by splenectomy. Angiogenesis inhibitor 2-ME and radiotherapy were administered after-wads. The growth inhibition effect on metastases and neovessel was examined. Results: The incidences of liver metastasis were 100% in this intrasplenic injection model. The mean weight and microvessel density 4 weeks after inoculation were 53.6 ± 4.7 mg, 8.4 ± 1.7 in treatment group as compared to 173.9 ± 11.6 mg, 41.2 ± 6.3 in control group respectively. Conclusion: 2-ME combined with radiotherapy has significant inhibition on the growth of liver metastases. Angiogenesis inhibition is one of the mechanisms of its efficiency. (authors)

  1. An oncofetal glycosaminoglycan modification provides therapeutic access to Cisplatin-resistant bladder cancer

    Seiler, Roland; Oo, Htoo Zarni; Tortora, Davide

    2017-01-01

    the malaria parasite Plasmodium falciparum, we can target these sugar chains, and our results showed a significant antitumor effect in cisplatin-resistant bladder cancer. This novel treatment paradigm provides therapeutic access to bladder cancers not responding to cisplatin.......BACKGROUND: Although cisplatin-based neoadjuvant chemotherapy (NAC) improves survival of unselected patients with muscle-invasive bladder cancer (MIBC), only a minority responds to therapy and chemoresistance remains a major challenge in this disease setting. OBJECTIVE: To investigate the clinical...... significance of oncofetal chondroitin sulfate (ofCS) glycosaminoglycan chains in cisplatin-resistant MIBC and to evaluate these as targets for second-line therapy. DESIGN, SETTING, AND PARTICIPANTS: An ofCS-binding recombinant VAR2CSA protein derived from the malaria parasite Plasmodium falciparum (rVAR2...

  2. Improving Therapeutic Ratio in Head and Neck Cancer with Adjuvant and Cisplatin-Based Treatments

    Loredana G. Marcu

    2013-01-01

    Full Text Available Advanced head and neck cancers are difficult to manage despite the large treatment arsenal currently available. The multidisciplinary effort to increase disease-free survival and diminish normal tissue toxicity was rewarded with better locoregional control and sometimes fewer side effects. Nevertheless, locoregional recurrence is still one of the main reasons for treatment failure. Today, the standard of care in head and neck cancer management is represented by altered fractionation radiotherapy combined with platinum-based chemotherapy. Targeted therapies as well as chronotherapy were trialled with more or less success. The aim of the current work is to review the available techniques, which could contribute towards a higher therapeutic ratio in the treatment of advanced head and neck cancer patients.

  3. A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution

    Grace R. Anderson

    2017-07-01

    Full Text Available Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.

  4. Therapeutic Strategies against Epstein-Barr Virus-Associated Cancers Using Proteasome Inhibitors.

    Hui, Kwai Fung; Tam, Kam Pui; Chiang, Alan Kwok Shing

    2017-11-21

    Epstein-Barr virus (EBV) is closely associated with several lymphomas (endemic Burkitt lymphoma, Hodgkin lymphoma and nasal NK/T-cell lymphoma) and epithelial cancers (nasopharyngeal carcinoma and gastric carcinoma). To maintain its persistence in the host cells, the virus manipulates the ubiquitin-proteasome system to regulate viral lytic reactivation, modify cell cycle checkpoints, prevent apoptosis and evade immune surveillance. In this review, we aim to provide an overview of the mechanisms by which the virus manipulates the ubiquitin-proteasome system in EBV-associated lymphoid and epithelial malignancies, to evaluate the efficacy of proteasome inhibitors on the treatment of these cancers and discuss potential novel viral-targeted treatment strategies against the EBV-associated cancers.

  5. Therapeutic effect of transcatheter arterial infusion chemotherapy in the treatment of advanced pancreatic cancer

    Lin Junhua; Song Mingzhi; Zhang Yuanyuan; Xu Yiyu; Chen Jing

    2001-01-01

    Objective: To evaluate the clinical efficacy of transcatheter arterial infusion (TAI) or transcatheter arterial chemo-embolization (TACE) in the treatment of advanced pancreatic cancer. Methods: 36 cases of advanced pancreatic cancer were divided into two groups, 18 cases were treated with TAI or TACE (group A), other 18 cases were treated with systemic chemotherapy (group B). Results: The clinical benefit response rate of the group A was 55.6% (10/18) and that of the group B was 16.7%(3/18), respectively (P 0.05). Conclusions: In the transcatheter arterial infusion group, no survival advantage could be demonstrated when compared with the controls, but TAI could effectively increase clinical benefit response and improve the quality of life of advanced pancreatic cancer

  6. Characterization of Prostate-Specific Membrane Antigen (PSMA) for Use in Therapeutic and Diagnostic Strategies Against Prostate Cancer

    O'Keefe, Denise

    2002-01-01

    Prostate-Specific Membrane Antigen (PSMA) appears to be an ideal prostate cancer marker and potential therapeutic target, however there have been reports of PSMA expression in non-prostatic tissues, including brain, kidney and liver...

  7. The Effect of Therapeutic Touch on Pain and Fatigue of Cancer Patients Undergoing Chemotherapy

    Aghabati, Nahid; Pour Esmaiel, Zahra

    2010-01-01

    Despite major advances in pain management, cancer pain is managed poorly in 80% of the patients with cancer. Due to deleterious side effects of pharmacology therapy in these people, there is an urgent need for clinical trials of non-pharmacological interventions. To examine the effect of therapeutic touch (TT) on the pain and fatigue of the cancer patients undergoing chemotherapy, a randomized and three-groups experimental study—experimental (TT), placebo (placebo TT), and control (usual care)—was carried out. Ninety patients undergoing chemotherapy, exhibiting pain and fatigue of cancer, were randomized into one of the three groups in the Cancer Center of Imam Khomeini Hospital in Tehran, Iran. Pain and fatigue were measured and recorded by participants before and after the intervention for 5 days (once a day). The intervention consisted of 30 min TT given once a day for 5 days between 10:00 a.m. and 10:30 a.m. The Visual Analogue Scale (VAS) of pain and the Rhoten Fatigue Scale (RFS) were completed for 5 days before and after the intervention by the subjects. The TT (significant) was more effective in decreasing pain and fatigue of the cancer patients undergoing chemotherapy than the usual care group, while the placebo group indicated a decreasing trend in pain and fatigue scores compared with the usual care group. PMID:18955319

  8. Role of MicroRNA-1 in Human Cancer and Its Therapeutic Potentials

    Chao Han

    2014-01-01

    Full Text Available While the mechanisms of human cancer development are not fully understood, evidence of microRNA (miRNA, miR dysregulation has been reported in many human diseases, including cancer. miRs are small noncoding RNA molecules that regulate posttranscriptional gene expression by binding to complementary sequences in the specific region of gene mRNAs, resulting in downregulation of gene expression. Not only are certain miRs consistently dysregulated across many cancers, but they also play critical roles in many aspects of cell growth, proliferation, metastasis, apoptosis, and drug resistance. Recent studies from our group and others revealed that miR-1 is frequently downregulated in various types of cancer. Through targeting multiple oncogenes and oncogenic pathways, miR-1 has been demonstrated to be a tumor suppressor gene that represses cancer cell proliferation and metastasis and promotes apoptosis by ectopic expression. In this review, we highlight recent findings on the aberrant expression and functional significance of miR-1 in human cancers and emphasize its significant values for therapeutic potentials.

  9. Nanoreporter PET predicts the efficacy of anti-cancer nanotherapy

    Pérez-Medina, Carlos; Abdel-Atti, Dalya; Tang, Jun; Zhao, Yiming; Fayad, Zahi A.; Lewis, Jason S.; Mulder, Willem J. M.; Reiner, Thomas

    2016-01-01

    The application of nanoparticle drug formulations, such as nanoliposomal doxorubicin (Doxil), is increasingly integrated in clinical cancer care. Despite nanomedicine's remarkable potential and growth over the last three decades, its clinical benefits for cancer patients vary. Here we report a

  10. Breaching the Castle Walls: Hyaluronan-Depletion as a Therapeutic Approach to Cancer Therapy

    H Michael eShepard

    2015-08-01

    Full Text Available Hyaluronan (HA has many functions in the extracellular milieu of normal and diseased tissues. Disease-associated HA accumulation has been shown to predict a worsened prognosis in cancer patients, with tumors having a high extracellular HA content (HA-high being more aggressive than their HA-low counterparts. HA-high tumor aggressiveness is derived from the specialized biomechanical and molecular properties of the HA-based assembly of HA binding proteins and the growth-promoting factors that accumulate in it. Biophysical characteristics of an HA-high tumor microenvironment include high tumor interstitial pressure, compression of tumor vasculature, and resulting tumor hypoxia. Within the tumor cell membrane, HA receptors, primarily CD44 and RHAMM, anchor the HA-high extracellular network. HA-CD44 association on the tumor cell surface enhances receptor tyrosine kinase activity to drive tumor progression and treatment resistance. Together, malignant cells in this HA-high matrix may evolve dependency on it for growth. This yields the hypothesis that depleting HA in HA-high tumors may be associated with a therapeutic benefit. A pegylated form of recombinant human hyaluronidase PH20 (PEGPH20 has been deployed as a potential cancer therapeutic in HA-high tumors. PEGPH20 can collapse this matrix by degrading the HA-assembled tumor extracellular framework, leading to tumor growth inhibition, preferentially in HA-high tumors. Enzymatic depletion of HA by PEGPH20 results in re-expansion of the tumor vasculature, reduction in tumor hypoxia, and increased penetration of therapeutic molecules into the tumor. Finally, HA depletion results in reduced signaling via CD44/RHAMM. Taken together, HA-depletion strategies accomplish their antitumor effects by multiple mechanisms that include targeting both biophysical and molecular signaling pathways. Ongoing clinical trials are examining the potential of PEGPH20 in combination with partner therapeutics in several

  11. Protein glycosylation in cancers and its potential therapeutic applications in neuroblastoma

    Wan-Ling Ho

    2016-09-01

    Full Text Available Abstract Glycosylation is the most complex post-translational modification of proteins. Altered glycans on the tumor- and host-cell surface and in the tumor microenvironment have been identified to mediate critical events in cancer pathogenesis and progression. Tumor-associated glycan changes comprise increased branching of N-glycans, higher density of O-glycans, generation of truncated versions of normal counterparts, and generation of unusual forms of terminal structures arising from sialylation and fucosylation. The functional role of tumor-associated glycans (Tn, sTn, T, and sLea/x is dependent on the interaction with lectins. Lectins are expressed on the surface of immune cells and endothelial cells or exist as extracellular matrix proteins and soluble adhesion molecules. Expression of tumor-associated glycans is involved in the dysregulation of glycogenes, which mainly comprise glycosyltransferases and glycosidases. Furthermore, genetic and epigenetic mechanisms on many glycogenes are associated with malignant transformation. With better understanding of all aspects of cancer-cell glycomics, many tumor-associated glycans have been utilized for diagnostic, prognostic, and therapeutic purposes. Glycan-based therapeutics has been applied to cancers from breast, lung, gastrointestinal system, melanomas, and lymphomas but rarely to neuroblastomas (NBs. The success of anti-disialoganglioside (GD2, a glycolipid antigen antibodies sheds light on glycan-based therapies for NB and also suggests the possibility of protein glycosylation-based therapies for NB. This review summarizes our understanding of cancer glycobiology with a focus of how protein glycosylation and associated glycosyltransferases affect cellular behaviors and treatment outcome of various cancers, especially NB. Finally, we highlight potential applications of glycosylation in drug and cancer vaccine development for NB.

  12. Therapeutic Potential of Curcumin in Treatment of Pancreatic Cancer: Current Status and Future Perspectives.

    Hosseini, Mina; Hassanian, Seyed Mahdi; Mohammadzadeh, Elham; ShahidSales, Soodabeh; Maftouh, Mina; Fayazbakhsh, Hasan; Khazaei, Majid; Avan, Amir

    2017-07-01

    Pancreatic cancer is among the leading cause of deaths due to cancer with extremely poor prognosis. Gemcitabine is being used in the treatment of patient with pancreatic ductal adenocarcinoma (PDAC), although, the response rate is bellow 12%. A recent phase III trial revealed that FOLFIRINOX could be an option for the treatment of metastatic PDAC patients, although it is associated with increased toxicity. Therefore, identification of novel agents that either improves gemcitabine activity, within novel combinatorial approaches, or with a better efficacy than gemcitabine is warranted. The antitumor activity of curcumin in several tumors, including prostate, breast and colorectal cancers have investigated. A recent phase II trial explored the effects of curcumin in advanced pancreatic cancer patient. They found that oral curcumin was well tolerated. Another trial showed the activity of 8,000 mg of curcumin in combination with gemcitabine in patients with advanced pancreatic cancer. This review summarizes the current knowledge about possible molecular mechanisms of curcumin in PDAC with particular emphasis on preclinical/clinical studies in pancreatic cancer treatment. J. Cell. Biochem. 118: 1634-1638, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. Systemic GLIPR1-ΔTM protein as a novel therapeutic approach for prostate cancer.

    Karantanos, Theodoros; Tanimoto, Ryuta; Edamura, Kohei; Hirayama, Takahiro; Yang, Guang; Golstov, Alexei A; Wang, Jianxiang; Kurosaka, Shinji; Park, Sanghee; Thompson, Timothy C

    2014-04-15

    GLIPR1 is a p53 target gene known to be downregulated in prostate cancer, and increased endogenous GLIPR1 expression has been associated with increased production of reactive oxygen species, increased apoptosis, decreased c-Myc protein levels and increased cell cycle arrest. Recently, we found that upregulation of GLIPR1 in prostate cancer cells increases mitotic catastrophe through interaction with heat shock cognate protein 70 (Hsc70) and downregulation of Aurora kinase A and TPX2. In this study, we evaluated the mechanisms of recombinant GLIPR1 protein (glioma pathogenesis-related protein 1-transmembrane domain deleted [GLIPR1-ΔTM]) uptake by prostate cancer cells and the efficacy of systemic GLIPR1-ΔTM administration in a prostate cancer xenograft mouse model. GLIPR1-ΔTM was selectively internalized by prostate cancer cells, leading to increased apoptosis through reactive oxygen species production and to decreased c-Myc protein levels. Interestingly, GLIPR1-ΔTM was internalized through clathrin-mediated endocytosis in association with Hsc70. Systemic administration of GLIPR1-ΔTM significantly inhibited VCaP xenograft growth. GLIPR1-ΔTM showed no evidence of toxicity following elimination from mouse models 8 hr after injection. Our results demonstrate that GLIPR1-ΔTM is selectively endocytosed by prostate cancer cells, leading to increased reactive oxygen species production and apoptosis, and that systemic GLIPR1-ΔTM significantly inhibits growth of VCaP xenografts without substantial toxicity. © 2013 UICC.

  14. Efficacy and Safety of Pomegranate Medicinal Products for Cancer

    Vlachojannis, Christian; Zimmermann, Benno F.; Chrubasik-Hausmann, Sigrun

    2015-01-01

    Preclinical in vitro and in vivo studies demonstrate potent effects of pomegranate preparations in cancer cell lines and animal models with chemically induced cancers. We have carried out one systematic review of the effectiveness of pomegranate products in the treatment of cancer and another on their safety. The PubMed search provided 162 references for pomegranate and cancer and 122 references for pomegranate and safety/toxicity. We identified 4 clinical studies investigating 3 pomegranate ...

  15. Systems approach for the selection of micro-RNAs as therapeutic biomarkers of anti-EGFR monoclonal antibody treatment in colorectal cancer

    Deyati, Avisek; Bagewadi, Shweta; Senger, Philipp; Hofmann-Apitius, Martin; Novac, Natalia

    2015-01-01

    miRNA plays an important role in tumourgenesis by regulating expression of oncogenes and tumour suppressors. Thus affects cell proliferation and differentiation, apoptosis, invasion and angiogenesis. miRNAs are potential biomarkers for diagnosis, prognosis and therapies of different forms of cancer. However, relationship between response of cancer patients towards targeted therapy and the resulting modifications of the miRNA transcriptome in the context of pathway regulation is poorly understood. With ever-increasing pathways and miRNA-mRNA interaction databases, freely available mRNA and miRNA expression data in multiple cancer therapy have produced an unprecedented opportunity to decipher the role of miRNAs in early prediction of therapeutic efficacy in diseases. Efficient translation of -omics data and accumulated knowledge to clinical decision-making are of paramount scientific and public health interest. Well-structured translational algorithms are needed to bridge the gap from databases to decisions. Herein, we present a novel SMARTmiR algorithm to prospectively predict the role of miRNA as therapeutic biomarker for an anti-EGFR monoclonal antibody i.e. cetuximab treatment in colorectal cancer.

  16. PD-1 and PD-L1 as emerging therapeutic targets in gastric cancer: current evidence

    Tran PN

    2017-05-01

    Full Text Available Phu N Tran,1* Sarmen Sarkissian,1* Joseph Chao,2 Samuel J Klempner3,4 1Division of Hematology-Oncology, University of California Irvine, Orange, 2Department of Medical Oncology and Developmental Therapeutics, City of Hope, Duarte, 3Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 4The Angeles Clinic and Research Institute, Los Angeles, CA, USA *These authors contributed equally to this work Abstract: Gastric adenocarcinoma is a leading cause of global cancer-related morbidity and mortality, and new therapeutic approaches are needed. Despite the improved outcomes with monoclonal antibodies targeting human epidermal growth factor receptor 2 and vascular endothelial growth factor receptor 2, durable responses are uncommon. Targeting immune checkpoints including PD-1, PD-L1 and CTLA-4 have led to improved survival across several tumor types, frequently characterized by prolonged benefit in responding patients. Tumoral and lymphocyte-derived immunohistochemical staining for PD-1, PD-L1, and tumor mutational burden have shown potential as predictive response biomarkers in several tumor types. Optimal incorporation of immune-mediated therapies into gastric cancer (GC is an area of intense ongoing investigation and benefit has been demonstrated in smaller studies of advanced patients. Important questions of biomarker selection, roles for molecular characterization, optimal combinatorial approaches, and therapeutic sequencing remain. In this study, current data are reviewed for immune checkpoint inhibitors in GC, and putative biomarkers, ongoing trials, and future considerations are discussed. Keywords: immunotherapy, stomach cancer, checkpoint inhibitor, nivolumab, pembrolizumab, tumor mutational burden

  17. Therapeutic efficacy of interleukin-2 activated killer cells against adriamycin resistant mouse B16-BL6 melanoma.

    Gautam, S C; Chikkala, N F; Lewis, I; Grabowski, D R; Finke, J H; Ganapathi, R

    1992-01-01

    Development of multidrug-resistance (MDR) remains a major cause of failure in the treatment of cancer with chemotherapeutic agents. In our efforts to explore alternative treatment regimens for multidrug-resistant tumors we have examined the sensitivity of MDR tumor cell lines to lymphokine activated killer (LAK) cells. Adriamycin (ADM) resistant B16-BL6 melanoma, L1210 and P388 leukemic cell lines were tested for sensitivity to lysis by LAK cells in vitro. While ADM-resistant B16-BL6 and L1210 sublines were found to exhibit at least 2-fold greater susceptibility to lysis by LAK cells, sensitivity of ADM-resistant P388 cell was similar to that of parental cells. Since ADM-resistant B16-BL6 cells were efficiently lysed by LAK cells in vitro, the efficacy of therapy with LAK cells against the ADM-resistant B16-BL6 subline in vivo was evaluated. Compared to mice bearing parental B16-BL6 tumor cells, the adoptive transfer of LAK cells and rIL2 significantly reduced formation of experimental metastases (P less than 0.009) and extended median survival time (P less than 0.001) of mice bearing ADM-resistant B16-BL6 tumor cells. Results suggest that immunotherapy with LAK cells and rIL2 may be a useful modality in the treatment of cancers with the MDR phenotype.

  18. Therapeutic potential of novel formulated forms of curcumin in the treatment of breast cancer by the targeting of cellular and physiological dysregulated pathways.

    Tajbakhsh, Amir; Hasanzadeh, Malihe; Rezaee, Mehdi; Khedri, Mostafa; Khazaei, Majid; ShahidSales, Soodabeh; Ferns, Gordon A; Hassanian, Seyed Mahdi; Avan, Amir

    2018-03-01

    Breast cancer is among the most important causes of cancer related death in women. There is a need for novel agents for targeting key signaling pathways to either improve the efficacy of the current therapy, or reduce toxicity. There is some evidence that curcumin may have antitumor activity in breast cancer. Several clinical trials have investigated its activity in patients with breast cancer, including a recent trial in breast cancer patients receiving radiotherapy, in whom it was shown that curcumin reduced the severity of radiation dermatitis, although it is associated with low bioavailability. Several approaches have been developed to increase its absorption rate (e.g., nano crystals, liposomes, polymers, and micelles) and co-delivery of curcumin with adjuvants as well as different conjugation to enhance its bioavailability. In particular, micro-emulsions is an option for transdermal curcumin delivery, which has been reported to increase its absorption. Lipid-based nano-micelles is another approach to enhance curcumin absorption via gastrointestinal tract, while polymer-based nano-formulations (e.g., poly D, L-lactic-co-glycolic [PLGA]) allows the release of curcumin at a sustained level. This review summarizes the current data of the therapeutic potential of novel formulations of curcumin with particular emphasis on recent preclinical and clinical studies in the treatment of breast cancer. © 2017 Wiley Periodicals, Inc.

  19. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    May, Felicity EB, E-mail: F.E.B.May@ncl.ac.uk [Northern Institute for Cancer Research and Department of Pathology, Faculty of Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne (United Kingdom)

    2014-05-23

    The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

  20. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    May, Felicity EB

    2014-01-01

    The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

  1. Identification of novel therapeutic targets in microdissected clear cell ovarian cancers.

    Michael P Stany

    Full Text Available Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.

  2. Elevated pressure, a novel cancer therapeutic tool for sensitizing cisplatin-mediated apoptosis in A549

    Oh, Sangnam [Cellular and Developmental Biology, Division of Biomedical Science, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Department of Preventive Medicine and Medical Research Center for Environmental Toxico-Genomics and Proteomics, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Kim, Yanghee [Department of Preventive Medicine and Medical Research Center for Environmental Toxico-Genomics and Proteomics, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Kim, Joonhee [Cellular and Developmental Biology, Division of Biomedical Science, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Department of Preventive Medicine and Medical Research Center for Environmental Toxico-Genomics and Proteomics, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Kwon, Daeho [Department of Preventive Medicine and Medical Research Center for Environmental Toxico-Genomics and Proteomics, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Lee, Eunil, E-mail: eunil@korea.ac.kr [Cellular and Developmental Biology, Division of Biomedical Science, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Department of Preventive Medicine and Medical Research Center for Environmental Toxico-Genomics and Proteomics, College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of)

    2010-08-13

    Research highlights: {yields} Sensitized apoptosis in cancer cells stimulated by EP precondition with p53 dependence. {yields} EP attenuates several CDDP-resistance mechanisms. {yields} No harmful effect of EP on normal fibroblasts. -- Abstract: Intensive cancer therapy strategies have thus far focused on sensitizing cancer cells to anticancer drug-mediated apoptosis to overcome drug resistance, and this strategy has led to more effective cancer therapeutics. Cisplatin (cis-diamminedichloroplatinum(II), CDDP) is an effective anticancer drug used to treat many types of cancer, including non-small cell lung carcinoma (NSCLC), and can be used in combination with various chemicals to enhance cancer cell apoptosis. Here, we introduce the use of elevated pressure (EP) in combination with CDDP for cancer treatment and explore the effects of EP on CDDP-mediated apoptosis in NSCLC cells. Our findings demonstrate that preconditioning NSCLC cells with EP sensitizes cells for CDDP-induced apoptosis. Enhanced apoptosis was dependent on p53 and HO-1 expression, and was associated with increased DNA damage and down-regulation of genes involved in nucleotide excision repair. The transcriptional levels of transporter proteins indicated that the mechanism by which EP-induced CDDP sensitization was intracellular drug accumulation. The protein levels of some antioxidants, such as hemeoxygenase-1 (HO-1), glutathione (GSH) and glutathione peroxidase (Gpx), were decreased in A549 cells exposed to EP via the down-regulation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Furthermore, normal human fibroblasts were resistant to EP treatment, with no elevated DNA damage or apoptosis. Collectively, these data show that administration of EP is a potential adjuvant tool for CDDP-based chemosensitivity of lung cancer cells that may reduce drug resistance.

  3. Elevated pressure, a novel cancer therapeutic tool for sensitizing cisplatin-mediated apoptosis in A549

    Oh, Sangnam; Kim, Yanghee; Kim, Joonhee; Kwon, Daeho; Lee, Eunil

    2010-01-01

    Research highlights: → Sensitized apoptosis in cancer cells stimulated by EP precondition with p53 dependence. → EP attenuates several CDDP-resistance mechanisms. → No harmful effect of EP on normal fibroblasts. -- Abstract: Intensive cancer therapy strategies have thus far focused on sensitizing cancer cells to anticancer drug-mediated apoptosis to overcome drug resistance, and this strategy has led to more effective cancer therapeutics. Cisplatin (cis-diamminedichloroplatinum(II), CDDP) is an effective anticancer drug used to treat many types of cancer, including non-small cell lung carcinoma (NSCLC), and can be used in combination with various chemicals to enhance cancer cell apoptosis. Here, we introduce the use of elevated pressure (EP) in combination with CDDP for cancer treatment and explore the effects of EP on CDDP-mediated apoptosis in NSCLC cells. Our findings demonstrate that preconditioning NSCLC cells with EP sensitizes cells for CDDP-induced apoptosis. Enhanced apoptosis was dependent on p53 and HO-1 expression, and was associated with increased DNA damage and down-regulation of genes involved in nucleotide excision repair. The transcriptional levels of transporter proteins indicated that the mechanism by which EP-induced CDDP sensitization was intracellular drug accumulation. The protein levels of some antioxidants, such as hemeoxygenase-1 (HO-1), glutathione (GSH) and glutathione peroxidase (Gpx), were decreased in A549 cells exposed to EP via the down-regulation of the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf-2). Furthermore, normal human fibroblasts were resistant to EP treatment, with no elevated DNA damage or apoptosis. Collectively, these data show that administration of EP is a potential adjuvant tool for CDDP-based chemosensitivity of lung cancer cells that may reduce drug resistance.

  4. Evaluation of the safety and efficacy of therapeutic bandage contact lenses on post-cataract surgery patients.

    Shi, Dan-Na; Song, Hang; Ding, Tong; Qiu, Wei-Qiang; Wang, Wei

    2018-01-01

    To evaluate the safety of therapeutic bandage contact lens for post-cataract surgery patients and to illustrate its efficacy on post-operative comfort and tear-film stability. A total of 40 participants were recruited and randomly divided into two groups. Group one was instructed to wear bandage contact lenses for a week and use antibiotic eye drops for a month since the first day after surgery. Group two received sub-conjunctival injection of tobramycin and was asked to wear eye pads on the first day after surgery and then were instructed to use antibiotic eye drops as the first group did. Ocular surface disease index (OSDI) questionnaire, slit-lamp microscope examination of tear break-up time (TBUT), corneal fluorescein score (CFS), tear meniscus height (TMH) together with anterior segment optical coherence tomography (AS-OCT) and corneal topography were evaluated preoperatively and postoperatively. The subjective feeling ( P =0.004), TBUT ( P <0.001) and TMH ( P =0.02) post-surgery had improved in patients who used bandage contact lenses compared with those who did not at 1wk post-surgery. Until three month postoperatively, the comfort degree ( P =0.004) and TMH ( P =0.01) of group two were still worse than group one. Moreover, TBUT ( P <0.001) and CFS ( P =0.004) of the group with eye pads got worse than the results before, whereas the group with bandage contact lenses recovered to normal. None of these patients had infections or other complications. Wearing therapeutic bandage contact lens after cataract surgery, compared with traditional eye-pads, is a safe method to improve tear-film stability and reduce post-operative discomfort without hindering corneal incision recovery.

  5. Evaluation of the safety and efficacy of therapeutic bandage contact lenses on post-cataract surgery patients

    Dan-Na Shi

    2018-02-01

    Full Text Available AIM: To evaluate the safety of therapeutic bandage contact lens for post-cataract surgery patients and to illustrate its efficacy on post-operative comfort and tear-film stability. METHODS: A total of 40 participants were recruited and randomly divided into two groups. Group one was instructed to wear bandage contact lenses for a week and use antibiotic eye drops for a month since the first day after surgery. Group two received sub-conjunctival injection of tobramycin and was asked to wear eye pads on the first day after surgery and then were instructed to use antibiotic eye drops as the first group did. Ocular surface disease index (OSDI questionnaire, slit-lamp microscope examination of tear break-up time (TBUT, corneal fluorescein score (CFS, tear meniscus height (TMH together with anterior segment optical coherence tomography (AS-OCT and corneal topography were evaluated preoperatively and postoperatively. RESULTS: The subjective feeling (P=0.004, TBUT (P<0.001 and TMH (P=0.02 post-surgery had improved in patients who used bandage contact lenses compared with those who did not at 1wk post-surgery. Until three month postoperatively, the comfort degree (P=0.004 and TMH (P=0.01 of group two were still worse than group one. Moreover, TBUT (P<0.001 and CFS (P=0.004 of the group with eye pads got worse than the results before, whereas the group with bandage contact lenses recovered to normal. None of these patients had infections or other complications. CONCLUSION: Wearing therapeutic bandage contact lens after cataract surgery, compared with traditional eye-pads, is a safe method to improve tear-film stability and reduce post-operative discomfort without hindering corneal incision recovery.

  6. Therapeutic efficacy of bipolar radiofrequency thermotherapy for patients with chronic prostatitis: a retrospective analysis of 26 cases.

    Lim, Ju Young; Shim, Seung Bum; Yoo, Dong Hoon; Park, Young Woong; Kim, Jong Yeon; Noh, Joon Hwa

    2012-07-01

    Chronic prostatitis (CP) does not yet have a universally successful therapy. Alternative treatments including thermotherapy have been adopted in the multimodal management of pain and voiding dysfunction. We retrospectively analyzed the therapeutic efficacy of bipolar radiofrequency thermotherapy for patients who were unsatisfied with conventional medication for CP. A retrospective study between October 2009 and September 2010 of 26 patients who were under 50 years old and diagnosed with CP (National Institutes of Health [NIH]-category III) was performed. Twenty patients were diagnosed with inflammatory CP (NIH-category IIIa) and the rest with noninflammatory CP (NIH-category IIIb). We used the Tempro system at an intraprostatic temperature of 55℃ for 50 minutes with a medium heating rate. All patients also completed the NIH-Chronic Prostatitis Symptom Index (CPSI) before and after treatment. In the patients diagnosed with CP, the mean serum prostate-specific antigen (PSA) level was 0.9±0.3 ng/ml, the prostate volume was 27.1±5.5 g, and the average score for all 3 domains on the NIH-CPSI significantly decreased. The total scores decreased from 19.8±7.1 to 11.1±7.0, the pain domain decreased from 8.6±3.1 to 4.8±3.1, the voiding symptom domain decreased from 5.1±1.8 to 2.9±1.8, and the effect on the quality of life decreased from 6.1±2.2 to 3.4±2.2 (pthermotherapy for patients with CP intractable to conventional medication can provide significant improvement in the NIH-CPSI. Large, randomized controlled trials will also be required to confirm the efficacy of this therapy.

  7. Determining efficacy of breast cancer therapy by PET imaging of HER2 mRNA

    Paudyal, Bishnuhari; Zhang, Kaijun; Chen, Chang-Po; Wampole, Matthew E.; Mehta, Neil; Mitchell, Edith P.; Gray, Brian D.; Mattis, Jeffrey A.; Pak, Koon Y.; Thakur, Mathew L.; Wickstrom, Eric

    2013-01-01

    Introduction: Monitoring the effectiveness of therapy early and accurately continues to be challenging. We hypothesize that determination of Human Epidermal Growth Factor Receptor 2 (HER2) mRNA in malignant breast cancer (BC) cells by positron emission tomography (PET) imaging, before and after treatment, would reflect therapeutic efficacy. Method: WT4340, a peptide nucleic acid (PNA) 12-mer complementary to HER2 mRNA was synthesized together with -CSKC, a cyclic peptide, which facilitated internalization of the PNA via IGFR expressed on BC cells, and DOTA that chelated Cu-64. Mice (n = 8) with BT474 ER +/HER2+ human BC received doxorubicin (DOX, 1.5 mg/kg) i.p. once a week for six weeks. Mice (n = 8) without DOX served as controls. All mice were PET imaged with F-18-FDG and 48 h later with Cu-64-WT4340. PET imaging were performed before and 72 h after each treatment. Standardized uptake values (SUVs) were determined and percent change calculated. Animal body weight (BW) and tumor volume (TV) were measured. Results: SUVs for Cu-64-WT4340 after DOX treatment declined by 54% ± 17% after the second dose, 41% ± 15% after the fourth dose, and 29% ± 7% after the sixth dose, compared with 42% ± 22%, 31% ± 18%, and 13% ± 9% (p < 0.05) for F-18-FDG. In untreated mice, the corresponding percent SUVs for Cu-64-WT4340 were 145% ± 82%, 165% ± 39%, and 212% ± 105% of pretreatment SUV, compared with 108% ± 28%, 151% ± 8%, and 152% ± 35.5%, (p < 0.08) for F-18-FDG. TV in mice after second dose was 114.15% ± 61.83%, compared with 144.7% ± 64.4% for control mice. BW of DOX-treated mice was 103.4% ± 7.6% of pretreatment, vs. 100.1% ± 4.3% for control mice. Conclusion: Therapeutic efficacy was apparent sooner by molecular PET imaging than by determination of reduction in TV

  8. ALK receptor activation, ligands and therapeutic targeting in glioblastoma and in other cancers

    Wellstein, Anton

    2012-01-01

    The intracellular anaplastic lymphoma kinase (ALK) fragment shows striking homology with members of the insulin receptor family and was initially identified as an oncogenic fusion protein resulting from a translocation in lymphoma and more recently in a range of cancers. The full-length ALK transmembrane receptor of ~220 kDa was identified based on this initial work. This tyrosine kinase receptor and its ligands, the growth factors pleiotrophin (PTN) and midkine (MK) are highly expressed during development of the nervous system and other organs. Each of these genes has been implicated in malignant progression of different tumor types and shown to alter phenotypes as well as signal transduction in cultured normal and tumor cells. Beyond its role in cancer, the ALK receptor pathway is thought to contribute to nervous system development, function, and repair, as well as metabolic homeostasis and the maintenance of tissue regeneration. ALK receptor activity in cancer can be up-regulated by amplification, overexpression, ligand binding, mutations in the intracellular domain of the receptor and by activity of the receptor tyrosine phosphatase PTPRz. Here we discuss the evidence for ligand control of ALK activity as well as the potential prognostic and therapeutic implications from gene expression and functional studies. An analysis of 18 published gene expression data sets from different cancers shows that overexpression of ALK, its smaller homolog LTK (leukocyte tyrosine kinase) and the ligands PTN and MK in cancer tissues from patients correlate significantly with worse course and outcome of the disease. This observation together with preclinical functional studies suggests that this pathway could be a valid therapeutic target for which complementary targeting strategies with small molecule kinase inhibitors as well as antibodies to ligands or the receptors may be used.

  9. An exploration of spiritual needs of Taiwanese patients with advanced cancer during the therapeutic processes.

    Hsiao, Szu-Mei; Gau, Meei-Ling; Ingleton, Christine; Ryan, Tony; Shih, Fu-Jin

    2011-04-01

    This study explores the spiritual needs of patients with advanced cancer during their therapeutic process in Taiwan and analyses the influence of Chinese culture in addressing their spiritual needs. Many nurse clinicians have concerns about the difficulties of providing spiritual care for ethnic-Chinese cancer clients within their cultural context, possibly as a result of lack of knowledge and training. There has been little research exploring the potential impact of Chinese cultural values on the spiritual needs of patients with advanced cancer. Explorative qualitative enquiry was used. Data were collected through participant observation and in-depth face-to-face interviews. Transcribed interview data were analysed by using qualitative content analysis. The purposive sample (n = 33) was drawn from a leading medical center (n = 19) with 3000 beds in the capital and a community-based rural teaching hospital (n = 14) with 581 beds in Taiwan. Four spiritual needs emerged from the analysis: the need to foster hope for survival and obtain a peaceful mindset, to fulfil the meanings of life and preserve one's dignity, to experience more reciprocal human love and finally, to receive assistance in facing death peacefully. This research has shown that patients with advanced cancer need caregivers, friends and the help of their religion to meet their spiritual needs during the therapeutic processes. The findings of this study could assist health professionals to detect the unmet spiritual needs of ethnic-Chinese patients with cancer in the context of their cultural or religious background as early as possible. © 2010 Blackwell Publishing Ltd.

  10. Consideration of therapeutic approach to advanced colorectal cancer in elderly patients

    Yasuhiro Inoue

    2014-02-01

    Full Text Available Colorectal cancer (CRC is predominantly a disease of elderly and is a major cause of morbidity and mortality in the elderly population. The increased availability of treatment options for CRC has made it more difficult for clinicians to decide on the optimal therapeutic approach in elderly patients, because of the potential for poorer outcomes due to an increased burden of comorbidities, functional dependency, and limited life expectancy. It is necessary to determine which elderly patients are likely to benefit from active cancer therapy, and the establishment of treatment markers for multimodality approaches is eagerly awaited. Elderly cancer patients are at risk of exposure to various intrinsic inflammatory mediators, such as tumor-generating cytokines and surgery-induced pro-inflammatory cytokines. It is therefore important to understand the immunological changes occurring in the elderly and to adjust treatment strategies accordingly to reduce the morbidity and mortality associated with multimodality therapy for CRC that induce systemic inflammation. Several inflammation-based factors such as the Glasgow Prognostic Score (GPS may reflect the balance between tumor progression and host-related immunity, especially in elderly CRC patients. Appropriate selection criteria for multimodality therapy in elderly CRC patients may include not only tumor characteristics, but also host- and/or treatment-related factors such as comorbidities or surrogate markers using inflammation-based factors.----------------------------------------------Cite this article as: Inoue Y, Toiyama Y, Tanaka K, Mohri Y, Kusunoki M. Consideration of therapeutic approach to advanced colorectal cancer in elderly patients. Int J Cancer Ther Oncol 2014; 2(1:02014.DOI: http://dx.doi.org/10.14319/ijcto.0201.4

  11. Targeting Androgen Receptor in Breast Cancer: Enzalutamide as a Novel Breast Cancer Therapeutic

    2016-09-01

    AR) is more widely expressed than estrogen receptor alpha (ER) or the progesterone receptor (PR) (1), which are used as therapeutic targets and...19 6. Products …………………………………….……….….…………….20 7. Participants & Other Collaborating Organizations……………22 8. Special Reporting...estrogen receptor alpha (ER) or the progesterone receptor (PR), which are used as therapeutic targets and biomarkers, suggesting a potential role

  12. Chemopreventive and therapeutic activity of dietary blueberry against estrogen-mediated breast cancer.

    Jeyabalan, Jeyaprakash; Aqil, Farrukh; Munagala, Radha; Annamalai, Lakshmanan; Vadhanam, Manicka V; Gupta, Ramesh C

    2014-05-07

    Berries are gaining increasing importance lately for their chemopreventive and therapeutic potential against several cancers. In earlier studies, a blueberry-supplemented diet has shown protection against 17β-estradiol (E2)-mediated mammary tumorigenesis. This study tested both preventive and therapeutic activities of diet supplemented with whole blueberry powder (50:50 blend of Tifblue and Rubel). Animals received 5% blueberry diet, either 2 weeks prior to or 12 weeks after E2 treatment in preventive and therapeutic groups, respectively. Both interventions delayed the tumor latency for palpable mammary tumors by 28 and 37 days, respectively. Tumor volume and multiplicity were also reduced significantly in both modes. The effect on mammary tumorigenesis was largely due to down-regulation of CYP 1A1 and ER-α gene expression and also favorable modulation of microRNA (miR-18a and miR-34c) levels. These data suggest that the blueberry blend tested is effective in inhibiting E2-mediated mammary tumorigenesis in both preventive and therapeutic modes.

  13. Targeting protein neddylation: a novel therapeutic strategy for the treatment of cancer.

    Wang, Meng; Medeiros, Bruno C; Erba, Harry P; DeAngelo, Daniel J; Giles, Francis J; Swords, Ronan T

    2011-03-01

    The NEDD8 (neural precursor cell-expressed developmentally downregulated 8) conjugation pathway regulates the post-translational modification of oncogenic proteins. This pathway has important potential for cancer therapeutics. Several proteins vital in cancer biology are regulated by protein neddylation. These observations led to the development of a small molecule inhibitor that disrupts protein neddylation and leads to cancer cell death and important activity in early phase clinical trials. This review provides an extensive coverage of cellular protein homeostasis with particular emphasis on the NEDD8 conjugation pathway. Insights into a new investigational drug that specifically disrupts the NEDD8 pathway are discussed. The clinical data for this agent are also updated. Neddylation controls key cellular pathways found to be dysregulated in many cancers. Protein neddylation is a relatively under-explored pathway for pharmacologic inhibition in cancer. Selective disruption of this pathway has demonstrated clinical activity in patients with myeloid neoplasms and is worth exploring further in combination with other anti-leukemia agents.

  14. PARP-1 and PARP-2 activity in cancer-induced cachexia: potential therapeutic implications.

    Barreiro, Esther; Gea, Joaquim

    2018-01-26

    Skeletal muscle dysfunction and mass loss is a characteristic feature in patients with chronic diseases including cancer and acute conditions such as critical illness. Maintenance of an adequate muscle mass is crucial for the patients' prognosis irrespective of the underlying condition. Moreover, aging-related sarcopenia may further aggravate the muscle wasting process associated with chronic diseases and cancer. Poly(adenosine diphosphate-ribose) polymerase (PARP) activation has been demonstrated to contribute to the pathophysiology of muscle mass loss and dysfunction in animal models of cancer-induced cachexia. Genetic inhibition of PARP activity attenuated the deleterious effects seen on depleted muscles in mouse models of oncologic cachexia. In the present minireview the mechanisms whereby PARP activity inhibition may improve muscle mass and performance in models of cancer-induced cachexia are discussed. Specifically, the beneficial effects of inhibition of PARP activity on attenuation of increased oxidative stress, protein catabolism, poor muscle anabolism and mitochondrial content and epigenetic modulation of muscle phenotype are reviewed in this article. Finally, the potential therapeutic strategies of pharmacological PARP activity inhibition for the treatment of cancer-induced cachexia are also being described in this review.

  15. Rectal cancer and Fournier’s gangrene - current knowledge and therapeutic options

    Bruketa, Tomislav; Majerovic, Matea; Augustin, Goran

    2015-01-01

    Fournier’s gangrene (FG) is a rapid progressive bacterial infection that involves the subcutaneous fascia and part of the deep fascia but spares the muscle in the scrotal, perianal and perineal region. The incidence has increased dramatically, while the reported incidence of rectal cancer-induced FG is unknown but is extremely low. Pathophysiology and clinical presentation of rectal cancer-induced FG per se does not differ from the other causes. Only rectal cancer-specific symptoms before presentation can lead to the diagnosis. The diagnosis of rectal cancer-induced FG should be excluded in every patient with blood on digital rectal examination, when urogenital and dermatological causes are excluded and when fever or sepsis of unknown origin is present with perianal symptomatology. Therapeutic options are more complex than for other forms of FG. First, the causative rectal tumor should be removed. The survival of patients with rectal cancer resection is reported as 100%, while with colostomy it is 80%. The preferred method of rectal resection has not been defined. Second, oncological treatment should be administered but the timing should be adjusted to the resolution of the FG and sometimes for the healing of plastic reconstructive procedures that are commonly needed for the reconstruction of large perineal, scrotal and lower abdominal wall defects. PMID:26290629

  16. Development and economic trends in cancer therapeutic drugs: a 5-year update 2010-2014.

    Savage, P; Mahmoud, S

    2015-03-17

    Over the past 20 years, the mechanisms of action, duration of benefits and economic costs of newly licenced cancer drugs have changed significantly; however, summary data on these characteristics are limited. In this study, using historical copies of the British National Formulary and relevant contemporary publications, we have documented for each new cancer drug the year of introduction, therapeutic classification, initial indication, median duration of treatment and the cost of treatment at introduction relative to the then current UK GDP per capita. Before 2000, there were 69 cancer treatment drugs available, of which 50 (72.5%) were classical cytotoxic drugs. In the subsequent 15 years, there have been 63 more new cancer treatment drugs added, including 20 kinase inhibitors and 11 monoclonal antibodies. The average median duration of treatment with a new drug has risen from 181 days in 1995-1999 to 263 days in 2010-2014. The average cost of treatment has also risen from £3036.91 (20.6% of UK per capita GDP) in 1995-1999 to £20 233 (89.0%) in 2005-2009 and now to £35 383 (141.7%) in 2010-2014. The last 5 years has seen 33 new cancer drugs. These drugs deliver significant benefits