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Sample records for targeted alpha therapy

  1. Targeted Alpha Therapy: From Alpha to Omega

    International Nuclear Information System (INIS)

    Allen, Barry J; Clarke, Raymond; Huang Chenyu

    2013-01-01

    This review covers the broad spectrum of Targeted Alpha Therapy (TAT) research in Australia; from in vitro and in vivo studies to clinical trials. The principle of tumour anti-vascular alpha therapy (TAVAT) is discussed in terms of its validation by Monte Carlo calculations of vascular models and the potential role of biological dosimetry is examined. Summmary of this review is as follows: 1. The essence of TAT 2. Therapeutic objectives 3. TAVAT and Monte Carlo microdosimetry 4. Biological dosimetry 5. Preclinical studies 6. Clinical trials 7. What next? 8. Obstacles. (author)

  2. Targeted alpha therapy: Applications and current status

    International Nuclear Information System (INIS)

    Bruchertseifer, Frank

    2017-01-01

    Full text: The field of targeted alpha therapy has been developed rapidly in the last decade. Besides 223 Ra, 211 At and 212 Pb/ 212 Bi the alpha emitters 225 Ac and 213 Bi are promising therapeutic radionuclides for application in targeted alpha therapy of cancer and infectious diseases. The presentation will give a short overview about the current clinical treatments with alpha emitting radionuclides and will place an emphasis on the most promising clinical testing of peptides and antibodies labelled with 225 Ac and 213 Bi for treatment of metastatic castration-resistant prostate cancer patients with glioma and glioblastoma multiform, PSMA-positive tumor phenotype and bladder carcinoma in situ. (author)

  3. Targeted alpha therapy: Applications and current status

    Energy Technology Data Exchange (ETDEWEB)

    Bruchertseifer, Frank, E-mail: frank.bruchertseifer@ec.europa.eu [European Commission, Joint Research Centre, Karlsruhe (Germany)

    2017-07-01

    Full text: The field of targeted alpha therapy has been developed rapidly in the last decade. Besides {sup 223}Ra, {sup 211}At and {sup 212}Pb/{sup 212}Bi the alpha emitters {sup 225}Ac and {sup 213}Bi are promising therapeutic radionuclides for application in targeted alpha therapy of cancer and infectious diseases. The presentation will give a short overview about the current clinical treatments with alpha emitting radionuclides and will place an emphasis on the most promising clinical testing of peptides and antibodies labelled with {sup 225}Ac and {sup 213}Bi for treatment of metastatic castration-resistant prostate cancer patients with glioma and glioblastoma multiform, PSMA-positive tumor phenotype and bladder carcinoma in situ. (author)

  4. Autoradiography Imaging in Targeted Alpha Therapy with Timepix Detector

    Directory of Open Access Journals (Sweden)

    Ruqaya AL Darwish

    2015-01-01

    Full Text Available There is a lack of data related to activity uptake and particle track distribution in targeted alpha therapy. These data are required to estimate the absorbed dose on a cellular level as alpha particles have a limited range and traverse only a few cells. Tracking of individual alpha particles is possible using the Timepix semiconductor radiation detector. We investigated the feasibility of imaging alpha particle emissions in tumour sections from mice treated with Thorium-227 (using APOMAB, with and without prior chemotherapy and Timepix detector. Additionally, the sensitivity of the Timepix detector to monitor variations in tumour uptake based on the necrotic tissue volume was also studied. Compartmental analysis model was used, based on the obtained imaging data, to assess the Th-227 uptake. Results show that alpha particle, photon, electron, and muon tracks were detected and resolved by Timepix detector. The current study demonstrated that individual alpha particle emissions, resulting from targeted alpha therapy, can be visualised and quantified using Timepix detector. Furthermore, the variations in the uptake based on the tumour necrotic volume have been observed with four times higher uptake for tumours pretreated with chemotherapy than for those without chemotherapy.

  5. Targeted Alpha Therapy Approach to the Management of Pancreatic Cancer

    International Nuclear Information System (INIS)

    Allen, Barry J.; Abbas Rizvi, Syed M.; Qu, Chang F.; Smith, Ross C.

    2011-01-01

    Evidence for the efficacy of targeted alpha therapy for the control of pancreatic cancer in preclinical models is reviewed. Results are given for in vitro pancreatic cancer cells and clusters and micro-metastatic cancer lesions in vivo. Two complementary targeting vectors are examined. These are the C595 monoclonal antibody that targets the MUC1 antigen and the PAI2 ligand that targets the uPA receptor. The expression of the tumor-associated antigen MUC-1 and the uPA receptor on three pancreatic cancer cell lines is reported for cell clusters, human mouse xenografts and lymph node metastases, as well as for human pancreatic cancer tissues, using immuno-histochemistry, confocal microscopy and flow cytometry. The targeting vectors C595 and PAI2 were labeled with the alpha emitting radioisotope 213 Bi using the chelators cDTPA and CHX-A″ to form the alpha-conjugates (AC). Cell clusters were incubated with the AC and examined at 48 hours. Apoptosis was documented using the TUNEL assay. In vivo, the anti-proliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AC by local or systemic administration. Changes in tumor progression were assessed by tumor size. MUC-1 and uPA are strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The ACs can target pancreatic cells and regress cell clusters (∼100 μm diameter), causing apoptosis in some 70–90 % of cells. At two days post-cell inoculation in mice, a single local injection of 74 MBq/kg of AC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of alpha-conjugate caused significant tumor growth delay in a dose dependent manner after 16 weeks, compared with the non-specific control at 333 MBq/kg. Cytotoxicity was assessed by the MTS and TUNEL assays. The C595 and PAI2-alpha conjugates are indicated for the treatment of micro

  6. C595 antibody: A potential vector for targeted alpha therapy

    International Nuclear Information System (INIS)

    Perkins, A.C.; Allen, B.J.

    2005-01-01

    Full text: Mucins are high molecular-weight heavily glycosylated glycoproteins with many oligosaccharide side-chains, linked to a protein backbone called apomucin. A total of 19 different mucin genes (MUC1-MUC4, MUC5B, MUC5AC, MUC6-MUC18) have been identified to date. Mucins are present on the surface of most epithelial cells and play a role in their protection and lubrication. In cancer cells the mucin molecule becomes altered, thus representing an important target for diagnosis and therapy. Urinary epithelial mucin1 (MUC1) is found to be frequently up-regulated and abnormally glycosylated in a number of common malignancies, including breast, bladder, colon, ovarian and gastric cancer. The monoclonal antibody C595 is an IgG3 murine MAb raised against the protein core of human MUC1. Epitope mapping has shown that C595 recognizes a tetrapeptide motif (RPAP) within the protein core of MUC1 mucin that contains a large domain of multiples of a highly conserved 20-amino-acid-repeat sequence (PDTRPAPGSTAPPAHGVTSA). This antibody has previously been radiolabelled with 99m Tc and 111 In and used for imaging a range of tumour types including ovary, breast and bladder. The antibody has also been radiolabelled with 67 Cu and 188 Re for the therapy of superficial bladder cancer. More recently we have investigated the pre-clinical use of the C595 antibody for targeted alpha therapy using 213 Bi which emits alpha particles with high linear energy transfer (LET), short range (80 m) radiation and has a short physical half-life of 45.6 minutes. Alpha particles are some 7300 times heavier than beta particles and in theory, following binding of an alpha immunocongugates to the target, a large fraction of the alpha particle energy is delivered to cancer cells, with minimal concomitant radiation of normal tissues. 213 Bi was produced from the 225 Ac/ 213 Bi generator. For antibody conjugation the chelator, cyclic diethylenetriaminepentacetic acid anhydride (DTPA) was used. Initial

  7. In vitro and preclinical targeted alpha therapy for cancer

    International Nuclear Information System (INIS)

    Allen, B.J.; Rizvi, S.; Li, Y.; Tian, Z.; University of Wollongong, NSW; Ranson, M.; Russell, P.J.

    2000-01-01

    Full text: Targeted Alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The alpha emitting radioisotope Bi-213 is produced by generator and chelated to a cancer affined monoclonal antibody or protein to form the alpha-conjugate (AC) against melanoma, leukaemia, colorectal, bladder, breast and prostate cancers. These ACs are tested for stability, specificity and cytotoxicity. Subcutaneous inoculation of 1.5 million cells into the flanks of nude mice causes tumours to grow in all mice. The tumour growth is compared between untreated controls, nonspecific RIC and specific RIC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. Results: Stable alpha-ACs can be produced which are highly specific and cytotoxic in vitro. Local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Local TAT can also completely regress (11/12) sc melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts. These results point to the potential application of local TAT and systemic TAT in the management of these cancers. A phase 1 and 2 clinical trial is planned for local TAT of sc recurrent melanoma. Copyright (2000) Australasian College of Physical Scientists and Engineers in Medicine

  8. Targeted alpha therapy for melanoma : from bench to bedside

    International Nuclear Information System (INIS)

    Allen, B.J.; Rizvi, S.M.A.; Li, Y.; Tsui, W.; Douglas, S.; Raja, C.; Graham, P.; Smart, R.; Butler, P.; Kearsley, J.; Thompson, J.

    2001-01-01

    Full text: The control of metastatic melanoma remains an elusive objective. Targeted alpha therapy (TAT) offers a new approach to the control of micrometastases and regression of tumours. The alpha emitting immunoconjugate (AIC) against malignant melanoma has been prepared by chelating Bi-213 to the anti-melanoma antibody 9.2.27, and injected locally at 2 d post-inoculation of 1.5 million melanoma cells, or intralesionally into skin tumours. Human subjects receive 50μCi intralesional dose, escalating to 1 mCi. The clearances from the tumour, kidneys and bladder are monitored by a NaI detector that detects the 440 keV gamma ray. Blood samples and tumour photographs are taken at O. 2 and 4 weeks; tumours are excised at 4 weeks. Isolated cancer cells and preangiogenic cell clusters in mice can be eliminated with 25 μCi local AIC injection, and intra-lesional injections of 100 μCi are sufficient to completely regress melanomas with volumes up to 300 mm 3 without side-effects. Systemic TAT with a single administration is less effective with 100% growth delay of tumours observed, and ∼20% complete inhibition. The clinical TAT trial for recurrent subcutaneous melanoma has been approved by the NSW Radiation Advisory Committee and the SES Human Ethics Committee. In a world first phase 1 study, the first 5 subjects have been treated by intralesional injection, 3 at 50 μCi, and 2 at 150 μCi. All subjects having unchanged blood profiles at 2 and 4 weeks post-therapy. Tumour volumes appear little changed. However, histology of a 3 cm melanoma shows that almost complete cell kill occurred at 150 μCi, with only a few small cell clusters surviving. Local TAT inhibits tumourogenesis and intralesional TAT completely regresses melanoma in mice. Intralesional TAT for melanoma in human subjects is non-toxic so far and appears to be a promising modality. The ultimate objective is to apply systemic TAT for the control of melanoma micrometastases. Copyright (2001) Australasian

  9. Therapeutic responses in systematic targeted alpha therapy trial for melanoma

    International Nuclear Information System (INIS)

    Raja, C.; Rizvi, S.M.A.; Song, E.Y.; Graham, P.; Kearsley, J.H.; Goldsmith, H.; Bosserhoff, A.; Morgenstern, A.; Apostolidis, C.; Reisfeld, R.

    2006-01-01

    Full text: The therapeutic response of melanoma patients after systemic alpha therapy has been investigated in an open-labeled Phase 1 dose escalation study to establish the effective dose of alpha-immunoconjugate 2l3 Bi-cDTPA-9.2.27 mAb (AIC). The tools used to investigate the effects were physical examination; the images of the tumours, pathology comparisons over 12 weeks; CT comparisons and changes in tumour marker over 8 weeks. The physical examination indicated varied tumour responses. One patient showed complete response at 12 weeks post-TAT, with 20 of 21 tumours completely regressing, the last reduced by 80%. The tumour beds were biopsied for staining; S l OO was negative and no viable cells were observed. Most patients showed stable disease at 2 weeks. In one patient the CT comparison of 8 weeks with baseline showed marked reduction in three lung lesions. At least 4/21 patients showed partial response at 4 to 8 weeks and the same number showed stable disease. The disease progressed in 7 patients. The tumour marker melanoma inhibitory activity protein (MIA) showed reductions over 8 weeks, and was consistent with observations in most patients. Complete and partial responses were observed in systemic TAT for stage IV melanoma, but there was no dose-response relationship

  10. Monte Carlo Simulations of Necrotic Cell Targeted Alpha Therapy

    International Nuclear Information System (INIS)

    Penfold, S.N.; Brown, M.P.; Bezak, E.

    2011-01-01

    Full text: Hypoxic tumour cells are radioresistant and are significant contributors to the locoregional recurrences and distant metastases that mark treatment failure. Due to restricted circulatory supply, hypoxic tumor cells frequently become necrotic and thus necrotic areas often lie near hypoxic tumour areas. In this study we investigate the feasibility of binding an alpha-emitting conjugate to necrotic cells located in the proximity of hypoxic, viable tumour cells. Monte Carlo radiation transport simulations were performed to investigate the dose distribution resulting from the thorium 227 (Th227) decay chain in a representative tumour geometry. The Geant4 software toolkit was used to simulate the decay and interactions of the Th227 decay chain. The distribution of Th227 was based on a study by Thomlinson and Gray of human lung cancer histological samples (Thomlinson RH, Gray LH. Br J Cancer 1955; 9:539). The normalized dose distribution obtained with Geant4 from a cylindrical Th227 source in water is illustrated in Fig. I. The relative contribution of the different decay channels is displayed, together with a profile through the centre of the accumulated dose map. The results support the hypothesis that significant α-particle doses will be deposited in the hypoxic tumor tissue immediately surrounding the necrotic core (where the majority of Th227 will be located). As an internal a-particle generator, the Th227-radioimmunoconjugate shows potential as an efficient hypoxic tumour sterilizer.

  11. Targeted alpha therapy using Radium-223: From physics to biological effects.

    Science.gov (United States)

    Marques, I A; Neves, A R; Abrantes, A M; Pires, A S; Tavares-da-Silva, E; Figueiredo, A; Botelho, M F

    2018-05-25

    With the advance of the use of ionizing radiation in therapy, targeted alpha therapy (TAT) has assumed an important role around the world. This kind of therapy can potentially reduce side effects caused by radiation in normal tissues and increased destructive radiobiological effects in tumor cells. However, in many countries, the use of this therapy is still in a pioneering phase. Radium-223 ( 223 Ra), an alpha-emitting radionuclide, has been the first of its kind to be approved for the treatment of bone metastasis in metastatic castration-resistant prostate cancer. Nevertheless, the interaction mechanism and the direct effects of this radiopharmaceutical in tumor cells are not fully understood neither characterized at a molecular level. In fact, the ways how TAT is linked to radiobiological effects in cancer is not yet revised. Therefore, this review introduces some physical properties of TAT that leads to biological effects and links this information to the hallmarks of cancer. The authors also collected the studies developed with 223 Ra to correlate with the three categories reviewed - properties of TAT, 5 R's of radiobiology and hallmarks of cancer- and with the promising future to this radiopharmaceutical. Copyright © 2018 Elsevier Ltd. All rights reserved.

  12. Preclinical studies and clinical trial of targeted alpha therapy for cancer

    International Nuclear Information System (INIS)

    Allen, B.J.

    2002-01-01

    Full text: Targeted Alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The practicality and efficacy of TAT is tested by in vitro and in vivo studies in melanoma, leukemia, colorectal, breast and prostate cancers. Materials and Methods: The alpha-emitting radioisotope is Bi-213, which is produced by the Ac-225 generator and chelated to a cancer specific monoclonal antibody (mab) or protein (eg plasmmogen activator inhibitor PAI2) to form the alpha-conjugate (AC). Stable alpha-ACs have been produced which have been tested for specificity and cytotoxicity in vitro against melanoma (9.2.27 mab), leukemia (WM60 mab), colorectal (C30.6 mab), breast (PAI2) and prostate (PAI2, J591 mab) cancers. Subcutaneous inoculation of 1-1.5 million human cancer cells into the flanks of nude mice causes tumours to grow in all mice. Tumour growth is compared for untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. Results: In vitro studies show that TAT is one to two orders of magnitude more cytotoxic to targeted cells than nonspecific ACs, specific beta emitting conjugates or free isotope. In vivo local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can also completely regress advanced sc melanomas but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts and gives almost complete control of breast and prostate cancer tumour growth. Conclusions: These results point to the application of local and systemic TAT in the management of secondary cancer. A phase 1 and 2 clinical trial of TAT of subcutaneous, secondary melanoma has commenced at St George Hospital, and 10/30 subjects have been treated by intralesional injection

  13. Preclinical targeted alpha therapy for melanoma, leukaemia, breast, prostate and colorectal cancers

    International Nuclear Information System (INIS)

    Allen, B.J.; Rizvi, S.; Li, Y.; Tian, Z.; University of Wollongong, NSW; Ranson, M.

    2000-01-01

    Full text: Targeted Alpha therapy (TAT) offers the potential to inhibit the growth of micro-metastases by selectively killing isolated and preangiogenic clusters of cancer cells. The alpha emitting radioisotopes Tb-149 and Bi-213 are produced by accelerator and generator respectively and are chelated to a cancer specific monoclonal antibody, peptide or protein to form the alpha-conjugates (AC) against melanoma, leukaemia, breast, prostate and colorectal cancers. These ACs are tested for stability, specificity and cytotoxicity in vitro and in vivo using several nude mouse models. The Australian TAT program began some 7 years at ANSTO but was still-born. Later, TAT had a second wind at St George Hospital, where collaborative research led to the investigation of Tb-149 as a new alpha emitting radionuclide. Subsequently, increased emphasis was placed on the Ac-225 generator to produce Bi-213. Although in-house funding was terminated in 1998, the project received its third wind with local fund raising in the Shire and a US grant in 1999, and continues to break new ground in the control of the above cancers. Stable alpha-ACs are produced which are highly specific and cytotoxic in vitro against melanoma, leukaemia, colorectal, breast and prostate cancers. Subcutaneous inoculation of 11.5 million cells into the flanks of nude mice causes tumours to grow in all mice. The tumour growth is compared with untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. Local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can completely regress melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of melanoma xenografts and gives almost complete control of breast cancer tumour growth in the primary site and metastatic invasion of the lymph nodes. These results point to the application of local

  14. Alpha-1 Antitrypsin Deficiency Targeted Testing and Augmentation Therapy: A Canadian Thoracic Society Clinical Practice Guideline

    Directory of Open Access Journals (Sweden)

    DD Marciniuk

    2012-01-01

    Full Text Available Alpha-1 antitrypsin (A1AT functions primarily to inhibit neutrophil elastase, and deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD. Severe A1AT deficiency occurs in one in 5000 to one in 5500 of the North American population. While the exact prevalence of A1AT deficiency in patients with diagnosed COPD is not known, results from small studies provide estimates of 1% to 5%. The present document updates a previous Canadian Thoracic Society position statement from 2001, and was initiated because of lack of consensus and understanding of appropriate patients suitable for targeted testing for A1AT deficiency, and for the use of A1AT augmentation therapy. Using revised guideline development methodology, the present clinical practice guideline document systematically reviews the published literature and provides an evidence-based update. The evidence supports the practice that targeted testing for A1AT deficiency be considered in individuals with COPD diagnosed before 65 years of age or with a smoking history of <20 pack years. The evidence also supports consideration of A1AT augmentation therapy in nonsmoking or exsmoking patients with COPD (forced expiratory volume in 1 s of 25% to 80% predicted attributable to emphysema and documented A1AT deficiency (level ≤11 μmol/L who are receiving optimal pharmacological and nonpharmacological therapies (including comprehensive case management and pulmonary rehabilitation because of benefits in computed tomography scan lung density and mortality.

  15. An eighteen-membered macrocyclic ligand for actinium-225 targeted alpha therapy

    International Nuclear Information System (INIS)

    Thiele, Nikki A.; MacMillan, Samantha N.; Wilson, Justin J.; Rodriguez-Rodriguez, Cristina

    2017-01-01

    The 18-membered macrocycle H 2 macropa was investigated for 225 Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225 Ac (26 kBq) in 5 min at RT. [ 225 Ac(macropa)] + remained intact over 7 to 8 days when challenged with either excess La 3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225 Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225 Ac in human serum after 7 days. In LNCaP xenograft mice, 225 Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225 Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225 Ac chelation that will facilitate the clinical development of 225 Ac TAT for the treatment of soft-tissue metastases. (copyright 2017 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim)

  16. An eighteen-membered macrocyclic ligand for actinium-225 targeted alpha therapy

    Energy Technology Data Exchange (ETDEWEB)

    Thiele, Nikki A.; MacMillan, Samantha N.; Wilson, Justin J. [Cornell Univ., Ithaca, NY (United States). Chemistry and Chemical Biology; Brown, Victoria; Jermilova, Una; Ramogida, Caterina F.; Robertson, Andrew K.H.; Schaffer, Paul; Radchenko, Valery [TRIUMF, Vancouver, BC (Canada). Life Science Div.; Kelly, James M.; Amor-Coarasa, Alejandro; Nikolopoulou, Anastasia; Ponnala, Shashikanth; Williams, Clarence Jr.; Babich, John W. [Radiology, Weill Cornell Medicine, New York, NY (United States); Rodriguez-Rodriguez, Cristina [British Columbia Univ., Vancouver, BC (Canada). Dept. of Physics and Astronomy and Centre for Comparative Medicine

    2017-11-13

    The 18-membered macrocycle H{sub 2}macropa was investigated for {sup 225}Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all {sup 225}Ac (26 kBq) in 5 min at RT. [{sup 225}Ac(macropa)]{sup +} remained intact over 7 to 8 days when challenged with either excess La{sup 3+} ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled {sup 225}Ac in just minutes at RT, and macropa-Tmab retained >99 % of its {sup 225}Ac in human serum after 7 days. In LNCaP xenograft mice, {sup 225}Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free {sup 225}Ac over 96 h. These findings establish macropa to be a highly promising ligand for {sup 225}Ac chelation that will facilitate the clinical development of {sup 225}Ac TAT for the treatment of soft-tissue metastases. (copyright 2017 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim)

  17. Targeted alpha therapy of mCRPC. Dosimetry estimate of {sup 213}bismuth-PSMA-617

    Energy Technology Data Exchange (ETDEWEB)

    Kratochwil, Clemens; Afshar-Oromieh, Ali; Rathke, Hendrik; Giesel, Frederik L. [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Schmidt, Karl [ABX-CRO, Dresden (Germany); Bruchertseifer, Frank; Morgenstern, Alfred [European Commission - Joint Research Centre, Directorate for Nuclear Safety and Security, Karlsruhe (Germany); Haberkorn, Uwe [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); German Cancer Research Center (DKFZ), Cooperation Unit Nuclear Medicine, Heidelberg (Germany)

    2018-01-15

    PSMA-617 is a small molecule targeting the prostate-specific membrane antigen (PSMA). In this work, we estimate the radiation dosimetry for this ligand labeled with the alpha-emitter {sup 213}Bi. Three patients with metastatic prostate cancer underwent PET scans 0.1 h, 1 h, 2 h, 3 h, 4 h and 5 h after injection of {sup 68}Ga-PSMA-617. Source organs were kidneys, liver, spleen, salivary glands, bladder, red marrow and representative tumor lesions. The imaging nuclide {sup 68}Ga was extrapolated to the half-life of {sup 213}Bi. The residence times of {sup 213}Bi were forwarded to the instable daughter nuclides. OLINDA was used for dosimetry calculation. Results are discussed in comparison to literature data for {sup 225}Ac-PSMA-617. Assuming a relative biological effectiveness of 5 for alpha radiation, the dosimetry estimate revealed equivalent doses of mean 8.1 Sv{sub RBE5}/GBq for salivary glands, 8.1 Sv{sub RBE5}/GBq for kidneys and 0.52 Sv{sub RBE5}/GBq for red marrow. Liver (1.2 Sv{sub RBE5}/GBq), spleen (1.4 Sv{sub RBE5}/GBq), bladder (0.28 Sv{sub RBE5}/GBq) and other organs (0.26 Sv{sub RBE5}/GBq) were not dose-limiting. The effective dose is 0.56 Sv{sub RBE5}/GBq. Tumor lesions were in the range 3.2-9.0 Sv{sub RBE5}/GBq (median 7.6 Sv{sub RBE5}/GBq). Kidneys would limit the cumulative treatment activity to 3.7 GBq; red marrow might limit the maximum single fraction to 2 GBq. Despite promising results, the therapeutic index was inferior compared to {sup 225}Ac-PSMA-617. Dosimetry of {sup 213}Bi-PSMA-617 is in a range traditionally considered reasonable for clinical application. Nevertheless, compared to {sup 225}Ac-PSMA-617, it suffers from higher perfusion-dependent off-target radiation and a longer biological half-life of PSMA-617 in dose-limiting organs than the physical half-life of {sup 213}Bi, rendering this nuclide as a second choice radiolabel for targeted alpha therapy of prostate cancer. (orig.)

  18. The alpha-cell as target for type 2 diabetes therapy

    DEFF Research Database (Denmark)

    Christensen, Mikkel; Bagger, Jonatan I; Vilsboll, Tina

    2011-01-01

    for type 2 diabetes. Several lines of preclinical evidence have paved the way for the development of drugs, which suppress glucagon secretion or antagonize the glucagon receptor. In this review, the physiological actions of glucagon and the role of glucagon in type 2 diabetic pathophysiology are outlined...... antagonists are confronted with several safety issues. At present, available pharmacological agents based on the glucose-dependent glucagonostatic effects of GLP-1 represent the most favorable way to apply constraints to the alpha-cell in type 2 diabetes.......-coupled receptors in the hepatocytes. Type 2 diabetic patients are characterized by elevated glucagon levels contributing decisively to hyperglycemia in these patients. Accumulating evidence demonstrates that targeting the pancreatic alpha-cell and its main secretory product glucagon is a possible treatment...

  19. The alpha-cell as target for type 2 diabetes therapy

    DEFF Research Database (Denmark)

    Christensen, Mikkel; Bagger, Jonatan I; Vilsboll, Tina

    2011-01-01

    -coupled receptors in the hepatocytes. Type 2 diabetic patients are characterized by elevated glucagon levels contributing decisively to hyperglycemia in these patients. Accumulating evidence demonstrates that targeting the pancreatic alpha-cell and its main secretory product glucagon is a possible treatment....... Furthermore, potential advantages and limitations of antagonizing the glucagon receptor or suppressing glucagon secretion in the treatment of type 2 diabetes are discussed with a focus on already marketed drugs and drugs in clinical development. It is concluded that the development of novel glucagon receptor...

  20. Quantification of activity by alpha-camera imaging and small-scale dosimetry within ovarian carcinoma micrometastases treated with targeted alpha therapy

    DEFF Research Database (Denmark)

    Chouin, N; Lindegren, S; Jensen, Holger

    2012-01-01

    Targeted alpha therapy (TAT) a promising treatment for small, residual, and micrometastatic diseases has questionable efficacy against malignant lesions larger than the α-particle range, and likely requires favorable intratumoral activity distribution. Here, we characterized and quantified......% IA/g at 4 h) in the outer tumor layer and a sharp drop beyond a depth of 50 µm. Small-scale dosimetry was performed on a multi-cellular micrometastasis model, using time-integrated activities derived from the experimental data. With injected activity of 400 kBq, tumors exhibiting uniform activity...... distribution received 100 µm might not be effectively treated by the examined regimen....

  1. Development of a Combination Therapy for Prostate Cancer by Targeting Stat3 and HIF-1alpha

    Science.gov (United States)

    2013-07-01

    inflammation-induced cancer, making it an attractive target (25-27). A3. Innovation 1. TEL03 is a novel anti-cancer agent from Chinese herbal medicine ...agents from Chinese herbal medicine (CHM) that targets HIF-1α /2α for prostate cancer therapy. Hypoxia orchestrated by HIF-1αis crucial for tumor...Stat3 for treatment of prostate and other cancers. TEL03, which is a novel anti-cancer agent derived from Chinese herbal medicine (CHM: Hypocrella

  2. Functionalized NaA nanozeolites labeled with 224,225Ra for targeted alpha therapy.

    Science.gov (United States)

    Piotrowska, Agata; Leszczuk, Edyta; Bruchertseifer, Frank; Morgenstern, Alfred; Bilewicz, Aleksander

    2013-01-01

    The 223 Ra, 224 Ra, and 225 Ra radioisotopes exhibit very attractive nuclear properties for application in radionuclide therapy. Unfortunately the lack of appropriate bifunctional ligand for radium is the reason why these radionuclides have not found application in receptor-targeted therapy. In the present work, the potential usefulness of the NaA nanozeolite as a carrier for radium radionuclides has been studied. 224 Ra and 225 Ra, α-particle emitting radionuclides, have been absorbed in the nanometer-sized NaA zeolite (30-70 nm) through simple ion exchange. 224,225 Ra-nanozeolites exhibited very high stability in solutions containing physiological salt, EDTA, amino acids, and human serum. To make NaA nanozeolite particles dispersed in water their surface was modified with a silane coupling agent containing poly(ethylene glycol) molecules. This functionalization approach let us covalently attach a biomolecule to the NaA nanozeolite surface.

  3. Targeting Interleukin-4 Receptor Alpha by Hybrid Peptide for Novel Biliary Tract Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Kahori Seto

    2014-01-01

    Full Text Available It is known that the interleukin-4 receptor α (IL-4Rα is highly expressed on the surface of various human solid tumors. We previously designed novel IL-4Rα-lytic hybrid peptide composed of binding peptide to IL-4Rα and cell-lytic peptide and reported that the designed IL-4Rα-lytic hybrid peptide exhibited cytotoxic and antitumor activity both in vitro and in vivo against the human pancreatic cancer cells expressing IL-4Rα. Here, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular targeted therapy for human biliary tract cancer (BTC. The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in six BTC cell lines with a concentration that killed 50% of all cells (IC50 as low as 5 μM. We also showed that IL-4Rα-lytic hybrid peptide in combination with gemcitabine exhibited synergistic cytotoxic activity in vitro. In addition, intravenous administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human BTC in vivo. Taken together, these results indicated that the IL-4Rα-lytic hybrid peptide is a potent agent that might provide a novel therapy for patients with BTC.

  4. Sci-Thur AM: YIS – 01: New technologies for astatine-211 targeted alpha therapy research

    Energy Technology Data Exchange (ETDEWEB)

    Crawford, Jason; Yang, Hua; Schaffer, Paul; Ruth, Thomas [University of Victoria, Victoria, BC (Canada); TRIUMF, Vancouver, BC (Canada)

    2016-08-15

    Purpose: The short-range, densely ionizing α-particles emitted by {sup 211}At (t{sub 1/2}=7.2h) are well suited for the treatment of diffuse microscopic disease, using cancer targeting biomolecules. {sup 211}At availability is limited by the rarity of α-cyclotrons required for standard production. Image-based dosimetry is also limited for {sup 211}At, which emits low intensity X-rays. Our goal was to leverage state-of-the-art infrastructure at TRIUMF to produce and evaluate two related isotopes, {sup 211}Rn (t{sub 1/2}=14.6h, 73% decay to {sup 211}At) as a generator for {sup 211}At, and {sup 209}At (t{sub 1/2}=5.4h, X-ray/gamma-ray emitter) as a novel 211At surrogate for preclinical imaging studies. Methods: Produced by spallation of uranium with 480 MeV protons, mass separated ion beams of short-lived francium isotopes were implanted into NaCl targets where {sup 211}Rn or {sup 209}At were produced by radioactive decay, in situ. {sup 211}Rn was transferred to dodecane from which {sup 211}At was efficiently extracted and evaluated for clinical applicability. High energy SPECT/CT was evaluated for measuring {sup 209}At activity distributions in mice and phantoms. Results: Our small scale {sup 211}Rn/{sup 211}At generator system provided high purity {sup 211}At samples. The methods are immediately scalable to the level of radioactivity required for in vivo experiments with {sup 211}At. {sup 209}At-based high energy SPECT imaging was determined suitable for pursuing image-based dosimetry in mouse tumour models. In the future, we will utilize quantitative {sup 209}At-SPECT for image-based dose calculations. Conclusion: These early studies provided a foundation for future endeavours with {sup 211}At-based α-therapy. Canada is now significantly closer to clinical targeted α-therapy of cancer.

  5. Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab

    International Nuclear Information System (INIS)

    Beyer, G.J.; Soloviev, D.; Buchegger, F.; Miederer, M.; Vranjes-Duric, S.; Comor, J.J.; Kuenzi, G.; Hartley, O.; Senekowitsch-Schmidtke, R.

    2004-01-01

    This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10 6 Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 μg unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%±4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%±2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with 149 Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach. (orig.)

  6. Targeting Alpha-Fetoprotein (AFP)-MHC Complex with CAR T-Cell Therapy for Liver Cancer.

    Science.gov (United States)

    Liu, Hong; Xu, Yiyang; Xiang, Jingyi; Long, Li; Green, Shon; Yang, Zhiyuan; Zimdahl, Bryan; Lu, Jingwei; Cheng, Neal; Horan, Lucas H; Liu, Bin; Yan, Su; Wang, Pei; Diaz, Juan; Jin, Lu; Nakano, Yoko; Morales, Javier F; Zhang, Pengbo; Liu, Lian-Xing; Staley, Binnaz K; Priceman, Saul J; Brown, Christine E; Forman, Stephen J; Chan, Vivien W; Liu, Cheng

    2017-01-15

    The majority of tumor-specific antigens are intracellular and/or secreted and therefore inaccessible by conventional chimeric antigen receptor (CAR) T-cell therapy. Given that all intracellular/secreted proteins are processed into peptides and presented by class I MHC on the surface of tumor cells, we used alpha-fetoprotein (AFP), a specific liver cancer marker, as an example to determine whether peptide-MHC complexes can be targets for CAR T-cell therapy against solid tumors. We generated a fully human chimeric antigen receptor, ET1402L1-CAR (AFP-CAR), with exquisite selectivity and specificity for the AFP 158-166 peptide complexed with human leukocyte antigen (HLA)-A*02:01. We report that T cells expressing AFP-CAR selectively degranulated, released cytokines, and lysed liver cancer cells that were HLA-A*02:01 + /AFP + while sparing cells from multiple tissue types that were negative for either expressed proteins. In vivo, intratumoral injection of AFP-CAR T cells significantly regressed both Hep G2 and AFP 158 -expressing SK-HEP-1 tumors in SCID-Beige mice (n = 8 for each). Moreover, intravenous administration of AFP-CAR T cells in Hep G2 tumor-bearing NSG mice lead to rapid and profound tumor growth inhibition (n = 6). Finally, in an established intraperitoneal liver cancer xenograft model, AFP-CAR T cells showed robust antitumor activity (n = 6). This study demonstrates that CAR T-cell immunotherapy targeting intracellular/secreted solid tumor antigens can elicit a potent antitumor response. Our approach expands the spectrum of antigens available for redirected T-cell therapy against solid malignancies and offers a promising new avenue for liver cancer immunotherapy. Clin Cancer Res; 23(2); 478-88. ©2016 AACR. ©2016 American Association for Cancer Research.

  7. Cross sections of the reaction Pa-231(d,3n)U-230 for the production of U-230/Th-226 for targeted alpha therapy

    Czech Academy of Sciences Publication Activity Database

    Morgenstern, A.; Lebeda, Ondřej; Štursa, Jan; Capote, R.; Sin, M.; Bruchertseifer, F.; Zielinska, B.; Apostolidis, C.

    2009-01-01

    Roč. 80, č. 5 (2009), 054612/1-054612/6 ISSN 0556-2813 Institutional research plan: CEZ:AV0Z10480505 Keywords : Pa-231 * U-230 * Th-226 * reaction cross section * targeted alpha therapy Subject RIV: BG - Nuclear, Atomic and Molecular Physics, Colliders Impact factor: 3.477, year: 2009

  8. Interleukin-1beta and TNF-alpha: reliable targets for protective therapies in Parkinson´s Disease?

    Directory of Open Access Journals (Sweden)

    María Celeste Leal

    2013-04-01

    Full Text Available Neuroinflammation has received increased attention as a target for putative neuroprotective therapies in Parkinson´s Disease (PD. Two prototypic pro-inflammatory cytokines Interleukin-1beta (IL-1 and Tumor necrosis factor-alpha (TNF have been implicated as main effectors of the functional consequences of neuroinflammation on neurodegeneration in PD models. In this review, we describe that the functional interaction between these cytokines in the brain differs from the periphery (e.g. their expression is not induced by each other and present data showing predominantly a toxic effect of these cytokines when expressed at high doses and for a sustained period of time in the substantia nigra pars compacta (SN. In addition, we highlight opposite evidence showing protective effects of these two main cytokines when conditions of duration, amount of expression or state of activation of the target or neighboring cells are changed. Furthermore, we discuss these results in the frame of previous disappointing results from anti-TNF clinical trials against Multiple Sclerosis, another neurodegenerative disease with a clear neuroinflammatory component. In conclusion, we hypothesize that the available evidence suggests that the duration and dose of IL-1 or TNF expression is crucial to predict their functional effect on the SN. Since these parameters are not amenable for measurement in the SN of PD patients, we call for an in-depth analysis to identify downstream mediators that could be common to the toxic (and not the protective effects of these cytokines in the SN. This strategy could spare the possible neuroprotective effect of these cytokines operative in the patient at the time of treatment, increasing the probability of efficacy in a clinical setting. Alternatively, receptor-specific agonists or antagonists could also provide a way to circumvent undesired effects of general anti-inflammatory or specific anti IL-1 or TNF therapies against PD.

  9. Is DTPA a good competing chelating agent for Th(IV) in human serum and suitable in targeted alpha therapy?

    Science.gov (United States)

    Le Du, Alicia; Sabatié-Gogova, Andrea; Morgenstern, Alfred; Montavon, Gilles

    2012-04-01

    The interaction between thorium and human serum components was studied using difference ultraviolet spectroscopy (DUS), ultrafiltration and high-pressure-anion exchange chromatography (HPAEC) with external inductively conducted plasma mass spectrometry (ICP-MS) analysis. Experimental data are compared with modelling results based on the law of mass action. Human serum transferrin (HSTF) interacts strongly with Th(IV), forming a ternary complex including two synergistic carbonate anions. This complex governs Th(IV) speciation under blood serum conditions. Considering the generally used Langmuir-type model, values of 10(33.5) and 10(32.5) were obtained for strong and weak sites, respectively. We showed that trace amounts of diethylene triamine pentaacetic acid (DTPA) cannot complex Th(IV) in the blood serum at equilibrium. Unexpectedly this effect is not related to the competition with HSTF but is due to the strong competition with major divalent metal ions for DTPA. However, Th-DTPA complex was shown to be stable for a few hours when it is formed before addition in the biological medium; this is related to the high kinetic stability of the complex. This makes DTPA a potential chelating agent for synthesis of (226)Th-labelled biomolecules for application in targeted alpha therapy. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Development of a preclinical 211Rn/211At generator system for targeted alpha therapy research with 211At.

    Science.gov (United States)

    Crawford, Jason R; Yang, Hua; Kunz, Peter; Wilbur, D Scott; Schaffer, Paul; Ruth, Thomas J

    2017-05-01

    The availability of 211 At for targeted alpha therapy research can be increased by the 211 Rn/ 211 At generator system, whereby 211 At is produced by 211 Rn electron capture decay. This study demonstrated the feasibility of using generator-produced 211 At to label monoclonal antibody (BC8, anti-human CD45) for preclinical use, following isolation from the 207 Po contamination also produced by these generators (by 211 Rn α-decay). 211 Rn was produced by 211 Fr electron capture decay following mass separated ion beam implantation and chemically isolated in liquid alkane hydrocarbon (dodecane). 211 At produced by the resulting 211 Rn source was extracted in strong base (2N NaOH) and purified by granular Te columns. BC8-B10 (antibody conjugated with closo-decaborate(2-)) was labeled with generator-produced 211 At and purified by PD-10 columns. Aqueous solutions extracted from the generator were found to contain 211 At and 207 Po, isolated from 211 Rn. High radionuclidic purity was obtained for 211 At eluted from Te columns, from which BC8-B10 monoclonal antibody was successfully labeled. If not removed, 207 Po was found to significantly contaminate the final 211 At-BC8-B10 product. High yield efficiencies (decay-corrected, n=3) were achieved for 211 At extraction from the generator (86%±7%), Te column purification (70%±10%), and antibody labeling (76%±2%). The experimental 211 Rn/ 211 At generator was shown to be well-suited for preclinical 211 At-based research. We believe that these experiments have furthered the knowledge-base for expanding accessibility to 211 At using the 211 Rn/ 211 At generator system. As established by this work, the 211 Rn/ 211 At generator has the capability of facilitating preclinical evaluations of 211 At-based therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Influence of tumour size on the efficacy of targeted alpha therapy with (213)Bi-[DOTA(0),Tyr(3)]-octreotate.

    Science.gov (United States)

    Chan, Ho Sze; Konijnenberg, Mark W; de Blois, Erik; Koelewijn, Stuart; Baum, Richard P; Morgenstern, Alfred; Bruchertseifer, Frank; Breeman, Wouter A; de Jong, Marion

    2016-12-01

    Targeted alpha therapy has been postulated to have great potential for the treatment of small clusters of tumour cells as well as small metastases. (213)Bismuth, an α-emitter with a half-life of 46 min, has shown to be effective in preclinical as well as in clinical applications. In this study, we evaluated whether (213)Bi-[DOTA(0), Tyr(3)]-octreotate ((213)Bi-DOTATATE), a (213)Bi-labelled somatostatin analogue with high affinity for somatostatin receptor subtype 2 (SSTR2), is suitable for the treatment of larger neuroendocrine tumours overexpressing SSTR2 in comparison to its effectiveness for smaller tumours. We performed a preclinical targeted radionuclide therapy study with (213)Bi-DOTATATE in animals bearing tumours of different sizes (50 and 200 mm(3)) using two tumour models: H69 (human small cell lung carcinoma) and CA20948 (rat pancreatic tumour). Pharmacokinetics was determined for calculation of dosimetry in organs and tumours. H69- or CA20948-xenografted mice with tumour volumes of approximately 120 mm(3) were euthanized at 10, 30, 60 and 120 min post injection of a single dose of (213)Bi-DOTATATE (1.5-4.8 MBq). To investigate the therapeutic efficacy of (213)Bi-DOTATATE, xenografted H69 and CA20948 tumour-bearing mice with tumour sizes of 50 and 200 mm(3) were administered daily with a therapeutic dose of (213)Bi-DOTATATE (0.3 nmol, 2-4 MBq) for three consecutive days. The animals were followed for 90 days after treatment. At day 90, mice were injected with 25 MBq (99m)Tc-DMSA and imaged by SPECT/CT to investigate possible renal dysfunction due to (213)Bi-DOTATATE treatment. Higher tumour uptakes were found in CA20948 tumour-bearing animals compared to those in H69 tumour-bearing mice with the highest tumour uptake of 19.6 ± 6.6 %IA/g in CA20948 tumour-bearing animals, while for H69 tumour-bearing mice, the highest tumour uptake was found to be 9.8 ± 2.4 %IA/g. Nevertheless, as the anti-tumour effect was more pronounced in H69

  12. Targeted Therapy for Melanoma

    International Nuclear Information System (INIS)

    Quinn, Thomas; Moore, Herbert

    2016-01-01

    The research project, entitled ''Targeted Therapy for Melanoma,'' was focused on investigating the use of kidney protection measures to lower the non-specific kidney uptake of the radiolabeled Pb-DOTA-ReCCMSH peptide. Previous published work demonstrated that the kidney exhibited the highest non-target tissue uptake of the "2"1"2"P"b"/"2"0"3Pb radiolabeled melanoma targeting peptide DOTA-ReCCMSH. The radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analog DOTA-Re(Arg"1"1)CCMSH, which binds the melanocortin-1 receptor over-expressed on melanoma tumor cells, has shown promise as a PRRT agent in pre-clinical studies. High tumor uptake of "2"1"2Pb labeled DOTA-Re(Arg"1"1)CCMSH resulted in tumor reduction or eradication in melanoma therapy studies. Of particular note was the 20-50% cure rate observed when melanoma mice were treated with alpha particle emitter "2"1"2Pb. However, as with most PRRT agents, high radiation doses to the kidneys where observed. To optimize tumor treatment efficacy and reduce nephrotoxicity, the tumor to kidney uptake ratio must be improved. Strategies to reduce kidney retention of the radiolabeled peptide, while not effecting tumor uptake and retention, can be broken into several categories including modification of the targeting peptide sequence and reducing proximal tubule reabsorption.

  13. Targeted Therapy for Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Quinn, Thomas [Alphamed, Jackson, TN (United States); Moore, Herbert [Alphamed, Jackson, TN (United States)

    2016-12-05

    The research project, entitled ”Targeted Therapy for Melanoma,” was focused on investigating the use of kidney protection measures to lower the non-specific kidney uptake of the radiolabeled Pb-DOTA-ReCCMSH peptide. Previous published work demonstrated that the kidney exhibited the highest non-target tissue uptake of the 212Pb/203Pb radiolabeled melanoma targeting peptide DOTA-ReCCMSH. The radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analog DOTA-Re(Arg11)CCMSH, which binds the melanocortin-1 receptor over-expressed on melanoma tumor cells, has shown promise as a PRRT agent in pre-clinical studies. High tumor uptake of 212Pb labeled DOTA-Re(Arg11)CCMSH resulted in tumor reduction or eradication in melanoma therapy studies. Of particular note was the 20-50% cure rate observed when melanoma mice were treated with alpha particle emitter 212Pb. However, as with most PRRT agents, high radiation doses to the kidneys where observed. To optimize tumor treatment efficacy and reduce nephrotoxicity, the tumor to kidney uptake ratio must be improved. Strategies to reduce kidney retention of the radiolabeled peptide, while not effecting tumor uptake and retention, can be broken into several categories including modification of the targeting peptide sequence and reducing proximal tubule reabsorption.

  14. Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting {sup 223}Ra-dichloride

    Energy Technology Data Exchange (ETDEWEB)

    Pacilio, Massimiliano [Azienda Ospealiera San Camillo Forlianini, Rome (Italy). Dept. of Medical Physics; Ventroni, Guido; Mango, Lucio [Azienda Ospealiera San Camillo Forlianini, Rome (Italy). Dept. of Nuclear Medicin; De Vincentis, Giuseppe; Di Castro, Elisabetta; Frantellizzi, Viviana; Follacchio, Giulia Anna; Garkavaya, Tatiana [Rome Univ. (Italy). Dept. of Radiological, Oncological and Anatomo Pathological Sciences; Cassano, Bartolomeo; Lorenzon, Leda [Rome Univ. (Italy). Postgraduate School of Medical Physics; Pellegrini, Rosanna; Pani, Roberto [Rome Univ. (Italy). Dept. of Molecular Medicine; Ialongo, Pasquale [Azienda Ospealiera San Camillo Forlianini, Rome (Italy). Dept. of Radiology

    2016-01-15

    Ra-dichloride is an alpha-emitting radiopharmaceutical used in the treatment of bone metastases from castration-resistant prostate cancer. Image-based dosimetric studies remain challenging because the emitted photons are few. The aim of this study was to implement a methodology for in-vivo quantitative planar imaging, and to assess the absorbed dose to lesions using the MIRD approach. The study included nine Caucasian patients with 24 lesions (6 humeral head lesions, 4 iliac wing lesions, 2 scapular lesions, 5 trochanter lesions, 3 vertebral lesions, 3 glenoid lesions, 1 coxofemoral lesion). The treatment consisted of six injections (one every 4 weeks) of 50 kBq per kg body weight. Gamma-camera calibrations for {sup 223}Ra included measurements of sensitivity and transmission curves. Patients were statically imaged for 30 min, using an MEGP collimator, double-peak acquisition, and filtering to improve the image quality. Lesions were delineated on {sup 99m}Tc-MDP whole-body images, and the ROIs superimposed on the {sup 223}Ra images after image coregistration. The activity was quantified with background, attenuation, and scatter correction. Absorbed doses were assessed deriving the S values from the S factors for soft-tissue spheres of OLINDA/EXM, evaluating the lesion volumes by delineation on the CT images. In 12 lesions with a wash-in phase the biokinetics were assumed to be biexponential, and to be monoexponential in the remainder. The optimal timing for serial acquisitions was between 1 and 5 h, between 18 and 24 h, between 48 and 60 h, and between 7 and 15 days. The error in cumulated activity neglecting the wash-in phase was between 2 % and 12 %. The mean effective half-life (T{sub 1/2eff}) of {sup 223}Ra was 8.2 days (range 5.5-11.4 days). The absorbed dose (D) after the first injection was 0.7 Gy (range 0.2-1.9 Gy). Considering the relative biological effectiveness (RBE) of alpha particles (RBE = 5), D{sub RBE} = 899 mGy/MBq (range 340-2,450 mGy/MBq). The

  15. Alpha Emitting Radionuclides and Radiopharmaceuticals for Therapy

    International Nuclear Information System (INIS)

    Chérel, Michel; Barbet, Jacques

    2013-01-01

    Today, cancer treatments mainly rely on surgery or external beam radiation to remove or destroy bulky tumors. Chemotherapy is given when tumours cannot be removed or when dissemination is suspected. However, these approaches cannot permanently treat all cancers and relapse occurs in up to 50% of the patients’ population. Radioimmunotherapy (RIT) and peptide receptor radionuclide therapy (PRRT) are effective against some disseminated and metastatic diseases, although they are rarely curative. Most preclinical and clinical developments in this field have involved electron-emitting radionuclides, particularly iodine-131, yttrium-90 and lutetium-177. The large range of the electrons emitted by these radionuclides reduces their efficacy against very small tumour cell clusters or isolated tumour cells present in residual disease and in many haematological tumours (leukaemia, myeloma). The range of alpha particles in biological tissues is very short, less than 0.1 mm, which makes alpha emitters theoretically ideal for treatment of such isolated tumour cells or micro-clusters of malignant cells. Thus, over the last decade, a growing interest for the use of alpha-emitting radionuclides has emerged. Research on targeted alpha therapy (TAT) began years ago in Nantes through cooperation between Subatech, a nuclear physics laboratory, CRCNA, a cancer research centre with a nuclear oncology team and ITU (Karlsruhe, Germany). CD138 was demonstrated as a potential target antigen for Multiple Myeloma, which is a target of huge clinical interest particularly suited for TAT because of the disseminated nature of the disease consisting primarily of isolated cells and small clusters of tumour cells mainly localized in the bone marrow. Thus anti-CD138 antibodies were labelled with bismuth-213 from actinium-225/bismuth-213 generators provided by ITU and used to target multiple myeloma cells. In vitro studies showed cell cycle arrest, synergism with chemotherapy and very little induction

  16. {sup 213}Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

    Energy Technology Data Exchange (ETDEWEB)

    Kratochwil, C.; Giesel, F.L.; Mier, W.; Haberkorn, U. [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Bruchertseifer, F.; Apostolidis, C.; Morgenstern, A. [European Commission, Institute for Transuranium Elements, Karlsruhe (Germany); Boll, R.; Murphy, K. [Oak Ridge National Laboratory, Oak Ridge, TN (United States)

    2014-11-15

    Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as {sup 90}Y/{sup 177}Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with {sup 213}Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with {sup 90}Y/{sup 177}Lu-DOTATOC were treated with an intraarterial infusion of {sup 213}Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of {sup 213}Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and {sup 68}Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. The biodistribution of {sup 213}Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. (orig.)

  17. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

    International Nuclear Information System (INIS)

    Kratochwil, C.; Giesel, F.L.; Mier, W.; Haberkorn, U.; Bruchertseifer, F.; Apostolidis, C.; Morgenstern, A.; Boll, R.; Murphy, K.

    2014-01-01

    Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as 90 Y/ 177 Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with 213 Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with 90 Y/ 177 Lu-DOTATOC were treated with an intraarterial infusion of 213 Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of 213 Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and 68 Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. The biodistribution of 213 Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. (orig.)

  18. In vitro radionuclide therapy and in vivo scintigraphic imaging of alpha fetoprotein producing hepatocellular carcinoma by targeted sodium iodide symporter gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kwang Il; Lee, Yong Jin; Lee, Tae Sup; Song, Inho; Cheon, Gi Jeong; Lim, Sang Moo; Kang, Joo Hyun [Korea Institute of Radiological and Medical and Medical Sciences, Seoul (Korea, Republic of); Chung, June Key [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2012-03-15

    This study aimed to develop a gene expression targeting method for specific imaging and therapy of alpha fetoprotein (AFP) producing hepatocellular carcinoma (HCC) cells, using an adenovirus vector containing the human sodium/iodide symporter (hNIS) gene driven by an AFP enhancer/promoter. The recombinant adenovirus vector, AdAFPhNIS (containing the hNIS gene driven by human AFP enhancer/promoter) was prepared. After in vitro infection by the adenovirus, hNIS gene expression in AFP producing cells and in AFP nonproducing cells was investigated using {sup 125}I uptake assay and semi quantitative reverse transcription polymerase chain reaction (RT-PCR). The killing effect of {sup 131}I vitro clonogenic assay. In addition, tumor bearing mice were intravenously injected with the adenovirus, and scintigraphic images were obtained. The expression of hNIS was efficiently demonstrated by {sup 125}I uptake assay in AFP producing cells, but not in AFP nonproducing cells. AFP producing HCC targeted gene expression was confirmed at the mRNA level. Furthermore, in vitro clonogenic assay showed that hNIS gene expression induced by AdAFPhNIS infection in AFP producing cells caused more sensitivity to {sup 131}I than that in AFP nonproducing cells. Injected intravenously in HuH-7 tumor xenografts mice by adenovirus, the functional hNIS gene expression was confirmed in tumor by in vivo scintigraphic imaging. An AFP producing HCC was targeted with an adenovirus vector containing the hNIS gene using the AFP enhancer/promoter in vitro and in vivo. These findings demonstrate that AFP producing HCC specific molecular imaging and radionuclide gene therapy are feasible using this recombinant adenovirus vector system.

  19. In vitro radionuclide therapy and in vivo scintigraphic imaging of alpha fetoprotein producing hepatocellular carcinoma by targeted sodium iodide symporter gene expression

    International Nuclear Information System (INIS)

    Kim, Kwang Il; Lee, Yong Jin; Lee, Tae Sup; Song, Inho; Cheon, Gi Jeong; Lim, Sang Moo; Kang, Joo Hyun; Chung, June Key

    2012-01-01

    This study aimed to develop a gene expression targeting method for specific imaging and therapy of alpha fetoprotein (AFP) producing hepatocellular carcinoma (HCC) cells, using an adenovirus vector containing the human sodium/iodide symporter (hNIS) gene driven by an AFP enhancer/promoter. The recombinant adenovirus vector, AdAFPhNIS (containing the hNIS gene driven by human AFP enhancer/promoter) was prepared. After in vitro infection by the adenovirus, hNIS gene expression in AFP producing cells and in AFP nonproducing cells was investigated using 125 I uptake assay and semi quantitative reverse transcription polymerase chain reaction (RT-PCR). The killing effect of 131 I vitro clonogenic assay. In addition, tumor bearing mice were intravenously injected with the adenovirus, and scintigraphic images were obtained. The expression of hNIS was efficiently demonstrated by 125 I uptake assay in AFP producing cells, but not in AFP nonproducing cells. AFP producing HCC targeted gene expression was confirmed at the mRNA level. Furthermore, in vitro clonogenic assay showed that hNIS gene expression induced by AdAFPhNIS infection in AFP producing cells caused more sensitivity to 131 I than that in AFP nonproducing cells. Injected intravenously in HuH-7 tumor xenografts mice by adenovirus, the functional hNIS gene expression was confirmed in tumor by in vivo scintigraphic imaging. An AFP producing HCC was targeted with an adenovirus vector containing the hNIS gene using the AFP enhancer/promoter in vitro and in vivo. These findings demonstrate that AFP producing HCC specific molecular imaging and radionuclide gene therapy are feasible using this recombinant adenovirus vector system

  20. Optimizing labelling conditions of 213Bi-DOTATATE for preclinical applications of peptide receptor targeted alpha therapy.

    Science.gov (United States)

    Chan, Ho Sze; de Blois, Erik; Konijnenberg, Mark W; Morgenstern, Alfred; Bruchertseifer, Frank; Norenberg, Jeffrey P; Verzijlbergen, Fred J; de Jong, Marion; Breeman, Wouter A P

    2017-01-01

    213 Bismuth ( 213 Bi, T 1/2 = 45.6 min) is one of the most frequently used α-emitters in cancer research. High specific activity radioligands are required for peptide receptor radionuclide therapy. The use of generators containing less than 222 MBq 225 Ac (actinium), due to limited availability and the high cost to produce large-scale 225 Ac/ 213 Bi generators, might complicate in vitro and in vivo applications though.Here we present optimized labelling conditions of a DOTA-peptide with an 225 Ac/ 213 Bi generator (< 222 MBq) for preclinical applications using DOTA-Tyr 3 -octreotate (DOTATATE), a somatostatin analogue. The following labelling conditions of DOTATATE with 213 Bi were investigated; peptide mass was varied from 1.7 to 7.0 nmol, concentration of TRIS buffer from 0.15 mol.L -1 to 0.34 mol.L -1 , and ascorbic acid from 0 to 71 mmol.L -1 in 800 μL. All reactions were performed at 95 °C for 5 min. After incubation, DTPA (50 nmol) was added to stop the labelling reaction. Besides optimizing the labelling conditions, incorporation yield was determined by ITLC-SG and radiochemical purity (RCP) was monitored by RP-HPLC up to 120 min after labelling. Dosimetry studies in the reaction vial were performed using Monte Carlo and in vitro clonogenic assay was performed with a rat pancreatic tumour cell line, CA20948. At least 3.5 nmol DOTATATE was required to obtain incorporation ≥ 99 % with 100 MBq 213 Bi (at optimized pH conditions, pH 8.3 with 0.15 mol.L -1 TRIS) in a reaction volume of 800 μL. The cumulative absorbed dose in the reaction vial was 230 Gy/100 MBq in 30 min. A minimal final concentration of 0.9 mmol.L -1 ascorbic acid was required for ~100 MBq (t = 0) to minimize radiation damage of DOTATATE. The osmolarity was decreased to 0.45 Osmol/L.Under optimized labelling conditions, 213 Bi-DOTATATE remained stable up to 2 h after labelling, RCP was ≥ 85 %. In vitro showed a negative correlation between ascorbic acid

  1. Targeted enzyme prodrug therapies.

    Science.gov (United States)

    Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

    2010-09-01

    The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

  2. Improved safety and efficacy of 213Bi-DOTATATE-targeted alpha therapy of somatostatin receptor-expressing neuroendocrine tumors in mice pre-treated with L-lysine.

    Science.gov (United States)

    Chan, Ho Sze; Konijnenberg, Mark W; Daniels, Tamara; Nysus, Monique; Makvandi, Mehran; de Blois, Erik; Breeman, Wouter A; Atcher, Robert W; de Jong, Marion; Norenberg, Jeffrey P

    2016-12-01

    Targeted alpha therapy (TAT) offers advantages over current β-emitting conjugates for peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. PRRT with 177 Lu-DOTATATE or 90 Y-DOTATOC has shown dose-limiting nephrotoxicity due to radiopeptide retention in the proximal tubules. Pharmacological protection can reduce renal uptake of radiopeptides, e.g., positively charged amino acids, to saturate in the proximal tubules, thereby enabling higher radioactivity to be safely administered. The aim of this preclinical study was to evaluate the therapeutic effect of 213 Bi-DOTATATE with and without renal protection using L-lysine in mice. Tumor uptake and kinetics as a function of injected mass of peptide (range 0.03-3 nmol) were investigated using 111 In-DOTATATE. These results allowed estimation of the mean radiation absorbed tumor dose for 213 Bi-DOTATATE. Pharmacokinetics and dosimetry of 213 Bi-DOTATATE was determined in mice, in combination with renal protection. A dose escalation study with 213 Bi-DOTATATE was performed to determine the maximum tolerated dose (MTD) with and without pre-administration of L-lysine as for renal protection. Neutrophil gelatinase-associated lipocalin (NGAL) served as renal biomarker to determine kidney injury. The maximum mean radiation absorbed tumor dose occurred at 0.03 nmol and the minimum at 3 nmol. Similar mean radiation absorbed tumor doses were determined for 0.1 and 0.3 nmol with a mean radiation absorbed dose of approximately 0.5 Gy/MBq 213 Bi-DOTATATE. The optimal mass of injected peptide was found to be 0.3 nmol. Tumor uptake was similar for 111 In-DOTATATE and 213 Bi-DOTATATE at 0.3 nmol peptide. Lysine reduced the renal uptake of 213 Bi-DOTATATE by 50% with no effect on the tumor uptake. The MTD was <13.0 ± 1.6 MBq in absence of L-lysine and 21.7 ± 1.9 MBq with L-lysine renal protection, both imparting an LD 50 mean renal radiation absorbed dose of 20 Gy. A correlation was found between the

  3. Targeted Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    David Cheng

    2011-10-01

    Full Text Available Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.

  4. Targeted Radionuclide Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ersahin, Devrim, E-mail: devrimersahin@yahoo.com; Doddamane, Indukala; Cheng, David [Department of Diagnostic Radiology, School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06520 (United States)

    2011-10-11

    Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.

  5. Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Ersahin, Devrim; Doddamane, Indukala; Cheng, David

    2011-01-01

    Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose

  6. Molecular Targets for Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Mather, S.J.

    2009-01-01

    Molecular targeted radionuclide cancer therapy is becoming of increasing importance, especially for disseminated diseases. Systemic chemotherapies often lack selectivity while targeted radionuclide therapy has important advantages as the radioactive cytotoxic unit of the targeting vector is specifically directed to the cancer, sparing normal tissues. The principle strategy to improve cancer selectivity is to couple therapeutic agents to tumour-targeting vectors. In targeted radionuclide therapy (TRT), the cytotoxic portion of the conjugates normally contains a therapeutic radiometal immobilised by a bifunctional chelator. The aim is therefore to use as ligand-targeted therapeutics vectors coupled to Auger-, alpha- and/or beta-emitting radionuclides. An advantage of using radiation instead of chemotherapeutics as the cytotoxic agent is the so called 'crossfire effect'. This allows sterilisation of tumour cells that are not directly targeted due to heterogeneity in target molecule expression or inhomogeneous vector delivery. However, before the targeting ligands can be selected, the target molecule on the tumour has to be selected. It should be uniquely expressed, or at least highly overexpressed, on or in the target cells relative to normal tissues. The target should be easily accessible for ligand delivery and should not be shed or down- regulated after ligand binding. An important property of a receptor (or antigen) is its potential to be internalized upon binding of the ligand. This provides an active uptake mechanism and allows the therapeutic agent to be trapped within the tumour cells. Molecular targets of current interest include: Receptors: G-protein coupled receptors are overexpressed on many major human tumours. The prototype of these receptors are somatostatin receptors which show very high density in neuroendocrine tumours, but there are many other most interesting receptors to be applied for TRT. The targeting ligands for these receptors are

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

    Directory of Open Access Journals (Sweden)

    Helen Heyerdahl

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

  8. Alpha-emitters for medical therapy workshop

    International Nuclear Information System (INIS)

    Feinendegen, L.E.; McClure, J.J.

    1996-01-01

    A workshop on ''Alpha-Emitters for Medical Therapy'' was held May 30-31, 1996 in Denver Colorado to identify research goals and potential clinical needs for applying alpha-particle emitters and to provide DOE with sufficient information for future planning. The workshop was attended by 36 participants representing radiooncology, nuclear medicine, immunotherapy, radiobiology, molecular biology, biochemistry, radiopharmaceutical chemistry, dosimetry, and physics. This report provides a summary of the key points and recommendations arrived at during the conference

  9. Alpha-emitters for medical therapy workshop

    Energy Technology Data Exchange (ETDEWEB)

    Feinendegen, L.E.; McClure, J.J.

    1996-12-31

    A workshop on ``Alpha-Emitters for Medical Therapy`` was held May 30-31, 1996 in Denver Colorado to identify research goals and potential clinical needs for applying alpha-particle emitters and to provide DOE with sufficient information for future planning. The workshop was attended by 36 participants representing radiooncology, nuclear medicine, immunotherapy, radiobiology, molecular biology, biochemistry, radiopharmaceutical chemistry, dosimetry, and physics. This report provides a summary of the key points and recommendations arrived at during the conference.

  10. WE-FG-BRA-10: Radiodosimetry of a Novel Alpha Particle Therapy Targeted to Uveal Melanoma: Absorbed Dose to Organs in Mice

    Energy Technology Data Exchange (ETDEWEB)

    Tichacek, Christopher J.; Tafreshi, Narges K.; Budzevich, Mikalai M.; Ruiz, Epifanio [Small Animal Imaging Core, Tampa, FL (United States); Wadas, Thaddeus J. [Wake Forest School of Medicine, Departments of Radiology and Cancer Biology, Winston-Salem, NC (United States); McLaughlin, Mark L. [Department of Chemistry, Tampa, FL (United States); H. Lee Moffitt Cancer Center & Research Institute (United States); Modulation Therapeutics, Inc., Tampa, FL (United States); Moros, Eduardo G.; Morse, David L.

    2016-06-15

    Purpose: The melanocortin-1 receptor (MC1R) is expressed in 94% of uveal melanomas and is described as an ideal target for this untreatable disease. MC1RL is a high affinity MC1R specific peptidomimetic ligand that can serve as a scaffold for therapeutic conjugates such as alpha particle emitting isotopes. The purpose of this study was to assess normal tissue distribution and risk as a result of using the DOTA chelator conjugated to MC1RL to deliver {sup 225}Ac: MC1RL-DOTA-{sup 225}Ac. Methods: 17 non-tumor bearing BALB/c mice were intravenously injected with the novel MC1RL-DOTA-{sup 225}Ac radiopharmaceutical with an average initial administered activity of 2.5 µCi. After the injection, three groups of animals (6, 6, and 5 per group) were euthanized at 24, 48, and 96 hour time points. A total of 11 organs of interest were harvested at each time point including kidneys and liver. Since the emitted alpha particles from {sup 225}Ac and its daughter products are not easy to detect directly, the isomeric gamma spectra were measured instead in the tissue samples using a modified Atomlab™ Gamma Counter (Biodex Medical Systems, Inc) and converted using factors for gamma ray abundance per alpha decay. Dosimetry was performed using measured radioactivity distribution in organs and the generalized internal dosimetry schema of MIRD pamphlet #21. Results: Our calculations have shown that the maximum absorbed dose was delivered to the liver with a total of 47 cGy per 96 hour period. The average dose per kidney was calculated to be 21 cGy. Heart, brain, lung, spleen, skin doses ranged from 0.01 to 1 cGy over the same time period. All animals gained weight over the 110 day decay period and no organ damage was observed by pathology. Conclusion: Based on our results, the risk of using the MC1RL-DOTA-{sup 225}Ac compound is relatively small in terms of deterministic radiation effects. Funding Support: NIH/NCI P50CA168536-03 Skin SPORE; NIH/NCI Phase I SBIR Contract #HHSN

  11. Manual for target thickness measurement by alpha particle irradiation

    International Nuclear Information System (INIS)

    Dias, J.F.; Martins, M.N.

    1990-04-01

    A system is described for thin-target thickness measurement through the alpha particle energy loss when them traverse the target. It is also described the program used in the analysis of the target thickness. (L.C.) [pt

  12. Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.

    Science.gov (United States)

    Bahia, Malkeet S; Silakari, Om

    2010-05-01

    Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.

  13. Tumor targeted gene therapy

    International Nuclear Information System (INIS)

    Kang, Joo Hyun

    2006-01-01

    Knowledge of molecular mechanisms governing malignant transformation brings new opportunities for therapeutic intervention against cancer using novel approaches. One of them is gene therapy based on the transfer of genetic material to an organism with the aim of correcting a disease. The application of gene therapy to the cancer treatment had led to the development of new experimental approaches such as suicidal gene therapy, inhibition of oncogenes and restoration of tumor-suppressor genes. Suicidal gene therapy is based on the expression in tumor cells of a gene encoding an enzyme that converts a prodrug into a toxic product. Representative suicidal genes are Herpes simplex virus type 1 thymidine kinase (HSV1-tk) and cytosine deaminase (CD). Especially, physicians and scientists of nuclear medicine field take an interest in suicidal gene therapy because they can monitor the location and magnitude, and duration of expression of HSV1-tk and CD by PET scanner

  14. Targeted radionuclide therapy

    African Journals Online (AJOL)

    target for which a speci c treatment/drug is intended (Fig. 1). eranostics .... Using an anti-CD20 antibody as a delivery device to target the follicular ... systems combine diagnostic imaging (Ga-68-DOTATATE PET/CT) .... Intra-articular injected ...

  15. Targeted Cancer Therapies

    Science.gov (United States)

    ... are sometimes referred to as the product of "rational" drug design.) One approach to identify potential targets ... molecules that stimulate new blood vessel growth. Immunotherapies trigger the immune system to destroy cancer cells. Some ...

  16. Targeted therapy for sarcomas

    Directory of Open Access Journals (Sweden)

    Forscher C

    2014-03-01

    Full Text Available Charles Forscher,1 Monica Mita,2 Robert Figlin3 1Sarcoma Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Academic Development Program, Samuel Oschin Comprehensive Cancer Institute, and Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Abstract: Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones described with ever-increasing frequency. One way to look at sarcomas is to divide them into categories on the basis of their genetic make-up. One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing's sarcoma. These specific abnormalities often lead to the presence of fusion proteins, such as EWS-FLI1 in Ewing's sarcoma, which are helpful as diagnostic tools and may become therapeutic targets in the future. Another group of sarcomas is characterized by complex genetic abnormalities as seen in leiomyosarcoma, osteosarcoma, and undifferentiated sarcoma. It is important to keep these distinctions in mind when contemplating the development of targeted agents for sarcomas. Different abnormalities in sarcoma could be divided by tumor subtype or by the molecular or pathway abnormality. However, some existing drugs or drugs in development may interfere with or alter more than one of the presented pathways. Keywords: sarcoma, targeted agents, tyrosine kinase inhibitors, mTor inhibition

  17. Enzyme replacement therapy for alpha-mannosidosis

    DEFF Research Database (Denmark)

    Borgwardt, Line Gutte; Dali, Christine I.; Fogh, J

    2013-01-01

    Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly...

  18. Intravenous alpha-1 antitrypsin augmentation therapy: systematic review

    DEFF Research Database (Denmark)

    Gøtzsche, Peter C; Johansen, Helle Krogh

    2010-01-01

    We reviewed the benefits and harms of augmentation therapy with alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease. We searched for randomised trials comparing augmentation therapy with placebo or no treatment in PubMed and ClinicalTrials (7 January 2010). Two...... (difference 1.14 g/l; 95% confidence interval 0.14 to 2.14; p = 0.03) over the total course of the trials. Augmentation therapy with alpha-1 antitrypsin cannot be recommended in view of the lack of evidence of clinical benefit and the cost of treatment....

  19. Production of alpha emitters for therapy

    International Nuclear Information System (INIS)

    Vucina, J.; Orlic, M.; Lukic, D.

    2006-01-01

    The basis for the introduction of alpha emitters into nuclear medical practice are their radiobiological properties. High LET values and short ranges in biological tissues are advantageous in comparison with nowadays most often used beta emitters, primarily 90 Y and 131 I. Given are the most important criteria for the introduction of a given radionuclide in the routine use. Shown are the procedures for the production of the most important alpha emitters 211 At, 212 Bi and 213 Bi. (author)

  20. Targeted therapies for bone sarcomas

    International Nuclear Information System (INIS)

    Mudry, P.

    2011-01-01

    Therapy success in bone sarcoma is significantly better compared to history cohorts with 60 - 70 % overall survival to date. Unfortunately, there is yet no shift and movement in better survival of patients with relapsed and refractory bone sarcomas during last twenty years. This article reviews targeted therapeutics for bone sarcomas which are under investigation and which could give chance to patients suffering from relapsed and chemo resistant bone sarcomas. Majority of the targeted drugs are given as part of phase 1 or 2 studies. (author)

  1. Adverse cutaneous reactions induced by TNF-alpha antagonist therapy.

    Science.gov (United States)

    Borrás-Blasco, Joaquín; Navarro-Ruiz, Andrés; Borrás, Consuelo; Casterá, Elvira

    2009-11-01

    To review adverse cutaneous drug reactions induced by tumor necrosis factor alpha (TNF-alpha) antagonist therapy. A literature search was performed using PubMed (1996-March 2009), EMBASE, and selected MEDLINE Ovid bibliography searches. All language clinical trial data, case reports, letters, and review articles identified from the data sources were used. Since the introduction of TNF-alpha antagonist, the incidence of adverse cutaneous drug reactions has increased significantly. A wide range of different skin lesions might occur during TNF-alpha antagonist treatment. New onset or exacerbation of psoriasis has been reported in patients treated with TNF-alpha antagonists for a variety of rheumatologic conditions. TNF-alpha antagonist therapy has been associated with a lupus-like syndrome; most of these case reports occurred in patients receiving either etanercept or infliximab. Serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely with the use of TNF-alpha antagonists. As the use of TNF-alpha antagonists continues to increase, the diagnosis and management of cutaneous side effects will become an increasingly important challenge. In patients receiving TNF-alpha antagonist treatment, skin disease should be considered, and clinicians need to be aware of the adverse reactions of these drugs.

  2. Targeted Therapies for Lung Cancer.

    Science.gov (United States)

    Stinchcombe, Thomas E

    Targeted therapies have become standard therapies for patients with non-small cell lung cancer (NSCLC). A phase III trial of carboplatin and paclitaxel with and without bevacizumab in patients with advanced NSCLC with non-squamous histology demonstrated a statistically significant improvement in efficacy. In patients with NSCLC with an activating epidermal growth factor receptor (EGFR) mutation (defined as exon 19 deletion and exon 21 L858R point mutation), phase III trials of EGFR tyrosine kinase inhibitors (TKI) compared to platinum-based chemotherapy have demonstrated superior efficacy in the first-line setting. In patients with NSCLC with anaplastic lymphoma kinase (ALK) rearrangements, phase III trials of crizotinib have demonstrated superior efficacy compared to platinum-pemetrexed in the first-line setting and standard chemotherapy in the second-line setting. A second-generation ALK inhibitor, ceritinib, is available for patients who have progressed after or were intolerant of crizotinib. Crizotinib has also demonstrated activity on patients with ROS1 rearrangements, and BRAF inhibitors (dabrafenib, vemurafenib) have demonstrated activity in patients with NSCLC with BRAF V600E mutation. The oncogenic mutations that are susceptible to targeted therapy are mainly found in non-squamous NSCLC. The development of targeted therapy in patients with squamous NSCLC has been more challenging due to the genomic complexity observed in the squamous histology and the low prevalence of EGFR, ALK, and ROS1 molecular alterations. A phase III trial of cisplatin and gemcitabine with and without necitumumab in patients with advanced NSCLC with squamous histology demonstrated a statistically significant improvement in progression-free and overall survival.

  3. Gene Therapy Targeting HIV Entry

    Directory of Open Access Journals (Sweden)

    Chuka Didigu

    2014-03-01

    Full Text Available Despite the unquestionable success of antiretroviral therapy (ART in the treatment of HIV infection, the cost, need for daily adherence, and HIV-associated morbidities that persist despite ART all underscore the need to develop a cure for HIV. The cure achieved following an allogeneic hematopoietic stem cell transplant (HSCT using HIV-resistant cells, and more recently, the report of short-term but sustained, ART-free control of HIV replication following allogeneic HSCT, using HIV susceptible cells, have served to both reignite interest in HIV cure research, and suggest potential mechanisms for a cure. In this review, we highlight some of the obstacles facing HIV cure research today, and explore the roles of gene therapy targeting HIV entry, and allogeneic stem cell transplantation in the development of strategies to cure HIV infection.

  4. Targeted drugs in radiation therapy

    International Nuclear Information System (INIS)

    Favaudon, V.; Hennequin, C.; Hennequin, C.

    2004-01-01

    New drugs aiming at the development of targeted therapies have been assayed in combination with ionizing radiation over the past few years. The rationale of this concept comes from the fact that the cytotoxic potential of targeted drugs is limited, thus requiring concomitant association with a cytotoxic agent for the eradication of tumor cells. Conversely a low level of cumulative toxicity is expected from targeted drugs. Most targeted drugs act through inhibition of post-translational modifications of proteins, such as dimerization of growth factor receptors, prenylation reactions, or phosphorylation of tyrosine or serine-threonine residues. Many systems involving the proteasome, neo-angiogenesis promoters, TGF-β, cyclooxygenase or the transcription factor NF-κB, are currently under investigation in hopes they will allow a control of cell proliferation, apoptosis, cell cycle progression, tumor angiogenesis and inflammation. A few drugs have demonstrated an antitumor potential in particular phenotypes. In most instances, however, radiation-drug interactions proved to be strictly additive in terms of cell growth inhibition or induced cell death. Strong potentiation of the response to radiotherapy is expected to require interaction with DNA repair mechanisms. (authors)

  5. Auger radiation targeted into DNA: a therapy perspective

    Energy Technology Data Exchange (ETDEWEB)

    Buchegger, Franz [University Hospital of Lausanne CHUV, Service of Nuclear Medicine, Lausanne (Switzerland); University Hospital of Lausanne, Service of Nuclear Medicine, Lausanne (Switzerland); Perillo-Adamer, Florence; Bischof Delaloye, Angelika [University Hospital of Lausanne CHUV, Service of Nuclear Medicine, Lausanne (Switzerland); Dupertuis, Yves M. [University Hospital of Geneva, Service of Nutrition, Geneva (Switzerland)

    2006-11-15

    Auger electron emitters that can be targeted into DNA of tumour cells represent an attractive systemic radiation therapy goal. In the situation of DNA-associated decay, the high linear energy transfer (LET) of Auger electrons gives a high relative biological efficacy similar to that of {alpha} particles. In contrast to {alpha} radiation, however, Auger radiation is of low toxicity when decaying outside the cell nucleus, as in cytoplasm or outside cells during blood transport. The challenge for such therapies is the requirement to target a high percentage of all cancer cells. An overview of Auger radiation therapy approaches of the past decade shows several research directions and various targeting vehicles. The latter include hormones, peptides, halogenated nucleotides, oligonucleotides and internalising antibodies. Here, we will discuss the basic principles of Auger electron therapy as compared with vector-guided {alpha} and {beta} radiation. We also review some radioprotection issues and briefly present the main advantages and disadvantages of the different targeting modalities that are under investigation. (orig.)

  6. Report of a Technical Meeting on ''Alpha emitting radionuclides and radiopharmaceuticals for therapy''

    International Nuclear Information System (INIS)

    2013-01-01

    Considering the high potential of α-emitters for future development of radionuclide therapy, the International Atomic Energy Agency (IAEA) organized a Technical Meeting on ‘Alpha Emitting Radionuclides and Radiopharmaceuticals for Therapy’, from June 24 to 28, 2013, at IAEA Headquarters in Vienna with the purpose of gathering eminent Experts in the field and discuss with them the status and future perspectives of the field. Sixteen Experts and two External Observers from ten different countries, and four IAEA Technical Officers attended this meeting. Outstanding lectures have been presented covering all relevant aspects of α-therapy, which were followed by extensive discussions and analysis. Selected arguments encompassed production methods and availability of alpha-emitting radionuclides, labelling chemistry of alpha-emittting radioelements, design and development of target-specific radiopharmaceuticals, physical principles of alpha-particle dosimetry and advanced dosimetric models, biological effects of alpha radiation at the cellular level, on-going preclinical and clinical studies with new radiopharmaceuticals, results of clinical trials on the use of radium-223 chloride solutions for the treatment of metastatic bone cancer. The broad scientific background of invited components of the Experts’ panel conferred a strong interdisciplinary trait to the overall discussion and stimulated a critical analysis of this emerging unexplored field. Results of this comprehensive overview on alpha therapy, including recommendations to the Agency on suitable initiatives that may help to promote and spread the knowledge to Members States on this emerging therapeutic modality, are summarized in the present Report

  7. Peroxisome Proliferator-Activated Receptor Alpha Target Genes

    Directory of Open Access Journals (Sweden)

    Maryam Rakhshandehroo

    2010-01-01

    Full Text Available The peroxisome proliferator-activated receptor alpha (PPARα is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.

  8. Targeted therapy of multiple myeloma.

    Science.gov (United States)

    Dolloff, Nathan G; Talamo, Giampaolo

    2013-01-01

    Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematologic cancer. MM is characterized by the accumulation of malignant plasma cells within the bone marrow, and presents clinically with a broad range of symptoms, including hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM is a heterogeneous disease associated with genomic instability, where patients may express multiple genetic abnormalities that affect several oncogenic pathways. Commonly detected genetic aberrations are translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)]. Advances in the basic understanding of MM and the development of novel agents, such as the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib, have increased therapeutic response rates and prolonged patient survival. Despite these advances MM remains incurable in the majority of patients, and it is therefore critical to identify additional therapeutic strategies and targets for its treatment. In this chapter, we review the underlying genetic components of MM and discuss the results of recent clinical trials that demonstrate the effectiveness of targeted agents in the management of MM. In addition, we discuss experimental therapies that are currently in clinical development along with their molecular rationale in the treatment of MM.

  9. Anti-TNF-alpha therapy for sight threatening uveitis.

    NARCIS (Netherlands)

    E.W. Lindstedt (Eric); G.S. Baarsma (Seerp); R.W.A.M. Kuijpers (Robert); P.M. van Hagen (Martin)

    2005-01-01

    textabstractAIM: To describe the effect of additional treatment with anti-TNF-alpha therapy in a case series of 13 patients with serious sight threatening uveitis. METHODS: 13 patients with serious sight threatening uveitis were included, of whom six had Behcet's disease, five had idiopathic

  10. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    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

  11. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    International Nuclear Information System (INIS)

    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

  12. Gene therapy and radionuclides targeting therapy in mammary carcinoma

    International Nuclear Information System (INIS)

    Song Jinhua

    2003-01-01

    Breast carcinoma's gene therapy is a hotspot in study of the tumor's therapy in the recent years. Currently the major therapy methods that in the experimentative and primary clinical application phases include immunological gene therapy, multidrug resistance gene therapy, antisense oligonucleotide therapy and suicide gene therapy. The gene targeting brachytherapy, which is combined with gene therapy and radiotherapy has enhanced the killer effects of the suicide gene and nuclide in tumor cells. That has break a new path in tumor's gene therapy. The further study in this field will step up it's space to the clinical application

  13. Targeted Therapy of Ewing's Sarcoma

    Directory of Open Access Journals (Sweden)

    Vivek Subbiah

    2011-01-01

    Full Text Available Refractory and/or recurrent Ewing's sarcoma (EWS remains a clinical challenge because the disease's resistance to therapy makes it difficult to achieve durable results with standard treatments that include chemotherapy, radiation, and surgery. Recently, insulin-like-growth-factor-1-receptor (IGF1R antibodies have been shown to have a modest single-agent activity in EWS. Patient selection using biomarkers and understanding response and resistance mechanisms in relation to IGF1R and mammalian target of rapamycin pathways are areas of active research. Since EWS has a unique tumor-specific EWS-FLI1 t(11;22 translocation and oncogenic fusion protein, inhibition of EWS-FLI1 transcription, translation, and/or protein function may be key to eradicating EWS at the stem-cell level. Recently, a small molecule that blocks the protein-protein interaction of EWS-FLI1 with RNA helicase A has been shown in preclinical models to inhibit EWS growth. The successful application of this first-in-class protein-protein inhibitor in the clinic could become a model system for translocation-associated cancers such as EWS.

  14. Improved targeting of the alpha(v)beta (3) integrin by multimerisation of RGD peptides.

    NARCIS (Netherlands)

    Dijkgraaf, I.; Kruijtzer, J.A.; Liu, S.; Soede, A.C.; Oyen, W.J.G.; Corstens, F.H.M.; Liskamp, R.M.; Boerman, O.C.

    2007-01-01

    PURPOSE: The integrin alpha(v)beta(3) is expressed on sprouting endothelial cells and on various tumour cell types. Due to the restricted expression of alpha(v)beta(3) in tumours, alpha(v)beta(3) is considered a suitable receptor for tumour targeting. In this study the alpha(v)beta(3) binding

  15. A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy.

    Science.gov (United States)

    Dirksen, A; Dijkman, J H; Madsen, F; Stoel, B; Hutchison, D C; Ulrik, C S; Skovgaard, L T; Kok-Jensen, A; Rudolphus, A; Seersholm, N; Vrooman, H A; Reiber, J H; Hansen, N C; Heckscher, T; Viskum, K; Stolk, J

    1999-11-01

    We have investigated whether restoration of the balance between neutrophil elastase and its inhibitor, alpha(1)-antitrypsin, can prevent the progression of pulmonary emphysema in patients with alpha(1)-antitrypsin deficiency. Twenty-six Danish and 30 Dutch ex-smokers with alpha(1)-antitrypsin deficiency of PI*ZZ phenotype and moderate emphysema (FEV(1) between 30% and 80% of predicted) participated in a double-blind trial of alpha(1)-antitrypsin augmentation therapy. The patients were randomized to either alpha(1)-antitrypsin (250 mg/kg) or albumin (625 mg/kg) infusions at 4-wk intervals for at least 3 yr. Self-administered spirometry performed every morning and evening at home showed no significant difference in decline of FEV(1) between treatment and placebo. Each year, the degree of emphysema was quantified by the 15th percentile point of the lung density histogram derived from computed tomography (CT). The loss of lung tissue measured by CT (mean +/- SEM) was 2.6 +/- 0.41 g/L/yr for placebo as compared with 1.5 +/- 0.41 g/L/yr for alpha(1)-antitrypsin infusion (p = 0.07). Power analysis showed that this protective effect would be significant in a similar trial with 130 patients. This is in contrast to calculations based on annual decline of FEV(1) showing that 550 patients would be needed to show a 50% reduction of annual decline. We conclude that lung density measurements by CT may facilitate future randomized clinical trials of investigational drugs for a disease in which little progress in therapy has been made in the past 30 yr.

  16. Cancer therapy with alpha-emitters labeled peptides.

    Science.gov (United States)

    Dadachova, Ekaterina

    2010-05-01

    Actively targeted alpha-particles offer specific tumor cell killing action with less collateral damage to surrounding normal tissues than beta-emitters. During the last decade, radiolabeled peptides that bind to different receptors on the tumors have been investigated as potential therapeutic agents both in the preclinical and clinical settings. Advantages of radiolabeled peptides over antibodies include relatively straightforward chemical synthesis, versatility, easier radiolabeling, rapid clearance from the circulation, faster penetration and more uniform distribution into tissues, and less immunogenicity. Rapid internalization of the radiolabeled peptides with equally rapid re-expression of the cell surface target is a highly desirable property that enhances the total delivery of these radionuclides into malignant sites. Peptides, such as octreotide, alpha-melanocyte-stimulating hormone analogues, arginine-glycine-aspartic acid-containing peptides, bombesin derivatives, and others may all be feasible for use with alpha-emitters. The on-going preclinical work has primarily concentrated on octreotide and octreotate analogues labeled with Bismuth-213 and Astatine-211. In addition, alpha-melanocyte-stimulating hormone analogue has been labeled with Lead-212/Bismuth-212 in vivo generator and demonstrated the encouraging therapeutic efficacy in treatment of experimental melanoma. Obstacles that continue to obstruct widespread acceptance of alpha-emitter-labeled peptides are primarily the supply of these radionuclides and concerns about potential kidney toxicity. New sources and methods for production of these medically valuable radionuclides and better understanding of mechanisms related to the peptide renal uptake and clearance should speed up the introduction of alpha-emitter-labeled peptides into the clinic. Copyright 2010 Elsevier Inc. All rights reserved.

  17. Why Targeted Therapies are Necessary for Systemic Lupus Erythematosus

    Science.gov (United States)

    Durcan, Laura; Petri, Michelle

    2016-01-01

    Systemic lupus erythematosus (SLE) continues to have important morbidity and accelerated mortality despite therapeutic advances. Targeted therapies offer the possibility of improved efficacy with fewer side-effects. Current management strategies rely heavily on non-specific immunosuppressive agents. Prednisone, in particular, is responsible for a considerable burden of later organ damage. There are a multitude of diverse mechanisms of disease activity, immunogenic abnormalities and clinical manifestations to take into consideration in SLE. Many targeted agents with robust mechanistic pre-clinical data and promising early phase studies have ultimately been disappointing in phase III randomized controlled studies. Recent efforts have focused on B cell therapies, in particular given the success of belimumab in clinical trials, with limited success. We remain optimistic regarding other specific therapies being evaluated including interferon alpha blockade. It is likely that in SLE, given the heterogeneity of the population involved, precision medicine is needed, rather than expecting that any single biologic will be universally effective. PMID:27497251

  18. Calculated /alpha/-induced thick target neutron yields and spectra, with comparison to measured data

    International Nuclear Information System (INIS)

    Wilson, W.B.; Bozoian, M.; Perry, R.T.

    1988-01-01

    One component of the neutron source associated with the decay of actinide nuclides in many environments is due to the interaction of decay /alpha/ particles in (/alpha/,n) reactions on low Z nuclides. Measurements of (/alpha/,n) thick target neutron yields and associated neutron spectra have been made for only a few combinations of /alpha/ energy and target nuclide or mixtures of actinide and target nuclides. Calculations of thick target neutron yields and spectra with the SOURCES code require /alpha/-energy-dependent cross sections for (/alpha/,n) reactions, as well as branching fractions leading to the energetically possible levels of the product nuclides. A library of these data has been accumulated for target nuclides of Z /le/ 15 using that available from measurements and from recent GNASH code calculations. SOURCES, assuming neutrons to be emitted isotopically in the center-of-mass system, uses libraries of /alpha/ stopping cross sections, (/alpha/,n) reaction cross reactions, product nuclide level branching fractions, and actinide decay /alpha/ spectra to calculate thick target (/alpha/,n) yields and neutron spectra for homogeneous combinations of nuclides. The code also calculates the thick target yield and angle intergrated neutron spectrum produced by /alpha/-particle beams on targets of homogeneous mixtures of nuclides. Illustrative calculated results are given and comparisons are made with measured thick target yields and spectra. 50 refs., 1 fig., 2 tabs

  19. Mapping of HNF4alpha target genes in intestinal epithelial cells

    DEFF Research Database (Denmark)

    Boyd, Mette; Bressendorff, Simon; Moller, Jette

    2009-01-01

    ABSTRACT: BACKGROUND: The role of HNF4alpha has been extensively studied in hepatocytes and pancreatic beta-cells, and HNF4alpha is also regarded as key regulator of intestinal epithelial cell differentiation as well. The aim of the present work is to identify novel HNF4alpha target genes....... The HNF4alpha ChIP-chip data was matched with gene expression and histone H3 acetylation status of the promoters in order to identify HNF4alpha binding to actively transcribed genes with an open chromatin structure. RESULTS: 1,541 genes were identified as potential HNF4alpha targets, many of which have...

  20. Interaction of C-terminal truncated human alphaA-crystallins with target proteins.

    Directory of Open Access Journals (Sweden)

    Anbarasu Kumarasamy

    2008-09-01

    Full Text Available Significant portion of alphaA-crystallin in human lenses exists as C-terminal residues cleaved at residues 172, 168, and 162. Chaperone activity, determined with alcohol dehydrogenase (ADH and betaL-crystallin as target proteins, was increased in alphaA(1-172 and decreased in alphaA(1-168 and alphaA(1-162. The purpose of this study was to show whether the absence of the C-terminal residues influences protein-protein interactions with target proteins.Our hypothesis is that the chaperone-target protein binding kinetics, otherwise termed subunit exchange rates, are expected to reflect the changes in chaperone activity. To study this, we have relied on fluorescence resonance energy transfer (FRET utilizing amine specific and cysteine specific fluorescent probes. The subunit exchange rate (k for ADH and alphaA(1-172 was nearly the same as that of ADH and alphaA-wt, alphaA(1-168 had lower and alphaA(1-162 had the lowest k values. When betaL-crystallin was used as the target protein, alphaA(1-172 had slightly higher k value than alphaA-wt and alphaA(1-168 and alphaA(1-162 had lower k values. As expected from earlier studies, the chaperone activity of alphaA(1-172 was slightly better than that of alphaA-wt, the chaperone activity of alphaA(1-168 was similar to that of alphaA-wt and alphaA(1-162 had substantially decreased chaperone activity.Cleavage of eleven C-terminal residues including Arg-163 and the C-terminal flexible arm significantly affects the interaction with target proteins. The predominantly hydrophilic flexible arm appears to be needed to keep the chaperone-target protein complex soluble.

  1. Targeted deficiency of the transcriptional activator Hnf1alpha alters subnuclear positioning of its genomic targets.

    Directory of Open Access Journals (Sweden)

    Reini F Luco

    2008-05-01

    Full Text Available DNA binding transcriptional activators play a central role in gene-selective regulation. In part, this is mediated by targeting local covalent modifications of histone tails. Transcriptional regulation has also been associated with the positioning of genes within the nucleus. We have now examined the role of a transcriptional activator in regulating the positioning of target genes. This was carried out with primary beta-cells and hepatocytes freshly isolated from mice lacking Hnf1alpha, an activator encoded by the most frequently mutated gene in human monogenic diabetes (MODY3. We show that in Hnf1a-/- cells inactive endogenous Hnf1alpha-target genes exhibit increased trimethylated histone H3-Lys27 and reduced methylated H3-Lys4. Inactive Hnf1alpha-targets in Hnf1a-/- cells are also preferentially located in peripheral subnuclear domains enriched in trimethylated H3-Lys27, whereas active targets in wild-type cells are positioned in more central domains enriched in methylated H3-Lys4 and RNA polymerase II. We demonstrate that this differential positioning involves the decondensation of target chromatin, and show that it is spatially restricted rather than a reflection of non-specific changes in the nuclear organization of Hnf1a-deficient cells. This study, therefore, provides genetic evidence that a single transcriptional activator can influence the subnuclear location of its endogenous genomic targets in primary cells, and links activator-dependent changes in local chromatin structure to the spatial organization of the genome. We have also revealed a defect in subnuclear gene positioning in a model of a human transcription factor disease.

  2. Novel Targeted Therapies for Inflammatory Breast Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0461 TITLE: Novel Targeted Therapies for Inflammatory Breast Cancer PRINCIPAL INVESTIGATOR: Jose Silva CONTRACTING...CONTRACT NUMBER Novel Targeted Therapies for Inflammatory Breast Cancer 5b. GRANT NUMBER W81XWH-16-1-0461 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) l 5d...NOTES 14. ABSTRACT Inflammatory breast cancer (IBC, ~5% of all breast cancers ) is the most lethal form of breast cancer , presenting a 5- year

  3. [Anti-TNF-alpha therapy in ulcerative colitis].

    Science.gov (United States)

    Lakatos, Péter László; Lakatos, László

    2008-05-18

    The most important factors that determine treatment strategy in ulcerative colitis (UC) are disease extent and severity. Orally-topically administered 5-aminosalicylates (5-ASA) remain the treatment of choice in mild-to-moderate UC. In contrast, the treatment of refractory (to steroids, azathioprine or 5-ASA) and fulminant cases is still demanding. New evidence supports a role for infliximab induction and/or maintenance therapy in these subgroup of patients leading to increased remission and decreased colectomy rates. The aim of this paper is to review the rationale for the use of TNF-alpha inhibitors in the treatment of UC.

  4. Chemotherapy and molecular target therapy combined with radiation therapy

    International Nuclear Information System (INIS)

    Akimoto, Tetsuo

    2012-01-01

    Combined chemotherapy and radiation therapy has been established as standard treatment approach for locally advanced head and neck cancer, esophageal cancer and so on through randomized clinical trials. However, radiation-related morbidity such as acute toxicity also increased as treatment intensity has increased. In underlining mechanism for enhancement of normal tissue reaction in chemo-radiation therapy, chemotherapy enhanced radiosensitivity of normal tissues in addition to cancer cells. Molecular target-based drugs combined with radiation therapy have been expected as promising approach that makes it possible to achieve cancer-specific enhancement of radiosensitivity, and clinical trials using combined modalities have been performed to evaluate the feasibility and efficacy of this approach. In order to obtain maximum radiotherapeutic gain, a detailed understanding of the mechanism underlying the interaction between radiation and Molecular target-based drugs is indispensable. Among molecular target-based drugs, inhibitors targeting epidermal growth factor receptor (EGFR) and its signal transduction pathways have been vigorously investigated, and mechanisms regarding the radiosensitizing effect have been getting clear. In addition, the results of randomized clinical trials demonstrated that radiation therapy combined with cetuximab resulted in improvement of overall and disease-specific survival rate compared with radiation therapy in locally advanced head and neck cancer. In this review, clinical usefulness of chemo-radiation therapy and potential molecular targets for potentiation of radiation-induced cell killing are summarized. (author)

  5. Low dose radiation and ALARA: the potential risks to patients and staff from alpha-therapy

    International Nuclear Information System (INIS)

    Priest, N.D.

    2014-01-01

    This year a new drug containing radium-223, an alpha-emitting radionuclide, was approved for use by the US Food and Drug Administration for the palliative treatment of advanced prostate cancer metastases. Other drugs containing short-lived alpha-emitters are on clinical trial in Europe. Commonly, these employ a radionuclide attached to an antibody that specifically targets tumor cells to produce a highly localized radio-therapeutic dose to the tumor. However, normal tissues within the body will also be irradiated, albeit sometimes at low dose, and the question arises as to whether this presents a significant additional risk to the patient. Similarly, medical staff that handle these radionuclides could receive intakes of the radionuclides. What is the risk to staff? To assess the risk resulting from small tissue alpha-doses the toxicological, both human and animal, database was re-examined. The results of 20 epidemiological and toxicological studies with alpha-emitting radionuclides were analysed. In all cases a polynomial function provided a better fit to the data than a linear, no thresholds function. Also, in 19 cases a threshold dose below which no cancer is seen was indicated. The position of this threshold varied according to cancer type, but was typically in the range 0.1 to 1.0Gy of tissue dose - with a mean of 0.5Gy. It is concluded that alpha-radiation induced tumorogenesis is a threshold response and that as long as tissue doses are kept below these thresholds no additional cancers would be seen in either patients receiving alpha-therapy or in staff exposed to 'spilt' radionuclide. The presence of thresholds questions the appropriateness of current ALARA practices that are mostly used to drive occupational alpha-radiation exposures to as close to zero as possible. (author)

  6. Low dose radiation and ALARA: the potential risks to patients and staff from alpha-therapy

    Energy Technology Data Exchange (ETDEWEB)

    Priest, N.D. [Atomic Energy of Canada Limited, Chalk River, ON (Canada)

    2014-07-01

    This year a new drug containing radium-223, an alpha-emitting radionuclide, was approved for use by the US Food and Drug Administration for the palliative treatment of advanced prostate cancer metastases. Other drugs containing short-lived alpha-emitters are on clinical trial in Europe. Commonly, these employ a radionuclide attached to an antibody that specifically targets tumor cells to produce a highly localized radio-therapeutic dose to the tumor. However, normal tissues within the body will also be irradiated, albeit sometimes at low dose, and the question arises as to whether this presents a significant additional risk to the patient. Similarly, medical staff that handle these radionuclides could receive intakes of the radionuclides. What is the risk to staff? To assess the risk resulting from small tissue alpha-doses the toxicological, both human and animal, database was re-examined. The results of 20 epidemiological and toxicological studies with alpha-emitting radionuclides were analysed. In all cases a polynomial function provided a better fit to the data than a linear, no thresholds function. Also, in 19 cases a threshold dose below which no cancer is seen was indicated. The position of this threshold varied according to cancer type, but was typically in the range 0.1 to 1.0Gy of tissue dose - with a mean of 0.5Gy. It is concluded that alpha-radiation induced tumorogenesis is a threshold response and that as long as tissue doses are kept below these thresholds no additional cancers would be seen in either patients receiving alpha-therapy or in staff exposed to 'spilt' radionuclide. The presence of thresholds questions the appropriateness of current ALARA practices that are mostly used to drive occupational alpha-radiation exposures to as close to zero as possible. (author)

  7. Identification of potential target genes of ROR-alpha in THP1 and HUVEC cell lines

    Energy Technology Data Exchange (ETDEWEB)

    Gulec, Cagri, E-mail: cagri.gulec@gmail.com; Coban, Neslihan, E-mail: neslic@istanbul.edu.tr; Ozsait-Selcuk, Bilge, E-mail: ozsaitb@istanbul.edu.tr; Sirma-Ekmekci, Sema, E-mail: semasirma@gmail.com; Yildirim, Ozlem, E-mail: ozlm-yildirim@hotmail.com; Erginel-Unaltuna, Nihan, E-mail: nihanerginel@yahoo.com

    2017-04-01

    ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. Due to its possible involvement in, and potential therapeutic target for atherosclerosis, we aimed to identify ROR-alpha target genes in monocytic and endothelial cell lines. We performed chromatin immunoprecipitation (ChIP) followed by tiling array (ChIP-on-chip) for ROR-alpha in monocytic cell line THP1 and endothelial cell line HUVEC. Following bioinformatic analysis of the array data, we tested four candidate genes in terms of dependence of their expression level on ligand-mediated ROR-alpha activity, and two of them in terms of promoter occupancy by ROR-alpha. Bioinformatic analyses of ChIP-on-chip data suggested that ROR-alpha binds to genomic regions near the transcription start site (TSS) of more than 3000 genes in THP1 and HUVEC. Potential ROR-alpha target genes in both cell types seem to be involved mainly in membrane receptor activity, signal transduction and ion transport. While SPP1 and IKBKA were shown to be direct target genes of ROR-alpha in THP1 monocytes, inflammation related gene HMOX1 and heat shock protein gene HSPA8 were shown to be potential target genes of ROR-alpha. Our results suggest that ROR-alpha may regulate signaling receptor activity, and transmembrane transport activity through its potential target genes. ROR-alpha seems also to play role in cellular sensitivity to environmental substances like arsenite and chloroprene. Although, the expression analyses have shown that synthetic ROR-alpha ligands can modulate some of potential ROR-alpha target genes, functional significance of ligand-dependent modulation of gene expression needs to be confirmed with further analyses.

  8. Targeting Mitochondrial Dysfunction with L-Alpha Glycerylphosphorylcholine.

    Directory of Open Access Journals (Sweden)

    Gerda Strifler

    Full Text Available We hypothesized that L-alpha-glycerylphosphorylcholine (GPC, a deacylatedphosphatidylcholine derivative, can influence the mitochondrial respiratory activity and in this way, may exert tissue protective effects.Rat liver mitochondria were examined with high-resolution respirometry to analyze the effects of GPC on the electron transport chain in normoxic and anoxic conditions. Besides, Sprague-Dawley rats were subjected to sham operation or standardized liver ischemia-reperfusion (IR, with or without GPC administration. The reduced glutathione (GSH and oxidized glutathione disulfide (GSSG, the tissue myeloperoxidase, xanthine oxidoreductase and NADPH oxidases activities were measured. Tissue malondialdehyde and nitrite/nitrate formation, together with blood superoxide and hydrogen-peroxide production were assessed.GPC increased the efficacy of complex I-linked mitochondrial oxygen consumption, with significantly lower in vitro leak respiration. Mechanistically, liver IR injury was accompanied by deteriorated mitochondrial respiration and enhanced ROS production and, as a consequence, by significantly increased inflammatory enzyme activities. GPC administration decreased the inflammatory activation in line with the reduced oxidative and nitrosative stress markers.GPC, by preserving the mitochondrial complex I function respiration, reduced the biochemical signs of oxidative stress after an IR episode. This suggests that GPC is a mitochondria-targeted compound that indirectly suppresses the activity of major intracellular superoxide-generating enzymes.

  9. Alpha particle emitters in cancer therapy: establishing the rationale and overcoming the difficulties

    International Nuclear Information System (INIS)

    Sgouros, G.

    1996-01-01

    Full text: Once a tumor has metastasized, the possibility of cure is significantly diminished, if not excluded. Since metastatic spread arises due to the release of single tumor cells or tumor cell clusters, treatment regimens following an overt metastasis must include agents that eradicate individual tumor cells and cell clusters or that prevent their dissemination. Alpha particles may be highly effective in eradicating rapidly accessible disease. The effectiveness of alpha particles arises because the amount of energy deposited per unit distance traveled (linear energy transfer or LET) is approximately 400 times greater than that of beta particles (80 keV/μm vs. 0.2 keV/μm). Each traversal of an alpha particle through a cell nucleus results in a very highly ionizing track. Cell survival studies have shown that alpha-particle killing is independent of oxygenation state or cell-cycle during irradiation and that as few as 1 to 6 tracks across the nucleus may result in cell death. Most studies with alpha-particle emitting radionuclides for therapy have examined either bismuth-212 or astatine-211. Both radionuclides are short-lived with 61 minute and 7.2 hour half-lives, respectively, yielding intermediates with 3-minute and 32 year half-lives, respectively. Both emit alpha particles whose range is 40 to 80 μm. Alpha-particle emitting radionuclides have been attached to antibodies against tumor cell associated antigen. Antibodies have been the most widely used vehicle for delivery of alpha particles due to their specificity. Bismuth-212 has demonstrated a significant curative potential with minimal toxicity. In an ascites tumor mouse model, specific targeting and 80% cure following injection of Bi-212-labeled antibody has been observed (Macklis RM et al, Science, 240:1024-1026, 1988). It is important to define the realm of applicability for alpha particle emitting radionuclides. The short half-life of most currently available radionuclides, limits their use to

  10. Targeted Therapies in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Jurjees Hasan

    2010-02-01

    Full Text Available Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.

  11. Targeted Therapies in Epithelial Ovarian Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Dean, Emma; El-Helw, Loaie; Hasan, Jurjees, E-mail: jurjees.hasan@christie.nhs.uk [Christie Hospital NHS Foundation Trust / Wilmslow Road, Manchester, M20 4BX (United Kingdom)

    2010-02-23

    Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.

  12. Metastasis Targeted Therapies in Renal Cell Cancer

    OpenAIRE

    K. Fehmi Narter; Bora Özveren

    2018-01-01

    Metastatic renal cell cancer is a malignant disease and its treatment has been not been described clearly yet. These patients are generally symptomatic and resistant to current treatment modalities. Radiotherapy, chemotherapy, and hormonal therapy are not curative in many of these patients. A multimodal approach consisting of cytoreductive nephrectomy, systemic therapy (immunotherapy or targeted molecules), and metastasectomy has been shown to be hopeful in prolonging the survival and improvi...

  13. Targeted Radiation Therapy for Cancer Initiative

    Science.gov (United States)

    2017-11-01

    AWARD NUMBER: W81XWH-08-2-0174 TITLE: Targeted Radiation Therapy for Cancer Initiative PRINCIPAL INVESTIGATOR: Dusten Macdonald, MD...for Cancer Initiative 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Dusten Macdonald, MD 5d. PROJECT NUMBER...Cancer Initiative Final Report INTRODUCTION: The full potential of radiation therapy has not been realized due to the inability to locate and

  14. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Fulda, Simone, E-mail: simone.fulda@kgu.de [Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt (Germany)

    2011-08-29

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  15. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    International Nuclear Information System (INIS)

    Fulda, Simone

    2011-01-01

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  16. Target marketing strategies for occupational therapy entrepreneurs.

    Science.gov (United States)

    Kautzmann, L N; Kautzmann, F N; Navarro, F H

    1989-01-01

    Understanding marketing techniques is one of the skills needed by successful entre renews. Target marketing is an effective method for occupational therapy entrepreneurs to use in determining when and where to enter the marketplace. The two components of target marketing, market segmentation and the development of marketing mix strategies for each identified market segment, are described. The Profife of Attitudes Toward Health Care (PATH) method of psychographic market segmentation of health care consumers is presented. Occupational therapy marketing mix strategies for each PATH consumer group are delineated and compatible groupings of market segments are suggested.

  17. Targeting Herpetic Keratitis by Gene Therapy

    Directory of Open Access Journals (Sweden)

    Hossein Mostafa Elbadawy

    2012-01-01

    Full Text Available Ocular gene therapy is rapidly becoming a reality. By November 2012, approximately 28 clinical trials were approved to assess novel gene therapy agents. Viral infections such as herpetic keratitis caused by herpes simplex virus 1 (HSV-1 can cause serious complications that may lead to blindness. Recurrence of the disease is likely and cornea transplantation, therefore, might not be the ideal therapeutic solution. This paper will focus on the current situation of ocular gene therapy research against herpetic keratitis, including the use of viral and nonviral vectors, routes of delivery of therapeutic genes, new techniques, and key research strategies. Whereas the correction of inherited diseases was the initial goal of the field of gene therapy, here we discuss transgene expression, gene replacement, silencing, or clipping. Gene therapy of herpetic keratitis previously reported in the literature is screened emphasizing candidate gene therapy targets. Commonly adopted strategies are discussed to assess the relative advantages of the protective therapy using antiviral drugs and the common gene therapy against long-term HSV-1 ocular infections signs, inflammation and neovascularization. Successful gene therapy can provide innovative physiological and pharmaceutical solutions against herpetic keratitis.

  18. Monte Carlo calculation of the maximum therapeutic gain of tumor antivascular alpha therapy

    Energy Technology Data Exchange (ETDEWEB)

    Huang, Chen-Yu; Oborn, Bradley M.; Guatelli, Susanna; Allen, Barry J. [Centre for Experimental Radiation Oncology, St. George Clinical School, University of New South Wales, Kogarah, New South Wales 2217 (Australia); Illawarra Cancer Care Centre, Wollongong, New South Wales 2522, Australia and Centre for Medical Radiation Physics, University of Wollongong, New South Wales 2522 (Australia); Centre for Medical Radiation Physics, University of Wollongong, New South Wales 2522 (Australia); Centre for Experimental Radiation Oncology, St. George Clinical School, University of New South Wales, Kogarah, New South Wales 2217 (Australia)

    2012-03-15

    Purpose: Metastatic melanoma lesions experienced marked regression after systemic targeted alpha therapy in a phase 1 clinical trial. This unexpected response was ascribed to tumor antivascular alpha therapy (TAVAT), in which effective tumor regression is achieved by killing endothelial cells (ECs) in tumor capillaries and, thus, depriving cancer cells of nutrition and oxygen. The purpose of this paper is to quantitatively analyze the therapeutic efficacy and safety of TAVAT by building up the testing Monte Carlo microdosimetric models. Methods: Geant4 was adapted to simulate the spatial nonuniform distribution of the alpha emitter {sup 213}Bi. The intraluminal model was designed to simulate the background dose to normal tissue capillary ECs from the nontargeted activity in the blood. The perivascular model calculates the EC dose from the activity bound to the perivascular cancer cells. The key parameters are the probability of an alpha particle traversing an EC nucleus, the energy deposition, the lineal energy transfer, and the specific energy. These results were then applied to interpret the clinical trial. Cell survival rate and therapeutic gain were determined. Results: The specific energy for an alpha particle hitting an EC nucleus in the intraluminal and perivascular models is 0.35 and 0.37 Gy, respectively. As the average probability of traversal in these models is 2.7% and 1.1%, the mean specific energy per decay drops to 1.0 cGy and 0.4 cGy, which demonstrates that the source distribution has a significant impact on the dose. Using the melanoma clinical trial activity of 25 mCi, the dose to tumor EC nucleus is found to be 3.2 Gy and to a normal capillary EC nucleus to be 1.8 cGy. These data give a maximum therapeutic gain of about 180 and validate the TAVAT concept. Conclusions: TAVAT can deliver a cytotoxic dose to tumor capillaries without being toxic to normal tissue capillaries.

  19. Designer interface peptide grafts target estrogen receptor alpha dimerization

    International Nuclear Information System (INIS)

    Chakraborty, S.; Asare, B.K.; Biswas, P.K.; Rajnarayanan, R.V.

    2016-01-01

    The nuclear transcription factor estrogen receptor alpha (ERα), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERα is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERα dimerization is therefore a complementary and alternative strategy to combat anti-estrogen resistance. Dimer interface peptide “I-box” derived from ER residues 503–518 specifically blocks ER dimerization. Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERα LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERα residues 479–485), LQQQHQRLAQ (residues 497–506), and LSHIRHMSNK (residues 511–520) and reported the suitability of using LQQQHQRLAQ (ER 497–506) as a template to design inhibitors of ERα dimerization. Stability and self-aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERα mediated activity in silico and in vitro. The Grafted peptides blocked ERα mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. - Highlights: • Designer peptide grafts retain core molecular recognition motif during MD simulations. • Designer peptide grafts with Poly-ALA helix form stable

  20. Designer interface peptide grafts target estrogen receptor alpha dimerization

    Energy Technology Data Exchange (ETDEWEB)

    Chakraborty, S. [Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174 (United States); Asare, B.K. [Department of Pharmacology and Toxicology, University of Buffalo, Buffalo, NY 14214 (United States); Biswas, P.K., E-mail: pbiswas@tougaloo.edu [Laboratory of Computational Biophysics & Bioengineering, Department of Physics, Tougaloo College, Tougaloo, MS 39174 (United States); Rajnarayanan, R.V., E-mail: rajendra@buffalo.edu [Department of Pharmacology and Toxicology, University of Buffalo, Buffalo, NY 14214 (United States)

    2016-09-09

    The nuclear transcription factor estrogen receptor alpha (ERα), triggered by its cognate ligand estrogen, regulates a variety of cellular signaling events. ERα is expressed in 70% of breast cancers and is a widely validated target for anti-breast cancer drug discovery. Administration of anti-estrogen to block estrogen receptor activation is still a viable anti-breast cancer treatment option but anti-estrogen resistance has been a significant bottle-neck. Dimerization of estrogen receptor is required for ER activation. Blocking ERα dimerization is therefore a complementary and alternative strategy to combat anti-estrogen resistance. Dimer interface peptide “I-box” derived from ER residues 503–518 specifically blocks ER dimerization. Recently using a comprehensive molecular simulation we studied the interaction dynamics of ERα LBDs in a homo-dimer. Based on this study, we identified three interface recognition peptide motifs LDKITDT (ERα residues 479–485), LQQQHQRLAQ (residues 497–506), and LSHIRHMSNK (residues 511–520) and reported the suitability of using LQQQHQRLAQ (ER 497–506) as a template to design inhibitors of ERα dimerization. Stability and self-aggregation of peptide based therapeutics poses a significant bottle-neck to proceed further. In this study utilizing peptide grafted to preserve their pharmacophoric recognition motif and assessed their stability and potential to block ERα mediated activity in silico and in vitro. The Grafted peptides blocked ERα mediated cell proliferation and viability of breast cancer cells but did not alter their apoptotic fate. We believe the structural clues identified in this study can be used to identify novel peptidometics and small molecules that specifically target ER dimer interface generating a new breed of anti-cancer agents. - Highlights: • Designer peptide grafts retain core molecular recognition motif during MD simulations. • Designer peptide grafts with Poly-ALA helix form stable

  1. Research progess on treatment of cancer with targeted radionuclide therapy

    International Nuclear Information System (INIS)

    Luo Jiawen; Zhang Caixia

    2008-01-01

    The new development and situation of targeted radionuclide therapy in oncology is described, which include radioimmunotherapy, peptide receptor radionuclide therapy, gene therapy and radionuclide labled chemotherapeutics therapy. The application research on labled carrier of those therapy is emphasized. Meanwhile, the research progess of indomethacin and its combined with targeted radionuclide therapy is also described. (authors)

  2. Immuno-vectorization of radioelements emitters of alpha particles: a new therapy in cancerology

    International Nuclear Information System (INIS)

    Bourgeois, M.

    2007-05-01

    The radio-immunotherapy is an anti cancerous therapy which consists in vectorising with immuno-specific agents very radio toxic radioelements on tumors or in their environment to destroy them. The first part of this report presents the different characteristics of antibodies as well as their means of production under monoclonal shapes specifically steered against a tumoral antigen of interest. The second part of this report replaces the importance of the immunological vectors in the context of the nuclear medicine. It is notably described that the different methods which allow to radio-label the vector, as well as the different ways of optimization which were envisaged to improve the targeting of radioelements on a tumor. These different developments allow to define the potential place of the alpha radio-immunotherapy in treatments and so re-place the interest of the experimental part. If the radio-immunotherapy, using beta emitters isotopes as the 131 iodine or the 90 yttrium, is today current in anti cancerous therapy, it finds limits because of the disintegration characteristics of the isotopes it uses. Indeed, compared with alpha particles, the beta particles deposit less energy by unit of length in the crossed material.The experimental part of this report aims at studying the feasibility of the coupling between an immunological vector and an alpha emitter isotope.The different tests led on the bismuth 213, the bismuth 212, the lead 212 and the astatine 211 demonstrated that the fixation of these radionuclides was possible. This research theme is strengthened by the construction in Nantes of a cyclotron with high energy ( A.R.R.O.N.A.X.) and the optimization of the obtained promising results should allow a therapeutic use in oncology of the alpha radio-immunotherapy. (N.C.)

  3. Targeted therapy using nanotechnology: focus on cancer.

    Science.gov (United States)

    Sanna, Vanna; Pala, Nicolino; Sechi, Mario

    2014-01-01

    Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication.

  4. Cardiotoxicity of novel HER2-targeted therapies.

    Science.gov (United States)

    Sendur, Mehmet A N; Aksoy, Sercan; Altundag, Kadri

    2013-08-01

    Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab. Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; 'trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib'; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib molecules are evaluated in the study. In a comprehensive analysis, 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was observed only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was observed with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T

  5. Introduction to radiobiology of targeted radionuclide therapy

    Directory of Open Access Journals (Sweden)

    Jean-Pierre ePOUGET

    2015-03-01

    Full Text Available During the last decades, new radionuclide-based targeted therapies have emerged as efficient tools for cancer treatment. Targeted radionuclide therapies (TRT are based on a multidisciplinary approach that involves the cooperation of specialists in several research fields. Among them, radiobiologists investigate the biological effects of ionizing radiation, specifically the molecular and cellular mechanisms involved in the radiation response. Most of the knowledge about radiation effects concerns external beam radiation therapy (EBRT and radiobiology has then strongly contributed to the development of this therapeutic approach. Similarly, radiobiology and dosimetry are also assumed to be ways for improving TRT, in particular in the therapy of solid tumors which are radioresistant. However, extrapolation of EBRT radiobiology to TRT is not straightforward. Indeed, the specific physical characteristics of TRT (heterogeneous and mixed irradiation, protracted exposure and low absorbed dose rate differ from those of conventional EBRT (homogeneous irradiation, short exposure and high absorbed dose rate, and consequently the response of irradiated tissues might be different. Therefore, specific TRT radiobiology needs to be explored. Determining dose-effect correlation is also a prerequisite for rigorous preclinical radiobiology studies because dosimetry provides the necessary referential to all TRT situations. It is required too for developing patient-tailored TRT in the clinic in order to estimate the best dose for tumor control, while protecting the healthy tissues, thereby improving therapeutic efficacy. Finally, it will allow to determine the relative contribution of targeted effects (assumed to be dose-related and non-targeted effects (assumed to be non-dose-related of ionizing radiation. However, conversely to EBRT where it is routinely used, dosimetry is still challenging in TRT. Therefore, it constitutes with radiobiology, one of the main

  6. Targeted Therapy in Nonmelanoma Skin Cancers

    Directory of Open Access Journals (Sweden)

    Giulia Spallone

    2011-05-01

    Full Text Available Nonmelanoma skin cancer (NMSC is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC, representing around 75% of NMSC and Squamous Cell Carcinomas (SCC. The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC.

  7. Targeted Therapy in Nonmelanoma Skin Cancers

    International Nuclear Information System (INIS)

    Spallone, Giulia; Botti, Elisabetta; Costanzo, Antonio

    2011-01-01

    Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC

  8. [Resistance to target-based therapy and its circumvention].

    Science.gov (United States)

    Nishio, Kazuto

    2004-07-01

    Intrinsic and acquired resistance to molecular target therapy critically limits the outcome of cancer treatments. Target levels including quantitative and gene alteration should be determinants for the resistance. Downstream of the target molecules, drug metabolism, and drug transport influences the tumor sensitivity to molecular target therapy. The mechanisms of resistance to antibody therapy have not been fully clarified. Correlative clinical studies using these biomarkers of resistance are extremely important for circumvention of clinical resistance to target based therapy.

  9. Radiation therapy following targeted therapy in oligometastatic renal cell carcinoma.

    Science.gov (United States)

    Gravis, Gwenaelle; Faure, Marjorie; Rybikowski, Stanislas; Dermeche, Slimane; Tyran, Marguerite; Calderon, Benoit; Thomassin, Jeanne; Walz, Jochen; Salem, Naji

    2015-11-01

    Up to 40% of patients with renal cell carcinoma (RCC) with initially localized disease eventually develop metastasis following nephrectomy. The current standard of care for metastatic RCC (mRCC) is targeted therapy. However, complete response remains rare. A state of oligometastatic disease may exist, in which metastases are present in a limited number of locations; such cases may benefit from metastasis-directed local therapy, based on the evidence supporting resection of limited-volume metastases, allowing for improved disease control. We retrospectively analyzed 7 cases of response of RCC metastases, in patients treated with targeted therapies followed by radiation therapy (RT) of residual metastatic lesions in Paoli-Calmettes Institute (Marseille, France). We analyzed disease response rates, response to sequential strategy, relapse at the irradiated locations and disease evolution. The median follow-up was 34.1 months (range, 19.2-54.5 months). No progression at the irradiated sites was observed. A total of 5 patients had stable disease at the irradiated locations at the last follow-up; 3 remained in complete remission at the assessment, and 2 were stable. Excellent local response and clinical benefit may be achieved without added toxicity. In conclusion, sequential therapeutic strategies with RT following systemic treatment using sunitinib appear to be highly effective in patients with progressive mRCC and prompt the conduction of further confirmatory trials.

  10. Alpha-synuclein suppression by targeted small interfering RNA in the primate substantia nigra.

    Directory of Open Access Journals (Sweden)

    Alison L McCormack

    Full Text Available The protein alpha-synuclein is involved in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. Its toxic potential appears to be enhanced by increased protein expression, providing a compelling rationale for therapeutic strategies aimed at reducing neuronal alpha-synuclein burden. Here, feasibility and safety of alpha-synuclein suppression were evaluated by treating monkeys with small interfering RNA (siRNA directed against alpha-synuclein. The siRNA molecule was chemically modified to prevent degradation by exo- and endonucleases and directly infused into the left substantia nigra. Results compared levels of alpha-synuclein mRNA and protein in the infused (left vs. untreated (right hemisphere and revealed a significant 40-50% suppression of alpha-synuclein expression. These findings could not be attributable to non-specific effects of siRNA infusion since treatment of a separate set of animals with luciferase-targeting siRNA produced no changes in alpha-synuclein. Infusion with alpha-synuclein siRNA, while lowering alpha-synuclein expression, had no overt adverse consequences. In particular, it did not cause tissue inflammation and did not change (i the number and phenotype of nigral dopaminergic neurons, and (ii the concentrations of striatal dopamine and its metabolites. The data represent the first evidence of successful anti-alpha-synuclein intervention in the primate substantia nigra and support further development of RNA interference-based therapeutics.

  11. Identification of the human ApoAV gene as a novel ROR{alpha} target gene

    Energy Technology Data Exchange (ETDEWEB)

    Lind, Ulrika [Department of Molecular Pharmacology, AstraZeneca R and D Moelndal (Sweden); Nilsson, Tina [Department of Molecular Pharmacology, AstraZeneca R and D Moelndal (Sweden); McPheat, Jane [Department of Molecular Pharmacology, AstraZeneca R and D Moelndal (Sweden); Stroemstedt, Per-Erik [Department of Molecular Pharmacology, AstraZeneca R and D Moelndal (Sweden); Bamberg, Krister [Department of Molecular Pharmacology, AstraZeneca R and D Moelndal (Sweden); Balendran, Clare [Department of Molecular Pharmacology, AstraZeneca R and D Moelndal (Sweden); Kang, Daiwu [Department of Molecular Pharmacology, AstraZeneca R and D Moelndal (Sweden)

    2005-04-29

    Retinoic acid receptor-related orphan receptor-{alpha} (ROR{alpha}) (NR1F1) is an orphan nuclear receptor with a potential role in metabolism. Previous studies have shown that ROR{alpha} regulates transcription of the murine Apolipoprotein AI gene and human Apolipoprotein CIII genes. In the present study, we present evidence that ROR{alpha} also induces transcription of the human Apolipoprotein AV gene, a recently identified apolipoprotein associated with triglyceride levels. Adenovirus-mediated overexpression of ROR{alpha} increased the endogenous expression of ApoAV in HepG2 cells and ROR{alpha} also enhanced the activity of an ApoAV promoter construct in transiently transfected HepG2 cells. Deletion and mutation studies identified three AGGTCA motifs in the ApoAV promoter that mediate ROR{alpha} transactivation, one of which overlaps with a previously identified binding site for PPAR{alpha}. Together, these results suggest a novel mechanism whereby ROR{alpha} modulates lipid metabolism and implies ROR{alpha} as a potential target for the treatment of dyslipidemia and atherosclerosis.

  12. AlphaSpace: Fragment-Centric Topographical Mapping To Target Protein–Protein Interaction Interfaces

    Science.gov (United States)

    2016-01-01

    Inhibition of protein–protein interactions (PPIs) is emerging as a promising therapeutic strategy despite the difficulty in targeting such interfaces with drug-like small molecules. PPIs generally feature large and flat binding surfaces as compared to typical drug targets. These features pose a challenge for structural characterization of the surface using geometry-based pocket-detection methods. An attractive mapping strategy—that builds on the principles of fragment-based drug discovery (FBDD)—is to detect the fragment-centric modularity at the protein surface and then characterize the large PPI interface as a set of localized, fragment-targetable interaction regions. Here, we introduce AlphaSpace, a computational analysis tool designed for fragment-centric topographical mapping (FCTM) of PPI interfaces. Our approach uses the alpha sphere construct, a geometric feature of a protein’s Voronoi diagram, to map out concave interaction space at the protein surface. We introduce two new features—alpha-atom and alpha-space—and the concept of the alpha-atom/alpha-space pair to rank pockets for fragment-targetability and to facilitate the evaluation of pocket/fragment complementarity. The resulting high-resolution interfacial map of targetable pocket space can be used to guide the rational design and optimization of small molecule or biomimetic PPI inhibitors. PMID:26225450

  13. Engineering liposomal nanoparticles for targeted gene therapy.

    Science.gov (United States)

    Zylberberg, C; Gaskill, K; Pasley, S; Matosevic, S

    2017-08-01

    Recent mechanistic studies have attempted to deepen our understanding of the process by which liposome-mediated delivery of genetic material occurs. Understanding the interactions between lipid nanoparticles and cells is still largely elusive. Liposome-mediated delivery of genetic material faces systemic obstacles alongside entry into the cell, endosomal escape, lysosomal degradation and nuclear uptake. Rational design approaches for targeted delivery have been developed to reduce off-target effects and enhance transfection. These strategies, which have included the modification of lipid nanoparticles with target-specific ligands to enhance intracellular uptake, have shown significant promise at the proof-of-concept stage. Control of physical and chemical specifications of liposome composition, which includes lipid-to-DNA charge, size, presence of ester bonds, chain length and nature of ligand complexation, is integral to the performance of targeted liposomes as genetic delivery agents. Clinical advances are expected to rely on such systems in the therapeutic application of liposome nanoparticle-based gene therapy. Here, we discuss the latest breakthroughs in the development of targeted liposome-based agents for the delivery of genetic material, paying particular attention to new ligand and cationic lipid design as well as recent in vivo advances.

  14. Radionuclide molecular target therapy for lung cancer

    International Nuclear Information System (INIS)

    Zhang Fuhai; Meng Zhaowei; Tan Jian

    2012-01-01

    Lung cancer harms people's health or even lives severely. Currently, the morbidity and mortality of lung cancer are ascending all over the world. Accounting for 38.08% of malignant tumor caused death in male and 16% in female in cities,ranking top in both sex. Especially, the therapy of non-small cell lung cancer has not been obviously improved for many years. Recently, sodium/iodide transporter gene transfection and the therapy of molecular target drugs mediated radionuclide are being taken into account and become the new research directions in treatment of advanced lung cancer patients with the development of technology and theory for medical molecular biology and the new knowledge of lung cancer's pathogenesis. (authors)

  15. MAIN MOLECULAR TARGETS FOR PROSTATE CANCER THERAPY

    Directory of Open Access Journals (Sweden)

    G. S. Krasnov

    2014-01-01

    Full Text Available Androgenic pathway plays a pivotal role in the development of benign and malignant prostate tumors. Most of the prostate neoplasms are hormone-dependent at the time of diagnosis. Therapeutic interventions aimed at reducing the level of testosterone in the blood allow to stop progression of the disease. But over time, the tumor almost inevitably starts to progress, moving in the castration-resistant state (CRPC, representing a serious problem of oncourology. In recent years, the possibility of CRRPC therapy increased significantly – there was developed a number of new drugs that effectively inhibit the development of castration-resistant tumors and significantly push back the start of chemotherapy. This review describes the major drug targets and mechanisms of action of abiraterone, enzalutamide, galeterone, VT-464 and other approved and promising CRPC therapies.

  16. Therapeutics: Gene Therapy for Alpha-1 Antitrypsin Deficiency.

    Science.gov (United States)

    Gruntman, Alisha M; Flotte, Terence R

    2017-01-01

    This review seeks to give an overview of alpha-1 antitrypsin deficiency, including the different disease phenotypes that it encompasses. We then describe the different therapeutic endeavors that have been undertaken to address these different phenotypes. Lastly we discuss future potential therapeutics, such as genome editing, and how they may play a role in treating alpha-1 antitrypsin deficiency.

  17. Delirium after interleukin-2 and alpha-interferon therapy for renal cell carcinoma

    NARCIS (Netherlands)

    Van Steijn, JHM; Nieboer, P; Hospers, GAP; De Vries, EGE; Mulder, NH

    2001-01-01

    A 55-year-old man receiving alpha-interferon and interieukin-2 therapy for renal cell carcinoma presented with seizures and delirium. A CT-scan of the cerebrum did not reveal any disorder. Both alpha-interferon and interleukin-2 were stopped Treatment with steroids led to complete regression of

  18. Cancer gene therapy with targeted adenoviruses.

    Science.gov (United States)

    Bachtarzi, Houria; Stevenson, Mark; Fisher, Kerry

    2008-11-01

    Clinical experience with adenovirus vectors has highlighted the need for improved delivery and targeting. This manuscript aims to provide an overview of the techniques currently under development for improving adenovirus delivery to malignant cells in vivo. Primary research articles reporting improvements in adenoviral gene delivery are described. Strategies include genetic modification of viral coat proteins, non-genetic modifications including polymer encapsulation approaches and pharmacological interventions. Reprogramming adenovirus tropism in vitro has been convincingly demonstrated using a range of genetic and physical strategies. These studies have provided new insights into our understanding of virology and the field is progressing. However, there are still some limitations that need special consideration before adenovirus-targeted cancer gene therapy emerges as a routine treatment in the clinical setting.

  19. Alpha-1-antitrypsin augmentation therapy in deficient individuals enrolled in the Alpha-1 Foundation DNA and Tissue Bank

    Directory of Open Access Journals (Sweden)

    Adriano R Tonelli

    2009-12-01

    Full Text Available Adriano R Tonelli1, Farshid Rouhani1, Ning Li2, Pam Schreck1, Mark L Brantly11Alpha-1 Research Program, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, 2Department of Epidemiology and Biostatistics, University of Florida, Gainesville, Florida, USAIntroduction: Intravenous augmentation therapy with purified intravenous alpha-1 antitrypsin replaces the deficient protein and is the only currently approved treatment for alpha-1 antitrypsin deficiency (AATD related lung disease. While augmentation therapy has been available for more than 20 years, there are a limited number of studies evaluating the effect of augmentation on lung function.Material and methods: We examined the decline in forced expiratory volume in one second (FEV1 in patients enrolled in the Alpha-1 Foundation DNA and Tissue Bank in relation to the use or not of alpha-1 antitrypsin augmentation therapy. For the purpose of our analysis we included 164 patients with AATD and PI ZZ genotype.Results: Mean age of the patients was 60 years, 52% were females, 94% were white and 78% ex-smokers. The mean FEV1 at baseline was 1.7 L and the mean FEV1 % of predicted was 51.3%. The mean follow-up time was 41.7 months. A total of 124 (76% patients received augmentation therapy (augmented group while 40 patients (24% did not received it (non-augmented group. When adjusted by age at baseline, sex, smoking status, baseline FEV1 % of predicted, the mean overall change in FEV1 was 47.6 mL/year, favoring the augmented group (?FEV1 10.6 ± 21.4 mL/year in comparison with the non-augmented group (?FEV1 −36.96 ± 12.1 mL/year (P = 0.05. Beneficial ?FEV1 were observed in ex-smokers and the group with initial FEV1 % of predicted of <50%. No differences were observed in mortality.Conclusions: In conclusion, augmentation therapy improves lung function in subjects with AATD when adjusted by age, gender, smoking status and baseline FEV1 % of predicted. The beneficial

  20. Oncolytic viral therapy: targeting cancer stem cells

    Directory of Open Access Journals (Sweden)

    Smith TT

    2014-02-01

    Full Text Available Tyrel T Smith,1 Justin C Roth,1 Gregory K Friedman,1 G Yancey Gillespie2 1Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA Abstract: Cancer stem cells (CSCs are defined as rare populations of tumor-initiating cancer cells that are capable of both self-renewal and differentiation. Extensive research is currently underway to develop therapeutics that target CSCs for cancer therapy, due to their critical role in tumorigenesis, as well as their resistance to chemotherapy and radiotherapy. To this end, oncolytic viruses targeting unique CSC markers, signaling pathways, or the pro-tumor CSC niche offer promising potential as CSCs-destroying agents/therapeutics. We provide a summary of existing knowledge on the biology of CSCs, including their markers and their niche thought to comprise the tumor microenvironment, and then we provide a critical analysis of the potential for targeting CSCs with oncolytic viruses, including herpes simplex virus-1, adenovirus, measles virus, reovirus, and vaccinia virus. Specifically, we review current literature regarding first-generation oncolytic viruses with their innate ability to replicate in CSCs, as well as second-generation viruses engineered to enhance the oncolytic effect and CSC-targeting through transgene expression. Keywords: oncolytic virotherapy, cancer stem cell niche

  1. Targeting embryonic signaling pathways in cancer therapy.

    Science.gov (United States)

    Harris, Pamela Jo; Speranza, Giovanna; Dansky Ullmann, Claudio

    2012-01-01

    The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed. This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field. CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established.

  2. Advances in the targeted therapy of liposarcoma

    Directory of Open Access Journals (Sweden)

    Guan Z

    2015-01-01

    Full Text Available Zhonghai Guan,1 Xiongfei Yu,1 Haohao Wang,1 Haiyong Wang,1 Jing Zhang,1 Guangliang Li,2 Jiang Cao,3 Lisong Teng1 1Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, 2Department of Medicine Oncology, Zhejiang Cancer Hospital, 3Clinical Research Center, The 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Abstract: Liposarcoma (LPS is the most common type of soft-tissue sarcoma. Complete surgical resection is the only curative means for localized disease; however, both radiation and conventional cytotoxic chemotherapy remain controversial for metastatic or unresectable disease. An increasing number of trials with novel targeted therapy of LPS have provided encouraging data during recent years. This review will provide an overview of the advances in our understanding of LPS and summarize the results of recent trials with novel therapies targeting different genetic and molecular aberrations for different subtypes of LPS. Keywords: well-/dedifferentiated, myxoid/round cell, pleomorphic, soft-tissue sarcoma

  3. Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy

    International Nuclear Information System (INIS)

    Ogawa, Kazuma; Mizuno, Yoshiaki; Washiyama, Kohshin; Shiba, Kazuhiro; Takahashi, Naruto; Kozaka, Takashi; Watanabe, Shigeki; Shinohara, Atsushi; Odani, Akira

    2015-01-01

    Introduction: Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated 131 I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[ 131 I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[ 131 I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[ 211 At]pAtV, an 211 At-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy. Methods: The radiolabeled sigma receptor ligand (+)-[ 211 At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[ 211 At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[ 211 At]pAtV and (+)-[ 125 I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice. Results: The lipophilicity of (+)-[ 211 At]pAtV was similar to that of (+)-[ 125 I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1 h post-injection were also similar between (+)-[ 211 At]pAtV and (+)-[ 125 I]pIV. Namely, (+)-[ 211 At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors. Conclusion: These results indicate that (+)-[ 211 At]pAtV could function as an new agent for alpha-radionuclide receptor therapy.

  4. Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy.

    Science.gov (United States)

    Ogawa, Kazuma; Mizuno, Yoshiaki; Washiyama, Kohshin; Shiba, Kazuhiro; Takahashi, Naruto; Kozaka, Takashi; Watanabe, Shigeki; Shinohara, Atsushi; Odani, Akira

    2015-11-01

    Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated (131)I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[(131)I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[(131)I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[(211)At]pAtV, an (211)At-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy. The radiolabeled sigma receptor ligand (+)-[(211)At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[(211)At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[(211)At]pAtV and (+)-[(125)I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice. The lipophilicity of (+)-[(211)At]pAtV was similar to that of (+)-[(125)I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1h post-injection were also similar between (+)-[(211)At]pAtV and (+)-[(125)I]pIV. Namely, (+)-[(211)At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors. These results indicate that (+)-[(211)At]pAtV could function as an new agent for alpha-radionuclide receptor therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Targeting DNA Replication Stress for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2016-08-01

    Full Text Available The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress.

  6. Targeted Therapy for Biliary Tract Cancer

    International Nuclear Information System (INIS)

    Furuse, Junji; Okusaka, Takuji

    2011-01-01

    It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer, because most of these patients are unsuitable candidates for surgery, and even patients undergoing curative surgery often have recurrence. Recently, the combination of cisplatin plus gemcitabine was reported to show survival benefits over gemcitabine alone in randomized clinical trials conducted in the United Kingdom and Japan. Thus, the combination of cisplatin plus gemcitabine is now recognized as the standard therapy for unresectable biliary tract cancer. One of the next issues that need to be addressed is whether molecular targeted agents might also be effective against biliary tract cancer. Although some targeted agents have been investigated as monotherapy for first-line chemotherapy, none were found to exert satisfactory efficacy. On the other hand, monoclonal antibodies such as bevacizumab and cetuximab have also been investigated in combination with a gemcitabine-based regimen and have been demonstrated to show promising activity. Furthermore, clinical trials using new targeted agents for biliary tract cancer are also proposed. This cancer is a relatively rare and heterogeneous tumor consisting of cholangiocarcinoma and gallbladder carcinoma. Therefore, a large randomized clinical trial is necessary to confirm the efficacy of chemotherapy, and international collaboration is important

  7. Molecular targeted therapy for advanced gastric cancer.

    Science.gov (United States)

    Kim, Jong Gwang

    2013-03-01

    Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration; the median survival is approximately 7 to 11 months, and survival at 2 years is exceptionally > 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, many molecular targeting agents have been evaluated in international randomized studies, and trastuzumab, an anti-HER-2 monoclonal antibody, has shown antitumor activity against HER-2-positive AGC. However, this benefit is limited to only ~20% of patients with AGC (patients with HER-2-positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of molecular predictive and prognostic markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.

  8. Liver-targeting of interferon-alpha with tissue-specific domain antibodies.

    Directory of Open Access Journals (Sweden)

    Edward Coulstock

    Full Text Available Interferon alpha (IFNα is used for the treatment of hepatitis C infection and whilst efficacious it is associated with multiple adverse events including reduced leukocyte, erythrocyte, and platelet counts, fatigue, and depression. These events are most likely caused by systemic exposure to interferon. We therefore hypothesise that targeting the therapeutic directly to the intended site of action in the liver would reduce exposure in blood and peripheral tissue and hence improve the safety and tolerability of IFNα therapy. We genetically fused IFN to a domain antibody (dAb specific to a hepatocyte restricted antigen, asialoglycoprotein receptor (ASGPR. Our results show that the murine IFNα2 homolog (mIFNα2 fused to an ASGPR specific dAb, termed DOM26h-196-61, could be expressed in mammalian tissue culture systems and retains the desirable biophysical properties and activity of both fusion partners when measured in vitro. Furthermore a clear increase in in vivo targeting of the liver by mIFNα2-ASGPR dAb fusion protein, compared to that observed with either unfused mIFNα2 or mIFNα2 fused to an isotype control dAb VHD2 (which does not bind ASGPR was demonstrated using microSPECT imaging. We suggest that these findings may be applicable in the development of a liver-targeted human IFN molecule with improved safety and patient compliance in comparison to the current standard of care, which could ultimately be used as a treatment for human hepatitis virus infections.

  9. Targeted Therapy for Breast Cancer Prevention

    Science.gov (United States)

    den Hollander, Petra; Savage, Michelle I.; Brown, Powel H.

    2013-01-01

    With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID:24069582

  10. Gene transfer technology and genetic radioisotope targeting therapy

    International Nuclear Information System (INIS)

    Wang Jiaqiong; Wang Zizheng

    2004-01-01

    With deeper cognition about mechanisms of disease at the cellular and molecular level, gene therapy has become one of the most important research fields in medical molecular biology at present. Gene transfer technology plays an important role during the course of gene therapy, and further improvement should be made about vectors carrying target gene sequences. Also, gene survey is needed during gene therapy, and gene imaging is the most effective method. The combination of gene therapy and targeted radiotherapy, that is, 'Genetic Radioisotope Targeting Therapy', will be a novel approach to tumor gene therapy

  11. TARGETED NANOPARTICLES FOR PEDIATRIC LEUKEMIA THERAPY

    Directory of Open Access Journals (Sweden)

    Riyaz eBasha

    2014-05-01

    Full Text Available The two major forms of leukemia, acute lymphoblastic leukemia (ALL and acute myeloid leukemia (AML account for about one third of the malignancies diagnosed in children. Despite the marked successes in ALL and AML treatment, concerns remain regarding the occurrence of resistant disease in subsets of patients the residual effects of therapy that often persist for decades beyond the cessation of treatment. Therefore, new approaches are needed to reduce or to avoid off target toxicities, associated with chemotherapy and their long term residual effects. Recently, nanotechnology has been employed to enhance cancer therapy, via improving the bioavailability and therapeutic efficacy of anti-cancer agents. While in the last several years, numerous review articles appeared detailing the size, composition, assembly and performance evaluation of different types of drug carrying nanoparticles, the description and evaluation of lipoprotein based drug carriers have been conspicuously absent from most of these major reviews. The current review focuses on such information regarding nanoparticles with an emphasis on high density lipoprotein (HDL-based drug delivery systems to examine their potential role(s in the enhanced treatment of children with leukemia.

  12. Does adjuvant systemic therapy with interferon-alpha for stage II-III melanoma prolong survival?

    NARCIS (Netherlands)

    Eggermont, Alexander M. M.; Punt, Cornelis J. A.

    2003-01-01

    The experience with interferon-alpha in malignant melanoma resembles, to some degree, the experience with various kinds of adjuvant immunotherapeutic agents where 25 years of phase III trials of adjuvant therapy in stage II-IIII melanoma have not defined a standard therapy. Most trials failed to

  13. Therapies targeting inflammation after stent implantation.

    Science.gov (United States)

    Okura, Hiroyuki; Takagi, Tsutomu; Yoshida, Kiyoshi

    2013-07-01

    Since the introduction of coronary vessel scaffold by metallic stent, percutaneous coronary intervention has become widely performed all over the world. Although drug-eluting stent technology has further decrease the incidence of in-stent restenosis, there still remaining issues related to stent implantation. Vessel inflammation is one of the causes that may be related to stent restenosis as well as stent thrombosis. Therefore, systemic therapies targeting inflammation emerged as adjunctive pharmacological intervention to improve outcome. Statins, corticosteroids, antiplatelets, and immunosuppresive or anti-cancer drugs are reported to favorably impact outcome after bare-metal stent implantation. In type 2 diabetic patients, pioglitazone may be the most promising drug that can lower neointimal proliferation and, as a result, lower incidence of restenosis and target lesion revascularization. On the other hand, several new stent platforms that might decrease inflammatory response after drug-eluting stent implantation have been introduced. Because durable polymer used in the first generation drug-eluting stents are recognized to be responsible for unfavorable vessel response, biocompatible or bioabsorbable polymer has been introduce and already used clinically. Furthermore, polymer-free drug-eluting stent and bioresorbable scaffold are under investigation. Although vessel inflammation may be reduced by using these new drug-eluting stents or scaffold, long-term impact needs to be investigated further.

  14. RLIP76 Targeted Therapy for Kidney Cancer.

    Science.gov (United States)

    Singhal, Sharad S; Singhal, Jyotsana; Figarola, James; Horne, David; Awasthi, Sanjay

    2015-10-01

    Despite recent improvements in chemotherapeutic approaches to treating kidney cancer, this malignancy remains deadly if not found and removed at an early stage of the disease. Kidney cancer is highly drug-resistant, which may at least partially result from high expression of transporter proteins in the cell membranes of kidney cells. Although these transporter proteins can contribute to drug-resistance, targeting proteins from the ATP-binding cassette transporter family has not been effective in reversing drug-resistance in kidney cancer. Recent studies have identified RLIP76 as a key stress-defense protein that protects normal cells from damage caused by stress conditions, including heat, ultra-violet light, X-irradiation, and oxidant/electrophilic toxic chemicals, and is crucial for protecting cancer cells from apoptosis. RLIP76 is the predominant glutathione-electrophile-conjugate (GS-E) transporter in cells, and inhibiting it with antibodies or through siRNA or antisense causes apoptosis in many cancer cell types. To date, blocking of RLIP76, either alone or in combination with chemotherapeutic drugs, as a therapeutic strategy for kidney cancer has not yet been evaluated in human clinical trials, although there is considerable potential for RLIP76 to be developed as a therapeutic agent for kidney cancer. In the present review, we discuss the mechanisms underlying apoptosis caused by RLIP76 depletion, the role of RLIP76 in clathrin-dependent endocytosis deficiency, and the feasibility of RLIP76-targeted therapy for kidney cancer.

  15. Targeted Gene Therapy of Cancer: Second Amendment toward Holistic Therapy.

    Science.gov (United States)

    Barar, Jaleh; Omidi, Yadollah

    2013-01-01

    It seems solid tumors are developing smart organs with specialized cells creating specified bio-territory, the so called "tumor microenvironment (TME)", in which there is reciprocal crosstalk among cancer cells, immune system cells and stromal cells. TME as an intricate milieu also consists of cancer stem cells (CSCs) that can resist against chemotherapies. In solid tumors, metabolism and vascularization appears to be aberrant and tumor interstitial fluid (TIF) functions as physiologic barrier. Thus, chemotherapy, immunotherapy and gene therapy often fail to provide cogent clinical outcomes. It looms that it is the time to accept the fact that initiation of cancer could be generation of another form of life that involves a cluster of thousands of genes, while we have failed to observe all aspects of it. Hence, the current treatment modalities need to be re-visited to cover all key aspects of disease using combination therapy based on the condition of patients. Perhaps personalized cluster of genes need to be simultaneously targeted.

  16. Targeted Gene Therapy of Cancer: Second Amendment toward Holistic Therapy

    Directory of Open Access Journals (Sweden)

    Jaleh Barar

    2013-02-01

    Full Text Available It seems solid tumors are developing smart organs with specialized cells creating specified bio-territory, the so called “tumor microenvironment (TME”, in which there is reciprocal crosstalk among cancer cells, immune system cells and stromal cells. TME as an intricate milieu also consists of cancer stem cells (CSCs that can resist against chemotherapies. In solid tumors, metabolism and vascularization appears to be aberrant and tumor interstitial fluid (TIF functions as physiologic barrier. Thus, chemotherapy, immunotherapy and gene therapy often fail to provide cogent clinical outcomes. It looms that it is the time to accept the fact that initiation of cancer could be generation of another form of life that involves a cluster of thousands of genes, while we have failed to observe all aspects of it. Hence, the current treatment modalities need to be re-visited to cover all key aspects of disease using combination therapy based on the condition of patients. Perhaps personalized cluster of genes need to be simultaneously targeted.

  17. Folate Receptor Targeted Alpha-Therapy Using Terbium-149

    CERN Document Server

    Müller, Cristina; Haller, Stephanie; Dorrer, Holger; Köster, Ulli; Johnston, Karl; Zhernosekov, Konstantin; Türler, Andreas; Schibli, Roger

    2014-01-01

    Terbium-149 is among the most interesting therapeutic nuclides for medical applications. It decays by emission of short-range α-particles (Eα = 3.967 MeV) with a half-life of 4.12 h. The goal of this study was to investigate the anticancer efficacy of a 149Tb-labeled DOTA-folate conjugate (cm09) using folate receptor (FR)-positive cancer cells in vitro and in tumor-bearing mice. 149Tb was produced at the ISOLDE facility at CERN. Radiolabeling of cm09 with purified 149Tb resulted in a specific activity of ~1.2 MBq/nmol. In vitro assays performed with 149Tb-cm09 revealed a reduced KB cell viability in a FR-specific and activity concentration-dependent manner. Tumor-bearing mice were injected with saline only (group A) or with 149Tb-cm09 (group B: 2.2 MBq; group C: 3.0 MBq). A significant tumor growth delay was found in treated animals resulting in an increased average survival time of mice which received 149Tb-cm09 (B: 30.5 d; C: 43 d) compared to untreated controls (A: 21 d). Analysis of blood parameters rev...

  18. Clinical targeting recombinant immunotoxins for cancer therapy

    Directory of Open Access Journals (Sweden)

    Li M

    2017-07-01

    Full Text Available Meng Li,1,* Zeng-Shan Liu,1,* Xi-Lin Liu,1,* Qi Hui,2,* Shi-Ying Lu,1 Lin-Lin Qu,1 Yan-Song Li,1 Yu Zhou,1 Hong-Lin Ren,1 Pan Hu1 1Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, China-Japan Union Hospital, The First Hospital, Jilin University, Changchun, 2School of Pharmacy, Wenzhou Medical University, Wenzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Recombinant immunotoxins (RITs are proteins that contain a toxin fused to an antibody or small molecules and are constructed by the genetic engineering technique. RITs can bind to and be internalized by cells and kill cancerous or non-cancerous cells by inhibiting protein synthesis. A wide variety of RITs have been tested against different cancers in cell culture, xenograft models, and human patients during the past several decades. RITs have shown activity in therapy of several kinds of cancers, but different levels of side effects, mainly related to vascular leak syndrome, were also observed in the treated patients. High immunogenicity of RITs limited their long-term or repeat applications in clinical cases. Recent advances in the design of immunotoxins, such as humanization of antibody fragment, PEGylation, and modification of human B- and T-cell epitopes, are overcoming the above mentioned problems, which predict the use of these immunotoxins as a potential therapeutic method to treat cancer patients. Keywords: targeted therapy, hematologic malignancies, solid tumors, vascular leak syndrome, immunogenicity 

  19. Target characterization by PIXE, alpha spectrometry and X-ray absorption

    International Nuclear Information System (INIS)

    Kheswa, N.Y.; Papka, P.; Pineda-Vargas, C.A.; Newman, R.T.

    2011-01-01

    We report on the thickness and homogeneity characterization of thin metallic targets of Zr-96 by means of alpha absorption spectrometry, Particle Induced X-ray Emission (PIXE) and X-ray absorption. The target thicknesses determined by means of the above mentioned methods are critically compared. The thicknesses were determined before and after irradiation with a 70 MeV beam of 14 N ions.

  20. Recombinant alpha-interferon as salvage therapy in multiple myeloma

    African Journals Online (AJOL)

    1989-08-05

    Aug 5, 1989 ... Ten patients with end-stage multiple myeloma refractory to conventional chemotherapy and ... malities and relief of pain using local radiotherapy. However, .... therapy programmes. However, the role of this agent remains.

  1. Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.

    Science.gov (United States)

    Shaginian, Alex; Whitby, Landon R; Hong, Sukwon; Hwang, Inkyu; Farooqi, Bilal; Searcey, Mark; Chen, Jiandong; Vogt, Peter K; Boger, Dale L

    2009-04-22

    The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.

  2. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency

    DEFF Research Database (Denmark)

    Dirksen, A; Piitulainen, E; Parr, D G

    2009-01-01

    for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency. In total, 77 subjects (protease inhibitor type Z) were randomised to weekly infusions of 60 mg x kg(-1) human alpha(1)-AT (Prolastin) or placebo for 2-2.5 yrs. The primary end...... was unaltered by treatment, but a reduction in exacerbation severity was observed. In patients with alpha(1)-AT deficiency, CT is a more sensitive outcome measure of emphysema-modifying therapy than physiology and health status, and demonstrates a trend of treatment benefit from alpha(1)-AT augmentation....

  3. Influences of target geometry on the microdosimetry of alpha particles in water

    International Nuclear Information System (INIS)

    Huston, T.E.

    1992-01-01

    Application of microdosimetric concepts to radiation exposure situations requires knowledge of the single-event density function, f 1 (z) , where z denotes specific energy imparted to target matter. Multiple-event density functions are calculated by taking convolutions of f 1 (z) with itself with the overall specific energy density function is then found by employing a compound Poisson process involving single and multiple-event spectra. The f l (z), depends strongly on the geometric details of a the source, target, and all intermediate matter. While most past applications of microdosimetry have been represented targets as spheres, may be better modeled as prolate or oblate spheroids. Using a ray-tracing technique coupled with a continuous-slowing-down approximation, methods are developed and presented for calculating single-event density functions for spheroidal targets irradiated by alpha-emitting point sources. Computational methods are incorporated into a fortran computer code entitled SEROID (single-event density functions for spheroids), which is listed in this paper. This was used to generate several single-event density functions, along with related means and standard deviations in specific energy, for spheroidal targets irradiated by alpha particles. Targets of varying shapes and orientations are examined. Results for non-spherical targets are compared to spherical targets of equal volume in order to assess influences which target geometry has on single-event quantities. From these comparisons it is found that both target shape and orientation are important in adequately characterizing the quantities examined in this study; over-simplifying the target geometry can lead to substantial error

  4. Recombinant enzyme therapy for Fabry disease: Absence of editing of human alpha-galactosidase A mRNA

    NARCIS (Netherlands)

    Blom, Daniël; Speijer, Dave; Linthorst, Gabor E.; Donker-Koopman, Wilma G.; Strijland, Anneke; Aerts, Johannes M. F. G.

    2003-01-01

    For more than a decade, protein-replacement therapy has been employed successfully for the treatment of Gaucher disease. Recently, a comparable therapy has become available for the related lipid-storage disorder Fabry disease. Two differently produced recombinant alpha-galactosidase A (alpha-gal A)

  5. Melanoma Therapy with Rhenium-Cyclized Alpha Melanocyte Stimulating Hormone Peptide Analogs

    Energy Technology Data Exchange (ETDEWEB)

    Thomas P Quinn

    2005-11-22

    Malignant melanoma is the 6th most commonly diagnosed cancer with increasing incidence in the United States. It is estimated that 54,200 cases of malignant melanoma will be newly diagnosed and 7,600 cases of death will occur in the United States in the year 2003 (1). At the present time, more than 1.3% of Americans will develop malignant melanoma during their lifetime (2). The average survival for patients with metastatic melanoma is about 6-9 months (3). Moreover, metastatic melanoma deposits are resistant to conventional chemotherapy and external beam radiation therapy (3). Systematic chemotherapy is the primary therapeutic approach to treat patients with metastatic melanoma. Dacarbazine is the only single chemotherapy agent approved by FDA for metastatic melanoma treatment (5). However, the response rate to Dacarbazine is only approximately 20% (6). Therefore, there is a great need to develop novel treatment approaches for metastatic melanoma. The global goal of this research program is the rational design, characterization and validation of melanoma imaging and therapeutic radiopharmaceuticals. Significant progress has been made in the design and characterization of metal-cyclized radiolabeled alpha-melanocyte stimulating hormone peptides. Therapy studies with {sup 188}Re-CCMSH demonstrated the therapeutic efficacy of the receptor-targeted treatment in murine and human melanoma bearing mice (previous progress report). Dosimetry calculations, based on biodistribution data, indicated that a significant dose was delivered to the tumor. However, {sup 188}Re is a very energetic beta-particle emitter. The longer-range beta-particles theoretically would be better for larger tumors. In the treatment of melanoma, the larger primary tumor is usually surgically removed leaving metastatic disease as the focus of targeted radiotherapy. Isotopes with lower beta-energies and/or shorter particle lengths should be better suited for targeting metastases. The {sup 177}Lu

  6. Melanome Therapy with Rhenium Cyclized Alpha Melanocyte Stimulating Hormone Peptide Analogs. Final report

    International Nuclear Information System (INIS)

    Quinn, Thomas P.

    2005-01-01

    Malignant melanoma is the 6th most commonly diagnosed cancer with increasing incidence in the United States. It is estimated that 54,200 cases of malignant melanoma will be newly diagnosed and 7,600 cases of death will occur in the United States in the year 2003 (1). At the present time, more than 1.3% of Americans will develop malignant melanoma during their lifetime (2). The average survival for patients with metastatic melanoma is about 6-9 months (3). Moreover, metastatic melanoma deposits are resistant to conventional chemotherapy and external beam radiation therapy (3). Systematic chemotherapy is the primary therapeutic approach to treat patients with metastatic melanoma. Dacarbazine is the only single chemotherapy agent approved by FDA for metastatic melanoma treatment (5). However, the response rate to Dacarbazine is only approximately 20% (6). Therefore, there is a great need to develop novel treatment approaches for metastatic melanoma. The global goal of this research program is the rational design, characterization and validation of melanoma imaging and therapeutic radiopharmaceuticals. Significant progress has been made in the design and characterization of metal-cyclized radiolabeled alpha-melanocyte stimulating hormone peptides. Therapy studies with 188 Re-CCMSH demonstrated the therapeutic efficacy of the receptor-targeted treatment in murine and human melanoma bearing mice (previous progress report). Dosimetry calculations, based on biodistribution data, indicated that a significant dose was delivered to the tumor. However, 188 Re is a very energetic beta-particle emitter. The longer-range beta-particles theoretically would be better for larger tumors. In the treatment of melanoma, the larger primary tumor is usually surgically removed leaving metastatic disease as the focus of targeted radiotherapy. Isotopes with lower beta-energies and/or shorter particle lengths should be better suited for targeting metastases. The 177 Lu-DOTA-Re(Arg11)CCMSH and

  7. Slower resting alpha frequency is associated with superior localisation of moving targets.

    Science.gov (United States)

    Howard, Christina J; Arnold, Craig P A; Belmonte, Matthew K

    2017-10-01

    We examined the neurophysiological underpinnings of individual differences in the ability to maintain up-to-date representations of the positions of moving objects. In two experiments similar to the multiple object tracking (MOT) task, we asked observers to monitor continuously one or several targets as they moved unpredictably for a semi-random period. After all objects disappeared, observers were immediately prompted to report the perceived final position of one queried target. Precision of these position reports declined with attentional load, and reports tended to best resemble positions occupied by the queried target between 0 and 30ms in the past. Measurement of event-related potentials showed a contralateral delay activity over occipital scalp, maximal in the right hemisphere. The peak power-spectral frequency of observers' eyes-closed resting occipital alpha oscillations reliably predicted performance, such that lower-frequency alpha was associated with superior spatial localisation. Slower resting alpha might be associated with a cognitive style that depends less on memory-related processing and instead emphasises attention to changing stimuli. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  8. Metallothionein bioconjugates as delivery vehicles for bismuth-212 alpha particle therapy

    International Nuclear Information System (INIS)

    Macklis, R.M.; Morris, C.; Humm, J.; Hines, J.; Atcher, R.

    1991-01-01

    Metallothioneins (MTHs) are small cysteine-rich polypeptides that binds cationic metals at physiologic pH ranges through noncovalent -SH ligand interactions. Some leucine-rich renal MTHs have a particular avidity for bismuth. The authors have examined the ability of MTHs to selectively incorporate Bi-212, a short-lived high-energy alpha particle emitter currently under exploration as a potential therapeutic radiolabel for use in molecularly targeted cancer therapy. They find that under physiologic conditions, MTH will selectively incorporate Bi-212 after incubation with an equilibrium mixture of its upstream and downstream parents. The MTH moieties may be linked to tumor-binding macromolecules such as antibodies via thiolation reactions using SPDP, and the resultant Bismuth-avid molecules may be used either as primary delivery vehicles for the Bi-212 or as part of a 2-step release-and-catch isotope localization system in which the MTH-antibody conjugate is pre-localized at the tumor site and the radiometal is then administered and chelated in situ. They present the chemistry, dosimetry and potential clinical applications of this system

  9. Molecular targeting of gene therapy and radiotherapy

    International Nuclear Information System (INIS)

    Weichselbaum, R.R.; Kufe, D.W.; Advani, S.J.; Roizman, B.

    2001-01-01

    The full promise of gene therapy has been limited by the lack of specificity of vectors for tumor tissue as well as the lack of antitumor efficacy of transgenes encoded by gene delivery systems. In this paper we review our studies investigating two modifications of gene therapy combined with radiotherapy. The first investigations described include studies of radiation inducible gene therapy. In this paradigm, radio-inducible DNA sequences from the CarG elements of the Egr-1 promoter are cloned upstream of a cDNA encoding TNFa. The therapeutic gene (TNFa) is induced by radiation within the tumor microenvironment. In the second paradigm, genetically engineered herpes simplex virus (HSV-1) is induced by ionizing radiation to proliferate within the tumor volume. These modifications of radiotherapy and gene therapy may enhance the efficacy of both treatments

  10. Inflammation as target in cancer therapy.

    Czech Academy of Sciences Publication Activity Database

    Marelli, G.; Sica, A.; Vannucci, Luca; Allavena, P.

    2017-01-01

    Roč. 35, August 2017 (2017), s. 57-65 ISSN 1471-4892 Institutional support: RVO:61388971 Keywords : cancer therapy * cancer-promoting inflammation * Tumour-Associated Macrophages Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 5.363, year: 2016

  11. Hitting the target with antithrombotic therapy.

    Science.gov (United States)

    Fritsma, Margaret G; Rodak, Bernadette F

    2007-05-01

    Thrombus treatment and prevention can be regulated by a number of intravenous or subcutaneous drugs, as well as oral warfarin. Many therapies require laboratory monitoring for efficacy and for detection of dangerous sequelae, such as bleeding, thrombosis, or heparin induced thrombocytopenia.

  12. Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

    Science.gov (United States)

    Tanila, H; Mustonen, K; Sallinen, J; Scheinin, M; Riekkinen, P

    1999-02-01

    The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

  13. Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2017-12-01

    deprivation therapy (ADT) or androgen receptor (AR) pathway inhibition (ARPI) but eventually develops into lethal castration resistance prostate cancer ...AWARD NUMBER: W81XWH-14-1-0553 TITLE: Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer PRINCIPAL INVESTIGATOR: Martin Gleave...Siah2 as Novel Therapy for Metastatic Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0553 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Martin Gleave 5d

  14. Targeting the Thioredoxin System for Cancer Therapy.

    Science.gov (United States)

    Zhang, Junmin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo

    2017-09-01

    Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. The alpha2-delta protein: an auxiliary subunit of voltage-dependent calcium channels as a recognized drug target.

    Science.gov (United States)

    Thorpe, Andrew J; Offord, James

    2010-07-01

    Currently, there are two drugs on the market, gabapentin (Neurontin) and pregabalin (Lyrica), that are proposed to exert their therapeutic effect through binding to the alpha2-delta subunit of voltage-sensitive calcium channels. This activity was unexpected, as the alpha2-delta subunit had previously been considered not to be a pharmacological target. In this review, the role of the alpha2-delta subunits is discussed and the mechanism of action of the alpha2-delta ligands in vitro and in vivo is summarized. Finally, new insights into the mechanism of drugs that bind to this protein are discussed.

  16. Traditionally used plants in diabetes therapy: phytotherapeutics as inhibitors of alpha-amylase activity

    Directory of Open Access Journals (Sweden)

    Ingrid Funke

    Full Text Available Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycaemia. There are many and diverse therapeutic strategies in the management of Type 2 diabetes. The inhibition of alpha-amylase activity is only one possibility to lower postprandial blood glucose levels. In our in-vitro studies we could demonstrate that different plants, mostly traditionally used in common diabetic therapy in Africa or Europe, are able to inhibit alpha-amylase, which is responsible for the breakdown of oligosaccharides into monosaccharides which are absorbed. An inhibition of alpha-amylase activity of 90% was seen with the extract of the leaves of Tamarindus indica. To quantify inhibtion rates, acarbose was used (IC50: 23.2 µM. Highest inhibition level of acarbose in our testmodel was about 85%. Additionally tests with pure polyphenolic compounds might explain the biological activity of the selected plants.

  17. Immunological targeting of cytomegalovirus for glioblastoma therapy

    OpenAIRE

    Nair, Smita K; Sampson, John H; Mitchell, Duane A

    2014-01-01

    Human cytomegalovirus (CMV) is purportedly present in glioblastoma (GBM) while absent from the normal brain, making CMV antigens potentially ideal immunological anti-GBM targets. We recently demonstrated that patient-derived CMV pp65-specific T cells are capable of recognizing and killing autologous GBM tumor cells. This data supports CMV antigen-directed immunotherapies against GBM.

  18. Bacterial proteases: targets for diagnostics and therapy

    NARCIS (Netherlands)

    Kaman, W.E.; Hays, J.P.; Endtz, H.P.; Bikker, F.J.

    2014-01-01

    Proteases are essential for the proliferation and growth of bacteria, and are also known to contribute to bacterial virulence. This makes them interesting candidates as diagnostic and therapeutic targets for infectious diseases. In this review, the authors discuss the most recent developments and

  19. Hepatocarcinoma: from pathogenic mechanisms to target therapy

    Directory of Open Access Journals (Sweden)

    Luigi Manzione

    2011-12-01

    Full Text Available Hepatocellular carcinoma (HCC is among the most prevalent and lethal cancers worldwide. It is currently estimated that there are 14,000–18,000 new cases of hepatocellular carcinoma in the United States each year. It is often difficult to identify individuals at risk for HCC. The main associated diseases are chronic hepatitis B and chronic hepatitis C viral infections. While a significant number of potential mutations have been generated including p53 and Insulin-like Growth Factor, our understanding of the molecular mechanisms driving the genesis and progression of HCC remain limited. HCC screening is recommended in high-risk patients. High-risk patients include virtually all patients with cirrhosis and some HBV-infected patients irrespective of cirrhosis (>40 years in men and >50 years in women. A diagnostic approach to HCC has been developed incorporating serology, cytohistology, and radiological characteristics. A precise staging of the disease may help decide on prognosis as well as choice of therapy with the greatest survival potential. Liver transplantation, in theory, is the optimal therapeutic option for HCC; it simultaneously removes the tumor and underlying cirrhosis thus minimizing the risk of HCC recurrence. When it is impossible for this to be performed, percutaneous ablation, chemoembolization, chemotherapy and the newer molecular therapies can be used. Sorafenib is the only drug registered today for the treatment of advanced HCC.

  20. Production and separation of terbium-149 and terbium-152 for targeted cancer therapy

    International Nuclear Information System (INIS)

    Sarkar, S.; Leigh, J.

    1997-01-01

    This work reports the production and separation of useful quantities of 149 , 152 Tb from natural neodymium ( nat Nd) and 141 Pr for in vitro studies by bombarding the targets with 12 C projectiles. The physical, chemical and nuclear properties of radionuclides determine their efficacy in therapy and diagnosis. Tb-149 is an alpha-emitter with a half-life of 4.1h and 152 Tb is a positron emitter with a half-life of 17.5 h. Both of the isotopes have suitable gamma emission with good branching ratio suggesting their application to diagnosis apart from therapy. Alpha-emitters are effective in controlling cancer because of their short range and high Relative Biological Effectiveness. Long-lived positron emitters are effective in studying physiological function in positron emission tomography other than therapy. The aim of this work is to optimise the production and carrier free separation of terbium. Because of the presence of other stable isotopes in nat Nd, a number of other lanthanides are produced by secondary reactions during the production of terbium. In order to remove the secondary products, α-hydroxyisobutyric acid of pH 5 was used as eluent. satisfactory separation of terbium was achieved and demonstrate that useful quantities of 144,152 Tb can be produced by Tandem accelerator from 141 Pr and nat Nd targets

  1. Design of a cryogenic deuterium gas target for neutron therapy

    International Nuclear Information System (INIS)

    Kuchnir, F.T.; Waterman, F.M.; Forsthoff, H.; Skaggs, L.S.; Vander Arend, P.C.; Stoy, S.

    1976-01-01

    A cryogenic deuterium gas target operating at 80 0 K and 10 atm pressure has been designed for use with a small cyclotron; the D(d,n) reaction is used to produce a neutron beam suitable for radiation therapy. The target is cooled by circulation of the gas in a closed loop between the target and an external heat exchanger immersed in liquid nitrogen

  2. Targeted therapy in lung and breast cancer: a big deal

    OpenAIRE

    Caffarra, Cristina

    2015-01-01

    Great strides have been done in treating cancer. For decades, the hallmark of medical treatment for cancer has been intravenous cytotoxic chemotherapy which targets all dividing cells. In the last ten years the identification of different driver oncogenic mutations has allowed the development of targeted drugs. Targeted cancer therapies are based on the use of drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. The ...

  3. [Basic and clinical studies of the gene product-targeting therapy based on leukemogenesis--editorial].

    Science.gov (United States)

    Chen, Sai-Juan; Chen, Li-Juan; Zhou, Guang-Biao

    2005-02-01

    In the last twenty years, using all-trans retinoic acid (ATRA) as a differentiation inducer, Shanghai Institute of Hematology has achieved an important breakthrough in the treatment of acute promyelocytic leukemia (APL), which realized the theory of reversing phenotype of cells and provided a successful model of differentiation therapy in cancers. Our group first discovered in the world the variant chromosome translocation t(11;17)(q23;q21) of APL, and cloned the PML-RAR alpha, PLZF-RAR alpha and NPM-RAR alpha fusion genes corresponding to the characterized chromosome translocations t(15;17); t(11;17) and t(5;17) in APL. Moreover, establishment of transgenic mice model of APL proved their effects on leukemogenesis. The ability of ATRA to modify the recruitment of nuclear receptor co-repressor with PML-RAR alpha but not PLZF-RAR alpha caused by the variant chromosome translocation elucidated the therapeutic mechanism of ATRA from the molecular level and provides new insight into transcription-modulating therapy. Since 1994, our group has successfully applied arsenic trioxide (As(2)O(3)) in treating relapsed APL patients, with the complete remission rate of 70% - 80%. The molecular mechanism study revealed that As(2)O(3) exerts a dose-dependent dual effect on APL. Low-dose As(2)O(3) induced partial differentiation of APL cells, while the higher dose induced apoptosis. As(2)O(3) binds ubiquitin like SUMO-1 through the lysine 160 of PML, resulting in the degradation of PML-RAR alpha. Taken together, ATRA and As(2)O(3) target the transcription factor PML-RAR alpha, the former by retinoic acid receptor and the latter by PML sumolization, both induce PML-RAR alpha degradation and APL cells differentiation and apoptosis. Because of the different acting pathways, ATRA and As(2)O(3) have no cross-resistance and can be used as combination therapy. Clinical trial in newly diagnosed APL patients showed that ATRA/As(2)O(3) in combination yields a longer disease-free survival

  4. The alpha-particle irradiator set up at the ISS for radiobiological studies on targeted and non-targeted effects

    International Nuclear Information System (INIS)

    Esposito, G.; Antonelli, F.; Belli, M.; Campa, A.; Simone, G.; Sorrentino, E.; Tabocchini, M.A.

    2008-01-01

    In this paper we describe the alpha-particle irradiator that has been set up at the Istituto Superiore di Sanita (ISS) for controlled exposure of cultured mammalian cells. It can be equipped with two different sources, namely 2'4'4'Cm and 2'4'1'Am, allowing irradiation at different dose-rates (typically 1-100 mGy/min). The irradiator has dimensions small enough to be inserted into a standard cell culture incubator to perform irradiation of cultured cells in physiological conditions. The dose uniformity is such that the variations in the irradiation area are less than ± 12% of the average dose value on different irradiation areas up to ∼ 25 cm'2. Moreover, in the framework of the FP6 Euratom Integrated Project Non-targeted effects of ionizing radiation (NOTE), Petri dishes were realized for housing permeable membrane insert(s) to be used in co-culture experiments. Aluminium shields were also realized for half shield irradiation experiments. The alpha-particle irradiator of the ISS has been successfully used for studying DNA damage, namely double strand breaks (DSB, as measured by the γ-H2AX assay), in directly hit and in bystander primary human fibroblasts [it

  5. Novel targeted therapies for cancer cachexia.

    Science.gov (United States)

    Argilés, Josep M; López-Soriano, Francisco Javier; Stemmler, Britta; Busquets, Sílvia

    2017-07-27

    Anorexia and metabolic alterations are the main components of the cachectic syndrome. Glucose intolerance, fat depletion, muscle protein catabolism and other alterations are involved in the development of cancer cachexia, a multi-organ syndrome. Nutritional approach strategies are not satisfactory in reversing the cachectic syndrome. The aim of the present review is to deal with the recent therapeutic targeted approaches that have been designed to fight and counteract wasting in cancer patients. Indeed, some promising targeted therapeutic approaches include ghrelin agonists, selective androgen receptor agonists, β-blockers and antimyostatin peptides. However, a multi-targeted approach seems absolutely essential to treat patients affected by cancer cachexia. This approach should not only involve combinations of drugs but also nutrition and an adequate program of physical exercise, factors that may lead to a synergy, essential to overcome the syndrome. This may efficiently reverse the metabolic changes described above and, at the same time, ameliorate the anorexia. Defining this therapeutic combination of drugs/nutrients/exercise is an exciting project that will stimulate many scientific efforts. Other aspects that will, no doubt, be very important for successful treatment of cancer wasting will be an optimized design of future clinical trials, together with a protocol for staging cancer patients in relation to their degree of cachexia. This will permit that nutritional/metabolic/pharmacological support can be started early in the course of the disease, before severe weight loss occurs. Indeed, timing is crucial and has to be taken very seriously when applying the therapeutic approach. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  6. Radiolabelled peptides: New radiopharmaceuticals for targeted therapy

    International Nuclear Information System (INIS)

    Chinol, M.

    2001-01-01

    Radiolabelled peptides have been the focus of an increasing interest by the nuclear medicine community within the last few years. This has mainly been due to successful development of one of these peptides, somatostatin, as a tool to visualise various pathologic conditions known to express a high number of somatostatin receptors. Somatostatin receptors have been identified in different tumours such as neuroendocrine tumours, tumours of the central nervous system, breast, lung and lymphatic tissue. These observations served as the biomolecular basis for the clinical use of radiolabelled somatostatin analogs, which are at present of great interest for diagnostic and therapeutic applications. A promising somatostatin analogue, DOTA-D-Phe 1 -Ty 3 -octreotide, named DOTATOC, has shown favourable biodistribution and high affinity binding to SSTR2 and SSTR5, high hydrophilicity and ease of labelling and stability with 111 In and 90 Y. A clinical trial aimed at evaluating the biodistribution and dosimetry of DOTATOC radiolabelled with 111 In, in anticipation of therapy trials with 90 Y-DOTATOC in patients was undertaken. 111 In-DOTATOC showed favourable pharmacokinetics (fast blood clearance and urinary excretion) and biodistribution, and high affinity to tumours expressing somatostatin receptors (thus, a high residence time in tumour). These results are promising for therapy trials with 90 Y-DOTAOC, for which radiation dosimetry appears acceptable for normal organs (including the red marrow). Moreover, labelling conditions of DOTATOC with 90 Y has been optimised in order to achieve labelling yields of more than 98% and specific activities of greater than 60 GBq (1.6 Ci)/μmol. (author)

  7. Molecular targeted therapies of aggressive thyroid cancer

    Directory of Open Access Journals (Sweden)

    Silvia Martina eFerrari

    2015-11-01

    Full Text Available Differentiated thyroid carcinomas (DTC that arise from follicular cells account > 90% of thyroid cancer (TC [papillary thyroid cancer (PTC 90%, follicular thyroid cancer (FTC 10%], while medullary thyroid cancer (MTC accounts < 5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts towards the development of new drugs.Several genetic alterations in different molecular pathways in TC have been shown in the last decades, associated with TC development and progression. Rearranged during transfection (RET/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the above-mentioned molecular pathways involved in growth, angiogenesis, local and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC and anaplastic thyroid cancer (ATC, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds, and to personalize

  8. Biomarkers and Targeted Therapy in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Fataneh Karandish

    2016-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%–3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

  9. Biomarkers and Targeted Therapy in Pancreatic Cancer.

    Science.gov (United States)

    Karandish, Fataneh; Mallik, Sanku

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%-3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

  10. Apoptosis and Molecular Targeting Therapy in Cancer

    Science.gov (United States)

    Hassan, Mohamed; Watari, Hidemichi; AbuAlmaaty, Ali; Ohba, Yusuke; Sakuragi, Noriaki

    2014-01-01

    Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction. PMID:25013758

  11. Targeted therapy for esophagogastric cancers: a review

    Directory of Open Access Journals (Sweden)

    Khattak MA

    2012-05-01

    Full Text Available Muhammad A Khattak,1 Hilary L Martin,2 Christos S Karapetis1,31Flinders Medical Centre, Adelaide, South Australia; 2Calvary Hospital, Adelaide, SA, Australia; 3Flinders University, Adelaide, SA, AustraliaAbstract: The incidence of esophagogastric cancers is increasing rapidly in the Western population. Despite better understanding of the biology and intense research in the treatment of these cancers, the long-term survival remains poor both in the locally advanced and metastatic settings. The addition of combined modality strategies has resulted in modest improvement in 5-year survival rates. A number of biologic agents targeting epidermal-derived growth factor receptor, vascular endothelial derived growth factor and its receptor, and mammalian target of rapamycin (mTOR are being currently evaluated in Phase II and III clinical trials. Some of these, like trastuzumab, cetuximab, and bevacizumab, have shown promising results. This review provides a brief overview of the recent developments in biologic agents for the treatment of esophagogastric cancers.Keywords: adenocarcinoma, squamous cell carcinoma, VEGF, trastuzumab, Her2- positive EGC

  12. Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency

    Directory of Open Access Journals (Sweden)

    Caitriona McLean

    2009-01-01

    Full Text Available Caitriona McLean*, Catherine M Greene*, Noel G McElvaneyRespiratory Research Division, Dept. Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland; *Each of these authors contributed equally to this workAbstract: Alpha-1 antitrypsin (A1AT is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys. ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs and RNA interference (RNAi, which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.Keywords: alpha-1 antitrypsin deficiency, siRNA, peptide nucleic acid, ribozymes

  13. Neoadjuvant targeted therapy in patients with renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    B. Ya. Alekseev

    2015-01-01

    Full Text Available Cytoreductive nephrectomy as an independent option in patients with metastatic renal cell carcinoma (mRCC cannot be considered as the only effective method, with rare exception, of a few patients with solitary metastases. Cytoreductive nephrectomy is now part of a multimodal approach encompassing surgical treatment and systemic drug therapy. Many retrospective and two prospective studies have demonstrated that it is expedient to perform cytoreductive nephrectomy. Immunotherapy should not be used as preoperatively in the era of cytokine therapy for mRCC due to that fact that it has no impact on primary tumor. In the current targeted therapy era, many investigators have concentrated attentionon the role of neoadjuvant targeted therapy for the treatment of patients with both localized and locally advanced mRCC. The potential benefits of neoadjuvant therapy for localized and locally advanced RCC include to make surgery easier and to increase the possibility of organsparing treatment, by decreasing the stage of primary tumor and the size of tumors. The possible potential advantages of neoadjuvant targeted therapy in patients with mRCC include prompt initiation of necessary systemic therapy; identification of patients with primary refractory tumors; and a preoperative reduction in the stage of primary tumor. Numerous retrospective and some prospective phase II studies have shown that neoadjuvant targeted therapy in patients with localized and locally advanced RCC is possible and tolerable and surgical treatment after neoadjuvant targeted therapy is safe and executable with a low incidence of complications. If neoadjuvant therapy is to be performed, it should be done within 2–4 months before surgery. Sorafenib and sunitinib are now most tested and suitable for neoadjuvant targeted therapy. Sorafenib is a more preferred drug due to its shorter half-life and accordingly to the possibility of discontinuing the drug immediately prior to

  14. Neutrophil superoxide-anion generating capacity in chronic smoking: effect of long-term alpha-tocopherol therapy

    NARCIS (Netherlands)

    Tits, van L.; Waart, de F.; Hak-Lemmers, H.L.M.; Graaf, de J.; Demacker, P.N.; Stalenhoef, A.F.

    2003-01-01

    We investigated whether long-term alpha-tocopherol therapy in chronic smoking affects superoxide generating capacity of neutrophils ex vivo. To this purpose, we randomly assigned 128 male chronic smokers (37 21 pack years of smoking) to treatment with placebo (n = 64) or alpha-tocopherol (400 IU

  15. Inflammation as target in cancer therapy.

    Science.gov (United States)

    Marelli, Giulia; Sica, Antonio; Vannucci, Luca; Allavena, Paola

    2017-08-01

    Cells of the innate immunity infiltrating tumour tissues promote, rather than halt, cancer cell proliferation and distant spreading. Tumour-Associated Macrophages (TAMs) are abundantly present in the tumour milieu and here trigger and perpetrate a state of chronic inflammation which ultimately supports disease development and contributes to an immune-suppressive environment. Therapeutic strategies to limit inflammatory cells and their products have been successful in pre-clinical tumour models. Early clinical trials with specific cytokine and chemokine inhibitors, or with strategies designed to target TAMs, are on their way in different solid malignancies. Partial clinical responses and stabilization of diseases were observed in some patients, in the absence of significant toxicity. These encouraging results open new perspectives of combination treatments aimed at reducing cancer-promoting inflammation to maximize the anti-tumour efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Expression of HIF-1{alpha} in irradiated tissue is altered by topical negative-pressure therapy

    Energy Technology Data Exchange (ETDEWEB)

    Grimm, A.; Stange, S.; Labanaris, A.; Horch, R.E. [Erlangen-Nuernberg Univ., Erlangen (Germany). Dept. of Plastic and Hand Surgery; Dimmler, A. [Erlangen-Nuernberg Univ., Erlangen (Germany). Dept. of Pathology; Sauer, R.; Grabenbauer, G. [Erlangen-Nuernberg Univ. (Germany). Dept. of Radiation Oncology

    2007-03-15

    Background and Purpose: Despite the enormous therapeutic potential of modern radiotherapy, common side effects such as radiation-induced wound healing disorders remain a well-known clinical phenomenon. Topical negative pressure therapy (TNP) is a novel tool to alleviate intraoperative, percutaneous irradiation or brachytherapy. Since TNP has been shown to positively influence the perfusion of chronic, poorly vascularized wounds, the authors applied this therapeutic method to irradiated wounds and investigated the effect on tissue oxygenation in irradiated tissue in five patients. Material and Methods: With informed patients' consent, samples prior to and 4 and 8 days after continuous TNP with -125 mmHg were obtained during routine wound debridements. Granulation tissue was stained with hematoxylin-eosin, and additionally with CD31, HIF-1{alpha} (hypoxia-inducible factor-1{alpha}), and D2-40 to detect blood vessels, measure indirect signs of hypoxia, and lymph vessel distribution within the pre- and post-TNP samples. Results: In this first series of experiments, a positive influence of TNP onto tissue oxygenation in radiation-induced wounds could be demonstrated. TNP led to a significant decrease of 53% HIF-1{alpha}-positive cell nuclei. At the same time, a slight reduction of CD31-stained capillaries was seen in comparison to samples before TNP. Immunostaining with D2-40 revealed an increased number of lymphatic vessels with distended lumina and an alteration of the parallel orientation within the post-TNP samples. Conclusion: This study is, to the authors' knowledge, the first report on a novel previously not described histological marker to demonstrate the effects of TNP on HIF-1{alpha} expression as an indirect marker of tissue oxygenation in irradiated wounds, as demonstrated by a reduction of HIF-1{alpha} concentration after TNP. Since this observation may be of significant value to develop possible new strategies to treat radiation-induced tissue

  17. Targeted therapy in the treatment of malignant gliomas

    Directory of Open Access Journals (Sweden)

    Rimas V Lukas

    2009-05-01

    Full Text Available Rimas V Lukas1, Adrienne Boire2, M Kelly Nicholas1,2 1Department of Neurology; 2Department of Medicine, University of Chicago, Chicago, IL, USAAbstract: Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In addition, we will discuss strategies that target the extracellular matrix in which these cells reside as well as angiogenesis, a process emerging as central to tumor development and growth. Finally, we will briefly touch on the role of neural stem cells as both potential targets as well as delivery vectors for other therapies. Interdependence between these varied pathways, both in maintaining health and in causing disease, is clear. Thus, attempts to easily classify some targeted therapies are problematic.Keywords: glioma, EGFR, mTOR, HDAC, Ras, angiogenesis

  18. Familial breast cancer - targeted therapy in secondary and tertiary prevention.

    Science.gov (United States)

    Kast, Karin; Rhiem, Kerstin

    2015-02-01

    The introduction of an increasing number of individualized molecular targeted therapies into clinical routine mirrors their importance in modern cancer prevention and treatment. Well-known examples for targeted agents are the monoclonal antibody trastuzumab and the selective estrogen receptor modulator tamoxifen. The identification of an unaltered gene in tumor tissue in colon cancer (KRAS) is a predictor for the patient's response to targeted therapy with a monoclonal antibody (cetuximab). Targeted therapy for hereditary breast and ovarian cancer has become a reality with the approval of olaparib for platin-sensitive late relapsed BRCA-associated ovarian cancer in December 2014. This manuscript reviews the status quo of poly-ADP-ribose polymerase inhibitors (PARPi) in the therapy of breast and ovarian cancer as well as the struggle for carboplatin as a potential standard of care for triple-negative and, in particular, BRCA-associated breast cancer. Details of the mechanism of action with information on tumor development are provided, and an outlook for further relevant research is given. The efficacy of agents against molecular targets together with the identification of an increasing number of cancer-associated genes will open the floodgates to a new era of treatment decision-making based on molecular tumor profiles. Current clinical trials involving patients with BRCA-associated cancer explore the efficacy of the molecular targeted therapeutics platinum and PARPi.

  19. Gene targeted therapeutics for liver disease in alpha-1 antitrypsin deficiency.

    LENUS (Irish Health Repository)

    McLean, Caitriona

    2009-01-01

    Alpha-1 antitrypsin (A1AT) is a 52 kDa serine protease inhibitor that is synthesized in and secreted from the liver. Although it is present in all tissues in the body the present consensus is that its main role is to inhibit neutrophil elastase in the lung. A1AT deficiency occurs due to mutations of the A1AT gene that reduce serum A1AT levels to <35% of normal. The most clinically significant form of A1AT deficiency is caused by the Z mutation (Glu342Lys). ZA1AT polymerizes in the endoplasmic reticulum of liver cells and the resulting accumulation of the mutant protein can lead to liver disease, while the reduction in circulating A1AT can result in lung disease including early onset emphysema. There is currently no available treatment for the liver disease other than transplantation and therapies for the lung manifestations of the disease remain limited. Gene therapy is an evolving field which may be of use as a treatment for A1AT deficiency. As the liver disease associated with A1AT deficiency may represent a gain of function possible gene therapies for this condition include the use of ribozymes, peptide nucleic acids (PNAs) and RNA interference (RNAi), which by decreasing the amount of aberrant protein in cells may impact on the pathogenesis of the condition.

  20. Recent advances in targeted drug therapy for hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    FAN Yongqiang

    2018-02-01

    Full Text Available More and more clinical trials have proved the efficacy of targeted drugs in the treatment of hepatocellular carcinoma (HCC. With the development of science and technology, more and more targeted drugs have appeared. In recent years, targeted drugs such as regorafenib and ramucirumab have shown great potential in related clinical trials. In addition, there are ongoing clinical trials for second-line candidate drugs, such as c-Met inhibitors tivantinib and cabozantinib and a VEGFR-2 inhibitor ramucirumab. This article summarizes the advances in targeted drug therapy for HCC and related trial data, which provides a reference for further clinical trials and treatment.

  1. Target volumes in gastric cancer radiation therapy

    International Nuclear Information System (INIS)

    Caudry, M.; Maire, J.P.; Ratoanina, J.L.; Escarmant, P.

    2001-01-01

    The spread of gastric adenocarcinoma may follow three main patterns: hemato-genic, lymphatic and intraperitoneal. A GTV should be considered in preoperative or exclusive radiation therapy. After non-radical surgery, a 'residual GTV' will be defined with the help of the surgeon. The CTV encompasses three intricated volumes. a) A 'tumor bed' volume. After radical surgery, local recurrences appear as frequent as distant metastases. The risk depends upon the depth of parietal invasion and the nodal status. Parietal infiltration may extend beyond macroscopic limits of the tumor, especially in dinitis plastica. Therefore this volume will include: the tumor and the remaining stomach or their 'bed of resection', a part of the transverse colon, the duodenum, the pancreas and the troncus of the portal vein. In postoperative RT, this CTV also includes the jejuno-gastric or jejuno-esophageal anastomosis. b) A peritoneal volume. For practical purposes, two degrees of spread must be considered: (1) contiguous microscopic extension from deeply invasive T3 and T4 tumors, that remain amenable to local sterilization with doses of 45-50 Gy, delivered in a CTV including the peritoneal cavity at the level of the gastric bed, and under the parietal incision; (2) true 'peritoneal carcinomatosis', with widespread seeds, where chemotherapy (systemic or intraperitoneal) is more appropriate. c) A lymphatic volume including the lymph node groups 1 to 16 of the Japanese classification. This volume must encompass the hepatic pedicle and the splenic hilum. In proximal tumors, it is possible to restrict the lover part of the CTV to the lymphatic volume, and therefore to avoid irradiation of large intestinal and renal volumes. In distal and proximal tumors, involvement of resection margins is of poor prognosis -a radiation boost must be delivered at this level. The CTV in tumors of the cardia should encompass the lover part of the thoracic esophagus and the corresponding posterior mediastinum. In

  2. The Alpha Stem Cell Clinic: a model for evaluating and delivering stem cell-based therapies.

    Science.gov (United States)

    Trounson, Alan; DeWitt, Natalie D; Feigal, Ellen G

    2012-01-01

    Cellular therapies require the careful preparation, expansion, characterization, and delivery of cells in a clinical environment. There are major challenges associated with the delivery of cell therapies and high costs that will limit the companies available to fully evaluate their merit in clinical trials, and will handicap their application at the present financial environment. Cells will be manufactured in good manufacturing practice or near-equivalent facilities with prerequisite safety practices in place, and cell delivery systems will be specialized and require well-trained medical and nursing staff, technicians or nurses trained to handle cells once delivered, patient counselors, as well as statisticians and database managers who will oversee the monitoring of patients in relatively long-term follow-up studies. The model proposed for Alpha Stem Cell Clinics will initially use the capacities and infrastructure that exist in the most advanced tertiary medical clinics for delivery of established bone marrow stem cell therapies. As the research evolves, they will incorporate improved procedures and cell preparations. This model enables commercialization of medical devices, reagents, and other products required for cell therapies. A carefully constructed cell therapy clinical infrastructure with the requisite scientific, technical, and medical expertise and operational efficiencies will have the capabilities to address three fundamental and critical functions: 1) fostering clinical trials; 2) evaluating and establishing safe and effective therapies, and 3) developing and maintaining the delivery of therapies approved by the Food and Drug Administration, or other regulatory agencies.

  3. New perspectives on biological HDL-targeted therapies

    OpenAIRE

    Muthuramu, Ilayaraja; Amin, Md Ruhul; De Geest, Bart

    2017-01-01

    According to a modified high-density lipoprotein (HDL) hypothesis, improving HDL function will lead to a decrease of coronary events. The stringent requirement for proving or refuting this hypothesis is that the causal pathway between the therapeutic intervention and a clinically meaningful endpoint obligatory passes through HDL. Infusion therapy of reconstituted HDL particles and human apolipoprotein A-I gene transfer are biological HDL-targeted therapies that are distinguished by HDL specif...

  4. Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Hongguang Sun

    2014-01-01

    Full Text Available Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed “chemical antibodies.” In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy.

  5. Rapid appearance of transient secondary adrenocortical insufficiency after alpha-particle radiation therapy for Cushing's disease

    International Nuclear Information System (INIS)

    Cook, D.M.; Jordan, R.M.; Kendall, J.W.; Linfoot, J.A.

    1976-01-01

    A 17-year-old woman received 12,000 rads of alpha-particle radiation for the treatment of Cushing's disease. One day after the completion of therapy, the patient developed nausea, vomiting, headache, and postural hypotension. Laboratory evaluation demonstrated a marked fall of the previously elevated urinary 17-hydroxycorticosteroids (17-OHCS) and undetectable plasma cortisols. The urinary 17-OHCS transiently returned to supranormal levels but over a 2 1 / 2 -week period decreased and then remained low. The patient also demonstrated a subnormal urinary aldosterone excretion in relation to plasma renin activity (PRA) during 10 mEq/24 h sodium restriction. The remainder of the endocrine evaluation was normal, suggesting that pituitary function otherwise remained intact. One and one-half years after alpha-particle therapy, the patient's urinary 17-OHCS were normal and responded normally to metyrapone. The relationship between urinary aldosterone excretion and PRA also was normal. It is postulated that there was an infarction of an ACTH secreting pituitary tumor leaving the remainder of the pituitary intact. A chronically elevated circulating level of ACTH with sudden loss of ACTH secretion appeared to have been responsible for the initial low urinary aldosterone as well as the low urinary 17-OHCS. This is the first reported case of a presumed pituitary tumor infarction in association with alpha-particle pituitary radiation

  6. Targeting therapy-resistant cancer stem cells by hyperthermia

    DEFF Research Database (Denmark)

    Oei, A L; Vriend, L E M; Krawczyk, P M

    2017-01-01

    Eradication of all malignant cells is the ultimate but challenging goal of anti-cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy-resistant. A subpopulation of cancer cells, the cancer stem cells...... are limited. Here, we argue that hyperthermia - a therapeutic approach based on local heating of a tumour - is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising...

  7. Individualized therapies in colorectal cancer: KRAS as a marker for response to EGFR-targeted therapy

    Directory of Open Access Journals (Sweden)

    Li Kuiyuan

    2009-04-01

    Full Text Available Abstract Individualized therapies that are tailored to a patient's genetic composition will be of tremendous value for treatment of cancer. Recently, Kirsten ras (KRAS status has emerged as a predictor of response to epidermal growth factor receptor (EGFR targeted therapies. In this article, we will discuss targeted therapies for colorectal cancers (CRC based on EGFR signaling pathway and review published data about the potential usefulness of KRAS as a biological marker for response to these therapies. Results from relevant studies published since 2005 and unpublished results presented at national meetings were retrieved and summarized. These studies reflected response (or lack of response to EGFR-targeted therapies in patients with metastatic CRC as a function of KRAS status. It has become clear that patients with colorectal cancer whose tumor has an activating mutation in KRAS do not respond to monoclonal antibody therapies targeting EGFR. It should now become a standard practice that any patients being considered for EGFR targeted therapies have their tumors tested for KRAS status and only those with wild-type KRAS being offered such therapies.

  8. Palliative nephrectomy until targeted therapy of disseminated kidney cancer patients

    Directory of Open Access Journals (Sweden)

    A. V. Klimov

    2015-01-01

    Full Text Available Objective: to assess the role of palliative nephrectomy in disseminated kidney cancer patients planned to undergo targeted antiangiogenic treatment.Subjects and methods. The investigation included data on 83 patients with T1-4N0 / +M1 disseminated renal cell carcinoma (RCC who had received at least 2 targeted therapy cycles in 2009 to 2011. In 48 (57.8 % patients, the treatment was preceded by palliative nephrectomy that was not carried out in 35 (42.2 %. Before starting targeted therapy, all the cases were confirmed to be diagnosed with clear cell RCC, with a sarcomatoid component being in 7 (8.4 % patients. The median follow-up of all the patients was 21 (12–36 months.Results. The unremoved affected kidney in disseminated kidney cancer patients receiving targeted antiangiogenic therapy is an independent factor for the poor prognosis of progression-free (odds ratio (OR, 2.4; 95 % confidence interval (CI, 1.2–4.7 and overall (OR, 2.8; 95 % CI, 1.3–6.3 survival. Palliative nephrectomy does not improve the prognosis in patients with a low somatic status, the N+ category, and metastases into the bones and nonregional lymph nodes.Conclusion. Palliative nephrectomy in the selected patients with disseminated kidney cancer on targeted antiangiogenic therapy increases progression-free and overall survival.

  9. Metastatic gastric cancer – focus on targeted therapies

    Directory of Open Access Journals (Sweden)

    Meza-Junco J

    2012-06-01

    Full Text Available Judith Meza-Junco, Michael B SawyerDepartment of Oncology, Cross Cancer Institute, Edmonton, Alberta, CanadaAbstract: Gastric cancer (GC is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.Keywords: gastric cancer, targeted therapy, antiangiogenesis drugs, anti-EGFR drugs

  10. Heart failure—potential new targets for therapy

    Science.gov (United States)

    Nabeebaccus, Adam; Zheng, Sean; Shah, Ajay M.

    2016-01-01

    Abstract Introduction/background Heart failure is a major cause of cardiovascular morbidity and mortality. This review covers current heart failure treatment guidelines, emerging therapies that are undergoing clinical trial, and potential new therapeutic targets arising from basic science advances. Sources of data A non-systematic search of MEDLINE was carried out. International guidelines and relevant reviews were searched for additional articles. Areas of agreement Angiotensin-converting enzyme inhibitors and beta-blockers are first line treatments for chronic heart failure with reduced left ventricular function. Areas of controversy Treatment strategies to improve mortality in heart failure with preserved left ventricular function are unclear. Growing points Many novel therapies are being tested for clinical efficacy in heart failure, including those that target natriuretic peptides and myosin activators. A large number of completely novel targets are also emerging from laboratory-based research. Better understanding of pathophysiological mechanisms driving heart failure in different settings (e.g. hypertension, post-myocardial infarction, metabolic dysfunction) may allow for targeted therapies. Areas timely for developing research Therapeutic targets directed towards modifying the extracellular environment, angiogenesis, cell viability, contractile function and microRNA-based therapies. PMID:27365454

  11. Inducement of radionuclides targeting therapy by gene transfection

    International Nuclear Information System (INIS)

    Luo Quanyong

    2001-01-01

    The author presents an overview of gene transfection methods to genetically induce tumor cells to express enhanced levels of cell surface antigens and receptors to intake radiolabeled antibody and peptide targeting and thus increase their therapeutic effect in radiotherapy. The current research include inducement of radioimmunotherapy through CEA gene transfection, inducement of iodine-131 therapy by sodium iodide symporter gene transfection and inducement of MIBG therapy by noradrenaline transporter gene transfection. These studies raise the prospect that gene-therapy techniques could be used to enable the treatment of a wide range of tumors with radiopharmaceuticals of established clinical acceptability

  12. Mutational analysis of target enzyme recognition of the beta-trefoil fold barley alpha-amylase/subtilisin inhibitor

    DEFF Research Database (Denmark)

    Bønsager, Birgit Christine; Nielsen, Per K.; Abou Hachem, Maher

    2005-01-01

    The barley alpha-amylase/subtilisin inhibitor ( BASI) inhibits alpha-amylase 2 (AMY2) with subnanomolar affinity. The contribution of selected side chains of BASI to this high affinity is discerned in this study, and binding to other targets is investigated. Seven BASI residues along the AMY2-BASI...... interface and four residues in the putative protease-binding loop on the opposite side of the inhibitor were mutated. A total of 15 variants were compared with the wild type by monitoring the alpha-amylase and protease inhibitory activities using Blue Starch and azoalbumin, respectively, and the kinetics...

  13. Targeted therapies for diarrhea-predominant irritable bowel syndrome

    OpenAIRE

    Olden, Kevin W

    2012-01-01

    Kevin W OldenDepartment of Medicine, St Joseph's Hospital and Medical Center, Phoenix, AZ, USAAbstract: Irritable bowel syndrome (IBS) causes gastrointestinal symptoms such as abdominal pain, bloating, and bowel pattern abnormalities, which compromise patients' daily functioning. Common therapies address one or two IBS symptoms, while others offer wider symptom control, presumably by targeting pathophysiologic mechanisms of IBS. The aim of this targeted literature review was t...

  14. Targeted Therapies for Myeloma and Metastatic Bone Cancers

    Science.gov (United States)

    2010-09-01

    Cancer J Clin 2003; 53:5. Kasugai S, Fujisawa R, Waki Y, Miyamoto K, Ohya K 2000 Selective drug delivery system to bone: small peptide (Asp)6...page. Bone targeted nanoparticles , bone cancer myeloma, mice studies, PLGA , Biodegradable materials. Targeted Therapies for Myeloma and Metastatic Bone...present results from this program at talk at the Particles 2006 –Medical/Biochemical Diagnostic , Pharmaceutical, and Drug Delivery . 3

  15. New Molecular Targets of Anticancer Therapy - Current Status and Perspectives.

    Science.gov (United States)

    Zajac, Marianna; Muszalska, Izabela; Jelinska, Anna

    2016-01-01

    Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their

  16. Nanobody-photosensitizer conjugates for targeted photodynamic therapy

    NARCIS (Netherlands)

    Heukers, Raimond; van Bergen en Henegouwen, P; Oliveira, Sabrina

    2014-01-01

    Photodynamic therapy (PDT) induces cell death through light activation of a photosensitizer (PS). Targeted delivery of PS via monoclonal antibodies has improved tumor selectivity. However, these conjugates have long half-lives, leading to relatively long photosensitivity in patients. In an attempt

  17. Auger radiation targeted into DNA: a therapy perspective

    International Nuclear Information System (INIS)

    Buchegger, Franz; Perillo-Adamer, Florence; Bischof Delaloye, Angelika; Dupertuis, Yves M.

    2006-01-01

    Auger electron emitters that can be targeted into DNA of tumour cells represent an attractive systemic radiation therapy goal. In the situation of DNA-associated decay, the high linear energy transfer (LET) of Auger electrons gives a high relative biological efficacy similar to that of α particles. In contrast to α radiation, however, Auger radiation is of low toxicity when decaying outside the cell nucleus, as in cytoplasm or outside cells during blood transport. The challenge for such therapies is the requirement to target a high percentage of all cancer cells. An overview of Auger radiation therapy approaches of the past decade shows several research directions and various targeting vehicles. The latter include hormones, peptides, halogenated nucleotides, oligonucleotides and internalising antibodies. Here, we will discuss the basic principles of Auger electron therapy as compared with vector-guided α and β radiation. We also review some radioprotection issues and briefly present the main advantages and disadvantages of the different targeting modalities that are under investigation. (orig.)

  18. Targeted therapies in the treatment of urothelial cancers.

    Science.gov (United States)

    Aragon-Ching, Jeanny B; Trump, Donald L

    2017-07-01

    Progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years. However, the recent approval of immunotherapy with atezolizumab and nivolumab for second-line salvage therapy may usher in an era of more rapid improvement. Systemic treatment is suboptimal and is an area of substantial unmet medical need. The recent findings from The Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies. Promising results with treatment using vascular endothelial growth factor inhibitors such as ramucirumab, sunitinib or bevacizumab, and human epidermal growth factor receptor 2 targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials and are discussed later. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

    Energy Technology Data Exchange (ETDEWEB)

    Fillat, Cristina, E-mail: cristina.fillat@crg.es; Jose, Anabel; Ros, Xavier Bofill-De; Mato-Berciano, Ana; Maliandi, Maria Victoria; Sobrevals, Luciano [Programa Gens i Malaltia, Centre de Regulació Genòmica-CRG, UPF, Parc de Recerca Biomedica de Barcelona-PRBB and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona (Spain)

    2011-01-18

    The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed.

  20. Chromatin-regulating proteins as targets for cancer therapy

    International Nuclear Information System (INIS)

    Oike, Takahiro; Ogiwara, Hideaki; Kohno, Takashi; Amornwichet, Napapat; Nakano, Takashi

    2014-01-01

    Chromatin-regulating proteins represent a large class of novel targets for cancer therapy. In the context of radiotherapy, acetylation and deacetylation of histones by histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in the repair of DNA double-strand breaks generated by ionizing irradiation, and are therefore attractive targets for radiosensitization. Small-molecule inhibitors of HATs (garcinol, anacardic acid and curcumin) and HDACs (vorinostat, sodium butyrate and valproic acid) have been shown to sensitize cancer cells to ionizing irradiation in preclinical models, and some of these molecules are being tested in clinical trials, either alone or in combination with radiotherapy. Meanwhile, recent large-scale genome analyses have identified frequent mutations in genes encoding chromatin-regulating proteins, especially in those encoding subunits of the SWI/SNF chromatin-remodeling complex, in various human cancers. These observations have driven researchers toward development of targeted therapies against cancers carrying these mutations. DOT1L inhibition in MLL-rearranged leukemia, EZH2 inhibition in EZH2-mutant or MLL-rearranged hematologic malignancies and SNF5-deficient tumors, BRD4 inhibition in various hematologic malignancies, and BRM inhibition in BRG1-deficient tumors have demonstrated promising anti-tumor effects in preclinical models, and these strategies are currently awaiting clinical application. Overall, the data collected so far suggest that targeting chromatin-regulating proteins is a promising strategy for tomorrow's cancer therapy, including radiotherapy and molecularly targeted chemotherapy. (author)

  1. Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy

    NARCIS (Netherlands)

    Cui, Jing; Saevarsdottir, Saedis; Thomson, Brian; Padyukov, Leonid; van der Helm-van Mil, Annette H. M.; Nititham, Joanne; Hughes, Laura B.; de Vries, Niek; Raychaudhuri, Soumya; Alfredsson, Lars; Askling, Johan; Wedrén, Sara; Ding, Bo; Guiducci, Candace; Wolbink, Gert Jan; Crusius, J. Bart A.; van der Horst-Bruinsma, Irene E.; Herenius, Marieke; Weinblatt, Michael E.; Shadick, Nancy A.; Worthington, Jane; Batliwalla, Franak; Kern, Marlena; Morgan, Ann W.; Wilson, Anthony G.; Isaacs, John D.; Hyrich, Kimme; Seldin, Michael F.; Moreland, Larry W.; Behrens, Timothy W.; Allaart, Cornelia F.; Criswell, Lindsey A.; Huizinga, Tom W. J.; Tak, Paul P.; Bridges, S. Louis; Toes, Rene E. M.; Barton, Anne; Klareskog, Lars; Gregersen, Peter K.; Karlson, Elizabeth W.; Plenge, Robert M.

    2010-01-01

    OBJECTIVE: Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. METHODS: A total

  2. Augmentation therapy with alpha1-antitrypsin: patterns of use and adverse events.

    Science.gov (United States)

    Stoller, James K; Fallat, Robert; Schluchter, Mark D; O'Brien, Ralph G; Connor, Jason T; Gross, Nicholas; O'Neil, Kevin; Sandhaus, Robert; Crystal, Ronald G

    2003-05-01

    To describe patterns of prescribing augmentation therapy, and types and rates of adverse events in the National Heart, Lung, and Blood Institute Registry for Individuals with Severe Deficiency of Alpha(1)-Antitrypsin. Observational cohort study with follow-up visits every 6 to 12 months for up to 7 years. The rate and dosing frequency with which Registry participants were prescribed to receive augmentation therapy by their managing physicians, and the type and frequency of adverse events, classified in two ways: severity of self-reported symptoms, and actions taken as a consequence of the symptom. Over the course of Registry follow-up, 66% (n = 747) of the participants received augmentation therapy at some time. In keeping with recommendations made in the 1989 American Thoracic Society (ATS) statement, 75% of participants with airflow obstruction at first visit (defined as FEV(1) or = 80% predicted (14%) also received augmentation therapy. Among those with COPD for whom augmentation therapy was not prescribed, financial constraints were the reported cause in 30%. Observed patterns also varied from approved practice, in that dosing frequencies other than the US Food and Drug Administration-approved, once-weekly regimen were frequently prescribed. The overall rate of reported adverse events was 0.02 per patient-month, with 83% of participants reporting no events. This overall rate was composed of 16% considered mild events, 76% moderate events, and 9% severe events. We conclude that augmentation therapy was generally well tolerated and, consistent with ATS guidelines, physicians generally did not prescribe augmentation therapy for subjects with FEV(1) > or = 80% predicted. However, the large percentage of subjects with FEV(1) <80% predicted not receiving augmentation therapy and the frequent use of 2- to 3-week or monthly dosing reflects variation of practice from suggested treatment guidelines.

  3. DNA repair in cancer: emerging targets for personalized therapy

    International Nuclear Information System (INIS)

    Abbotts, Rachel; Thompson, Nicola; Madhusudan, Srinivasan

    2014-01-01

    Genomic deoxyribonucleic acid (DNA) is under constant threat from endogenous and exogenous DNA damaging agents. Mammalian cells have evolved highly conserved DNA repair machinery to process DNA damage and maintain genomic integrity. Impaired DNA repair is a major driver for carcinogenesis and could promote aggressive cancer biology. Interestingly, in established tumors, DNA repair activity is required to counteract oxidative DNA damage that is prevalent in the tumor microenvironment. Emerging clinical data provide compelling evidence that overexpression of DNA repair factors may have prognostic and predictive significance in patients. More recently, DNA repair inhibition has emerged as a promising target for anticancer therapy. Synthetic lethality exploits intergene relationships where the loss of function of either of two related genes is nonlethal, but loss of both causes cell death. Exploiting this approach by targeting DNA repair has emerged as a promising strategy for personalized cancer therapy. In the current review, we focus on recent advances with a particular focus on synthetic lethality targeting in cancer

  4. Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy

    Science.gov (United States)

    Yu, Mi Kyung; Park, Jinho; Jon, Sangyong

    2012-01-01

    Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications. PMID:22272217

  5. RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Stéphane Mathis

    2018-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

  6. RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Mathis, Stéphane; Le Masson, Gwendal

    2018-01-15

    Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

  7. Anti-TNF-alpha therapy does not modulate leptin in patients with severe rheumatoid arthritis.

    Science.gov (United States)

    Gonzalez-Gay, M A; Garcia-Unzueta, M T; Berja, A; Gonzalez-Juanatey, C; Miranda-Filloy, J A; Vazquez-Rodriguez, T R; de Matias, J M; Martin, J; Dessein, P H; Llorca, J

    2009-01-01

    The adipocytokine leptin regulates weight centrally and participates in the regulation of the immune and inflammatory responses. Chronic systemic inflammation is of major importance in the development of atherosclerosis in rheumatoid arthritis (RA). In the present study we investigated whether inflammation, obesity or both of these characteristics are potential determinants of circulating leptin concentrations in a group of RA patients on periodical treatment with the TNF-alpha-blocker-infliximab due to severe disease. We also assessed whether the infusion of infliximab may alter circulating leptin concentrations in patients with severe RA. We investigated 33 patients with RA on periodical treatment with infliximab. Serum leptin levels were determined immediately prior to and after infliximab infusion. There was a positive correlation between body mass index of RA patients and baseline serum level of leptin (rho=0.665, pghrelin or the cumulative prednisone dose at the time of the study were found. Leptin levels did not change upon infliximab infusion (p=0.48). In RA patients on TNF-alpha blocker treatment, circulating leptin levels are unrelated to disease activity but constitute a manifestation of adiposity. The beneficial effect of anti-TNF-alpha therapy on cardiovascular mortality in RA does not seem to be mediated by reduction in serum levels of leptin.

  8. Alpha-1 antitrypsin protein and gene therapies decrease autoimmunity and delay arthritis development in mouse model

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    Atkinson Mark A

    2011-02-01

    Full Text Available Abstract Background Alpha-1 antitrypsin (AAT is a multi-functional protein that has anti-inflammatory and tissue protective properties. We previously reported that human AAT (hAAT gene therapy prevented autoimmune diabetes in non-obese diabetic (NOD mice and suppressed arthritis development in combination with doxycycline in mice. In the present study we investigated the feasibility of hAAT monotherapy for the treatment of chronic arthritis in collagen-induced arthritis (CIA, a mouse model of rheumatoid arthritis (RA. Methods DBA/1 mice were immunized with bovine type II collagen (bCII to induce arthritis. These mice were pretreated either with hAAT protein or with recombinant adeno-associated virus vector expressing hAAT (rAAV-hAAT. Control groups received saline injections. Arthritis development was evaluated by prevalence of arthritis and arthritic index. Serum levels of B-cell activating factor of the TNF-α family (BAFF, antibodies against both bovine (bCII and mouse collagen II (mCII were tested by ELISA. Results Human AAT protein therapy as well as recombinant adeno-associated virus (rAAV8-mediated hAAT gene therapy significantly delayed onset and ameliorated disease development of arthritis in CIA mouse model. Importantly, hAAT therapies significantly reduced serum levels of BAFF and autoantibodies against bCII and mCII, suggesting that the effects are mediated via B-cells, at least partially. Conclusion These results present a new drug for arthritis therapy. Human AAT protein and gene therapies are able to ameliorate and delay arthritis development and reduce autoimmunity, indicating promising potential of these therapies as a new treatment strategy for RA.

  9. Interferon alpha 2 maintenance therapy may enable high rates of treatment discontinuation in chronic myeloid leukemia.

    Science.gov (United States)

    Burchert, A; Saussele, S; Eigendorff, E; Müller, M C; Sohlbach, K; Inselmann, S; Schütz, C; Metzelder, S K; Ziermann, J; Kostrewa, P; Hoffmann, J; Hehlmann, R; Neubauer, A; Hochhaus, A

    2015-06-01

    A minority of chronic myeloid leukemia (CML) patients is capable of successfully discontinuing imatinib. Treatment modalities to increase this proportion are currently unknown. Here, we assessed the role of interferon alpha 2a (IFN) on therapy discontinuation in a previously reported cohort of 20 chronic phase CML patients who were treated upfront with IFN alpha plus imatinib followed by IFN monotherapy to maintain cytogenetic or molecular remission (MR) after imatinib discontinuation. After a median follow-up of 7.9 years (range, 5.2-12.2), relapse-free survival was 73% (8/11 patients) and 84% (5/6 patients) for patients who discontinued imatinib in major MR (MMR) and MR4/MR4.5, respectively. Ten patients discontinued IFN after a median of 4.5 years (range, 0.24-9.3). After a median of 2.8 years (range, 0.7-5.1), nine of them remain in ongoing treatment-free remission with MR5 (n=6) and MR4.5 (n=3). The four patients who still administer IFN are in stable MR5, MR4.5, MR4, and MMR, respectively. In conclusion, an IFN/imatinib induction treatment followed by a temporary IFN maintenance therapy may enable a high rate of treatment discontinuation in CML patients in at least MMR when stopping imatinib.

  10. Financial relationships in economic analyses of targeted therapies in oncology.

    Science.gov (United States)

    Valachis, Antonis; Polyzos, Nikolaos P; Nearchou, Andreas; Lind, Pehr; Mauri, Davide

    2012-04-20

    A potential financial relationship between investigators and pharmaceutical manufacturers has been associated with an increased likelihood of reporting favorable conclusions about a sponsor's proprietary agent in pharmacoeconomic studies. The purpose of this study is to investigate whether there is an association between financial relationships and outcome in economic analyses of new targeted therapies in oncology. We searched PubMed (last update June 2011) for economic analyses of targeted therapies (including monoclonal antibodies, tyrosine-kinase inhibitors, and mammalian target of rapamycin inhibitors) in oncology. The trials were qualitatively rated regarding the cost assessment as favorable, neutral, or unfavorable on the basis of prespecified criteria. Overall, 81 eligible studies were identified. Economic analyses that were funded by pharmaceutical companies were more likely to report favorable qualitative cost estimates (28 [82%] of 34 v 21 [45%] of 47; P = .003). The presence of an author affiliated with manufacturer was not associated with study outcome. Furthermore, if only studies including a conflict of interest statement were included (66 of 81), studies that reported any financial relationship with manufacturers (author affiliation and/or funding and/or other financial relationship) were more likely to report favorable results of targeted therapies compared with studies without financial relationship (32 [71%] of 45 v nine [43%] of 21; P = .025). Our study reveals a potential threat for industry-related bias in economic analyses of targeted therapies in oncology in favor of analyses with financial relationships between authors and manufacturers. A more balanced funding of economic analyses from other sources may allow greater confidence in the interpretation of their results.

  11. Cancer gene therapy targeting angiogenesis: An updated Review

    Science.gov (United States)

    Liu, Ching-Chiu; Shen, Zan; Kung, Hsiang-Fu; Lin, Marie CM

    2006-01-01

    Since the relationship between angiogenesis and tumor growth was established by Folkman in 1971, scientists have made efforts exploring the possibilities in treating cancer by targeting angiogenesis. Inhibition of angiogenesis growth factors and administration of angiogenesis inhibitors are the basics of anti-angiogenesis therapy. Transfer of anti-angiogenesis genes has received attention recently not only because of the advancement of recombinant vectors, but also because of the localized and sustained expression of therapeutic gene product inside the tumor after gene transfer. This review provides the up-to-date information about the strategies and the vectors studied in the field of anti-angiogenesis cancer gene therapy. PMID:17109514

  12. Alpha-bungarotoxin binding to target cell in a developing visual system by carboxylated nanodiamond

    Energy Technology Data Exchange (ETDEWEB)

    Liu, K-K; Chen, P-Y; Lee, Tony J F; Chao, J-I [Institute of Pharmacology and Toxicology, Tzu Chi University, Hualien 970, Taiwan (China); Chen, M-F [Neuro-Medical Scientific Center, Tzu Chi General Hospital, Hualien 970, Taiwan (China); Cheng, C-L [Department of Physics, National Dong Hwa University, Hualien 974, Taiwan (China); Chang, C-C [Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu 300, Taiwan (China); Ho, Y-P [Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan (China)], E-mail: chaoji@mail.tcu.edu.tw

    2008-05-21

    Biological molecules conjugating with nanoparticles are valuable for applications including bio-imaging, bio-detection, and bio-sensing. Nanometer-sized diamond particles have excellent electronic and chemical properties for bio-conjugation. In this study, we manipulated the carboxyl group produced on the surface of nanodiamond (carboxylated nanodiamond, cND) for conjugating with alpha-bungarotoxin ({alpha}-BTX), a neurotoxin derived from Bungarus multicinctus with specific blockade of alpha7-nicotinic acetylcholine receptor ({alpha}7-nAChR). The electrostatic binding of cND-{alpha}-BTX was mediated by the negative charge of the cND and the positive charge of the {alpha}-BTX in physiological pH conditions. Sodium dodecyl sulfate-polyacrylamide gel analysis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF-MS) spectra displayed that {alpha}-BTX proteins were conjugated with cND particles via non-covalent bindings. The green fluorescence of the cND particles combining with the red fluorescence of tetramethylrhodamine-labeled {alpha}-BTX presented a yellow color at the same location, which indicated that {alpha}-BTX proteins were conjugated with cND particles. Xenopus laevis's oocytes expressed the human {alpha}7-nAChR proteins by microinjection with {alpha}7-nAChR mRNA. The cND-{alpha}-BTX complexes were bound to {alpha}7-nAChR locating on the cell membrane of oocytes and human lung A549 cancer cells analyzed by laser scanning confocal microscopy. The choline-evoked {alpha}7-nAChR-mediated inward currents of the oocytes were blocked by cND-{alpha}-BTX complexes in a concentration-dependent manner using two-electrode voltage-clamp recording. Furthermore, the fluorescence intensity of cND-{alpha}-BTX binding on A549 cells could be quantified by flow cytometry. These results indicate that cND-conjugated {alpha}-BTX still preserves its biological activity in blocking the function of {alpha}7-nAChR, and provide a visual

  13. Development of lithium target for accelerator based neutron capture therapy

    International Nuclear Information System (INIS)

    Taskaev, Sergey; Bayanov, Boris; Belov, Victor; Zhoorov, Eugene

    2006-01-01

    Pilot innovative accelerator based neutron source for neutron capture therapy of cancer is now of the threshold of its operation at the BINP, Russia. One of the main elements of the facility is lithium target producing neutrons via threshold 7 Li(p,n) 7 Be reaction at 25 kW proton beam with energies 1.915 MeV or 2.5 MeV. The main problems of lithium target were determined to be: 7 Be radioactive isotope activation keeping lithium layer solid, presence of photons due to proton inelastic scattering on lithium nuclei, and radiation blistering. The results of thermal test of target prototype were presented as previous NCT Congress. It becomes clear that water is preferable for cooling the target, and that lithium target 10 cm in diameter is able to run before melting. In the present report, the conception of optimal target is proposed: thin metal disk 10 cm in diameter easy for detaching, with evaporated thin layer of pure lithium from the side of proton beam exposure, its back being intensively cooled with turbulent water flow to maintain lithium layer solid. Design of the target for the neutron source constructed at BINP is shown. The results of investigation of radiation blistering and lithium layer are presented. Target unit of facility is under construction now, and obtaining neutrons is expected in nearest future. (author)

  14. Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies.

    Science.gov (United States)

    Ransohoff, Julia D; Kwong, Bernice Y

    2017-12-01

    The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies. We systematically review according to drug-targeting pathway the cutaneous AE profiles of these drugs, and offer insight when possible into whether pharmacologic target versus immunologic modulation primarily underlie presentation. We include discussion of tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib), blinatumomab, ibrutinib, idelalisib, anti-B cell antibodies (rituximab, ibritumomab, obinutuzumab, ofatumumab, tositumomab), immune checkpoint inhibitors (nivolumab, pembrolizumab), alemtuzumab, brentuximab, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib). We highlight skin reactions seen with antiliquid but not solid tumor agents, draw attention to serious cutaneous AEs that might require therapy modification or cessation, and offer management strategies to permit treatment tolerability. We emphasize the importance of early diagnosis and treatment to minimize disruptions to care, optimize prognosis and quality of life, and promptly address life-threatening skin or infectious events. This evolving partnership between oncologists and dermatologists in the iterative characterization and management of skin toxicities will contribute to a better understanding of these drugs' cutaneous targets and improved patient care. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Targeting Jurkat T Lymphocyte Leukemia Cells by an Engineered Interferon-Alpha Hybrid Molecule

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    Dehai Yu

    2017-06-01

    Full Text Available Background/Aims: Adult T-cell leukemia/lymphoma (ATL is a very aggressive T cell malignancy that carries a poor prognosis, primarily due to its resistance to chemotherapy and to life-threatening infectious complications. Interferon-alpha (IFNα has been used in combination with the anti-retroviral drug zidovudine to treat patients with ATL. However, the efficacy of long-term therapy is significantly limited due to the systemic toxicity of IFNα. Methods: We utilized phage display library screening to identify short peptides that specifically bind to Jurkat T lymphocyte leukemia cells. By fusing the Jurkat-binding peptide to the C-terminus of IFNα, we constructed an engineered chimeric IFNα molecule (IFNP for the treatment of ATL. Results: We found that IFNP exhibited significantly higher activity than wild type IFNα in inhibiting the growth of leukemia cells and inducing cell blockage at the G0/G1 phase. The synthetic IFNP molecule exerted its antitumor activity by upregulating the downstream genes involved in the STAT1 pathway and in apoptosis. Using a cell receptor binding assay, we showed that this Jurkat-binding peptide facilitated the binding affinity of IFNα to the cell surface type I IFN receptor. Conclusion: The isolated Jurkat-binding peptide significantly potentiates the therapeutic activity of IFNα in T lymphocyte leukemia cells. The engineered IFNP molecule may prove to a novel antitumor approach in the treatment of patients with ATL.

  16. Epithelioid Sarcoma: Opportunities for Biology-driven Targeted Therapy

    Directory of Open Access Journals (Sweden)

    Jonathan eNoujaim

    2015-08-01

    Full Text Available Epithelioid sarcoma is a soft tissue sarcoma of children and young adults for which the preferred treatment for localised disease is wide surgical resection. Medical management is to a great extent undefined, and therefore for patients with regional and distal metastases, the development of targeted therapies is greatly desired. In this review we will summarize clinically-relevant biomarkers (e.g., SMARCB1, CA125, dysadherin and others with respect to targeted therapeutic opportunities. We will also examine the role of EGFR, mTOR and polykinase inhibitors (e.g., sunitinib in the management of local and disseminated disease. Towards building a consortium of pharmaceutical, academic and non-profit collaborators, we will discuss the state of resources for investigating epithelioid sarcoma with respect to cell line resources, tissue banks, and registries so that a roadmap can be developed towards effective biology-driven therapies.

  17. Epithelioid Sarcoma: Opportunities for Biology-Driven Targeted Therapy.

    Science.gov (United States)

    Noujaim, Jonathan; Thway, Khin; Bajwa, Zia; Bajwa, Ayeza; Maki, Robert G; Jones, Robin L; Keller, Charles

    2015-01-01

    Epithelioid sarcoma (ES) is a soft tissue sarcoma of children and young adults for which the preferred treatment for localized disease is wide surgical resection. Medical management is to a great extent undefined, and therefore for patients with regional and distal metastases, the development of targeted therapies is greatly desired. In this review, we will summarize clinically relevant biomarkers (e.g., SMARCB1, CA125, dysadherin, and others) with respect to targeted therapeutic opportunities. We will also examine the role of EGFR, mTOR, and polykinase inhibitors (e.g., sunitinib) in the management of local and disseminated disease. Toward building a consortium of pharmaceutical, academic, and non-profit collaborators, we will discuss the state of resources for investigating ES with respect to cell line resources, tissue banks, and registries so that a roadmap can be developed toward effective biology-driven therapies.

  18. Cancer Nanomedicine: From Targeted Delivery to Combination Therapy

    Science.gov (United States)

    Xu, Xiaoyang; Ho, William; Zhang, Xueqing; Bertrand, Nicolas; Farokhzad, Omid

    2015-01-01

    The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of a variety of diseases, including cancer. The unique properties of nanoparticles, such as large surface-to volume ratio, small size, the ability to encapsulate a variety of drugs, and tunable surface chemistry, gives them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make nanoparticles a mode of treatment potentially superior to conventional cancer therapies. This article highlights the most recent developments in cancer treatment using nanoparticles as drug-delivery vehicles, including promising opportunities in targeted and combination therapy. PMID:25656384

  19. Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

    NARCIS (Netherlands)

    Kuijper, Arno; Groep, P. van der; Wall, E. van der; Diest, P.J. van

    2005-01-01

    INTRODUCTION Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance

  20. Adoptive T cell therapy targeting CD1 and MR1

    Directory of Open Access Journals (Sweden)

    Tingxi eGuo

    2015-05-01

    Full Text Available Adoptive T cell immunotherapy has demonstrated clinically relevant efficacy in treating malignant and infectious diseases. However, much of these therapies have been focused on enhancing, or generating de novo, effector functions of conventional T cells recognizing HLA molecules. Given the heterogeneity of HLA alleles, mismatched patients are ineligible for current HLA-restricted adoptive T cell therapies. CD1 and MR1 are class I-like monomorphic molecules and their restricted T cells possess unique T cell receptor specificity against entirely different classes of antigens. CD1 and MR1 molecules present lipid and vitamin B metabolite antigens, respectively, and offer a new front of targets for T cell therapies. This review will cover the recent progress in the basic research of CD1, MR1, and their restricted T cells that possess translational potential.

  1. Targeted therapies for diarrhea-predominant irritable bowel syndrome

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    Olden KW

    2012-05-01

    Full Text Available Kevin W OldenDepartment of Medicine, St Joseph's Hospital and Medical Center, Phoenix, AZ, USAAbstract: Irritable bowel syndrome (IBS causes gastrointestinal symptoms such as abdominal pain, bloating, and bowel pattern abnormalities, which compromise patients' daily functioning. Common therapies address one or two IBS symptoms, while others offer wider symptom control, presumably by targeting pathophysiologic mechanisms of IBS. The aim of this targeted literature review was to capture clinical trial reports of agents receiving the highest recommendation (Grade 1 for treatment of IBS from the 2009 American College of Gastroenterology IBS Task Force, with an emphasis on diarrhea-predominant IBS. Literature searches in PubMed captured articles detailing randomized placebo-controlled trials in IBS/diarrhea-predominant IBS for agents receiving Grade I (strong 2009 American College of Gastroenterology IBS Task Force recommendations: tricyclic antidepressants, nonabsorbable antibiotics, and the 5-HT3 receptor antagonist alosetron. Studies specific for constipation-predominant IBS were excluded. Tricyclic antidepressants appear to improve global IBS symptoms but have variable effects on abdominal pain and uncertain tolerability; effects on stool consistency, frequency, and urgency were not adequately assessed. Nonabsorbable antibiotics show positive effects on global symptoms, abdominal pain, bloating, and stool consistency but may be most efficacious in patients with altered intestinal microbiota. Alosetron improves global symptoms and abdominal pain and normalizes bowel irregularities, including stool frequency, consistency, and fecal urgency. Both the nonabsorbable antibiotic rifaximin and the 5-HT3 receptor antagonist alosetron improve quality of life. Targeted therapies provide more complete relief of IBS symptoms than conventional agents. Familiarization with the quantity and quality of evidence of effectiveness can facilitate more individualized

  2. Targeting Signaling to YAP for the Therapy of NF2

    Science.gov (United States)

    2015-10-01

    which encodes the FERM domain-containing protein Merlin. Children and young adults, who inherit an NF2 mutation, develop Schwannomas, usually of the...targeted therapy in the same way Chronic Myelogenous Leukemia is cured by Gleevec. The prospect of resistance is minimal, as Schwannoma cells do not seem to... treatment with Verteporfin, suggesting that this reporter system is not sensitive enough in physiopathologically relevant cell types. In parallel, it

  3. Targeted Therapy for Medullary Thyroid Cancer: A Review

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    S. R. Priya

    2017-10-01

    Full Text Available Medullary thyroid cancers (MTCs constitute between 2 and 5% of all thyroid cancers. The 10-year overall survival (OS rate of patients with localized disease is around 95% while that of patients with regional stage disease is about 75%. Only 20% of patients with distant metastases at diagnosis survive 10 years which is significantly lower than for differentiated thyroid cancers. Cases with regional metastases at presentation have high recurrence rates. Adjuvant external radiation confers local control but not improved OS. The management of residual, recurrent, or metastatic disease till a few years ago was re-surgery with local measures such as radiation. Chemotherapy was used with marginal benefit. The development of targeted therapy has brought in a major advantage in management of such patients. Two drugs—vandetanib and cabozantinib—have been approved for use in progressive or metastatic MTC. In addition, several drugs acting on other steps of the molecular pathway are being investigated with promising results. Targeted radionuclide therapy also provides an effective treatment option with good quality of life. This review covers the rationale of targeted therapy for MTC, present treatment options, drugs and methods under investigation, as well as an outline of the adverse effects and their management.

  4. Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives

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    Salvatore Giovanni Vitale

    2017-05-01

    Full Text Available Carcinosarcomas (CS in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%. Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms “uterine carcinosarcoma”, “uterine Malignant Mixed Müllerian Tumors”, “target therapies”, “angiogenesis therapy”, “cancer stem cell therapy”, “prognostic biomarker”, and “novel antibody-drug”. Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2 open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes.

  5. New perspectives on targeted therapy in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Coward JIG

    2015-02-01

    Full Text Available Jermaine IG Coward,1–3 Kathryn Middleton,1 Felicity Murphy1 1Mater Health Services, Raymond Terrace, South Brisbane, QLD, Australia; 2Inflammtion and Cancer Therapeutics Group, Mater Research, University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, Australia; 3School of Medicine, University of Queensland, Brisbane, QLD, Australia Abstract: Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer. Keywords: antiangiogenic therapy, high-grade serous, low grade ovarian cancer, PARP inhibition, cancer-related inflammation

  6. Selective targeted delivery of the TNF-alpha receptor p75 and uteroglobin to the vasculature of inflamed tissues: a preliminary report

    Directory of Open Access Journals (Sweden)

    Ventura Elisa

    2011-11-01

    Full Text Available Abstract Background Ligand-targeted approaches have proven successful in improving the therapeutic index of a number of drugs. We hypothesized that the specific targeting of TNF-alpha antagonists to inflamed tissues could increase drug efficacy and reduce side effects. Results Using uteroglobin (UG, a potent anti-inflammatory protein, as a scaffold, we prepared a bispecific tetravalent molecule consisting of the extracellular ligand-binding portion of the human TNF-alpha receptor P75 (TNFRII and the scFv L19. L19 binds to the ED-B containing fibronectin isoform (B-FN, which is expressed only during angiogenesis processes and during tissue remodeling. B-FN has also been demonstrated in the pannus in rheumatoid arthritis. L19-UG-TNFRII is a stable, soluble homodimeric protein that maintains the activities of both moieties: the immuno-reactivity of L19 and the capability of TNFRII to inhibit TNF-alpha. In vivo bio-distribution studies demonstrated that the molecule selectively accumulated on B-FN containing tissues, showing a very fast clearance from the blood but a very long residence time on B-FN containing tissues. Despite the very fast clearance from the blood, this fusion protein was able to significantly improve the severe symptomatology of arthritis in collagen antibody-induced arthritis (CAIA mouse model. Conclusions The recombinant protein described here, able to selectively deliver the TNF-alpha antagonist TNFRII to inflamed tissues, could yield important contributions for the therapy of degenerative inflammatory diseases.

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

    Science.gov (United States)

    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.

  8. [50 years of hepatology - from therapeutic nihilism to targeted therapies].

    Science.gov (United States)

    Manns, Michael P

    2013-04-01

    Over the past 50 years significant progress has been made in the whole field of hepatology. Part of this is translation of basic research (biochemistry, immunology, virology, molecular biology and others) into clinical hepatology. This enabled us to understand more about the pathogenesis of liver diseases and led to the discovery of the five major hepatotropic viruses, the identification of hepatocellular autoantigens, and to the development of specific therapies for chronic hepatitis B, C and D. In addition, the molecular basis of most genetic liver diseases has been identified. Significant progress was made in the development of medical therapies for various liver diseases with different underlying etiologies. Surgery significantly contributed to the progress in the management of liver diseases; examples are laparoscopic cholecystectomy and the development of liver transplantation. A multimodal therapeutic algorithm has been established for the therapy of hepatocelluar carcinoma (HCC); with Sorafenib "targeted therapy" has entered the area of HCC. The progress made over the last 50 years not only led to an aetiological differentiation of acute and chronic liver diseases but also to specific therapies based on the identification and understanding of the underlying etiology. © Georg Thieme Verlag KG Stuttgart · New York.

  9. Current Molecular Targeted Therapies for Bone and Soft Tissue Sarcomas

    Directory of Open Access Journals (Sweden)

    Kenji Nakano

    2018-03-01

    Full Text Available Systemic treatment options for bone and soft tissue sarcomas remained unchanged until the 2000s. These cancers presented challenges in new drug development partly because of their rarity and heterogeneity. Many new molecular targeting drugs have been tried in the 2010s, and some were approved for bone and soft tissue sarcoma. As one of the first molecular targeted drugs approved for solid malignant tumors, imatinib’s approval as a treatment for gastrointestinal stromal tumors (GISTs has been a great achievement. Following imatinib, other tyrosine kinase inhibitors (TKIs have been approved for GISTs such as sunitinib and regorafenib, and pazopanib was approved for non-GIST soft tissue sarcomas. Olaratumab, the monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR-α, was shown to extend the overall survival of soft tissue sarcoma patients and was approved in 2016 in the U.S. as a breakthrough therapy. For bone tumors, new drugs are limited to denosumab, a receptor activator of nuclear factor κB ligand (RANKL inhibitor, for treating giant cell tumors of bone. In this review, we explain and summarize the current molecular targeting therapies approved and in development for bone and soft tissue sarcomas.

  10. Folate-targeted nanoparticles for rheumatoid arthritis therapy.

    Science.gov (United States)

    Nogueira, Eugénia; Gomes, Andreia C; Preto, Ana; Cavaco-Paulo, Artur

    2016-05-01

    Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting almost 1% of the world population. Although the cause of RA remains unknown, the complex interaction between immune mediators (cytokines and effector cells) is responsible for the joint damage that begins at the synovial membrane. Activated macrophages are critical in the pathogenesis of RA and showed specifically express a receptor for the vitamin folic acid (FA), folate receptor β (FRβ). This particular receptor allows internalization of FA-coupled cargo. In this review we will address the potential of nanoparticles as an effective drug delivery system for therapies that will directly target activated macrophages. Special attention will be given to stealth degree of the nanoparticles as a strategy to avoid clearance by macrophages of the mononuclear phagocytic system (MPS). This review summarizes the application of FA-target nanoparticles as drug delivery systems for RA and proposes prospective future directions. Rheumatoid arthritis is a debilitating autoimmune disease of the joints which affects many people worldwide. Up till now, there is a lack of optimal therapy against this disease. In this review article, the authors outlined in depth the current mechanism of disease for rheumatoid arthritis and described the latest research in using folic acid-targeted nanoparticles to target synovial macrophages in the fight against rheumatoid arthritis. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Alpha-fetoprotein-targeted reporter gene expression imaging in hepatocellular carcinoma.

    Science.gov (United States)

    Kim, Kwang Il; Chung, Hye Kyung; Park, Ju Hui; Lee, Yong Jin; Kang, Joo Hyun

    2016-07-21

    Hepatocellular carcinoma (HCC) is one of the most common cancers in Eastern Asia, and its incidence is increasing globally. Numerous experimental models have been developed to better our understanding of the pathogenic mechanism of HCC and to evaluate novel therapeutic approaches. Molecular imaging is a convenient and up-to-date biomedical tool that enables the visualization, characterization and quantification of biologic processes in a living subject. Molecular imaging based on reporter gene expression, in particular, can elucidate tumor-specific events or processes by acquiring images of a reporter gene's expression driven by tumor-specific enhancers/promoters. In this review, we discuss the advantages and disadvantages of various experimental HCC mouse models and we present in vivo images of tumor-specific reporter gene expression driven by an alpha-fetoprotein (AFP) enhancer/promoter system in a mouse model of HCC. The current mouse models of HCC development are established by xenograft, carcinogen induction and genetic engineering, representing the spectrum of tumor-inducing factors and tumor locations. The imaging analysis approach of reporter genes driven by AFP enhancer/promoter is presented for these different HCC mouse models. Such molecular imaging can provide longitudinal information about carcinogenesis and tumor progression. We expect that clinical application of AFP-targeted reporter gene expression imaging systems will be useful for the detection of AFP-expressing HCC tumors and screening of increased/decreased AFP levels due to disease or drug treatment.

  12. Targeting Gene-Viro-Therapy with AFP driving Apoptin gene shows potent antitumor effect in hepatocarcinoma

    Directory of Open Access Journals (Sweden)

    Zhang Kang-Jian

    2012-02-01

    Full Text Available Abstract Background Gene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory. Our aim was to construct a new recombinant adenovirus which is more efficient to kill hepatocarcinoma cells but more safe to normal cells. Methods By using the Cancer Targeting Gene-Viro-Therapy strategy, Apoptin, a promising cancer therapeutic gene was inserted into the double-regulated oncolytic adenovirus AD55 in which E1A gene was driven by alpha fetoprotein promoter along with a 55 kDa deletion in E1B gene to form AD55-Apoptin. The anti-tumor effects and safety were examined by western blotting, virus yield assay, real time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl-2, 5-diphenyltetrazolium bromide assay, Hoechst33342 staining, Fluorescence-activated cell sorting, xenograft tumor model, Immunohistochemical assay, liver function analysis and Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay. Results The recombinant virus AD55-Apoptin has more significant antitumor effect for hepatocelluar carcinoma cell lines (in vitro than that of AD55 and even ONYX-015 but no or little impair on normal cell lines. Furthermore, it also shows an obvious in vivo antitumor effect on the Huh-7 liver carcinoma xenograft in nude mice with bigger beginning tumor volume till about 425 mm3 but has no any damage on the function of liver. The induction of apoptosis is involved in AD55-Apoptin induced antitumor effects. Conclusion The AD55-Apoptin can be a potential anti-hepatoma agent with remarkable antitumor efficacy as well as higher safety in cancer targeting gene-viro-therapy system.

  13. Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target

    Science.gov (United States)

    Asim, Mohammad; Massie, Charles E.; Orafidiya, Folake; Pértega-Gomes, Nelma; Warren, Anne Y.; Esmaeili, Mohsen; Selth, Luke A.; Zecchini, Heather I.; Luko, Katarina; Qureshi, Arham; Baridi, Ajoeb; Menon, Suraj; Madhu, Basetti; Escriu, Carlos; Lyons, Scott; Vowler, Sarah L.; Zecchini, Vincent R.; Shaw, Greg; Hessenkemper, Wiebke; Russell, Roslin; Mohammed, Hisham; Stefanos, Niki; Lynch, Andy G.; Grigorenko, Elena; D’Santos, Clive; Taylor, Chris; Lamb, Alastair; Sriranjan, Rouchelle; Yang, Jiali; Stark, Rory; Dehm, Scott M.; Rennie, Paul S.; Carroll, Jason S.; Griffiths, John R.; Tavaré, Simon; Mills, Ian G.; McEwan, Iain J.; Baniahmad, Aria; Tilley, Wayne D.; Neal, David E.

    2016-01-01

    Background: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling. Methods: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ2 tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided. Results: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts. Conclusions: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa. PMID:26657335

  14. Targeting SR-BI for cancer diagnostics, imaging and therapy

    Directory of Open Access Journals (Sweden)

    Maneesha Amrita Rajora

    2016-09-01

    Full Text Available Scavenger receptor class B type I (SR-BI plays an important role in trafficking cholesteryl esters between the core of high density lipoprotein and the liver. Interestingly, this integral membrane protein receptor is also implicated in the metabolism of cholesterol by cancer cells, whereby overexpression of SR-BI has been observed in a number of tumours and cancer cell lines, including breast and prostate cancers. Consequently, SR-BI has recently gained attention as a cancer biomarker and exciting target for the direct cytosolic delivery of therapeutic agents. This brief review highlights these key developments in SR-BI-targeted cancer therapies and imaging probes. Special attention is given to the exploration of high density lipoprotein nanomimetic platforms that take advantage of upregulated SR-BI expression to facilitate targeted drug-delivery and cancer diagnostics, and promising future directions in the development of these agents.

  15. A Surgical Perspective on Targeted Therapy of Hepatocellular Carcinoma

    Science.gov (United States)

    Faltermeier, Claire; Busuttil, Ronald W.; Zarrinpar, Ali

    2015-01-01

    Hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide, is difficult to treat and highly lethal. Since HCC is predominantly diagnosed in patients with cirrhosis, treatment planning must consider both the severity of liver disease and tumor burden. To minimize the impact to the patient while treating the tumor, techniques have been developed to target HCC. Anatomical targeting by surgical resection or locoregional therapies is generally reserved for patients with preserved liver function and minimal to moderate tumor burden. Patients with decompensated cirrhosis and small tumors are optimal candidates for liver transplantation, which offers the best chance of long-term survival. Yet, only 20%–30% of patients have disease amenable to anatomical targeting. For the majority of patients with advanced HCC, chemotherapy is used to target the tumor biology. Despite these treatment options, the five-year survival of patients in the United States with HCC is only 16%. In this review we provide a comprehensive overview of current approaches to target HCC. We also discuss emerging diagnostic and prognostic biomarkers, novel therapeutic targets identified by recent genomic profiling studies, and potential applications of immunotherapy in the treatment of HCC. PMID:28943622

  16. A Surgical Perspective on Targeted Therapy of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Claire Faltermeier

    2015-09-01

    Full Text Available Hepatocellular carcinoma (HCC, the second leading cause of cancer deaths worldwide, is difficult to treat and highly lethal. Since HCC is predominantly diagnosed in patients with cirrhosis, treatment planning must consider both the severity of liver disease and tumor burden. To minimize the impact to the patient while treating the tumor, techniques have been developed to target HCC. Anatomical targeting by surgical resection or locoregional therapies is generally reserved for patients with preserved liver function and minimal to moderate tumor burden. Patients with decompensated cirrhosis and small tumors are optimal candidates for liver transplantation, which offers the best chance of long-term survival. Yet, only 20%–30% of patients have disease amenable to anatomical targeting. For the majority of patients with advanced HCC, chemotherapy is used to target the tumor biology. Despite these treatment options, the five-year survival of patients in the United States with HCC is only 16%. In this review we provide a comprehensive overview of current approaches to target HCC. We also discuss emerging diagnostic and prognostic biomarkers, novel therapeutic targets identified by recent genomic profiling studies, and potential applications of immunotherapy in the treatment of HCC.

  17. Nanoparticle delivered vascular disrupting agents (VDAs): use of TNF-alpha conjugated gold nanoparticles for multimodal cancer therapy.

    Science.gov (United States)

    Shenoi, Mithun M; Iltis, Isabelle; Choi, Jeunghwan; Koonce, Nathan A; Metzger, Gregory J; Griffin, Robert J; Bischof, John C

    2013-05-06

    Surgery, radiation and chemotherapy remain the mainstay of current cancer therapy. However, treatment failure persists due to the inability to achieve complete local control of the tumor and curtail metastatic spread. Vascular disrupting agents (VDAs) are a class of promising systemic agents that are known to synergistically enhance radiation, chemotherapy or thermal treatments of solid tumors. Unfortunately, there is still an unmet need for VDAs with more favorable safety profiles and fewer side effects. Recent work has demonstrated that conjugating VDAs to other molecules (polyethylene glycol, CNGRCG peptide) or nanoparticles (liposomes, gold) can reduce toxicity of one prominent VDA (tumor necrosis factor alpha, TNF-α). In this report, we show the potential of a gold conjugated TNF-α nanoparticle (NP-TNF) to improve multimodal cancer therapies with VDAs. In a dorsal skin fold and hindlimb murine xenograft model of prostate cancer, we found that NP-TNF disrupts endothelial barrier function and induces a significant increase in vascular permeability within the first 1-2 h followed by a dramatic 80% drop in perfusion 2-6 h after systemic administration. We also demonstrate that the tumor response to the nanoparticle can be verified using dynamic contrast-enhanced magnetic resonance imaging (MRI), a technique in clinical use. Additionally, multimodal treatment with thermal therapies at the perfusion nadir in the sub- and supraphysiological temperature regimes increases tumor volumetric destruction by over 60% and leads to significant tumor growth delays compared to thermal therapy alone. Lastly, NP-TNF was found to enhance thermal therapy in the absence of neutrophil recruitment, suggesting that immune/inflammatory regulation is not central to its power as part of a multimodal approach. Our data demonstrate the potential of nanoparticle-conjugated VDAs to significantly improve cancer therapy by preconditioning tumor vasculature to a secondary insult in a targeted

  18. Therapy with high LET Radioisotopes: Can sufficient levels of attractive Auger and alpha emitters be produced to make their use practical?

    International Nuclear Information System (INIS)

    Knapp, F.F. Jr.; Mirzadeh, S.; Stabin, M.; Brill, A.B.

    2005-01-01

    Because of localized energy deposition within a very small volume, cellular targeted therapy with high linear energy transfer (LET) Auger-electron and alpha-particle emitting radioisotopes is of great interest. While the energy deposition from alpha particles usually encompasses several cell diameters, the dose from Auger electrons is confined to a single cell. Two major challenges for broader use of Alpha and Auger emitters are the efficient and cost effective routine production of sufficient levels of these radioisotopes, and the availability of targeting molecules to which the radioisotopes can be attached for cellular delivery of sufficient levels of activity for effective therapy. Examples of several Alpha-and Auger-emitting radioisotopes of current interest are presented. Alpha- and Auger electron-emitting radioisotopes can be produced in accelerators (A) and nuclear reactors (R), and several alpha emitter congeners (i.e. thorium-229) can be obtained from uranium decay products. The challenge for reactor production, is the availability and exploitation of methods - other then the usual radiative (n,γ) production route which will provide no-carrier-added (nca) or the high specific activity radioisotopes of interest. The submitted manuscript has been authored by a contractor of the U.S. Government under contract DE-AC05-00OR22725. Accordingly, the U.S. Government retains a nonexclusive, royalty-free license to publish or reproduce the published form of this contribution, or allow others to do so, for U.S. Government purposes High LET radioisotopes of current interest which are in the initial stages of development and/or which demonstrate practical use in clinical trials include several alpha-emitters, in particular bismuth-213 - and also the actinium-225 parent - astatine-211 and bismuth-212. Extensive experimental studies have been reported with Auger iododeoxyuridine (IdUR) radiolabeled with the iodine-125 emitter-labeled. However, development of production

  19. Monte Carlo treatment planning and high-resolution alpha-track autoradiography for neutron capture therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zamenhof, R.G.; Lin, K.; Ziegelmiller, D.; Clement, S.; Lui, C.; Harling, O.K.

    Monte Carlo simulations of thermal neutron flux distributions in a mathematical head model have been compared to experimental measurements in a corresponding anthropomorphic gelatin-based head phantom irradiated by a thermal neutron beam as presently available at the MITR-II Research Reactor. Excellent agreement between Monte Carlo and experimental measurements has encouraged us to employ the Monte Carlo simulation technique to approach treatment planning problems in neutron capture therapy. We have also implemented a high-resolution alpha-track autoradiography technique originally developed in our laboratory at MIT. Initial autoradiograms produced by this technique meet our expectations in terms of the high resolution available and the ability to etch tracks without concommitant destruction of stained tissue. Our preliminary results with computer-aided track distribution analysis indicate that this approach is very promising in being able to quantify boron distributions in tissue at the subcellular level with a minimum amount of operator effort necessary.

  20. Targeted radionuclide therapy with astatine-211: Oxidative dehalogenation of astatobenzoate conjugates.

    Science.gov (United States)

    Teze, David; Sergentu, Dumitru-Claudiu; Kalichuk, Valentina; Barbet, Jacques; Deniaud, David; Galland, Nicolas; Maurice, Rémi; Montavon, Gilles

    2017-05-31

    211 At is a most promising radionuclide for targeted alpha therapy. However, its limited availability and poorly known basic chemistry hamper its use. Based on the analogy with iodine, labelling is performed via astatobenzoate conjugates, but in vivo deastatination occurs, particularly when the conjugates are internalized in cells. Actually, the chemical or biological mechanism responsible for deastatination is unknown. In this work, we show that the C-At "organometalloid" bond can be cleaved by oxidative dehalogenation induced by oxidants such as permanganates, peroxides or hydroxyl radicals. Quantum mechanical calculations demonstrate that astatobenzoates are more sensitive to oxidation than iodobenzoates, and the oxidative deastatination rate is estimated to be about 6 × 10 6 faster at 37 °C than the oxidative deiodination one. Therefore, we attribute the "internal" deastatination mechanism to oxidative dehalogenation in biological compartments, in particular lysosomes.

  1. Engineering of magnetic DNA nanoparticles for tumor-targeted therapy

    International Nuclear Information System (INIS)

    Hosseinkhani, Hossein; Chen Yiru; He Wenjie; Hong Poda; Yu, Dah-Shyong; Domb, Abraham J.

    2013-01-01

    This study aims to engineer novel targeted delivery system composed of magnetic DNA nanoparticles to be effective as an efficient targeted gene therapy vehicle for tumor therapy. A polysaccharide, dextran, was chosen as the vector of plasmid DNA-encoded NK4 that acts as an HGF-antagonist and anti-angiogenic regulator for inhibitions of tumor growth, invasion, and metastasis. Spermine (Sm) was chemically introduced to the hydroxyl groups of dextran to obtain dextran-Sm. When Fe 2+ solution was added to the mixture of dextran-Sm and a plasmid DNA, homogenous DNA nanoparticles were formed via chemical metal coordination bonding with average size of 230 nm. Characterization of DNA nanoparticles was performed via dynamic light scattering measurement, electrophoretic light scattering measurement, as well as transmission electron microscope. DNA nanoparticles effectively condensed plasmid DNA into nanoparticles and enhanced the stability of DNA, while significantly improved transfection efficiency in vitro and tumor accumulation in vivo. In addition, magnetic DNA nanoparticles exhibited high efficiency in antitumor therapy with regards to tumor growth as well as survival of animals evaluated in the presence of external magnetic field. We conclude that the magnetic properties of these DNA nanoparticles would enhance the tracking of non-viral gene delivery systems when administrated in vivo in a test model. These findings suggest that DNA nanoparticles effectively deliver DNA to tumor and thereby inhibiting tumor growth.

  2. Engineering of magnetic DNA nanoparticles for tumor-targeted therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hosseinkhani, Hossein, E-mail: hosseinkhani@yahoo.com [Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology (Taiwan Tech) (China); Chen Yiru [National Yang-Ming University, Department of Biomedical Engineering (China); He Wenjie; Hong Poda [Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology (Taiwan Tech) (China); Yu, Dah-Shyong [Nanomedicine Research Center, National Defense Medical Center (China); Domb, Abraham J. [Institute of Drug Research, The Center for Nanoscience and Nanotechnology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem (Israel)

    2013-01-15

    This study aims to engineer novel targeted delivery system composed of magnetic DNA nanoparticles to be effective as an efficient targeted gene therapy vehicle for tumor therapy. A polysaccharide, dextran, was chosen as the vector of plasmid DNA-encoded NK4 that acts as an HGF-antagonist and anti-angiogenic regulator for inhibitions of tumor growth, invasion, and metastasis. Spermine (Sm) was chemically introduced to the hydroxyl groups of dextran to obtain dextran-Sm. When Fe{sup 2+} solution was added to the mixture of dextran-Sm and a plasmid DNA, homogenous DNA nanoparticles were formed via chemical metal coordination bonding with average size of 230 nm. Characterization of DNA nanoparticles was performed via dynamic light scattering measurement, electrophoretic light scattering measurement, as well as transmission electron microscope. DNA nanoparticles effectively condensed plasmid DNA into nanoparticles and enhanced the stability of DNA, while significantly improved transfection efficiency in vitro and tumor accumulation in vivo. In addition, magnetic DNA nanoparticles exhibited high efficiency in antitumor therapy with regards to tumor growth as well as survival of animals evaluated in the presence of external magnetic field. We conclude that the magnetic properties of these DNA nanoparticles would enhance the tracking of non-viral gene delivery systems when administrated in vivo in a test model. These findings suggest that DNA nanoparticles effectively deliver DNA to tumor and thereby inhibiting tumor growth.

  3. Targeted radionuclide therapy for solid tumors: An overview

    International Nuclear Information System (INIS)

    De Nardo, Sally J.; De Nardo, Gerald L.

    2006-01-01

    Although radioimmunotherapy (RIT) has been effective in non-Hodgkin's lymphoma (NHL) as a single agent, solid tumors have shown less clinically significant therapeutic response to RIT alone. The clinical impact of RIT or other forms of targeted radionuclide therapy for solid tumors depends on the development of a high therapeutic index (TI) for the tumor vs. normal tissue effect, and the implementation of RIT as part of synergistic combined modality therapy (CMRIT). Preclinical and clinical studies have provided a wealth of information, and new prototypes or paradigms have shed light on future possibilities in many instances. Evidence suggests that combination and sequencing of RIT in CMRIT appropriately can provide effective treatment for many solid tumors. Vascular targets provide RIT enhancement opportunities and nanoparticles may prove to be effective carriers for RIT combined with intracellular drug delivery or alternating magnetic frequency (AMF) induced thermal tumor necrosis. The sequence and timing of combined modality treatments will be of critical importance to achieve synergy for therapy while minimizing toxicity. Fortunately, the radionuclide used for RIT also provides a signal useful for nondestructive quantitation of the influence of sequence and timing of CMRIT on events in animals and patients. This can be readily accomplished clinically using quantitative high-resolution imaging (e.g., positron emission tomography [PET])

  4. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis.

    Science.gov (United States)

    Mocellin, Simone; Pasquali, Sandro; Rossi, Carlo R; Nitti, Donato

    2010-04-07

    Based on previous meta-analyses of randomized controlled trials (RCTs), the use of interferon alpha (IFN-alpha) in the adjuvant setting improves disease-free survival (DFS) in patients with high-risk cutaneous melanoma. However, RCTs have yielded conflicting data on the effect of IFN-alpha on overall survival (OS). We conducted a systematic review and meta-analysis to examine the effect of IFN-alpha on DFS and OS in patients with high-risk cutaneous melanoma. The systematic review was performed by searching MEDLINE, EMBASE, Cancerlit, Cochrane, ISI Web of Science, and ASCO databases. The meta-analysis was performed using time-to-event data from which hazard ratios (HRs) and 95% confidence intervals (CIs) of DFS and OS were estimated. Subgroup and meta-regression analyses to investigate the effect of dose and treatment duration were also performed. Statistical tests were two-sided. The meta-analysis included 14 RCTs, published between 1990 and 2008, and involved 8122 patients, of which 4362 patients were allocated to the IFN-alpha arm. IFN-alpha alone was compared with observation in 12 of the 14 trials, and 17 comparisons (IFN-alpha vs comparator) were generated in total. IFN-alpha treatment was associated with a statistically significant improvement in DFS in 10 of the 17 comparisons (HR for disease recurrence = 0.82, 95% CI = 0.77 to 0.87; P < .001) and improved OS in four of the 14 comparisons (HR for death = 0.89, 95% CI = 0.83 to 0.96; P = .002). No between-study heterogeneity in either DFS or OS was observed. No optimal IFN-alpha dose and/or treatment duration or a subset of patients more responsive to adjuvant therapy was identified using subgroup analysis and meta-regression. In patients with high-risk cutaneous melanoma, IFN-alpha adjuvant treatment showed statistically significant improvement in both DFS and OS.

  5. IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer.

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M; Wang, Liya; Wang, Y Andrew; Chen, Hongyu; Kooby, David; Yu, Qian; Lipowska, Malgorzata; Staley, Charles A; Mao, Hui; Yang, Lily

    2015-08-25

    Overcoming resistance to chemotherapy is a major and unmet medical challenge in the treatment of pancreatic cancer. Poor drug delivery due to stromal barriers in the tumor microenvironment and aggressive tumor biology are additional impediments toward a more successful treatment of pancreatic cancer. In attempts to address these challenges, we developed IGF1 receptor (IGF1R)-directed, multifunctional theranostic nanoparticles for targeted delivery of therapeutic agents into IGF1R-expressing drug-resistant tumor cells and tumor-associated stromal cells. These nanoparticles were prepared by conjugating recombinant human IGF1 to magnetic iron oxide nanoparticles (IONPs) carrying the anthracycline doxorubicin (Dox) as the chemotherapeutic payload. Intravenously administered IGF1-IONPs exhibited excellent tumor targeting and penetration in an orthotopic patient-derived xenograft (PDX) model of pancreatic cancer featuring enriched tumor stroma and heterogeneous cancer cells. IGF1R-targeted therapy using the theranostic IGF1-IONP-Dox significantly inhibited the growth of pancreatic PDX tumors. The effects of the intratumoral nanoparticle delivery and therapeutic responses in the orthotopic pancreatic PDX tumors could be detected by magnetic resonance imaging (MRI) with IONP-induced contrasts. Histological analysis showed that IGF1R-targeted delivery of Dox significantly inhibited cell proliferation and induced apoptotic cell death of pancreatic cancer cells. Therefore, further development of IGF1R-targeted theranostic IONPs and MRI-guided cancer therapy as a precision nanomedicine may provide the basis for more effective treatment of pancreatic cancer.

  6. Radiotherapy in combination with vascular-targeted therapies

    International Nuclear Information System (INIS)

    Ciric, Eva; Sersa, Gregor

    2010-01-01

    Given the critical role of tumor vasculature in tumor development, considerable efforts have been spent on developing therapeutic strategies targeting the tumor vascular network. A variety of agents have been developed, with two general approaches being pursued. Antiangiogenic agents (AAs) aim to interfere with the process of angiogenesis, preventing new tumor blood vessel formation. Vascular-disrupting agents (VDAs) target existing tumor vessels causing tumor ischemia and necrosis. Despite their great therapeutic potential, it has become clear that their greatest clinical utility may lie in combination with conventional anticancer therapies. Radiotherapy is a widely used treatment modality for cancer with its distinct therapeutic challenges. Thus, combining the two approaches seems reasonable. Strong biological rationale exist for combining vascular-targeted therapies with radiation. AAs and VDAs were shown to alter the tumor microenvironment in such a way as to enhance responses to radiation. The results of preclinical and early clinical studies have confirmed the therapeutic potential of this new treatment strategy in the clinical setting. However, concerns about increased normal tissue toxicity, have been raised

  7. HER3 signaling and targeted therapy in cancer

    Directory of Open Access Journals (Sweden)

    Rosalin Mishra

    2018-05-01

    Full Text Available ERBB family members including epidermal growth factor receptor (EGFR also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance. Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs. Studies also implicate HER3 contributing significantly to treatment failure, mostly through the activation of PI3K/AKT, MAPK/ERK and JAK/STAT pathways. Moreover, activating mutations in HER3 have highlighted the role of HER3 as a direct therapeutic target. Therapeutic targeting of HER3 includes abrogating its dimerization partners’ kinase activity using small molecule inhibitors (lapatinib, erlotinib, gefitinib, afatinib, neratinib or direct targeting of its extracellular domain. In this review, we focus on HER3-mediated signaling, its role in drug resistance and discuss the latest advances to overcome resistance by targeting HER3 using mono- and bispecific antibodies and small molecule inhibitors.

  8. Targeted radionuclide therapy for neuroendocrine tumours: principles and application.

    Science.gov (United States)

    Druce, Maralyn R; Lewington, Val; Grossman, Ashley B

    2010-01-01

    Neuroendocrine tumours comprise a group of neoplasms with variable clinical behaviour. Their growth and spread is often very slow and initially asymptomatic, and thus they are often metastatic at the time of diagnosis and incurable by surgery. An exciting therapeutic strategy for cytoreduction, both for stabilisation of tumour growth and inhibition of hormone production, is the use of targeted radionuclide therapy. Evidence from large-scale, randomised, placebo-controlled trials is very difficult to obtain in these rare diseases, but current data appear promising. It is timely to review the principles underlying the use of these therapies, together with the clinical outcomes to date and potential directions for future research. Copyright 2009 S. Karger AG, Basel.

  9. Denosumab for bone diseases: translating bone biology into targeted therapy.

    Science.gov (United States)

    Tsourdi, Elena; Rachner, Tilman D; Rauner, Martina; Hamann, Christine; Hofbauer, Lorenz C

    2011-12-01

    Signalling of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) through RANK is a critical pathway to regulate the differentiation and activity of osteoclasts and, hence, a master regulator of bone resorption. Increased RANKL activity has been demonstrated in diseases characterised by excessive bone loss such as osteoporosis, rheumatoid arthritis and osteolytic bone metastases. The development and approval of denosumab, a fully MAB against RANKL, has heralded a new era in the treatment of bone diseases by providing a potent, targeted and reversible inhibitor of bone resorption. This article summarises the molecular and cellular biology of the RANKL/RANK system and critically reviews preclinical and clinical studies that have established denosumab as a promising novel therapy for metabolic and malignant bone diseases. We will discuss the potential indications for denosumab along with a critical review of safety and analyse its potential within the concert of established therapies.

  10. Neutrophils, a candidate biomarker and target for radiation therapy?

    Science.gov (United States)

    Schernberg, Antoine; Blanchard, Pierre; Chargari, Cyrus; Deutsch, Eric

    2017-11-01

    Neutrophils are the most abundant blood-circulating white blood cells, continuously generated in the bone marrow. Growing evidence suggests they regulate the innate and adaptive immune system during tumor evolution. This review will first summarize the recent findings on neutrophils as a key player in cancer evolution, then as a potential biomarker, and finally as therapeutic targets, with respective focuses on the interplay with radiation therapy. A complex interplay: Neutrophils have been associated with tumor progression through multiple pathways. Ionizing radiation has cytotoxic effects on cancer cells, but the sensitivity to radiation therapy in vivo differ from isolated cancer cells in vitro, partially due to the tumor microenvironment. Different microenvironmental states, whether baseline or induced, can modulate or even attenuate the effects of radiation, with consequences for therapeutic efficacy. Inflammatory biomarkers: Inflammation-based scores have been widely studied as prognostic biomarkers in cancer patients. We have performed a large retrospective cohort of patients undergoing radiation therapy (1233 patients), with robust relationship between baseline blood neutrophil count and 3-year's patient's overall survival in patients with different cancer histologies. (Pearson's correlation test: p = .001, r = -.93). Therapeutic approaches: Neutrophil-targeting agents are being developed for the treatment of inflammatory and autoimmune diseases. Neutrophils either can exert antitumoral (N1 phenotype) or protumoral (N2 phenotype) activity, depending on the Tumor Micro Environment. Tumor associated N2 neutrophils are characterized by high expression of CXCR4, VEGF, and gelatinase B/MMP9. TGF-β within the tumor microenvironment induces a population of TAN with a protumor N2 phenotype. TGF-β blockade slows tumor growth through activation of CD8 + T cells, macrophages, and tumor associated neutrophils with an antitumor N1 phenotype. This supports

  11. Nanoparticle targeted therapy against childhood acute lymphoblastic leukemia

    Science.gov (United States)

    Satake, Noriko; Lee, Joyce; Xiao, Kai; Luo, Juntao; Sarangi, Susmita; Chang, Astra; McLaughlin, Bridget; Zhou, Ping; Kenney, Elaina; Kraynov, Liliya; Arnott, Sarah; McGee, Jeannine; Nolta, Jan; Lam, Kit

    2011-06-01

    The goal of our project is to develop a unique ligand-conjugated nanoparticle (NP) therapy against childhood acute lymphoblastic leukemia (ALL). LLP2A, discovered by Dr. Kit Lam, is a high-affinity and high-specificity peptidomimetic ligand against an activated α4β1 integrin. Our study using 11 fresh primary ALL samples (10 precursor B ALL and 1 T ALL) showed that childhood ALL cells expressed activated α4β1 integrin and bound to LLP2A. Normal hematopoietic cells such as activated lymphocytes and monocytes expressed activated α4β1 integrin; however, normal hematopoietic stem cells showed low expression of α4β1 integrin. Therefore, we believe that LLP2A can be used as a targeted therapy for childhood ALL. The Lam lab has developed novel telodendrimer-based nanoparticles (NPs) which can carry drugs efficiently. We have also developed a human leukemia mouse model using immunodeficient NOD/SCID/IL2Rγ null mice engrafted with primary childhood ALL cells from our patients. LLP2A-conjugated NPs will be evaluated both in vitro and in vivo using primary leukemia cells and this mouse model. NPs will be loaded first with DiD near infra-red dye, and then with the chemotherapeutic agents daunorubicin or vincristine. Both drugs are mainstays of current chemotherapy for childhood ALL. Targeting properties of LLP2A-conjugated NPs will be evaluated by fluorescent microscopy, flow cytometry, MTS assay, and mouse survival after treatment. We expect that LLP2A-conjugated NPs will be preferentially delivered and endocytosed to leukemia cells as an effective targeted therapy.

  12. Identification of the interleukin 4 receptor alpha gene as a direct target for p73.

    Science.gov (United States)

    Sasaki, Yasushi; Mita, Hiroaki; Toyota, Minoru; Ishida, Setsuko; Morimoto, Ichiro; Yamashita, Toshiharu; Tanaka, Toshihiro; Imai, Kohzoh; Nakamura, Yusuke; Tokino, Takashi

    2003-12-01

    p73 has a high degree of structural homology to p53 and can activate transcription of p53-responsive genes. However, analysis of p73-deficient mice revealed a marked divergence in the physiological activities of p53 family genes and distinguishes p73 from p53. Mice deficient for p73 exhibit profound defects, including hippocampal dysgenesis, chronic infection, and inflammation, as well as abnormalities in pheromone sensory pathways. p73 plays important roles in neurogenesis, sensory pathways, and homeostatic regulation. Here, we found that the interleukin 4 receptor alpha (IL-4Ralpha) gene is up-regulated by p73 but not significantly by p53 in several human cancer cell lines. IL-4Ralphatranscription is also activated in response to cisplatin, a DNA-damaging agent known to induce p73. By using small interference RNA designed to target p73, we demonstrated that silencing endogenous p73 abrogates the induction of the IL-4Ralpha gene after cisplatin treatment. Furthermore, we identified a p73-binding site in the first intron of the IL-4Ralpha gene that can directly interact with the p73 protein in vivo. This p73-binding site consists of eight copies of a 10-bp consensus p53-binding motif and is a functional response element that is relatively specific for p73 among the p53 family. p73beta promoted localized nucleosomal acetylation through recruitment of coactivator p300, indicating that p73 regulates transcription of IL-4Ralpha through the unique p73-binding site. We also found that p73beta-transfected tumor cells are sensitive to IL-4-mediated apoptosis. Our data suggest that IL-4Ralpha could mediate, in part, certain immune responses and p73-dependent cell death.

  13. Target volumes in radiation therapy of childhood brain tumours

    International Nuclear Information System (INIS)

    Habrand, J.L.; Abdulkarim, B.; Beaudre, A.; El Khouri, M.; Kalifa, C.

    2001-01-01

    Pediatric tumors have enjoyed considerable improvements for the past 30 years. This is mainly due to the extensive use of combined therapeutical modalities in which chemotherapy plays a prominent role. In many children, local treatment including radiotherapy, can nowadays be adapted in terms of target volume and dose to the 'response' to an initial course of chemotherapy almost on a case by case basis. This makes precise recommendation on local therapy highly difficult in this age group. We will concentrate in this paper on brain tumors in which chemotherapy is of limited value and radiotherapy still plays a key-role. (authors)

  14. Interleukin-1 beta targeted therapy for type 2 diabetes

    DEFF Research Database (Denmark)

    Maedler, K.; Dharmadhikari, G.; Schumann, D.M.

    2009-01-01

    Since having been cloned in 1984, IL-1beta has been the subject of over 22,000 citations in Pubmed, among them over 800 reviews. This is because of its numerous effects. IL-1beta is a regulator of the body's inflammatory response and is produced after infection, injury, and antigenic challenge. I....... We highlight recent clinical studies and experiments in animals and isolated islets using IL-1beta as a potential target for the therapy of type 2 diabetes Udgivelsesdato: 2009/9...

  15. Novel drugs targeting Toll-like receptors for antiviral therapy.

    Science.gov (United States)

    Patel, Mira C; Shirey, Kari Ann; Pletneva, Lioubov M; Boukhvalova, Marina S; Garzino-Demo, Alfredo; Vogel, Stefanie N; Blanco, Jorge Cg

    2014-09-01

    Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release 'danger-associated molecular patterns' that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.

  16. Histone lysine demethylases as targets for anticancer therapy

    DEFF Research Database (Denmark)

    Højfeldt, Jonas W; Agger, Karl; Helin, Kristian

    2013-01-01

    It has recently been demonstrated that the genes controlling the epigenetic programmes that are required for maintaining chromatin structure and cell identity include genes that drive human cancer. This observation has led to an increased awareness of chromatin-associated proteins as potentially...... interesting drug targets. The successful introduction of DNA methylation and histone deacetylase (HDAC) inhibitors for the treatment of specific subtypes of cancer has paved the way for the use of epigenetic therapy. Here, we highlight key biological findings demonstrating the roles of members of the histone...... lysine demethylase class of enzymes in the development of cancers, discuss the potential and challenges of therapeutically targeting them, and highlight emerging small-molecule inhibitors of these enzymes....

  17. Biomedical nanotechnology for molecular imaging, diagnostics, and targeted therapy.

    Science.gov (United States)

    Nie, Shuming

    2009-01-01

    Biomedical nanotechnology is a cross-disciplinary area of research in science, engineering and medicine with broad applications for molecular imaging, molecular diagnosis, and targeted therapy. The basic rationale is that nanometer-sized particles such as semiconductor quantum dots and iron oxide nanocrystals have optical, magnetic or structural properties that are not available from either molecules or bulk solids. When linked with biotargeting ligands such as monoclonal antibodies, peptides or small molecules, these nanoparticles can be used to target diseased cells and organs (such as malignant tumors and cardiovascular plaques) with high affinity and specificity. In the "mesoscopic" size range of 5-100 nm diameter, nanoparticles also have large surface areas and functional groups for conjugating to multiple diagnostic (e.g., optical, radioisotopic, or magnetic) and therapeutic (e.g., anticancer) agents.

  18. Small interfering RNA targeting HIF-1{alpha} reduces hypoxia-dependent transcription and radiosensitizes hypoxic HT 1080 human fibrosarcoma cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Staab, Adrian [Wuerzburg Univ. (Germany). Dept. of Radiation Oncology; Paul Scherrer Institute (PSI), Villigen (Switzerland); Fleischer, Markus [Wuerzburg Univ. (Germany). Dept. of Radiation Oncology; Wuerzburg Univ. (Germany). Medical Clinic II; Loeffler, Juergen; Einsele, Herrmann [Wuerzburg Univ. (Germany). Medical Clinic II; Said, Harun M.; Katzer, Astrid; Flentje, Michael [Wuerzburg Univ. (Germany). Dept. of Radiation Oncology; Plathow, Christian [Freiburg Univ. (Germany). Dept. of Nuclear Medicine; Vordermark, Dirk [Wuerzburg Univ. (Germany). Dept. of Radiation Oncology; Halle-Wittenberg Univ. (Germany). Dept. of Radiation Oncology

    2011-04-15

    Background: Hypoxia inducible factor-1 has been identified as a potential target to overcome hypoxia-induced radioresistance The aim of the present study was to investigate whether selective HIF-1 inhibition via small interfering RNA (siRNA) targeting hypoxia-inducible factor 1{alpha} (HIF-1{alpha}) affects hypoxia-induced radioresistance in HT 1080 human fibrosarcoma cells. Material and Methods: HIF-1{alpha} expression in HT 1080 human fibrosarcoma cells in vitro was silenced using HIF-1{alpha} siRNA sequence primers. Quantitative real-time polymerase chain reaction assay was performed to quantify the mRNA expression of HIF-1{alpha}. HIF-1{alpha} protein levels were studied by Western blotting at 20% (air) or after 12 hours at 0.1% O{sub 2} (hypoxia). Cells were assayed for clonogenic survival after irradiation with 2, 5, or 10 Gy, under normoxic or hypoxic conditions in the presence of HIF-1{alpha}-targeted or control siRNA sequences. A modified oxygen enhancement ratio (OER') was calculated as the ratio of the doses to achieve the same survival at 0.1% O{sub 2} as at ambient oxygen tensions. OER' was obtained at cell survival levels of 50%, 37%, and 10%. Results: HIF-1{alpha}-targeted siRNA enhanced radiation treatment efficacy under severely hypoxic conditions compared to tumor cells treated with scrambled control siRNA. OER was reduced on all survival levels after treatment with HIF-1{alpha}-targeted siRNA, suggesting that inhibition of HIF-1 activation by using HIF-1{alpha}-targeted siRNA increases radiosensitivity of hypoxic tumor cells in vitro. Conclusion: Inhibition of HIF-1 activation by using HIF-1{alpha}-targeted siRNA clearly acts synergistically with radiotherapy and increase radiosensitivity of hypoxic cells in vitro. (orig.)

  19. Comparison of thick-target (alpha,n yield calculation codes

    Directory of Open Access Journals (Sweden)

    Fernandes Ana C.

    2017-01-01

    Full Text Available Neutron production yields and energy distributions from (α,n reactions in light elements were calculated using three different codes (SOURCES, NEDIS and USD and compared with the existing experimental data in the 3.5-10 MeV alpha energy range. SOURCES and NEDIS display an agreement between calculated and measured yields in the decay series of 235U, 238U and 232Th within ±10% for most materials. The discrepancy increases with alpha energy but still an agreement of ±20% applies to all materials with reliable elemental production yields (the few exceptions are identified. The calculated neutron energy distributions describe the experimental data, with NEDIS retrieving very well the detailed features. USD generally underestimates the measured yields, in particular for compounds with heavy elements and/or at high alpha energies. The energy distributions exhibit sharp peaks that do not match the observations. These findings may be caused by a poor accounting of the alpha particle energy loss by the code. A big variability was found among the calculated neutron production yields for alphas from Sm decay; the lack of yield measurements for low (~2 MeV alphas does not allow to conclude on the codes’ accuracy in this energy region.

  20. Evaluation of Fibroblast Activation Protein-Alpha (FAP) as a Diagnostic Marker and Therapeutic Target in Prostate Cancer

    Science.gov (United States)

    2009-12-01

    low molecular weight recombinant human gelatin: development of a substitute for animal- derived gelatin with superior features, Protein Expr. Purif...by the honey - bee , could be modified to a form that was no longer hydro- lyzed by the native activator protease DPP4 but, instead, was hydrolyzed by...TITLE: Evaluation of Fibroblast Activation Protein -Alpha (FAP) as a Diagnostic Marker and Therapeutic Target in Prostate Cancer PRINCIPAL

  1. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy

    Directory of Open Access Journals (Sweden)

    Xiang-Hong Peng

    2008-10-01

    Full Text Available Xiang-Hong Peng1,4, Ximei Qian2,4, Hui Mao3,4, Andrew Y Wang5, Zhuo (Georgia Chen1,4, Shuming Nie2,4, Dong M Shin1,4*1Department of Medical Oncology/Hematology; 2Department of Biomedical Engineering; 3Department of Radiology; 4Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 5Ocean Nanotech, LLC, Fayetteville, AR, USAAbstract: Magnetic iron oxide (IO nanoparticles with a long blood retention time, biodegradability and low toxicity have emerged as one of the primary nanomaterials for biomedical applications in vitro and in vivo. IO nanoparticles have a large surface area and can be engineered to provide a large number of functional groups for cross-linking to tumor-targeting ligands such as monoclonal antibodies, peptides, or small molecules for diagnostic imaging or delivery of therapeutic agents. IO nanoparticles possess unique paramagnetic properties, which generate significant susceptibility effects resulting in strong T2 and T*2 contrast, as well as T1 effects at very low concentrations for magnetic resonance imaging (MRI, which is widely used for clinical oncology imaging. We review recent advances in the development of targeted IO nanoparticles for tumor imaging and therapy.Keywords: iron oxide nanoparticles, tumor imaging, MRI, therapy

  2. New Targets for End-Stage Chronic Kidney Disease Therapy

    Directory of Open Access Journals (Sweden)

    Prakoura Niki

    2015-05-01

    Full Text Available Severe forms of chronic kidney disease can lead to a critical, end-stage condition, requiring renal replacement therapy, which may involve a form of dialysis or renal transplantation. Identification and characterization of novel markers and/or targets of therapy that could be applied in these critically ill patients remains the focus of the current research in the field of critical care medicine and has been the objective of our studies for some years past. To this end, we used models of renal vascular disease, Ang II, L-NAME or mice overexpressing renin, treated with AT1 antagonists at different stages of progression, to create cohorts of animals during progression, reversal or escape from therapy. Transcriptomic analysis and comparisons were performed and genes were selected according to the following criteria: a not previously described in the kidney, b highly upregulated during progression and returning to the normal levels during reversal, and c producing proteins that are either circulating or membrane receptors.

  3. Update in Systemic and Targeted Therapies in Gastrointestinal Oncology

    Directory of Open Access Journals (Sweden)

    Nelson S. Yee

    2018-03-01

    Full Text Available Progress has been made in the treatment of gastrointestinal cancers through advances in systemic therapies, surgical interventions, and radiation therapy. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this sub-specialty. This conference paper highlights the new development in systemic treatment of various malignant diseases in the digestive system. Results of the recent clinical trials that investigated the clinical efficacy of pegylated hyaluronidase, napabucasin, and L-asparaginase in pancreatic carcinoma are presented. The use of peri-operative chemotherapy comprised of 5-fluorouracil or capecitabine, leucovorin, oxaliplatin, and docetaxel (FLOT, and immunotherapy including pembrolizumab, nivolumab, and ipilimumab in gastroesophageal carcinoma are discussed. Data from clinical trials that investigated the targeted therapeutics including nivolumab, ramucirumab, lenvatinib, and BLU-554 are reported. The role of adjuvant capecitabine in resected biliary tract carcinoma (BTC and nab-paclitaxel in combination with gemcitabine and cisplatin in advanced BTC are presented. In colorectal carcinoma, the efficacy of nivolumab, adjuvant FOLFOX or CAPOX, irinotecan/cetuximab/vemurafenib, and trifluridine/tipiracil/bevacizumab, is examined. In summary, some of the above systemic therapies have become or are expected to become new standard of care, while the others demonstrate the potential of becoming new treatment options.

  4. Stem cells’ guided gene therapy of cancer: New frontier in personalized and targeted therapy

    Directory of Open Access Journals (Sweden)

    Mavroudi M

    2014-01-01

    Full Text Available Diagnosis and therapy of cancer remain to be the greatest challenges for all physicians working in clinical oncology and molecular medicine. The grim statistics speak for themselves with reports of 1,638,910 men and women diagnosed with cancer and nearly 577,190 patients passed away due to cancer in the USA in 2012. For practicing clinicians, who treat patients suffering from advanced cancers with contemporary systemic therapies, the main challenge is to attain therapeutic efficacy, while minimizing side effects. Unfortunately, all contemporary systemic therapies cause side effects. In treated patients, these side effects may range from nausea to damaged tissues. In cancer survivors, the iatrogenic outcomes of systemic therapies may include genomic mutations and their consequences. Therefore, there is an urgent need for personalized and targeted therapies. Recently, we reviewed the current status of suicide gene therapy for cancer. Herein, we discuss the novel strategy: genetically engineered stem guided gene therapy. Stem cells have the unique potential for self-renewal and differentiation. This potential is the primary reason for introducing them into medicine to regenerate injured or degenerated organs, as well as to rejuvenate aging tissues. Recent advances in genetic engineering and stem cell research have created the foundations for genetic engineering of stem cells as the vectors for delivery of therapeutic transgenes. Specifically in oncology, the stem cells are genetically engineered to deliver the cell suicide inducing genes selectively to the cancer cells. Expression of the transgenes kills the cancer cells, while leaving healthy cells unaffected. Herein, we present various strategies to bioengineer suicide inducing genes and stem cell vectors. Moreover, we review results of the main preclinical studies and clinical trials. However, the main risk for therapeutic use of stem cells is their cancerous transformation. Therefore, we

  5. Effect of antioxidant therapy with dl-alpha-tocopherol on cardiovascular structure in experimental renal failure.

    Science.gov (United States)

    Amann, Kerstin; Törnig, Johannes; Buzello, Mareike; Kuhlmann, Alexander; Gross, Marie-Luise; Adamczak, Marcin; Buzello, Moriz; Ritz, Eberhard

    2002-09-01

    Chronic renal failure is characterized by remodeling of the structure of the heart and the vasculature, for example, left ventricular hypertrophy, myocardial fibrosis, capillary/myocyte mismatch, as well as thickening of intramyocardial arteries and of peripheral arteries and veins. Furthermore, uremia is a state of increased oxygen stress. It was the purpose of this study to examine whether these findings are interrelated. To investigate whether antioxidative therapy with dl-alpha-tocopherol (Toco; vitamin E) interferes with the development of abnormal cardiovascular structure in experimental renal failure, 28 male Sprague-Dawley rats were subjected to partial renal ablation (subtotal nephrectomy, SNX) or to sham operation (sham). SNX were either left untreated or received the antioxidant Toco (2 x 1500 IE/kg BW/week in the pellets). Blood pressure was measured using tail plethysmography. The experiment was terminated after 12 weeks. Heart and left ventricular weight were determined and the following parameters were measured using morphometry and stereology: volume densities of cardiomyocytes, capillaries and non-vascular interstitium; length density and total length of cardiac capillaries, wall thickness of intramyocardial arterioles and of the aorta. Systolic blood pressure and body weight were comparable in all groups. Treatment with Toco led to significantly increased plasma concentrations of Toco. Left ventricular weight and wall thickness of intramyocardial arteries were significantly higher in both SNX groups compared to sham controls. Volume density of the cardiac interstitial tissue was significantly higher in untreated SNX than in Toco treated SNX and sham control rats. Length density of capillaries was significantly lower in untreated SNX than in control rats; however, the values were significantly higher, and even higher than in sham controls, when SNX were treated with Toco. Treatment with the antioxidant dl-alpha-tocopherol prevented cardiomyocyte

  6. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    Directory of Open Access Journals (Sweden)

    Ilaria Naldi

    Full Text Available Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine, hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap and hormone refractory (DU145 prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs drug delivery system (DDS carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  7. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    Science.gov (United States)

    Naldi, Ilaria; Taranta, Monia; Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

    2014-01-01

    Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  8. Choline kinase-alpha by regulating cell aggressiveness and drug sensitivity is a potential druggable target for ovarian cancer.

    Science.gov (United States)

    Granata, A; Nicoletti, R; Tinaglia, V; De Cecco, L; Pisanu, M E; Ricci, A; Podo, F; Canevari, S; Iorio, E; Bagnoli, M; Mezzanzanica, D

    2014-01-21

    Aberrant choline metabolism has been proposed as a novel cancer hallmark. We recently showed that epithelial ovarian cancer (EOC) possesses an altered MRS-choline profile, characterised by increased phosphocholine (PCho) content to which mainly contribute over-expression and activation of choline kinase-alpha (ChoK-alpha). To assess its biological relevance, ChoK-alpha expression was downmodulated by transient RNA interference in EOC in vitro models. Gene expression profiling by microarray analysis and functional analysis was performed to identify the pathway/functions perturbed in ChoK-alpha-silenced cells, then validated by in vitro experiments. In silenced cells, compared with control, we observed: (I) a significant reduction of both CHKA transcript and ChoK-alpha protein expression; (II) a dramatic, proportional drop in PCho content ranging from 60 to 71%, as revealed by (1)H-magnetic spectroscopy analysis; (III) a 35-36% of cell growth inhibition, with no evidences of apoptosis or modification of the main cellular survival signalling pathways; (IV) 476 differentially expressed genes, including genes related to lipid metabolism. Ingenuity pathway analysis identified cellular functions related to cell death and cellular proliferation and movement as the most perturbed. Accordingly, CHKA-silenced cells displayed a significant delay in wound repair, a reduced migration and invasion capability were also observed. Furthermore, although CHKA silencing did not directly induce cell death, a significant increase of sensitivity to platinum, paclitaxel and doxorubicin was observed even in a drug-resistant context. We showed for the first time in EOC that CHKA downregulation significantly decreased the aggressive EOC cell behaviour also affecting cells' sensitivity to drug treatment. These observations open the way to further analysis for ChoK-alpha validation as a new EOC therapeutic target to be used alone or in combination with conventional drugs.

  9. A case of reversible dilated cardiomyopathy after alpha-interferon therapy in a patient with renal cell carcinoma.

    Science.gov (United States)

    Kuwata, Akiko; Ohashi, Masuo; Sugiyama, Masaya; Ueda, Ryuzo; Dohi, Yasuaki

    2002-12-01

    A 47-year-old man with renal cell carcinoma underwent nephrectomy, and postoperative chemotherapy was performed with recombinant alpha-interferon. Five years later, he experienced dyspnea during physical exertion. An echocardiogram revealed dilatation and systolic dysfunction of the left ventricle, and thallium-201 myocardial scintigraphy showed diffuse heterogeneous perfusion. We diagnosed congestive heart failure because of cardiomyopathy induced by alpha-interferon therapy. Withdrawal of interferon therapy and the combination of an angiotensin-converting enzyme inhibitor, diuretics, and digitalis improved left ventricular systolic function. Furthermore, myocardial scintigraphy using [123I] beta-methyl-p-iodophenylpentadecanoic acid (123I-BMIPP) or [123 I]metaiodobenzylguanidine (123I-MIBG) revealed normal perfusion after the improvement of congestive heart failure. This is a rare case of interferon-induced cardiomyopathy that resulted in normal myocardial images in 123I-BMIPP and 123I-MIBG scintigrams after withdrawal of interferon therapy.

  10. Targeted therapies for diarrhea-predominant irritable bowel syndrome

    Science.gov (United States)

    Olden, Kevin W

    2012-01-01

    Irritable bowel syndrome (IBS) causes gastrointestinal symptoms such as abdominal pain, bloating, and bowel pattern abnormalities, which compromise patients’ daily functioning. Common therapies address one or two IBS symptoms, while others offer wider symptom control, presumably by targeting pathophysiologic mechanisms of IBS. The aim of this targeted literature review was to capture clinical trial reports of agents receiving the highest recommendation (Grade 1) for treatment of IBS from the 2009 American College of Gastroenterology IBS Task Force, with an emphasis on diarrhea-predominant IBS. Literature searches in PubMed captured articles detailing randomized placebo-controlled trials in IBS/diarrhea-predominant IBS for agents receiving Grade I (strong) 2009 American College of Gastroenterology IBS Task Force recommendations: tricyclic antidepressants, nonabsorbable antibiotics, and the 5-HT3 receptor antagonist alosetron. Studies specific for constipation-predominant IBS were excluded. Tricyclic antidepressants appear to improve global IBS symptoms but have variable effects on abdominal pain and uncertain tolerability; effects on stool consistency, frequency, and urgency were not adequately assessed. Nonabsorbable antibiotics show positive effects on global symptoms, abdominal pain, bloating, and stool consistency but may be most efficacious in patients with altered intestinal microbiota. Alosetron improves global symptoms and abdominal pain and normalizes bowel irregularities, including stool frequency, consistency, and fecal urgency. Both the nonabsorbable antibiotic rifaximin and the 5-HT3 receptor antagonist alosetron improve quality of life. Targeted therapies provide more complete relief of IBS symptoms than conventional agents. Familiarization with the quantity and quality of evidence of effectiveness can facilitate more individualized treatment plans for patients with this heterogeneous disorder. PMID:22754282

  11. Anti-tumor necrosis factor-alpha therapies attenuate adaptive arteriogenesis in the rabbit

    NARCIS (Netherlands)

    Grundmann, Sebastian; Hoefer, Imo; Ulusans, Susann; van Royen, Niels; Schirmer, Stephan H.; Ozaki, C. Keith; Bode, Christoph; Piek, Jan J.; Buschmann, Ivo

    2005-01-01

    The specific antagonists of tumor necrosis factor-alpha (TNF-alpha), infliximab and etanercept, are established therapeutic agents for inflammatory diseases such as rheumatoid arthritis and Crohn's disease. Although the importance of TNF-alpha in chronic inflammatory diseases is well established,

  12. Effect of DOTA position on melanoma targeting and pharmacokinetic properties of 111In-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone peptide.

    Science.gov (United States)

    Guo, Haixun; Yang, Jianquan; Gallazzi, Fabio; Prossnitz, Eric R; Sklar, Larry A; Miao, Yubin

    2009-11-01

    The purpose of this study was to examine the effect of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) position on melanoma targeting and pharmacokinetics of radiolabeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (alpha-MSH) peptide. A novel lactam bridge-cyclized alpha-MSH peptide, Ac-GluGlu-CycMSH[DOTA] {Ac-Glu-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Lys(DOTA)]}, was synthesized using standard 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry. DOTA was directly attached to the alpha-amino group of Lys in the cyclic ring, while the N-terminus of the peptide was acetylated to generate Ac-GluGlu-CycMSH[DOTA]. The MC1 receptor binding affinity of Ac-GluGlu-CycMSH[DOTA] was determined in B16/F1 melanoma cells. Melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In were determined in B16/F1 melanoma-bearing C57 mice and compared to that of 111In-DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp] (111In-DOTA-GlyGlu-CycMSH; DOTA was coupled to the N-terminus of the peptide). Ac-GluGlu-CycMSH[DOTA] displayed 0.6 nM MC1 receptor binding affinity in B16/F1 cells. Ac-GluGlu-CycMSH[DOTA]-111In was readily prepared with greater than 95% radiolabeling yield. Ac-GluGlu-CycMSH[DOTA]-111In exhibited high tumor uptake (11.42 +/- 2.20% ID/g 2 h postinjection) and prolonged tumor retention (9.42 +/- 2.41% ID/g 4 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<1.3% ID/g) except for the kidneys 2, 4, and 24 h postinjection. DOTA position exhibited profound effect on melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In, providing a new insight into the design of lactam bridge-cyclized peptide for melanoma imaging and therapy.

  13. Presynaptic type III neuregulin1-ErbB signaling targets {alpha}7 nicotinic acetylcholine receptors to axons.

    Science.gov (United States)

    Hancock, Melissa L; Canetta, Sarah E; Role, Lorna W; Talmage, David A

    2008-05-05

    Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of alpha7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface alpha7 nAChRs, which results from a redistribution of preexisting intracellular pools of alpha7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting alpha7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function.

  14. Presynaptic type III neuregulin1-ErbB signaling targets alpha7 nicotinic acetylcholine receptors to axons.

    Science.gov (United States)

    Hancock, Melissa L; Canetta, Sarah E; Role, Lorna W; Talmage, David A

    2008-06-01

    Type III Neuregulin1 (Nrg1) isoforms are membrane-tethered proteins capable of participating in bidirectional juxtacrine signaling. Neuronal nicotinic acetylcholine receptors (nAChRs), which can modulate the release of a rich array of neurotransmitters, are differentially targeted to presynaptic sites. We demonstrate that Type III Nrg1 back signaling regulates the surface expression of alpha7 nAChRs along axons of sensory neurons. Stimulation of Type III Nrg1 back signaling induces an increase in axonal surface alpha7 nAChRs, which results from a redistribution of preexisting intracellular pools of alpha7 rather than from increased protein synthesis. We also demonstrate that Type III Nrg1 back signaling activates a phosphatidylinositol 3-kinase signaling pathway and that activation of this pathway is required for the insertion of preexisting alpha7 nAChRs into the axonal plasma membrane. These findings, in conjunction with prior results establishing that Type III Nrg1 back signaling controls gene transcription, demonstrate that Type III Nrg1 back signaling can regulate both short-and long-term changes in neuronal function.

  15. Biologic Drugs: A New Target Therapy in COPD?

    Science.gov (United States)

    Yousuf, Ahmed; Brightling, Christopher E

    2018-04-23

    Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease associated with significant morbidity and mortality. Current diagnostic criteria based on the presence of fixed airflow obstruction and symptoms do not integrate the complex pathological changes occurring within the lung and they do not define different airway inflammatory patterns. The current management of COPD is based on 'one size fits all' approach and does not take the importance of heterogeneity in COPD population into account. The available treatments aim to alleviate symptoms and reduce exacerbation frequency but do not alter the course of the disease. Recent advances in molecular biology have furthered our understanding of inflammatory pathways in pathogenesis of COPD and have led to development of targeted therapies (biologics and small molecules) based on predefined biomarkers. Herein we shall review the trials of biologics in COPD and potential future drug developments in the field.

  16. Physics at the biomolecular interface fundamentals for molecular targeted therapy

    CERN Document Server

    Fernández, Ariel

    2016-01-01

    This book focuses primarily on the role of interfacial forces in understanding biological phenomena at the molecular scale. By providing a suitable statistical mechanical apparatus to handle the biomolecular interface, the book becomes uniquely positioned to address core problems in molecular biophysics. It highlights the importance of interfacial tension in delineating a solution to the protein folding problem, in unravelling the physico-chemical basis of enzyme catalysis and protein associations, and in rationally designing molecular targeted therapies. Thus grounded in fundamental science, the book develops a powerful technological platform for drug discovery, while it is set to inspire scientists at any level in their careers determined to address the major challenges in molecular biophysics. The acknowledgment of how exquisitely the structure and dynamics of proteins and their aqueous environment are related attests to the overdue recognition that biomolecular phenomena cannot be effectively understood w...

  17. Vibrio cholerae infection, novel drug targets and phage therapy.

    Science.gov (United States)

    Fazil, Mobashar Hussain Urf Turabe; Singh, Durg V

    2011-10-01

    Vibrio cholerae is the causative agent of the diarrheal disease cholera. Although antibiotic therapy shortens the duration of diarrhea, excessive use has contributed to the emergence of antibiotic resistance in V. cholerae. Mobile genetic elements have been shown to be largely responsible for the shift of drug resistance genes in bacteria, including some V. cholerae strains. Quorum sensing communication systems are used for interaction among bacteria and for sensing environmental signals. Sequence analysis of the ctxB gene of toxigenic V. cholerae strains demonstrated its presence in multiple cholera toxin genotypes. Moreover, bacteriophage that lyse the bacterium have been reported to modulate epidemics by decreasing the required infectious dose of the bacterium. In this article, we will briefly discuss the disease, its clinical manifestation, antimicrobial resistance and the novel approaches to locate drug targets to treat cholera.

  18. The nucleolus: an emerging target for cancer therapy.

    Science.gov (United States)

    Hein, Nadine; Hannan, Katherine M; George, Amee J; Sanij, Elaine; Hannan, Ross D

    2013-11-01

    For over 100 years, pathologists have utilised an increase in size and number of nucleoli, the subnuclear site of ribosome synthesis, as a marker of aggressive tumours. Despite this, the contribution of the nucleolus and ribosomal RNA synthesis to cancer has been largely overlooked. This concept has recently changed with the demonstration that the nucleolus indirectly controls numerous other cellular functions, in particular, the cellular activity of the critical tumour suppressor protein, p53. Moreover, selective inhibition of ribosomal gene transcription in the nucleolus has been shown to be an effective therapeutic strategy to promote cancer-specific activation of p53. This article reviews the largely untapped potential of the nucleolus and ribosomal gene transcription as exciting new targets for cancer therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Chemokine Signaling in Allergic Contact Dermatitis: Toward Targeted Therapies.

    Science.gov (United States)

    Smith, Jeffrey S; Rajagopal, Sudarshan; Atwater, Amber Reck

    2018-06-22

    Allergic contact dermatitis (ACD) is a common skin disease that results in significant cost and morbidity. Despite its high prevalence, therapeutic options are limited. Allergic contact dermatitis is regulated primarily by T cells within the adaptive immune system, but also by natural killer and innate lymphoid cells within the innate immune system. The chemokine receptor system, consisting of chemokine peptides and chemokine G protein-coupled receptors, is a critical regulator of inflammatory processes such as ACD. Specific chemokine signaling pathways are selectively up-regulated in ACD, most prominently CXCR3 and its endogenous chemokines CXCL9, CXCL10, and CXCL11. Recent research demonstrates that these 3 chemokines are not redundant and indeed activate distinct intracellular signaling profiles such as those activated by heterotrimeric G proteins and β-arrestin adapter proteins. Such differential signaling provides an attractive therapeutic target for novel ACD therapies and other inflammatory diseases.

  20. Structural and functional imaging for vascular targeted photodynamic therapy

    Science.gov (United States)

    Li, Buhong; Gu, Ying; Wilson, Brian C.

    2017-02-01

    Vascular targeted photodynamic therapy (V-PDT) has been widely used for the prevention or treatment of vascular-related diseases, such as localized prostate cancer, wet age-related macular degeneration, port wine stains, esophageal varices and bleeding gastrointestinal mucosal lesions. In this study, the fundamental mechanisms of vascular responses during and after V-PDT will be introduced. Based on the V-PDT treatment of blood vessels in dorsal skinfold window chamber model, the structural and functional imaging, which including white light microscopy, laser speckle imaging, singlet oxygen luminescence imaging, and fluorescence imaging for evaluating vascular damage will be presented, respectively. The results indicate that vessel constriction and blood flow dynamics could be considered as the crucial biomarkers for quantitative evaluation of vascular damage. In addition, future perspectives of non-invasive optical imaging for evaluating vascular damage of V-PDT will be discussed.

  1. Serial Changes in Alpha-Fetoprotein Levels During Therapy for Chronic Hepatitis C

    Directory of Open Access Journals (Sweden)

    Altug Senol

    2014-12-01

    Full Text Available Aim: Alpha-fetoprotein (AFP has been widely used as a diagnostic marker for hepatocellular carcinoma. Some patients with hepatitis C show high AFP values, but no evidence of hepatocellular carcinoma. The aim of this study is to assess the influence of antiviral treatment on the serum AFP in patients with chronic hepatitis C without hepatocellular carcinoma. Material and Method: Thirty seven chronic hepatitis C patients (20 females and 17 males were included in the study. All patients were given a combined treatment of pegylated or conventional interferon (IFN and ribavirin. Serum AFP was measured at baseline and on months 3-6-12 of the therapy. Results: Compared to the pretreatment levels of ALT (88,59 ± 57,22 IU, those at 3, 6 and 12 months were statistically lower (p0,05, to 4,34 ± 4,64 (p>0,05 and to 2,63 ± 2,17 (p10 ng/ml. In these patients, mean serum AFP levels were decreased from pretreatment level of 15,09 ± 5,92 ng/ml to 11,39±3,30, to 6,97±2,53 (p

  2. Osteosarcoma target therapy with stem cell transplant: A case review

    International Nuclear Information System (INIS)

    Fawzy, A.

    2005-01-01

    Full text: Radioisotopes with medium-energy beta emission and half life of a few days are attractive option for systemic delivery of targeted irradiation. Samarium-153 ethylene diamine tetra-ethylene phosphonale (153Sm-EDTMP), a bone-seeking radiopharmaceutical, provides therapeutic irradiation to osteoblastic osseous lesion. The usual dose of Sm-153 in metastatic disease is 1mCi/Kg (37MBq/Kg) and the dose limiting toxicity is thrombocytopenia. As local radiotherapy has only a limited therapeutic role in the treatment of osteosarcoma, and some types of the tumour portray an unpredictable response to chemotherapy. High dose Sm-153 (30mCi/Kg) was proposed for the target management of recurrent osteosarcoma, this was followed by stem cell transplant (peripheral-blood progenitor, PBPCs). A female child, 10 years old, with polyostotic osteosarcoma with local recurrence in the right hipbone was chosen for therapy. She had left knee prosthesis, right lower limb dis-articulation, and was given chemotherapy in multiple regions. She was subjected to MDP bone scan showing active uptake in an expanding bone lesion in the right hip bone, and was also subjected to MIBI scan, which showed negative uptake. She received 30mCi/Kg Sm-153 (660mCi in total dose), with no major events occurring in the post-injection period. After 10 days the patient went into pancytopenia, which necessitated haematological support. By day 14, there was minimal radiation in the whole body image and the child received her bone marrow transplant. There was marked improvement in the tumour size after 6 weeks of therapy, with improvement in the alkaline phosphatase level (from 1350Iu, before treatment to 350 post treatment). This was confirmed by serial MDP bone scan. High dose Sm-153 with stem cell transplant is considered view a promising method in the management of osteosarcoma. (author)

  3. Dual drug loaded superparamagnetic iron oxide nanoparticles for targeted cancer therapy.

    Science.gov (United States)

    Dilnawaz, Fahima; Singh, Abhalaxmi; Mohanty, Chandana; Sahoo, Sanjeeb K

    2010-05-01

    The primary inadequacy of chemotherapeutic drugs is their relative non-specificity and potential side effects to the healthy tissues. To overcome this, drug loaded multifunctional magnetic nanoparticles are conceptualized. We report here an aqueous based formulation of glycerol monooleate coated magnetic nanoparticles (GMO-MNPs) devoid of any surfactant capable of carrying high payload hydrophobic anticancer drugs. The biocompatibility was confirmed by tumor necrosis factor alpha assay, confocal microscopy. High entrapment efficiency approximately 95% and sustained release of encapsulated drugs for more than two weeks under in vitro conditions was achieved for different anticancer drugs (paclitaxel, rapamycin, alone or combination). Drug loaded GMO-MNPs did not affect the magnetization properties of the iron oxide core as confirmed by magnetization study. Additionally the MNPs were functionalized with carboxylic groups by coating with DMSA (Dimercaptosuccinic acid) for the supplementary conjugation of amines. For targeted therapy, HER2 antibody was conjugated to GMO-MNPs and showed enhanced uptake in human breast carcinoma cell line (MCF-7). The IC(50) doses revealed potential antiproliferative effect in MCF-7. Therefore, antibody conjugated GMO-MNPs could be used as potential drug carrier for the active therapeutic aspects in cancer therapy. Copyright 2010 Elsevier Ltd. All rights reserved.

  4. HIV-derived vectors for gene therapy targeting dendritic cells.

    Science.gov (United States)

    Rossetti, Maura; Cavarelli, Mariangela; Gregori, Silvia; Scarlatti, Gabriella

    2013-01-01

    Human immunodeficiency virus type 1 (HIV-1)-derived lentiviral vectors (LV) have the potential to mediate stable therapeutic gene transfer. However, similarly to other viral vectors, their benefit is compromised by the induction of an immune response toward transgene-expressing cells that closely mimics antiviral immunity. LV share with the parental HIV the ability to activate dendritic cells (DC), while lack the peculiar ability of subverting DC functions, which is responsible for HIV immune escape. Understanding the interaction between LV and DC, with plasmacytoid and myeloid DC playing fundamental and distinct roles, has paved the way to novel approaches aimed at regulating transgene-specific immune responses. Thanks to the ability to target either DC subsets LV might be a powerful tool to induce immunity (i.e., gene therapy of cancer), cell death (i.e., in HIV/AIDS infection), or tolerance (i.e., gene therapy strategies for monogenic diseases). In this chapter, similarities and differences between the LV-mediated and HIV-mediated induction of immune responses, with specific focus on their interactions with DC, are discussed.

  5. Sox4 is a key oncogenic target in C/EBP alpha mutant acute myeloid leukemia

    Czech Academy of Sciences Publication Activity Database

    Zhang, H.; Alberich-Jorda, Meritxell; Amabile, G.; Yang, H.; Staber, P.B.; DiRuscio, A.; Welner, R.S.; Ebralidze, A.; Zhang, J.; Levantini, E.; Lefebvre, V.; Valk, P.J.; Delwel, R.; Hoogenkamp, M.; Nerlov, C.; Cammenga, J.; Saez, B.; Scadden, D.T.; Bonifer, C.; Ye, M.; Tenen, D.G.

    2013-01-01

    Roč. 24, č. 5 (2013), s. 575-588 ISSN 1535-6108 R&D Projects: GA MŠk LK21307 Institutional support: RVO:68378050 Keywords : Sox4 * C/EBP alpha * acute myeloid leukemia Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 23.893, year: 2013

  6. Reduction in high blood tumor necrosis factor-alpha levels after manipulative therapy in 2 cervicogenic headache patients.

    Science.gov (United States)

    Ormos, Gábor; Mehrishi, J N; Bakács, Tibor

    2009-09-01

    This case report discusses the treatment of 2 patients with cervicogenic headache (CHA) attending the Outpatient Clinic of the Hungarian National Institute for Rheumatology and Physiotherapy (Budapest, Hungary) and reviews the pathophysiology, therapeutic strategy, and problems associated with the treatment of CHA. Patient 1 was a 27-year-old female who sustained a whiplash injury. A sharp, shooting headache developed, readily induced, and aggravated by just bending the neck backward or by turning her head. Magnetic resonance imaging revealed a disk protrusion at C4-C5 pressing the anterior cerebrospinal space. Patient 2 was a 62-year-old female who sustained a whiplash injury; her cervical movements became restricted, which precipitated headaches. Magnetic resonance imaging revealed a paramedian disk hernia between the C4 and C5 vertebrae that intruded into the right ventral cerebrospinal space. After 4 weeks of manipulative therapy for patient 1, both active and passive range of motion returned to normal, and the high tumor necrosis factor-alpha (TNF-alpha) level (63 pg/mL) was substantially reduced (28 pg/mL). Patient 2 was started on manipulative therapy twice a week for 4 weeks; after 2 months, the patient became symptom-free, and high TNF-alpha level (72 pg/mL) was reduced greatly (35 pg/mL). Two patients with whiplash injury and disk herniation developed CHA associated with very high TNF-alpha levels. After manipulative therapy, these patients became symptom-free, and their TNF-alpha levels decreased substantially.

  7. Dermatologic adverse events associated with chemotherapy and targeted anticancer therapy

    Directory of Open Access Journals (Sweden)

    Maria Kowalska

    2016-05-01

    Full Text Available Chemotherapeutic agents and drugs used for targeted tumor therapy often cause undesirable side effects of the skin which typically are toxic cutaneous reactions (toxicity grade 1 to 4. The first group of drugs that cause toxicities affecting the skin are inhibitors of epidermal growth factor receptor (EGFR. They cause a variety of skin changes (PRIDE syndrome, which are mainly manifested by papulopustular rash, also referred to as acneiform rash, occurring in 44–74% of patients. Another drug which causes cutaneous toxicities is inhibitor of CTLA4 (cytotoxic T lymphocyte-associated protein 4, which is represented by ipilimumab, used in the treatment of metastatic melanoma. The most common dermatological adverse event, observed in 40–64% of patients receiving ipilimumab, is generalized maculopapular rash with pruritus and dry skin, and in some cases vitiligo is also observed. BRAF and MEK inhibitors introduced for the treatment of advanced melanoma also cause skin rashes. BRAF inhibitors also affecting the proliferation of keratinocytes stimulate hypertrophic changes and cause the whole spectrum of lesions from benign and keratoacanthoma to squamous cell carcinoma. A hedgehog pathway inhibitor (vismodegib is used for the treatment of metastatic basal cell carcinoma. The most common adverse events it causes are reversible alopecia and dysgeusia, but it can also cause the development of keratoacanthoma and squamous cell carcinoma. Among the most common side effects of chemotherapy and targeted therapy are toxic changes within the hands and feet (hand-foot skin reaction – HFSR that early manifest as a neurological symptoms (numbness, paresthesia, and skin symptoms (erythematous swelling changes, blisters, hyperkeratosis occur later. Anti-cancer drugs can also cause serious skin diseases such as Stevens-Johnson syndrome (SJS, toxic epidermal necrolysis (TEN and DRESS (drug rash with eosinophilia and systemic symptoms, whose course and prognosis

  8. Acetyl-CoA carboxylase-a as a novel target for cancer therapy.

    Science.gov (United States)

    Wang, Chun; Rajput, Sandeep; Watabe, Kounosuke; Liao, Duan-Fang; Cao, Deliang

    2010-01-01

    Acetyl-CoA carboxylases (ACC) are rate-limiting enzymes in de novo fatty acid synthesis, catalyzing ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA. Malonyl-CoA is a critical bi-functional molecule, i.e., a substrate of fatty acid synthase (FAS) for acyl chain elongation (fatty acid synthesis) and an inhibitor of carnitine palmitoyltransferase I (CPT-I) for fatty acid beta-oxidation. Two ACC isoforms have been identified in mammals, i.e. ACC-alpha (ACCA, also termed ACC1) and ACC-beta (ACCB, also designated ACC2). ACC has long been used as a target for the management of metabolic diseases, such as obesity and metabolic syndrome, and various inhibitors have been developed in clinical trials. Recently, ACCA up-regulation has been recognized in multiple human cancers, promoting lipogenesis to meet the need of cancer cells for rapid growth and proliferation. Therefore, ACCA might be effective as a potent target for cancer intervention, and the inhibitors developed for the treatment of metabolic diseases would be potential therapeutic agents for cancer therapy. This review summarizes our recent findings and updates the current understanding of the ACCA with focus on cancer research.

  9. BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells.

    Science.gov (United States)

    Ambrosini, Grazia; Sawle, Ashley D; Musi, Elgilda; Schwartz, Gary K

    2015-10-20

    Uveal melanoma (UM) is an aggressive intraocular malignancy with limited therapeutic options. Both primary and metastatic UM are characterized by oncogenic mutations in the G-protein alpha subunit q and 11. Furthermore, nearly 40% of UM has amplification of the chromosomal arm 8q and monosomy of chromosome 3, with consequent anomalies of MYC copy number. Chromatin regulators have become attractive targets for cancer therapy. In particular, the bromodomain and extra-terminal (BET) inhibitor JQ1 has shown selective inhibition of c-Myc expression with antiproliferative activity in hematopoietic and solid tumors. Here we provide evidence that JQ1 had cytotoxic activity in UM cell lines carrying Gnaq/11 mutations, while in cells without the mutations had little effects. Using microarray analysis, we identified a large subset of genes modulated by JQ1 involved in the regulation of cell cycle, apoptosis and DNA repair. Further analysis of selected genes determined that the concomitant silencing of Bcl-xL and Rad51 represented the minimal requirement to mimic the apoptotic effects of JQ1 in the mutant cells, independently of c-Myc. In addition, administration of JQ1 to mouse xenograft models of Gnaq-mutant UM resulted in significant inhibition of tumor growth.Collectively, our results define BRD4 targeting as a novel therapeutic intervention against UM with Gnaq/Gna11 mutations.

  10. Targeted therapies in development for non-small cell lung cancer

    Directory of Open Access Journals (Sweden)

    Thanyanan Reungwetwattana

    2013-01-01

    Full Text Available The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by "druggable" protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC, the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2], RAS (rat sarcoma gene, BRAF (v-raf murine sarcoma viral oncogene homolog B1, MAPK (mitogen-activated protein kinase c-MET (c-mesenchymal-epithelial transition, FGFR (fibroblast growth factor receptor, DDR2 (discoidin domain receptor 2, PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha, PTEN (phosphatase and tensin homolog, AKT (protein kinase B, ALK (anaplastic lym phoma kinase, RET (rearranged during transfection, ROS1 (reactive oxygen species 1 and EPH (erythropoietin-producing hepatoma are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and

  11. New Trends in Cancer Therapy: Targeting Ion Channels and Transporters

    Directory of Open Access Journals (Sweden)

    Annarosa Arcangeli

    2010-04-01

    Full Text Available The expression and activity of different channel types mark and regulate specific stages of cancer establishment and progression. Blocking channel activity impairs the growth of some tumors, both in vitro and in vivo, which opens a new field for pharmaceutical research. However, ion channel blockers may produce serious side effects, such as cardiac arrhythmias. For instance, Kv11.1 (hERG1 channels are aberrantly expressed in several human cancers, in which they control different aspects of the neoplastic cell behaviour. hERG1 blockers tend to inhibit cancer growth. However they also retard the cardiac repolarization, thus lengthening the electrocardiographic QT interval, which can lead to life-threatening ventricular arrhythmias. Several possibilities exist to produce less harmful compounds, such as developing specific drugs that bind hERG1 channels in the open state or disassemble the ion channel/integrin complex which appears to be crucial in certain stages of neoplastic progression. The potential approaches to improve the efficacy and safety of ion channel targeting in oncology include: (1 targeting specific conformational channel states; (2 finding ever more specific inhibitors, including peptide toxins, for channel subtypes mainly expressed in well-identified tumors; (3 using specific ligands to convey traceable or cytotoxic compounds; (4 developing channel blocking antibodies; (5 designing new molecular tools to decrease channel expression in selected cancer types. Similar concepts apply to ion transporters such as the Na+/K+ pump and the Na+/H+ exchanger. Pharmacological targeting of these transporters is also currently being considered in anti-neoplastic therapy.

  12. Triple-negative breast cancer: new perspectives for targeted therapies

    Directory of Open Access Journals (Sweden)

    Tomao F

    2015-01-01

    Full Text Available Federica Tomao,1 Anselmo Papa,2 Eleonora Zaccarelli,2 Luigi Rossi,2 Davide Caruso,2 Marina Minozzi,2 Patrizia Vici,3 Luigi Frati,4 Silverio Tomao21Department of Gynecology and Obstetrics, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, 2Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, Oncology Unit, Istituto Chirurgico Ortopedico Traumatologico, Latina, 3Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, Italy; 4Department of Molecular Medicine, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, ItalyAbstract: Breast cancer is a heterogeneous disease, encompassing a large number of entities showing different morphological features and having clinical behaviors. It has became apparent that this diversity may be justified by distinct patterns of genetic, epigenetic, and transcriptomic aberrations. The identification of gene-expression microarray-based characteristics has led to the identification of at least five breast cancer subgroups: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2, and basal-like. Triple-negative breast cancer is a complex disease diagnosed by immunohistochemistry, and it is characterized by malignant cells not expressing estrogen receptors or progesterone receptors at all, and human epidermal growth factor receptor 2. Along with this knowledge, recent data show that triple-negative breast cancer has specific molecular features that could be possible targets for new biological targeted drugs. The aim of this article is to explore the use of new drugs in this particular setting, which is still associated with poor prognosis and high risk of distant recurrence and death.Keywords: basal-like breast cancer, estrogen–progesterone receptors, gene-expression microarray, human epidermal growth factor receptor 2, chemotherapy, target therapy

  13. Individualized targeted therapy for glioblastoma: fact or fiction?

    Science.gov (United States)

    Weller, Michael; Stupp, Roger; Hegi, Monika; Wick, Wolfgang

    2012-01-01

    This review will address the current state of individualized cancer therapy for glioblastoma. Glioblastomas are highly malignant primary brain tumors presumably originating from neuroglial progenitor cells. Median survival is less than 1 year. Recent developments in the morphologic, clinical, and molecular classification of glioblastoma were reviewed, and their impact on clinical decision making was analyzed. Glioblastomas can be classified by morphology, clinical characteristics, complex molecular signatures, single biomarkers, or imaging parameters. Some of these characteristics, including age and Karnofsky Performance Scale score, provide important prognostic information. In contrast, few markers help to choose between various treatment options. Promoter methylation of the O-methylguanine methyltransferase gene seems to predict benefit from alkylating agent chemotherapy. Hence, it is used as an entry criterion for alkylator-free experimental combination therapy with radiotherapy. Screening for a specific type of epidermal growth factor receptor mutation is currently being explored as a biomarker for selecting patients for vaccination. Positron emission tomography for the detection of ανβ3/5 integrins could be used to select patients for treatment with anti-integrin antiangiogenic approaches. Despite extensive efforts at defining biological markers as a basis for selecting therapies, most treatment decisions for glioblastoma patients are still based on age and performance status. However, several ongoing clinical trials may enrich the repertoire of criteria for clinical decision making in the very near future. The concept of individualized or personalized targeted cancer therapy has gained significant attention throughout oncology. Yet, data in support of such an approach to glioblastoma, the most malignant subtype of glioma, are limited, and personalized medicine plays a minor role in current clinical neuro-oncology practice. In essence, this concept proposes

  14. Mitochondrial targets of photodynamic therapy and their contribution to cell death

    Science.gov (United States)

    Oleinick, Nancy L.; Usuda, Jitsuo; Xue, Liang-yan; Azizuddin, Kashif; Chiu, Song-mao; Lam, Minh C.; Morris, Rachel L.; Nieminen, Anna-Liisa

    2002-06-01

    In response to photodynamic therapy (PDT), many cells in culture or within experimental tumors are eliminated by apoptosis. PDT with photosensitizers that localize in or target mitochondria, such as the phthalocyanine Pc 4, causes prompt release of cytochrome c into the cytoplasm and activation of caspases-9 and -3, among other caspases, that are responsible for initiating cell degradation. Some cells appear resistant to apoptosis after PDT; however, if they have sustained sufficient damage, they will die by a necrotic process or through a different apoptotic pathway. In the case of PDT, the distinction between apoptosis and necrosis may be less important than the mechanism that triggers both processes, since critical lethal damage appears to occur during treatment and does not require the major steps in apoptosis to be expressed. We earlier showed, for example, that human breast cancer MCF-7 cells that lack caspase-3 are resistant to the induction of apoptosis by PDT, but are just as sensitive to the loss of clonogenicity as MCF-7 cells stably expressing transfected procaspase-3. Many photosensitizers that target mitochondria specifically attack the anti-apoptotic protein Bcl-2, generating a variety of crosslinked and cleaved photoproducts. Recent evidence suggests that the closely related protein Bcl-xL is also a target of Pc 4-PDT. Transient transfection of an expression vector encoding deletion mutants of Bcl-2 have identified the critical sensitive site in the protein that is required for photodamage. This region contains two alpha helices that form a secondary membrane anchorage site and are thought to be responsible for pore formation by Bcl-2. As specific protein targets are identified, we are becoming better able to model the critical events in PDT-induced cell death.

  15. Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBP alpha expression

    Czech Academy of Sciences Publication Activity Database

    Yong, K.J.; Basseres, D.S.; Welner, R.S.; Zhang, W.C.; Yang, H.; Yan, B.; Alberich-Jorda, Meritxell; Zhang, J.; de Figueiredo-Pontes, L.L.; Battelli, C.; Hetherington, C.J.; Ye, M.; Zhang, H.; Maroni, G.; O'Brien, K.; Magli, M.C.; Borczuk, A.C.; Varticovski, L.; Kocher, O.; Zhang, P.; Moon, Y.C.; Sydorenko, N.; Cao, L.; Davis, T.W.; Thakkar, B.M.; Soo, R.A.; Iwama, A.; Lim, B.; Halmos, B.; Neuberg, D.; Tenen, D.G.; Levantini, E.

    2016-01-01

    Roč. 8, č. 350 (2016), č. článku 350ra104. ISSN 1946-6234 R&D Projects: GA MŠk LK21307 Institutional support: RVO:68378050 Keywords : ccaat/enhancer-binding-protein * acute myeloid-leukemia * factor-c/ebp-alpha * posttranscriptional control * adjuvant chemotherapy * cell-proliferation * down-regulation * drug discovery * gene signature * self-renewal Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 16.796, year: 2016

  16. Colorectal cancer heterogeneity and targeted therapy: a case for molecular disease subtypes

    NARCIS (Netherlands)

    Linnekamp, Janneke F.; Wang, Xin; Medema, Jan Paul; Vermeulen, Louis

    2015-01-01

    Personalized cancer medicine is becoming increasingly important in colorectal cancer treatment. Especially for targeted therapies, large variations between individual treatment responses exist. Predicting therapy response is of utmost significance, as it prevents overtreatment and adverse effects in

  17. Characterization of actinide targets by low solid-angle alpha particle counting

    CERN Document Server

    Denecke, B; Pauwels, J; Robouch, P; Gilliam, D M; Hodge, P; Hutchinson, J M R; Nico, J S

    1999-01-01

    Actinide samples were characterized in an interlaboratory comparison between IRMM and NIST, including alpha-particle counting at defined low solid angle and counting in a 2 pi proportional gas counter. For this comparison, nine sup 2 sup 3 sup 3 UF sub 4 samples with high uniformity in the layer thickness were prepared at IRMM by deposition under vacuum. Polished silicon wafers were used as source substrates, and these were rotated during the deposition using a planetary rotation system. The estimated uncertainties for the defined low solid-angle methods were about 0.1% at both NIST and IRMM. The agreement of reported alpha-particle emission rates in the energy range 2.5-5.09 MeV was better than or equal to 0.02% for the defined solid-angle methods. When comparing total alpha-particle emission rates over the larger energy range 0-9 MeV (which includes all emissions from the daughter nuclides and the impurities), the agreement of the defined solid-angle methods was better than or equal to 0.05%. The 2 pi propo...

  18. EMMPRIN as a novel target for pancreatic cancer therapy

    Science.gov (United States)

    Kim, Hyunki; Zhai, Guihua; Liu, Zhiyong; Samuel, Sharon; Shah, Nemil; Helman, Emily E.; Knowles, Joseph A.; Stockard, Cecil R.; Fineberg, Naomi S.; Grizzle, William E.; Zhou, Tong; Zinn, Kurt R.; Rosenthal, Eben L.

    2013-01-01

    The objective of this study was to evaluate extracelluar matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic-cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3-7, while MIA PaCa-2 EMMPRIN knockdown cells were implanted in group 2. Dosing with anti-EMMPRIN antibody started immediately after implantation for groups 1-3 (residual tumor model) and at 21 days after cell implantation for groups 4-7 (established tumor model). Groups 3, 5, and 7 were treated with anti-EMMRPIN antibody (0.2-1.0 mg) twice weekly for 2-3 weeks, while the other groups served as the control. In residual tumor model, tumor growth of anti-EMMPRIN treated group was successfully arrested for 21 days (15±4 mm3), significantly lower than that of EMMPRIN knockdown group (80±15 mm3; p=0.001) or control group (240±41 mm3; pEMMPRIN therapy lowered tumor-volume increase about 40% compared with control regardless of dose amount. Ki67-expressed cell densities of group 5 was 939±150 mm−2, significantly lower than that of group 4 (1709±145 mm−2; p=0.006). Microvessel density of group 5 (30±6 mm−2) was also significantly lower than that of group 4 (53±5 mm−2; p=0.014), while the microvessel size of group 5 (191±22 μm2) was significantly larger than that of group 4 (113±26 μm2; p=0.049). These data show the high potential of anti-EMMPRIN therapy for pancreatic cancer, and support its clinical translation. PMID:21730821

  19. Tuning flux: autophagy as a target of heart disease therapy

    Science.gov (United States)

    Xie, Min; Morales, Cyndi R.; Lavandero, Sergio; Hill, Joseph A.

    2013-01-01

    Purpose of review Despite maximum medical and mechanical support therapy, heart failure remains a relentlessly progressive disorder with substantial morbidity and mortality. Autophagy, an evolutionarily conserved process of cellular cannibalization, has been implicated in virtually all forms of cardiovascular disease. Indeed, its role is context dependent, antagonizing or promoting disease depending on the circumstance. Here, we review current understanding of the role of autophagy in the pathogenesis of heart failure and explore this pathway as a target of therapeutic intervention. Recent findings In preclinical models of heart disease, cardiomyocyte autophagic flux is activated; indeed, its role in disease pathogenesis is the subject of intense investigation to define mechanism. Similarly, in failing human heart of a variety of etiologies, cardiomyocyte autophagic activity is upregulated, and therapy, such as with mechanical support systems, elicits declines in autophagy activity. However, when suppression of autophagy is complete, rapid and catastrophic cell death occurs, consistent with a model in which basal autophagic flux is required for proteostasis. Thus, a narrow zone of ‘optimal’ autophagy seems to exist. The challenge moving forward is to tune the stress-triggered autophagic response within that ‘sweet spot’ range for therapeutic benefit. Summary Whereas we have known for some years of the participation of lysosomal mechanisms in heart disease, it is only recently that upstream mechanisms (autophagy) are being explored. The challenge for the future is to dissect the underlying circuitry and titrate the response into an optimal, proteostasis-promoting range in hopes of mitigating the ever-expanding epidemic of heart failure. PMID:21415729

  20. Thyroid disorders in patients with chronic hepatitis C using interferon-alpha and ribavirin therapy

    Directory of Open Access Journals (Sweden)

    Luis Jesuino de Oliveira Andrade

    Full Text Available OBJECTIVE: To investigate the frequency of thyroid disorders (TD in patients with chronic hepatitis C before and during interferon-alpha (IFN-α and ribavirin (RIB treatment. STUDY DESIGN: Prospective study. PATIENTS AND METHODS: We prospectively studied 65 anti-HCV and viral RNA positive patients. Free thyroxine, thyroid-stimulating hormone, and thyroid peroxidase antibodies (TPO-Ab were systematically tested at entry (m0, week 12 (m3 and week 24 (m6 of treatment. RESULTS: Mean age of the 65 patients (38 females and 27 males was 49.61 ± 11.83 years. Seven (10.76% patients presented baseline thyroid disorders (m0, three had thyroid dysfunction, and four were TPO-Ab positive. Thyroid disorders occurred in the first 12 weeks of treatment in 11 (16.92% patients, four with thyroid dysfunction, and seven with TPO-Ab positive (m3. A total of 18 patients (27.69% developed TD after 24 weeks of treatment, 7 with thyroid dysfunction, and 11 with TPO-Ab positive (m6. The relative risk of developing hypothyroidism found in this study was 1.3 (95% CI: 1.1 to 1.6, hyperthyroidism 1.2 (95% CI: 1.1 to 1.4, and TPO-Ab positivity 7.6 (95% CI: 3.9 to 14.5. The study showed a significant association between female sex and thyroid disease (p = 0.009. CONCLUSION: Thyroid dysfunction and autoimmune TD were observed during IFN-α and RIB therapy.

  1. Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy

    International Nuclear Information System (INIS)

    Safa, Ahmad R.; Pollok, Karen E.

    2011-01-01

    Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor and critical anti-apoptotic regulator that inhibits tumor necrosis factor-alpha (TNF-alpha), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well as chemotherapy-triggered apoptosis in malignant cells. c-FLIP is expressed as long (c-FLIP L ), short (c-FLIP S ), and c-FLIP R splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 in a ligand-dependent and-independent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. Moreover, c-FLIP L and c-FLIP S are known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective signaling molecules. Upregulation of c-FLIP has been found in various tumor types, and its downregulation has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. For example, small interfering RNAs (siRNAs) that specifically knockdown the expression of c-FLIP L in diverse human cancer cell lines augmented TRAIL-induced DISC recruitment and increased the efficacy of chemotherapeutic agents, thereby enhancing effector caspase stimulation and apoptosis. Moreover, small molecules causing degradation of c-FLIP as well as decreasing mRNA and protein levels of c-FLIP L and c-FLIP S splice variants have been found, and efforts are underway to develop other c-FLIP-targeted cancer therapies. This review focuses on (1) the functional role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and drug resistance; (2) the molecular mechanisms that regulate c-FLIP expression; and (3) strategies to inhibit c-FLIP expression and function

  2. The combination of IL-21 and IFN-alpha boosts STAT3 activation, cytotoxicity and experimental tumor therapy

    DEFF Research Database (Denmark)

    Eriksen, Karsten W; Søndergaard, Henrik; Woetmann, Anders

    2008-01-01

    such as IFN-alpha and IL-2 have multiple and severe side effects. Accordingly, they are generally used at sub-optimal doses, which limit their clinical efficacy. Here we hypothesized that a combination of IFN-alpha and IL-21, a novel cytokine of the IL-2 family with anti-cancer effects, will increase the anti......-cancer efficacy at sub-optimal cytokine doses. We show that the combined stimulation of target-cells with IFN-alpha and IL-21 triggers an increased STAT3 activation whereas the activation of other STATs including STAT1/2 is unaffected. In parallel, the combined stimulation with IFN-alpha and IL-21 triggers...... a selective increase in MHC class I expression and NK- and CD8(+) T-cell-mediated cytotoxicity. In an experimental in vivo model of renal carcinoma, the combined treatment of IFN-alpha and IL-21 also produces a significant anti-cancer effect as judged by an inhibition of tumor growth and an increased survival...

  3. Evaluation of pGL1-TNF-alpha therapy in combination with radiation

    Science.gov (United States)

    Li, J.; Andres, M. L.; Fodor, I.; Nelson, G. A.; Gridley, D. S.

    1998-01-01

    Long-term control of high-grade brain tumors is rarely achieved with current therapeutic regimens. In this study a new plasmid-based human tumor necrosis factor-alpha (TNF-alpha) expression vector was synthesized (pGL1-TNF-alpha) and evaluated together with radiation in the aggressive, rapidly growing C6 rat glioma model. pGL1-TNF-alpha was successfully transfected into C6 cells in vitro using a cationic polyamine method. Expression was detected up to 7 days and averaged 0.4 ng of TNF-alpha in the culture medium from 1x10(5) cells. The expressed protein was biologically functional, as evidenced by growth inhibition of L929, a TNF-alpha-susceptible cell line. Using fluorescence-labeled monoclonal antibodies and laser scanning cytometry, we confirmed that both the P55 and P75 receptors for TNF-alpha were present on the C6 cell membrane. However, the receptors were present at low density and P55 was expressed more than the P75 receptor. These findings were in contrast to results obtained with TNF-alpha-susceptible L929 cells. Tests in athymic mice showed that pGL1-TNF-alpha administered intratumorally 16-18 h before radiation (each modality given three times) significantly inhibited C6 tumor progression (Palpha alone did not slow tumor growth and radiation alone had little effect on tumor growth. These results indicate that pGL1-TNF-alpha has potential to augment the antitumor effects of radiation against a tumor type that is virtually incurable.

  4. Alpha particle emitters in medicine

    International Nuclear Information System (INIS)

    Fisher, D.R.

    1989-09-01

    Radiation-induced cancer of bone, liver and lung has been a prominent harmful side-effect of medical applications of alpha emitters. In recent years, however, the potential use of antibodies labeled with alpha emitting radionuclides against cancer has seemed promising because alpha particles are highly effective in cell killing. High dose rates at high LET, effectiveness under hypoxic conditions, and minimal expectancy of repair are additional advantages of alpha emitters over antibodies labeled with beta emitting radionuclides for cancer therapy. Cyclotron-produced astatine-211 ( 211 At) and natural bismuth-212 ( 212 Bi) have been proposed and are under extensive study in the United States and Europe. Radium-223 ( 223 Ra) also has favorable properties as a potential alpha emitting label, including a short-lived daughter chain with four alpha emissions. The radiation dosimetry of internal alpha emitters is complex due to nonuniformly distributed sources, short particle tracks, and high relative specific ionization. The variations in dose at the cellular level may be extreme. Alpha-particle radiation dosimetry, therefore, must involve analysis of statistical energy deposition probabilities for cellular level targets. It must also account fully for nonuniform distributions of sources in tissues, source-target geometries, and particle-track physics. 18 refs., 4 figs

  5. Production of 177Lu for targeted radionuclide therapy: Available options

    International Nuclear Information System (INIS)

    Dah, Ashutosh; Pillai, Maroor Raghavan Ambikalmajan; Knapp, Furn F. Jr.

    2015-01-01

    This review provides a comprehensive summary of the production of 177 Lu to meet expected future research and clinical demands. Availability of options represents the cornerstone for sustainable growth for the routine production of adequate activity levels of 177 Lu having the required quality for preparation of a variety of 177 Lu-labeled radiopharmaceuticals. The tremendous prospects associated with production of 177 Lu for use in targeted radionuclide therapy (TRT) dictate that a holistic consideration should evaluate all governing factors that determine its success. While both “direct” and “indirect” reactor production routes offer the possibility for sustainable 177 Lu availability, there are several issues and challenges that must be considered to realize the full potential of these production strategies. This article presents a mini review on the latest developments, current status, key challenges and possibilities for the near future. A broad understanding and discussion of the issues associated with 177 Lu production and processing approaches would not only ensure sustained growth and future expansion for the availability and use of 177 Lu-labeled radiopharmaceuticals, but also help future developments

  6. Aptamer-Targeted Plasmonic Photothermal Therapy of Cancer

    Directory of Open Access Journals (Sweden)

    Olga S. Kolovskaya

    2017-12-01

    Full Text Available Novel nanoscale bioconjugates combining unique plasmonic photothermal properties of gold nanoparticles (AuNPs with targeted delivery using cell-specific DNA aptamers have a tremendous potential for medical diagnostics and therapy of many cell-based diseases. In this study, we demonstrate the high anti-cancer activity of aptamer-conjugated, 37-nm spherical gold nanoparticles toward Ehrlich carcinoma in tumor-bearing mice after photothermal treatment. The synthetic anti-tumor aptamers bring the nanoparticles precisely to the desired cells and selectively eliminate cancer cells after the subsequent laser treatment. To prove tumor eradication, we used positron emission tomography (PET utilizing radioactive glucose and computer tomography, followed by histological analysis of cancer tissue. Three injections of aptamer-conjugated AuNPs and 5 min of laser irradiations are enough to make the tumor undetectable by PET. Histological analysis proves PET results and shows lower damage of healthy tissue in addition to a higher treatment efficiency and selectivity of the gold nanoparticles functionalized with aptamers in comparison to control experiments using free unconjugated nanoparticles.

  7. Targeting sarcoma tumor-initiating cells through differentiation therapy

    Directory of Open Access Journals (Sweden)

    Dan Han

    2017-05-01

    Full Text Available Human leukocyte antigen class I (HLA-I down-regulation has been reported in many human cancers to be associated with poor clinical outcome. However, its connection to tumor-initiating cells (TICs remains unknown. In this study, we report that HLA-I is down-regulated in a subpopulation of cells that have high tumor initiating capacity in different types of human sarcomas. Detailed characterization revealed their distinct molecular profiles regarding proliferation, apoptosis and stemness programs. Notably, these TICs can be induced to differentiate along distinct mesenchymal lineages, including the osteogenic pathway. The retinoic acid receptor signaling pathway is overexpressed in HLA-1 negative TICs. All-trans retinoic acid treatment successfully induced osteogenic differentiation of this subpopulation, in vitro and in vivo, resulting in significantly decreased tumor formation. Thus, our findings indicate down-regulated HLA-I is a shared feature of TICs in a variety of human sarcomas, and differentiation therapy strategies may specifically target undifferentiated TICs and inhibit tumor formation.

  8. A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Deng L

    2012-09-01

    Full Text Available Li Deng,1,# Xingfa Ke,4,# Zhiying He,3,# Daoqiu Yang,5 Hai Gong,6 Yingying Zhang,1 Xiaolong Jing,4 Jianzhong Yao,2 Jianming Chen11Department of Pharmaceutics, 2Department of Medicinal Chemistry, School of Pharmacy, 3Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China; 4Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian, People's Republic of China; 5Department of Dermatology, 107th Hospital of PLA, Yantai, People's Republic of China; 6Department of Radiation Oncology, General Hospital of Jinan Military Region, Jinan, People’s Republic of China#These authors contributed equally to this workAbstract: Pancreatic cancer is a highly lethal disease with a 5-year survival rate less than 5% due to the lack of an early diagnosis method and effective therapy. To provide a novel early diagnostic method and targeted therapy for pancreatic cancer, a multifunctional nanoimmunoliposome with high loading of ultrasmall superparamagnetic iron oxides (USPIOs and doxorubicin (DOX was prepared by transient binding and reverse-phase evaporation method, and was conjugated with anti-mesothelin monoclonal antibody by post-insertion method to target anti-mesothelin-overexpressed pancreatic cancer cells. The in vitro and in vivo properties of this anti-mesothelin antibody-conjugated PEGlyated liposomal DOX and USPIOs (M-PLDU; and PEGlyated nanoimmunoliposome without antibody conjugation [PLDU] were evaluated both in human pancreatic cancer cell line Panc-1 cell and in a pancreatic cancer xenograft animal model. Results showed that M-PLDUs were spherical and uniform with a diameter about ~180 nm, with a zeta potential of about −28~−30 mV, and had good efficacy encapsulating DOX and USPIOs. The in vitro study demonstrated that M-PLDUs possessed good magnetic resonance imaging (MRI capability with a transverse relaxivity (r2 of about 58.5 mM–1 • s–1. Confocal microscopy showed more

  9. Relativistic electron beam interaction and $K_{\\alpha}$-generation in solid targets

    CERN Document Server

    Fill, E; Eder, D; Eidmann, K; Saemann, A

    1999-01-01

    When fs laser pulses interact with solid surfaces at intensities I lambda /sup 2/ >10/sup 18/ W/cm/sup 2/ mu m/sup 2/, collimated relativistic electron beams are generated. These electrons can be used for producing intense X-radiation (bremsstrahlung or K/sub alpha /) for pumping an innershell X-ray laser. The basic concept of such a laser involves the propagation of the electron beam in a material which converts electron energy into appropriate pump photons. Using the ATLAS titanium-sapphire laser at Max-Planck-Institut fur Quantenoptik, we investigate the generation of hot electrons and of characteristic radiation in copper. The laser (200 mJ/130 fs) is focused by means of an off-axis parabola to a diameter of about 10 mu m. By varying the position of the focus, we measure the copper K/sub alpha /-yield as a function of intensity in a range from 10/sup 15/ to 2 x 10/sup 18/ W/cm/sup 2/ while keeping the laser pulse energy constant. Surprisingly, the highest emission is obtained at an intensity of about 10/s...

  10. Opportunity of interventional radiology: advantages and application of interventional technique in biological target therapy

    International Nuclear Information System (INIS)

    Teng Gaojun; Lu Qin

    2007-01-01

    Interventional techniques not only provide opportunity of treatment for many diseases, but also alter the traditional therapeutic pattern. With the new century of wide application of biological therapies, interventional technique also shows extensive roles. The current biological therapy, including gene therapy, cell transplantation therapy, immunobiologic molecule therapy containing cell factors, tumor antibody or vaccine, recombined proteins, radioactive-particles and targeting materials therapy, can be locally administrated by interventional techniques. The combination of targeting biological therapies and high-targeted interventional technique holds advantages of minimal invasion, accurate delivery, vigorous local effect, and less systemic adverse reactions. Authors believe that the biological therapy may arise a great opportunity for interventional radiology, therefore interventional colleagues should grasp firmly and promptly for the development and extension in this field. (authors)

  11. Suicide genes or p53 gene and p53 target genes as targets for cancer gene therapy by ionizing radiation

    International Nuclear Information System (INIS)

    Liu Bing; Chinese Academy of Sciences, Beijing; Zhang Hong

    2005-01-01

    Radiotherapy has some disadvantages due to the severe side-effect on the normal tissues at a curative dose of ionizing radiation (IR). Similarly, as a new developing approach, gene therapy also has some disadvantages, such as lack of specificity for tumors, limited expression of therapeutic gene, potential biological risk. To certain extent, above problems would be solved by the suicide genes or p53 gene and its target genes therapies targeted by ionizing radiation. This strategy not only makes up the disadvantage from radiotherapy or gene therapy alone, but also promotes success rate on the base of lower dose. By present, there have been several vectors measuring up to be reaching clinical trials. This review focused on the development of the cancer gene therapy through suicide genes or p53 and its target genes mediated by IR. (authors)

  12. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis

    NARCIS (Netherlands)

    Baert, F. J.; D'Haens, G. R.; Peeters, M.; Hiele, M. I.; Schaible, T. F.; Shealy, D.; Geboes, K.; Rutgeerts, P. J.

    1999-01-01

    Anti-tumor necrosis factor alpha monoclonal antibody treatment (infliximab) reduces clinical signs and symptoms in patients with Crohn's disease. The effects of infliximab on mucosal histopathologic abnormalities in Crohn's ileocolitis were studied. Thirteen patients with steroid-refractory Crohn's

  13. Emerging targeted therapies for plaque psoriasis – impact of ixekizumab

    Directory of Open Access Journals (Sweden)

    Kazemi T

    2017-04-01

    Full Text Available Tiana Kazemi,1 Benjamin Farahnik,2 John Koo,3 Kourosh Beroukhim1 1University of California – Los Angeles, David Geffen School of Medicine, Los Angeles, CA, 2University of Vermont College of Medicine, Burlington, VT, 3University of California – San Francisco, Department of Dermatology, Psoriasis and Skin Treatment Center, San Francisco, CA, USA Background: Recent studies into the pathogenesis of psoriasis have identified the importance of interleukin 17 (IL-17 in disease activity and have thus provided a new target for biologic therapy. Ixekizumab, the most recent US Food and Drug Administration (FDA-approved anti-IL-17 biologic agent, appears to be a promising medication for patients suffering from moderate-to-severe plaque psoriasis. Methods: We reviewed the results of phase III trials for ixekizumab in order to assess the efficacy, safety, and impact on quality of life of this agent in the treatment of plaque psoriasis. Additionally, we compared these results to phase II and phase III trials for other biologic psoriasis medications including the anti-IL-23 agents tildrakizumab and guselkumab, the combined anti-IL-12 and anti-IL-23 agent ustekinumab, and the anti-IL-17 agents brodalumab and secukinumab. Results: Pooled results from individual studies demonstrate that among the most efficacious dosing regimens of these anti-interleukin therapies, ixekizumab achieves higher Psoriasis Area and Severity Index 75 rates and similar or higher static Physician Global Assessment 0-1 rates than the other anti-IL-17 and anti-IL-23 agents. The safety profile of ixekizumab is similar to these agents, with nasopharyngitis, upper respiratory infection, headache, arthralgia, and injection-site erythema as the most commonly reported adverse events. Conclusion: Ixekizumab is a highly efficacious, newly FDA-approved treatment for moderate-to-severe plaque psoriasis that demonstrates a robust clinical response, significant improvement in patient quality of

  14. Nitric oxide production and monoamine oxidase activity in cancer patients during interferon-alpha therapy.

    Science.gov (United States)

    Fekkes, Durk; Van Gool, Arthur R; Bannink, Marjolein; Sleijfer, Stefan; Kruit, Wim H J; van der Holt, Bronno; Eggermont, Alexander M M; Hengeveld, Michiel W; Stoter, Gerrit

    2009-10-01

    Both increased and decreased nitric oxide (NO) synthesis have been reported in patients treated with interferon-alpha (IFN-alpha). Animal studies showed that IFN-alpha administration results in increased levels of biogenic amines, subsequent activation of monoamine oxidases (MAOs), and finally in a change in NO production due to the H(2)O(2) generated by MAOs. We examined the potential relationship between NO production in plasma and MAO-B activity in platelets of 43 cancer patients during 8 weeks of treatment with IFN-alpha. NO synthesis was quantitated by measuring both the ratio of citrulline and arginine (CIT/ARG-ratio) and total nitrite/nitrate (NOx) levels. Compared to baseline, MAO activity and NOx increased, while the CIT/ARG-ratio decreased. No associations were found between NOx, MAO and CIT/ARG-ratio. Only few associations were observed between changes in the biochemical parameters and changes in psychopathology induced by IFN-alpha, of which the association between changes in CIT and lassitude was the most consistent. The results suggest that peripheral NO production and MAO activity are unrelated to each other, and that peripheral changes in these biochemical parameters induced by IFN-alpha are unlikely to contribute to definite psychiatric disturbance.

  15. Vascular-targeted therapies for Duchenne muscular dystrophy

    Science.gov (United States)

    2013-01-01

    -receptor type 1 (VEGFR-1 or Flt-1). The pro-angiogenic approaches also seem to be pro-myogenic and could resolve the age-related decline in satellite cell (SC) quantity seen in mdx models through expansion of the SC juxtavascular niche. Here we review these four vascular targeted treatment strategies for DMD and discuss mechanisms, proof of concept, and the potential for clinical relevance associated with each therapy. PMID:23618411

  16. Integral excitation functions for proton and alpha induced reactions on target elements 22 <= Z <= 28

    International Nuclear Information System (INIS)

    Brinkmann, G.

    1979-01-01

    In the framework of a systematic study which is also important for certain cosmological questions a series of integral excitation functions of p- and α-induced nuclear reactions on target elements 22 [de

  17. New strategy of cancer therapy by targeting the hypoxic circumstances

    International Nuclear Information System (INIS)

    Yasui, Hironobu; Yamamori, Tohru; Meike, Shunsuke; Eitaki, Masato; Kuwabara, Mikinori; Inanami, Osamu; Iizuka, Daisuke

    2010-01-01

    Described are studies on the sensitization of tumor cells in hypoxic circumstances (known as radio-resistant cells) by authors' recent molecular targeting to adaptive response as well as by the usual agents like nitro-imidazole compounds, and on the intermittent hypoxia, a new topic in this field. The hypoxia-inducible factor-1 (HIF-1) is a transcriptional factor and has been known to activate its many downstream genes to cause adoptive response of hypoxic cells. Authors have studied the anti-tumor and radiation sensitizing effects of ethynyl-cytidine (EC) which is found to suppress RNA synthesis through cytidine kinase (CK) inhibition, and the compound is of specificity to tumor cells as they have 5-10 times higher CK activity than normal cells. Authors have also found that EC is of the sensitizing efficacy to normoxic and hypoxic cells by enhancing the radiation-induced apoptosis essentially through inhibition of HIF-1 expression. Intermittent hypoxia in the tumor which has characteristic abnormal vascular morphology and function, occurs by the transient reduction of blood flow and occlusion of vessels in the tissue within minute to hour time cycles. Little is known about the regional hypoxic region and its distribution in the tumor due to difficulty of their detection and quantification. For this, authors have measured the temporal changes of oxygen levels in the mouse tumor with triaryl methyl radical, an oxygen-sensitive contrast compound continuously injected, by microwave-pulsed electron spin resonance imaging (EPRI). By superimposing the EPRI and T2-weighted MRI, the oxymetric imaging is possible in the tumor, which reveals the difference of oxygen level variation depending on the cell type and tissue size. Findings in the field are expected to give important information for more effective cancer therapy and its prognostic prediction in future. (T.T.)

  18. Tunneling nanotubes: A versatile target for cancer therapy.

    Science.gov (United States)

    Sahoo, Pragyaparamita; Jena, Soumya Ranjan; Samanta, Luna

    2017-11-29

    Currently Cancer is the leading cause of death worldwide. Malignancy or cancer is a class of diseases characterized by uncontrolled cell growth that eventually invade other tissues and dvelop secondary malignant growth at other sites by metastasis. Intercellular communication plays a major in cancer, particularly in the process of cell proliferation and coordination which in turn leads to tumor invasion, metastasis and development of resistance to therapy. Cells communicate among themselves in a variety of ways, namely, i) via gap junctions with adjacent cells, ii) via exosomes with nearby cells and iii) via chemical messengers with distant cells. Besides, cell - cell connection by tunneling nanotubes (TnTs) is recently gaining importance where intercellular components are transferred between cells. In general cell organelles like Golgi vesicle and mitochondria; and biomolecules like nucleic acids and proteins are transferred through these TnTs. These TnTs are long cytoplasmic extensions made up of actin that function as intercellular bridge and connect a wide verity of cell types. Malignant cells form TnTs with either another malignant cells or cells of the surrounding tumor matrix. These TnTs help in the process of initiation of tumor formation, its organization and propagation. The current review focuses on the role of TnTs mediated cell – cell signaling in cancer micro-environment. Drugs that inhibit TnT-formation such as metformin and everolimus can be targeted towards TnTs in the management of cancer growth, proliferation, tumor invasion and metastasis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Relation of estrogen receptor-alpha gene polymorphism and hormone replacement therapy to fall risk and muscle strength in early postmenopausal women.

    Science.gov (United States)

    Salmén, Timo; Heikkinen, Anna-Mari; Mahonen, Anitta; Kröger, Heikki; Komulainen, Marja; Saarikoski, Seppo; Honkanen, Risto; Partanen, Juhani; Mäenpää, Pekka H

    2002-01-01

    Several factors may increase fracture risk, among them reduced bone mineral density (BMD), increased bone resorption, microarchitectural deterioration of bone, increased fall risk, and decreased muscle strength. We have previously reported that PvuII polymorphism of the estrogen receptor-alpha (ER alpha) gene is associated with bone loss rate, fracture risk, and response to hormone replacement therapy (HRT) in early postmenopausal Finnish women. We studied the influence of the ER alpha genotype on fall risk and muscle strength in a 5-year randomized HRT trial of 331 early postmenopausal women (subgroup of the population-based OSTPRE study, Kuopio, Finland). A 5-year postal inquiry in May 1994 included questions on falls during the previous 12 months. Grip strength was measured with dynamometer. The ER alpha gene polymorphism was analysed using PCR and PvuII restriction enzyme digestion. RESULTS. In all, 97 out of the 331 women reported falls. Half of those (56%) were slip falls, mostly during the winter season. In the HRT group, the ER alpha genotype was associated with fall risk (P = 0.002, logistic regression). The risk of falls (RR) was higher in women with the PP genotype than in those with the Pp (RR = 5.26, 95% CI 1.98-13.94, P = 0.001) or the pp (RR = 3.84, 95% CI 1.46-10.12, P = 0.007) genotype. When the falls were divided into slip (environment-related) and non-slip (endogenous) falls, the non-slip falls were associated with the genotype (P = 0.004), but the slip falls were not so clearly (P = 0.061). When all falls and non-slip falls were adjusted to the number of chronic health disorders and the variable time-since-menopause, the difference between the genotypes persisted (P = 0.003 and P = 0.010, respectively). In the non-HRT group, the ER alpha genotype was not associated with fall risk. The baseline or the 5-year grip strength values were not influenced by the ER alpha genotype. In conclusion, ER alpha polymorphism is associated with fall risk

  20. Assessing the Response to Targeted Therapies in Renal Cell Carcinoma: Technical Insights and Practical Considerations

    NARCIS (Netherlands)

    Bex, A.; Fournier, L.; Lassau, N.; Mulders, P.F.A.; Nathan, P.; Oyen, W.J.G.; Powles, T.

    2014-01-01

    CONTEXT: The introduction of targeted agents for the treatment of renal cell carcinoma (RCC) has resulted in new challenges for assessing response to therapy, and conventional response criteria using computed tomography (CT) are limited. It is widely recognised that targeted therapies may lead to

  1. Prostate Specific Membrane Antigen (PSMA) Targeted Bio-orthogonal Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0595 TITLE: Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate Cancer...Sep 2016 - 14 Sep 2017 4. TITLE AND SUBTITLE Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate

  2. SU-C-303-02: Correlating Metabolic Response to Radiation Therapy with HIF-1alpha Expression

    International Nuclear Information System (INIS)

    Campos, D; Peeters, W; Nickel, K; Eliceiri, K; Kimple, R; Van Der Kogel, A; Kissick, M

    2015-01-01

    Purpose: To understand radiation induced alterations in cellular metabolism which could be used to assess treatment or normal tissue response to aid in patient-specific adaptive radiotherapy. This work aims to compare the metabolic response of two head and neck cell lines, one malignant (UM-SCC-22B) and one benign (Normal Oral Keratinocyte), to ionizing radiation. Responses are compared to alterations in HIF-1alpha expression. These dynamics can potentially serve as biomarkers in assessing treatment response allowing for patient-specific adaptive radiotherapy. Methods: Measurements of metabolism and HIF-1alpha expression were taken before and X minutes after a 10 Gy dose of radiation delivered via an orthovoltage x-ray source. In vitro changes in metabolic activity were measured via fluorescence lifetime imaging (FLIM) to assess the mean lifetime of NADH autofluorescence following a dose of 10 Gy. HIF-1alpha expression was measured via immunohistochemical staining of in vitro treated cells and expression was quantified using the FIJI software package. Results: FLIM demonstrated a decrease in the mean fluorescence lifetime of NADH by 100 ps following 10 Gy indicating a shift towards glycolytic pathways for malignant cells; whereas this benign cell line showed little change in metabolic signature. Immunohistochemical analysis showed significant changes in HIF-1alpha expression in response to 10 Gy of radiation that correlate to metabolic profiles. Conclusion: Radiation induces significant changes in metabolic activity and HIF-1alpha expression. These alterations occur on time scales approximating the duration of common radiation treatments (approximately tens of minutes). Further understanding these dynamics has important implications with regard to improvement of therapy and biomarkers of treatment response

  3. SU-C-303-02: Correlating Metabolic Response to Radiation Therapy with HIF-1alpha Expression

    Energy Technology Data Exchange (ETDEWEB)

    Campos, D [University of Wisconsin Madison, Madison, WI (United States); Peeters, W [Radboud University Medical Center, Nijmegen, GA (United States); Nickel, K [University of Wisconsin, Madison, WI (United States); Eliceiri, K; Kimple, R; Van Der Kogel, A; Kissick, M [University of Wisconsin, Madison, Wisconsin (United States)

    2015-06-15

    Purpose: To understand radiation induced alterations in cellular metabolism which could be used to assess treatment or normal tissue response to aid in patient-specific adaptive radiotherapy. This work aims to compare the metabolic response of two head and neck cell lines, one malignant (UM-SCC-22B) and one benign (Normal Oral Keratinocyte), to ionizing radiation. Responses are compared to alterations in HIF-1alpha expression. These dynamics can potentially serve as biomarkers in assessing treatment response allowing for patient-specific adaptive radiotherapy. Methods: Measurements of metabolism and HIF-1alpha expression were taken before and X minutes after a 10 Gy dose of radiation delivered via an orthovoltage x-ray source. In vitro changes in metabolic activity were measured via fluorescence lifetime imaging (FLIM) to assess the mean lifetime of NADH autofluorescence following a dose of 10 Gy. HIF-1alpha expression was measured via immunohistochemical staining of in vitro treated cells and expression was quantified using the FIJI software package. Results: FLIM demonstrated a decrease in the mean fluorescence lifetime of NADH by 100 ps following 10 Gy indicating a shift towards glycolytic pathways for malignant cells; whereas this benign cell line showed little change in metabolic signature. Immunohistochemical analysis showed significant changes in HIF-1alpha expression in response to 10 Gy of radiation that correlate to metabolic profiles. Conclusion: Radiation induces significant changes in metabolic activity and HIF-1alpha expression. These alterations occur on time scales approximating the duration of common radiation treatments (approximately tens of minutes). Further understanding these dynamics has important implications with regard to improvement of therapy and biomarkers of treatment response.

  4. Monte Carlo simulation of age-dependent radiation dose from alpha- and beta-emitting radionuclides to critical trabecular bone and bone marrow targets

    Science.gov (United States)

    Dant, James T.; Richardson, Richard B.; Nie, Linda H.

    2013-05-01

    Alpha (α) particles and low-energy beta (β) particles present minimal risk for external exposure. While these particles can induce leukemia and bone cancer due to internal exposure, they can also be beneficial for targeted radiation therapies. In this paper, a trabecular bone model is presented to investigate the radiation dose from bone- and marrow-seeking α and β emitters to different critical compartments (targets) of trabecular bone for different age groups. Two main issues are addressed with Monte Carlo simulations. The first is the absorption fractions (AFs) from bone and marrow to critical targets within the bone for different age groups. The other issue is the application of 223Ra for the radiotherapy treatment of bone metastases. Both a static model and a simulated bone remodeling process are established for trabecular bone. The results show significantly lower AFs from radionuclide sources in the bone volume to the peripheral marrow and the haematopoietic marrow for adults than for newborns and children. The AFs from sources on the bone surface and in the bone marrow to peripheral marrow and haematopoietic marrow also varies for adults and children depending on the energy of the particles. Regarding the use of 223Ra as a radionuclide for the radiotherapy of bone metastases, the simulations show a significantly higher dose from 223Ra and its progeny in forming bone to the target compartment of bone metastases than that from two other more commonly used β-emitting radiopharmaceuticals, 153Sm and 89Sr. There is also a slightly lower dose from 223Ra in forming bone to haematopoietic marrow than that from 153Sm and 89Sr. These results indicate a higher therapy efficiency and lower marrow toxicity from 223Ra and its progeny. In conclusion, age-related changes in bone dimension and cellularity seem to significantly affect the internal dose from α and β emitters in the bone and marrow to critical targets, and 223Ra may be a more efficient

  5. Alpha-bungarotoxin binding to target cell in a developing visual system by carboxylated nanodiamond

    International Nuclear Information System (INIS)

    Liu, K-K; Chen, P-Y; Lee, Tony J F; Chao, J-I; Chen, M-F; Cheng, C-L; Chang, C-C; Ho, Y-P

    2008-01-01

    Biological molecules conjugating with nanoparticles are valuable for applications including bio-imaging, bio-detection, and bio-sensing. Nanometer-sized diamond particles have excellent electronic and chemical properties for bio-conjugation. In this study, we manipulated the carboxyl group produced on the surface of nanodiamond (carboxylated nanodiamond, cND) for conjugating with alpha-bungarotoxin (α-BTX), a neurotoxin derived from Bungarus multicinctus with specific blockade of alpha7-nicotinic acetylcholine receptor (α7-nAChR). The electrostatic binding of cND-α-BTX was mediated by the negative charge of the cND and the positive charge of the α-BTX in physiological pH conditions. Sodium dodecyl sulfate-polyacrylamide gel analysis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF-MS) spectra displayed that α-BTX proteins were conjugated with cND particles via non-covalent bindings. The green fluorescence of the cND particles combining with the red fluorescence of tetramethylrhodamine-labeled α-BTX presented a yellow color at the same location, which indicated that α-BTX proteins were conjugated with cND particles. Xenopus laevis's oocytes expressed the human α7-nAChR proteins by microinjection with α7-nAChR mRNA. The cND-α-BTX complexes were bound to α7-nAChR locating on the cell membrane of oocytes and human lung A549 cancer cells analyzed by laser scanning confocal microscopy. The choline-evoked α7-nAChR-mediated inward currents of the oocytes were blocked by cND-α-BTX complexes in a concentration-dependent manner using two-electrode voltage-clamp recording. Furthermore, the fluorescence intensity of cND-α-BTX binding on A549 cells could be quantified by flow cytometry. These results indicate that cND-conjugated α-BTX still preserves its biological activity in blocking the function of α7-nAChR, and provide a visual system showing the binding of α-BTX to α7-nAChR

  6. Sirtuin 3, a new target of PGC-1alpha, plays an important role in the suppression of ROS and mitochondrial biogenesis.

    Directory of Open Access Journals (Sweden)

    Xingxing Kong

    2010-07-01

    Full Text Available Sirtuin 3 (SIRT3 is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin with a reported association with the human life span. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1alpha induces several key reactive oxygen species (ROS-detoxifying enzymes, but the molecular mechanism underlying this is not well understood.Here we show that PGC-1alpha strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Knockdown of PGC-1alpha led to decreased Sirt3 gene expression. PGC-1alpha activated the mouse SIRT3 promoter, which was mediated by an estrogen-related receptor (ERR binding element (ERRE (-407/-399 mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that ERRalpha bound to the identified ERRE and PGC-1alpha co-localized with ERRalpha in the mSirt3 promoter. Knockdown of ERRalpha reduced the induction of Sirt3 by PGC-1alpha in C(2C(12 myotubes. Furthermore, Sirt3 was essential for PGC-1alpha-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1alpha in C(2C(12 myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1alpha on cellular ROS production. Finally, SIRT3 stimulated mitochondrial biogenesis, and SIRT3 knockdown decreased the stimulatory effect of PGC-1alpha on mitochondrial biogenesis in C(2C(12 myotubes.Our results indicate that Sirt3 functions as a downstream target gene of PGC-1alpha and mediates the PGC-1alpha effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy

  7. Current Status and Future Directions of Targeted Peptide Radionuclide Therapy

    International Nuclear Information System (INIS)

    Valkema, R.

    2009-01-01

    Current status: Peptide receptor radionuclide therapy (PRRT) is currently almost exclusively targeted at the somatostatin receptor (sst). Of the 5 receptor subtypes, sst2 is frequently very highly expressed at the cell surface of neuroendocrine tumors (NET). Octreotide is a small and stable derivative of native somatostatin, which can be very well labeled with therapeutic radionuclides such as the beta-emitters ''9''0Y, ''1''7''7Lu or the Auger emitter ''1''1''1In, chelated in DTPA or DOTA, linked to the peptide. All current therapeutic octreotide derivatives are agonists that are internalized in the cell. The affinity for the sst2 receptor is better for [DOTA,Tyr''3]octreotate than for [DOTA,Tyr''3]octreotide or [DTPA]octreotide. ''9''0Y is a pure beta-emitter, with a half-life of 2.7 days, a high energy of 2.270 MeV, and a maximum penetration in tissue of 12mm. ''1''7''7Lu with a half-life of 6.7 days emits a low abundance of gamma photons as well as beta particles of 497 keV, with a maximum tissue penetration of 2 mm. ''1''7''7Lu-[DOTA,Tyr''3]octreotate (Lu-DOTATE), ''9''0Y-[DOTA,Tyr''3]octreotate (Y-DOTATATE) and ''9''0Y-[DOTA,Tyr''3]octreotide (Y-DOTATOC) are today the most frequently used therapeutic radiopeptides. Main inclusion criteria: inoperable and/or metastatic NET, receptor-positivity in all known lesions demonstrated by sufficient uptake on ''1''1''1In-octreotide scintigraphy (intensity > liver parenchyma), life expectancy at least 3-6 months, sufficient bone marrow reserve (hemoglobin (HGB) ≥ 5 mmol/L, white blood cells (WBC) ≥ 2*10 9 /L, platelets (PLT) ≥ 75*10 12 /L), sufficient renal function (serum creatinine 40 mL/min), sufficient hepatic and cardiac reserve. Karnofski score ≥50. Efficacy: several groups have reported objective response rates (RECIST or WHO/SWOG; CT or MRI based). Complete remission (CR) is rarely seen, partial remission (PR; >50% shrinkage SWOG) in 7% - 37%, minor remission (MR, 25% - 50% shrinkage) in 13% - 17

  8. Risky business: target choice in adoptive cell therapy.

    Science.gov (United States)

    Morgan, Richard A

    2013-11-14

    In this issue of Blood, Casucci et al present an elegant study that describes a potential new target for adoptive cell transfer (ACT), in this case CD44 splice variant 6 (CD44v6), and detail why it may be a good target for ACT and how to manage expected off-tumor/on-target toxicities.

  9. Specifically targeted gene therapy for small-cell lung cancer

    DEFF Research Database (Denmark)

    Christensen, C.L.; Zandi, R.; Gjetting, T.

    2009-01-01

    Small-cell lung cancer (SCLC) is a highly malignant disease with poor prognosis. Hence, there is great demand for new therapies that can replace or supplement the current available treatment regimes. Gene therapy constitutes a promising strategy and relies on the principle of introducing exogenous...

  10. Tumor Necrosis Factor-Alpha Targeting Can Protect against Arthritis with Low Sensitization to Infection

    Directory of Open Access Journals (Sweden)

    Nadia Belmellat

    2017-11-01

    Full Text Available Tumor necrosis factor-alpha (TNF-α blockade is an effective treatment for rheumatoid arthritis (RA and other inflammatory diseases, but in patients, it is associated with reduced resistance to the infectious agents Mycobacterium tuberculosis and Listeria monocytogenes, among others. Our goal was to model infection and arthritis in mice and to compare etanercept, a currently used anti-TNF-α inhibitor, to an anti-TNF-α vaccine. We developed a murine surrogate of the TNF-α kinoid and produced an anti-murine TNF-α vaccine (TNFKi composed of keyhole limpet hemocyanin conjugated to TNF-α, which resulted in anti-TNF-α antibody production in mice. We also used etanercept (a soluble receptor of TNF commonly used to treat RA as a control of TNF neutralization. In a mouse model of collagen-induced arthritis, TNFKi protected against inflammation similar to etanercept. In a mouse model of acute L. monocytogenes infection, all TNFKi-treated mice showed cleared bacterial infection and survived, whereas etanercept-treated mice showed large liver granulomas and quickly died. Moreover, TNFKi mice infected with the virulent H37Rv M. tuberculosis showed resistance to infection, in contrast with etanercept-treated mice or controls. Depending on the TNF-α blockade strategy, treating arthritis with a TNF-α inhibitor could result in a different profile of infection suceptibility. Our TNFKi vaccine allowed for a better remaining host defense than did etanercept.

  11. IMMUNOMODULATING THERAPY BY RECOMBINANT ALPHA-2B INTERFERON AMONG CHILDREN WITH TIMOMEGALIA

    Directory of Open Access Journals (Sweden)

    L.A. Nikulin

    2007-01-01

    Full Text Available The study of the enlarged thymus gland syndrome is extremely important for understanding of the immune system formation and functioning mechanisms. the purpose of this study is to conduct clinical and immunological analysis of the children, suffering from the syndrome of the enlarged thymus gland II and III degrees, who received recombinant alpha2b interferon (in suppositories. The revealed changes in the immune sys tem during timomegalia are complex and conducive to the development of the infectious and inflammatory diseases among infants, thus, determining the necessity for the adequate immune correction. The application of the recombinant alpha 2b interferon among such children allows one to uncover the immunomodulating effects, normalizing the imbalances in the immune system of children with timomegalia.Key words: timomegalia, alpha 2b interferon, immunity, immune correction, children.

  12. Alpha interferon therapy in Danish haemophiliac patients with chronic hepatitis C

    DEFF Research Database (Denmark)

    Laursen, A L; Scheibel, E; Ingerslev, Jørgen

    1998-01-01

    Following a survey among all Danish haemophiliac patients 49 HIV-negative patients with chronic hepatitis C were offered enrollment in a randomized controlled open label study comparing two different maintenance regimens following standard interferon-alpha-2b treatment. Dose modifications...... and biochemical response after 6 months of follow up. Overall, the individualized treatment regimen did not seem to offer any advantage over the fixed dose regimen. The response to alpha interferon treatment in Danish haemophiliac patients with chronic hepatitis C immediately after treatment is comparable...... and treatment discontinuation were based upon changes in transaminase levels. Forty-seven patients enrolled received 3 MU of alpha interferon thrice weekly (TIW) for 3 months. Twenty-six nonresponders had their dose increased to 6 MU TIW for an additional 3 months, while 21 responding patients continued on 3 MU...

  13. Combination of vascular targeting agents with thermal or radiation therapy

    International Nuclear Information System (INIS)

    Horsman, Michael R.; Murata, Rumi

    2002-01-01

    Purpose: The most likely clinical application of vascular targeting agents (VTAs) is in combination with more conventional therapies. In this study, we report on preclinical studies in which VTAs were combined with hyperthermia and/or radiation. Methods and Materials: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was treated when at 200 mm 3 in size. The VTAs were combretastatin A-4 disodium phosphate (CA4DP, 25 mg/kg), flavone acetic acid (FAA, 150 mg/kg), and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, 20 mg/kg), and were all injected i.p. Hyperthermia and radiation were locally administered to tumors of restrained, nonanesthetized mice, and response was assessed using either a tumor growth or tumor control assay. Results: Heating tumors at 41.5 degree sign C gave rise to a linear relationship between the heating time and tumor growth with a slope of 0.02. This slope was increased to 0.06, 0.09, and 0.08, respectively, by injecting the VTAs either 30 min (CA4DP), 3 h (FAA), or 6 h (DMXAA) before heating. The radiation dose (±95% confidence interval) that controls 50% of treated tumors (the TCD 50 value) was estimated to be 53 Gy (51-55 Gy) for radiation alone. This was decreased to 48 Gy (46-51 Gy), 45 Gy (41-49 Gy), and 42 Gy (39-45 Gy), respectively, by injecting CA4DP, DMXAA, or FAA 30-60 min after irradiating. These values were further decreased to around 28-33 Gy if the tumors of VTA-treated mice were also heated to 41.5 degree sign C for 1 h, starting 4 h after irradiation, and this effect was much larger than the enhancement seen with either 41.5 degree sign C or even 43 degree sign C alone. Conclusions: Our preclinical studies and those of others clearly demonstrate that VTAs can enhance tumor response to hyperthermia and/or radiation and support the concept that such combination studies should be undertaken clinically for the full potential of VTAs to be realized

  14. Treatment outcome of radiation therapy and concurrent targeted molecular therapy in spinal metastasis from renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sang Joon; Kim, Kyung Hwan; Rhee, Woo Joong; Lee, Jeong Shin; Cho, Yeo Na; Koom, Woong Sub [Dept. of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2016-06-15

    To evaluate the clinical outcomes of patients who underwent radiation therapy with or without targeted molecular therapy for the treatment of spinal metastasis from renal cell carcinoma (RCC). A total of 28 spinal metastatic lesions from RCC patients treated with radiotherapy between June 2009 and June 2015 were retrospectively reviewed. Thirteen lesions were treated concurrently with targeted molecular therapy (concurrent group) and 15 lesions were not (nonconcurrent group). Local control was defined as lack of radiographically evident local progression and neurological deterioration. At a median follow-up of 11 months (range, 2 to 58 months), the 1-year local progression-free rate (LPFR) was 67.0%. The patients with concurrent targeted molecular therapy showed significantly higher LPFR than those without (p = 0.019). After multivariate analysis, use of concurrent targeted molecular therapy showed a tendency towards improved LPFR (hazard ratio, 0.13; 95% confidence interval, 0.01 to 1.16). There was no difference in the incidence of systemic progression between concurrent and nonconcurrent groups. No grade ≥2 toxicities were observed during or after radiotherapy. Our study suggests the possibility that concurrent use of targeted molecular therapy during radiotherapy may improve LPFR. Further study with a large population is required to confirm these results.

  15. Treatment outcome of radiation therapy and concurrent targeted molecular therapy in spinal metastasis from renal cell carcinoma

    International Nuclear Information System (INIS)

    Park, Sang Joon; Kim, Kyung Hwan; Rhee, Woo Joong; Lee, Jeong Shin; Cho, Yeo Na; Koom, Woong Sub

    2016-01-01

    To evaluate the clinical outcomes of patients who underwent radiation therapy with or without targeted molecular therapy for the treatment of spinal metastasis from renal cell carcinoma (RCC). A total of 28 spinal metastatic lesions from RCC patients treated with radiotherapy between June 2009 and June 2015 were retrospectively reviewed. Thirteen lesions were treated concurrently with targeted molecular therapy (concurrent group) and 15 lesions were not (nonconcurrent group). Local control was defined as lack of radiographically evident local progression and neurological deterioration. At a median follow-up of 11 months (range, 2 to 58 months), the 1-year local progression-free rate (LPFR) was 67.0%. The patients with concurrent targeted molecular therapy showed significantly higher LPFR than those without (p = 0.019). After multivariate analysis, use of concurrent targeted molecular therapy showed a tendency towards improved LPFR (hazard ratio, 0.13; 95% confidence interval, 0.01 to 1.16). There was no difference in the incidence of systemic progression between concurrent and nonconcurrent groups. No grade ≥2 toxicities were observed during or after radiotherapy. Our study suggests the possibility that concurrent use of targeted molecular therapy during radiotherapy may improve LPFR. Further study with a large population is required to confirm these results

  16. MicroRNA-195 induced apoptosis in hypoxic chondrocytes by targeting hypoxia-inducible factor 1 alpha.

    Science.gov (United States)

    Bai, R; Zhao, A-Q; Zhao, Z-Q; Liu, W-L; Jian, D-M

    2015-02-01

    The chondrocytes, the resident cells of cartilage, are maintained and take effects in the whole life upon chronic hypoxic exposure, which hypoxia-inducible factor 1 alpha (HIF-1α) play pivotal roles in response to. Dysregulation of some microRNA (miRNAs) have also been identified to be involved in hypoxia-related physiologic and pathophysiologic responses in some tissues or cell lines. However, the mechanism of miRNAs reponse to hypoxia remain largely unknown in chondrocytes, including the microRNA-195 (miR-195). AIM To investigate the effects of microRNAs (miRNAs) and hypoxia-inducible factor 1 alpha (HIF-1α) on chondrocytes in physiologic environment. We compared the expression of miR-195 and HIF-1α mRNA on hypoxia with that on normoxia in ATDC 5 cells by qRT-PCR. Further experiments was performed to confirmed the relationships of miR-195 and HIF-1α by bioinformatics analysis and dual reporter gene assay. we also assessed the effect of miR-195 on apoptosis in hypoxic ATDC 5 cells by transfect with miR-195 mimics. It was found the downregulated miR-195 and upregulated HIF-1α were present in hypoxic ATDC 5 cells. miR-195 negatively regulated HIF-1α by targeting its 3'-untranslated region. Moreover, the founding indicated miR-195 greatly increased apoptosis and downregulated HIF-1α mRNA occurred simultaneously in hypoxic chondrocytes. We concluded that miR-195 induced apoptosis in hypoxic chondrocytes by directly targeting HIF-1α.

  17. Mitochondrial targeting of alpha-tocopheryl succinate enhances its anti-mesothelioma efficacy

    Czech Academy of Sciences Publication Activity Database

    Kovářová, Jaromíra; Bajziková, Martina; Vondrusová, Magdaléna; Štursa, Jan; Goodwin, J.; Nguyen, M.; Zobalová, Renata; Pesdar, E.A.; Truksa, Jaroslav; Tomasetti, M.; Dong, L. F.; Neužil, Jiří

    2014-01-01

    Roč. 19, č. 1 (2014), s. 16-25 ISSN 1351-0002 R&D Projects: GA ČR(CZ) GAP301/10/1937; GA ČR GAP305/12/1708 Institutional support: RVO:86652036 ; RVO:61388963 Keywords : Vitamin E analogues * Mitochondrial targeting * Reactive oxygen species Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.522, year: 2014

  18. Effectiveness of Alpha-toxin Fab Monoclonal Antibody Therapy in Limiting the Pathology of Staphylococcus aureus Keratitis.

    Science.gov (United States)

    Caballero, Armando R; Foletti, Davide L; Bierdeman, Michael A; Tang, Aihua; Arana, Angela M; Hasa-Moreno, Adela; Sangalang, Emma Ruth B; O'Callaghan, Richard J

    2015-08-01

    To investigate the effectiveness of a high-affinity human monoclonal antibody Fab fragment to Staphylococcus aureus alpha-toxin (LTM14 Fab) as therapy for S. aureus keratitis. A single topical drop of the LTM14 Fab antibody to alpha-toxin alone, or in 0.006% benzalkonium chloride (BAK), was applied every 30 min to S. aureus-infected rabbit corneas from 9 to 14 hours post-infection. Erosions and pathology were measured at 15 h post-infection. LTM14 Fab with BAK limited corneal erosions better than LTM14 Fab alone (p = 0.036), and both limited erosions compared to untreated eyes (p ≤ 0.0001). Overall pathology was similar in all groups (p ≥ 0.070), but iritis and chemosis were reduced by treatment (p ≤ 0.036). The high-affinity human monoclonal Fab fragment antibody (LTM14 Fab) to S. aureus alpha-toxin was effective in reducing corneal damage during S. aureus keratitis.

  19. Targeted Therapies in Hematology and Their Impact on Patient Care: Chronic and Acute Myeloid Leukemia

    Science.gov (United States)

    Cortes, Elias Jabbour Jorge; Ravandi, Farhad; O’Brien, Susan; Kantarjian, Hagop

    2014-01-01

    Advances in the genetic and molecular characterizations of leukemias have enhanced our capabilities to develop targeted therapies. The most dramatic examples of targeted therapy in cancer to date are the use of targeted BCR-ABL protein tyrosine kinase inhibitors (TKI) which has revolutionized the treatment of chronic myeloid leukemia (CML). Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target, transforming the prognosis of patients with CML. In contrast, acute myeloid leukemia (AML) is an extremely heterogeneous disease with outcomes that vary widely according to subtype of the disease. Targeted therapy with monoclonal antibodies and small molecule kinase inhibitors are promising strategies to help improve the cure rates in AML. In this review, we will highlight the results of recent clinical trials in which outcomes of CML and AML have been influenced significantly. Also, novel approaches to sequencing and combining available therapies will be covered. PMID:24246694

  20. Targeted Therapies for Myeloma and Metastatic Bone Cancers

    National Research Council Canada - National Science Library

    Vail, Neal

    2008-01-01

    ... done. Quantified functional groups available for ligand conjugation using S35-labeled ligands. Developed alternative assay to confirm affinity of bone-targeting nanoparticles to hydroxyapatite substrates...

  1. Targeting of alpha-v integrins reduces malignancy of bladder carcinoma.

    Directory of Open Access Journals (Sweden)

    Geertje van der Horst

    Full Text Available Low survival rates of metastatic cancers emphasize the need for a drug that can prevent and/or treat metastatic cancer. αv integrins are involved in essential processes for tumor growth and metastasis and targeting of αv integrins has been shown to decrease angiogenesis, tumor growth and metastasis. In this study, the role of αv integrin and its potential as a drug target in bladder cancer was investigated. Treatment with an αv integrin antagonist as well as knockdown of αv integrin in the bladder carcinoma cell lines, resulted in reduced malignancy in vitro, as illustrated by decreased proliferative, migratory and clonogenic capacity. The CDH1/CDH2 ratio increased, indicating a shift towards a more epithelial phenotype. This shift appeared to be associated with downregulation of EMT-inducing transcription factors including SNAI2. The expression levels of the self-renewal genes NANOG and BMI1 decreased as well as the number of cells with high Aldehyde Dehydrogenase activity. In addition, self-renewal ability decreased as measured with the urosphere assay. In line with these observations, knockdown or treatment of αv integrins resulted in decreased metastatic growth in preclinical in vivo models as assessed by bioluminescence imaging. In conclusion, we show that αv integrins are involved in migration, EMT and maintenance of Aldehyde Dehydrogenase activity in bladder cancer cells. Targeting of αv integrins might be a promising approach for treatment and/or prevention of metastatic bladder cancer.

  2. Mitochondrial targeting overcomes ABCA1-dependent resistance of lung carcinoma to alpha-tocopheryl succinate

    Czech Academy of Sciences Publication Activity Database

    Procházka, L.; Koudelka, Š.; Dong, L. F.; Štursa, Jan; Goodwin, J.; Neca, J.; Slavík, J.; Cigánek, M.; Mašek, J.; Klučková, Katarína; Nguyen, M.; Turánek, J.; Neužil, Jiří

    2013-01-01

    Roč. 18, č. 3 (2013), s. 286-299 ISSN 1360-8185 R&D Projects: GA ČR GAP301/10/1937; GA ČR(CZ) GAP304/10/1951 Grant - others:GA ČR(CZ) GP204/09/P632 Institutional research plan: CEZ:AV0Z50520701; CEZ:AV0Z40550506 Keywords : vitamin E analogues * apoptosis * mitochondrial targeting * ABCA1 * acquired resistance Subject RIV: CE - Biochemistry; EA - Cell Biology (BTO-N) Impact factor: 3.614, year: 2013

  3. Fucosylation Is a Promising Target for Cancer Diagnosis and Therapy

    Directory of Open Access Journals (Sweden)

    Shinichiro Shinzaki

    2012-01-01

    Full Text Available Oligosaccharides, sequences of carbohydrates conjugated to proteins and lipids, are arguably the most abundant and structurally diverse class of molecules. Fucosylation is one of the most important oligosaccharide modifications involved in cancer and inflammation. Recent advances in glycomics have identified several types of glyco-biomarkers containing fucosylation that are linked to certain types of cancer. Fucosylated alpha-fetoprotein (AFP is widely used in the diagnosis of hepatocellular carcinoma because it is more specific than alpha-fetoprotein. High levels of fucosylated haptoglobin have also been found in sera of patients with various carcinomas. We have recently established a simple lectin-antibody ELISA to measure fucosylated haptoglobin and to investigate its clinical use. Cellular fucosylation is dependent upon fucosyltransferase activity and the level of its donor substrate, guanosine diphosphate (GDP-fucose. GDP-mannose-4,6-dehydratase (GMDS is a key enzyme involved in the synthesis of GDP-fucose. Mutations of GMDS found in colon cancer cells induced a malignant phenotype, leading to rapid growth in athymic mice resistant to natural killer cells. This review describes the role of fucosylated haptoglobin as a cancer biomarker, and discusses the possible biological role of fucosylation in cancer development.

  4. IGF-IR targeted therapy: Past, present and future

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); A.J. Varewijck (Aimee)

    2014-01-01

    textabstractThe IGF-I receptor (IGF-IR) has been studied as an anti-cancer target. However, monotherapy trials with IGF-IR targeted antibodies or with IGF-IR specific tyrosine kinase inhibitors have, overall, been very disappointing in the clinical setting. This review discusses potential reasons

  5. Characterization of Hepatitis C Virus genotype 3a Hypervariable region 1 in patients achieved rapid virological response to alpha interferon and Ribavirin Combination therapy

    Directory of Open Access Journals (Sweden)

    Badar Sadaf

    2011-05-01

    Full Text Available Abstract Background Hepatitis C virus roots a chronic liver disease. Currently approved treatment strategy includes administration of alpha interferon and ribavirin combined therapy for 24-48 weeks. One of the predictor of sustained virological response is an early virological response to treatment characterized as rapid response. Hyper variable region 1 (HVR1 of E2 protein is responsible for viral entry and acts as a target for neutralizing antibodies. Any mutation in this region would effect virus interaction with target cell and viral persistence. Methods Thirty one clones of six pre-treatment samples subjected to combination therapy were investigated. Three of the patients were rapid responders (R1, R2 and R3 and two were breakthrough responders (BT1 and BT2. Envelope 2 gene was amplified, cloned and sequenced. Amino acid substitution, frequency, composition and antigenic properties of HVR 1 of E2 protein were studied. Results In both rapid responders (R.R (14 amino acid sites and breakthrough responders (BT.R (13 amino acid sites half of the amino acid sites were either conserved or resistant to any physiochemical change due to amino acid substitution. It also indicated that average composition of hydrophilic and basic amino acids were comparatively lower in rapid responders than other samples affecting probable interaction of virus with target cells. A central non antigenic region was constant among the breakthrough responders but differed in length significantly among rapid responders reflecting the adaptive nature of HVR1 to the immune response. Conclusions We observed that although HVR1is quite variable region in HCV 3a patients responding differently to treatment it still maintains its physiochemical properties for its proper functioning and viability.

  6. Morphometry for alpha particle hits of critical targets in the lungs. Final technical report

    International Nuclear Information System (INIS)

    Mercer, R.R.

    1998-01-01

    The objective of this study is to provide detailed data on the number, location and type of critical target cells in the airspaces and to use these data in order to make risk assessments of the health effects of radon and radon progeny in the lungs. This will be done by quantitative morphometric study of the distribution of the various cell types and mucous lining layers in the lungs. The results provide anatomically correct models for dosimetry in the rate and human airways which significantly improve the ability to do risk assessment for radon exposures by providing quantitative data for specific cell types and provide a basis for mechanism based comparison between data available in animal exposures and human epidemiology

  7. Prediction of therapy response to interferon-alpha in chronic viral hepatitis-B by liver and hepatobiliary scintigraphy

    International Nuclear Information System (INIS)

    Caglar, M.; Sari, O.; Akcan, Y.

    2002-01-01

    Interferon (IFN) provides effective treatment in some patients with chronic hepatitis. The clarification of factors predictive of therapy response would be helpful in identifying patients who would benefit from treatment. In this study, we evaluated the potential utility of Tc-99m sulfur colloid liver/spleen and Tc-99m-disofenin hepatobiliary scintigraphy to predict therapy response to IFN in patients with chronic active hepatitis. The study group consisted of ten patients with chronic viral hepatitis B who were treated with 4.5 units of interferon alpha for 12 months. Prior to the start of the therapy, sulfur colloid scintigraphy was obtained by which the liver/spleen ratios were derived. Hepatobiliary scintigraphy was performed on a separate day and time-activity curves were generated from regions of interest drawn over the liver, heart and gall-bladder. The index of blood and liver clearance time was calculated. Histological grading and laboratory values were obtained for clinical correlation. Responders (n=6) to IFN were defined as those who improved clinically with normalized transaminase levels and had hepatitis B envelope antigen (HBeAg) seroconversion. On sulfur colloid (SC) scintigraphy, the liver/spleen ratio of non-responders was significantly lower than responders (median values: 0.69 vs. 1.16, p=0.01) but on hepatobiliary scintigraphy no statistically significant parameters were found to predict response to interferon therapy. (author)

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

    Science.gov (United States)

    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.

  9. Interferon alpha therapy for hepatitis C: treatment completion and response rates among patients with substance use disorders

    Directory of Open Access Journals (Sweden)

    Loftis Jennifer M

    2007-01-01

    Full Text Available Abstract Background Individuals with substance use disorders (SUDs are at increased risk for hepatitis C viral infection (HCV, and few studies have explored their treatment responses empirically. The objective of this study was to assess interferon alpha therapy (IFN completion and response rates among patients with HCV who had a history of comorbid SUDs. More data is needed to inform treatment strategies and guidelines for these patients. Using a medical record database, information was retrospectively collected on 307,437 veterans seen in the Veterans Integrated Service Network 20 (VISN 20 of the Veterans Healthcare Administration (VHA between 1998 and 2003. For patients treated with any type of IFN (including regular or pegylated IFN or combination therapy (IFN and ribavirin who had a known HCV genotype, IFN completion and response rates were compared among patients with a history of SUD (SUD+ Group and patients without a history of SUD (SUD- Group. Results Odds ratio analyses revealed that compared with the SUD- Group, the SUD+ Group was equally likely to complete IFN therapy if they had genotypes 2 and 3 (73.1% vs. 68.0%, and if they had genotypes 1 and 4 (39.5% vs. 39.9%. Within the sample of all patients who began IFN therapy, the SUD- and SUD+ groups were similarly likely to achieve an end of treatment response (genotypes 2 and 3, 52.8% vs. 54.3%; genotypes 1 and 4, 24.5% vs. 24.8% and a sustained viral response (genotypes 2 and 3, 42.6% vs. 41.1%; genotypes 1 and 4: 16.0% vs. 22.3%. Conclusion Individuals with and without a history of SUD responded to antiviral therapy for HCV at similar rates. Collectively, these findings suggest that patients who have co-morbid SUD and HCV diagnoses can successfully complete a course of antiviral therapy.

  10. Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies

    Science.gov (United States)

    2017-10-01

    prostate cancer . Cancer Res 70: 7992-8002, 2010 8. Nelson PS: Molecular states underlying an- drogen receptor activation: A framework for thera- peutics...targeting androgen signaling in prostate cancer . J Clin Oncol 30:644-646, 2012 9. Thadani-Mulero M, Nanus DM, Giannakakou P: Androgen receptor on the... prostate cancer . Clin Cancer Res 21:795-807, 2015 17. van Soest RJ, de Morrée ES, Kweldam CF, et al: Targeting the androgen receptor confers in vivo

  11. Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy

    International Nuclear Information System (INIS)

    Kim, Dong Wook; Huamani, Jessica; Fu, Allie; Hallahan, Dennis E.

    2006-01-01

    The tumor microenvironment, in particular, the tumor vasculature, as an important target for the cytotoxic effects of radiation therapy is an established paradigm for cancer therapy. We review the evidence that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated in endothelial cells exposed to ionizing radiation (IR) and is a molecular target for the development of novel radiation sensitizing agents. On the basis of this premise, several promising preclinical studies that targeted the inhibition of the PI3K/Akt activation as a potential method of sensitizing the tumor vasculature to the cytotoxic effects of IR have been conducted. An innovative strategy to guide cytotoxic therapy in tumors treated with radiation and PI3K/Akt inhibitors is presented. The evidence supports a need for further investigation of combined-modality therapy that involves radiation therapy and inhibitors of PI3K/Akt pathway as a promising strategy for improving the treatment of patients with cancer

  12. RANKL-Targeted Therapies: The Next Frontier in the Treatment of Male Osteoporosis

    Directory of Open Access Journals (Sweden)

    Alicia K. Morgans

    2011-01-01

    Full Text Available Male osteoporosis is an increasingly recognized problem in aging men. A common cause of male osteoporosis is hypogonadism. Thousands of men with prostate cancer are treated with androgen deprivation therapy, a treatment that dramatically reduces serum testosterone and causes severe hypogonadism. Men treated with androgen deprivation therapy experience a decline in bone mineral density and have an increased rate of fracture. This paper describes prostate cancer survivors as a model of hypogonadal osteoporosis and discusses the use of RANKL-targeted therapies in osteoporosis. Denosumab, the only RANKL-targeted therapy currently available, increases bone mineral density and decreases fracture rate in men with prostate cancer. Denosumab is also associated with delayed time to first skeletal-related event and an increase in bone metastasis-free survival in these men. It is reasonable to investigate the use of RANKL-targeted therapy in male osteoporosis in the general population.

  13. Apoptosis and cancer stem cells : Implications for apoptosis targeted therapy

    NARCIS (Netherlands)

    Kruyt, Frank A. E.; Schuringa, Jan Jacob

    2010-01-01

    Evidence is accumulating showing that cancer stem cells or tumor-initiating cells are key drivers of tumor formation and progression. Successful therapy must therefore eliminate these cells, which is hampered by their high resistance to commonly used treatment modalities. Thus far, only a limited

  14. Stimuli-responsive biodegradable polymeric micelles for targeted cancer therapy

    NARCIS (Netherlands)

    Talelli, M.A.

    2011-01-01

    Thermosensitive and biodegradable polymeric micelles based on mPEG-b-pHPMAmLacn have shown very promising results during the past years. The results presented in this thesis illustrate the high potential of these micelles for anticancer therapy and imaging and fully justify further pharmaceutical

  15. MicroRNA-139 suppresses proliferation in luminal type breast cancer cells by targeting Topoisomerase II alpha

    Energy Technology Data Exchange (ETDEWEB)

    Hua, Wei [Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); Sa, Ke-Di; Zhang, Xiang; Jia, Lin-Tao; Zhao, Jing [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); Yang, An-Gang [State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, 710032 Xi' an (China); Zhang, Rui, E-mail: ruizhang@fmmu.edu.cn [State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, 710032 Xi' an (China); Fan, Jing, E-mail: jingfan@fmmu.edu.cn [Department of Vascular and Endocrine Surgery, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Bian, Ka, E-mail: kakamax85@hotmail.com [State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, 710032 Xi' an (China); Department of Otolaryngology, Tangdu Hospital, Fourth Military Medical University, Xi' an 710038 (China)

    2015-08-07

    The classification of molecular subtypes of breast cancer improves the prognostic accuracy and therapeutic benefits in clinic. However, because of the complexity of breast cancer, more biomarkers and functional molecules need to be explored. Here, analyzing the data in a huge cohort of breast cancer patients, we found that Topoisomerase II alpha (TOP2a), an important target of chemotherapy is a biomarker for prognosis in luminal type breast cancer patients, but not in basal like or HER2 positive breast cancer patients. We identified that miR-139, a previous reported anti-metastatic microRNA targets 3’-untranslated region (3′UTR) of TOP2a mRNA. Further more, we revealed that the forced expression of miR-139 reduces the TOP2a expression at both mRNA and protein levels. And our functional experiments showed that the ectopic expression of miR-139 remarkably inhibits proliferation in luminal type breast cancer cells, while exogenous TOP2a expression could rescue inhibition of cell proliferation mediated by miR-139. Collectively, our present study demonstrates the miR-139-TOP2a regulatory axis is important for proliferation in luminal type breast cancer cells. This functional link may help us to further understand the specificity of subtypes of breast cancer and optimize the strategy of cancer treatment. - Highlights: • High levels of TOP2a expression are closely associated with poor prognosis in luminal type breast cancer patients. • TOP2a is a novel target of miR-139. • Overexpression of miR-139 inhibits proliferation in luminal type breast cancer cells. • TOP2a is essential for miR-139-induced growth arrest in luminal type breast cancer cells.

  16. MicroRNA-139 suppresses proliferation in luminal type breast cancer cells by targeting Topoisomerase II alpha

    International Nuclear Information System (INIS)

    Hua, Wei; Sa, Ke-Di; Zhang, Xiang; Jia, Lin-Tao; Zhao, Jing; Yang, An-Gang; Zhang, Rui; Fan, Jing; Bian, Ka

    2015-01-01

    The classification of molecular subtypes of breast cancer improves the prognostic accuracy and therapeutic benefits in clinic. However, because of the complexity of breast cancer, more biomarkers and functional molecules need to be explored. Here, analyzing the data in a huge cohort of breast cancer patients, we found that Topoisomerase II alpha (TOP2a), an important target of chemotherapy is a biomarker for prognosis in luminal type breast cancer patients, but not in basal like or HER2 positive breast cancer patients. We identified that miR-139, a previous reported anti-metastatic microRNA targets 3’-untranslated region (3′UTR) of TOP2a mRNA. Further more, we revealed that the forced expression of miR-139 reduces the TOP2a expression at both mRNA and protein levels. And our functional experiments showed that the ectopic expression of miR-139 remarkably inhibits proliferation in luminal type breast cancer cells, while exogenous TOP2a expression could rescue inhibition of cell proliferation mediated by miR-139. Collectively, our present study demonstrates the miR-139-TOP2a regulatory axis is important for proliferation in luminal type breast cancer cells. This functional link may help us to further understand the specificity of subtypes of breast cancer and optimize the strategy of cancer treatment. - Highlights: • High levels of TOP2a expression are closely associated with poor prognosis in luminal type breast cancer patients. • TOP2a is a novel target of miR-139. • Overexpression of miR-139 inhibits proliferation in luminal type breast cancer cells. • TOP2a is essential for miR-139-induced growth arrest in luminal type breast cancer cells

  17. Graves' disease radioiodine-therapy: Choosing target absorbed doses for therapy planning

    Energy Technology Data Exchange (ETDEWEB)

    Willegaignon, J., E-mail: j.willegaignon@gmail.com; Sapienza, M. T.; Coura-Filho, G. B.; Buchpiguel, C. A. [Cancer Institute of São Paulo State (ICESP), Clinical Hospital, School of Medicine, University of São Paulo, São Paulo 01246-000 (Brazil); Nuclear Medicine Service, Department of Radiology, School of Medicine, University of São Paulo, Sao Paulo 01246-000 (Brazil); Watanabe, T. [Nuclear Medicine Service, Department of Radiology, School of Medicine, University of São Paulo, São Paulo 01246-000 (Brazil); Traino, A. C. [Unit of Medical Physics, Azienda Ospedaliero-Universitaria Pisana, Pisa 56126 (Italy)

    2014-01-15

    {sup ~} was determined by the integration of measured {sup 131}I activity in the thyroid gland and based on T{sub eff}, respectively. No statistically significant relationship was found between therapeutic response and patients’ age, administered {sup 131}I activity (MBq), 24-h thyroid {sup 131}I uptake (%) or T{sub eff} (p ≥ 0.064); nonetheless, a good relationship was found between the therapeutic response and m{sub th} (p ≤ 0.035). Conclusions: According to the results of this study, the most effective thyroid absorbed dose to be targeted in GD therapy should not be based on a fixed dose but rather should be individualized based on the patient'sm{sub th} and A{sup ~}. To achieve a therapeutic success (i.e., durable euthyroidism or hypothyroidism) rate of at least 95%, a thyroid absorbed dose of 200 or 330 Gy is required depending on the methodology used for estimating m{sub th} and A{sup ~}.

  18. Development of a Novel Targeted RNAi Delivery Technology inTherapies for Metabolic Diseases

    Science.gov (United States)

    2017-10-01

    report Impact on other disciplines: Nothing to report Impact on technology transfer: Nothing to report Impact on society : Nothing to report 5. CHANGES...AWARD NUMBER: W81XWH-15-1-0569 TITLE: Development of a Novel Targeted RNAi Delivery Technology in Therapies for Metabolic Diseases PRINCIPAL...COVERED 30Sep2016 - 29Sep2017 4. TITLE AND SUBTITLE Development of a Novel Targeted RNAi Delivery Technology in Therapies for Metabolic Diseases 5a

  19. Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    2017-09-01

    AWARD NUMBER: W81XWH-15-1-0419 TITLE: Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease...COVERED 1 Sep 2016 - 31 Aug 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal...inappropriate cell growth, fluid secretion, and dysregulation of cellular energy metabolism. The enzyme AMPK regulates a number of cellular pathways, including

  20. Direct-acting antiviral-based triple therapy on alpha-fetoprotein level in chronic hepatitis C patients.

    Science.gov (United States)

    Takayama, Koji; Furusyo, Norihiro; Ogawa, Eiichi; Ikezaki, Hiroaki; Shimizu, Motohiro; Murata, Masayuki; Hayashi, Jun

    2015-04-21

    To investigate the impact of telaprevir-based triple therapy on the serum alpha-fetoprotein (AFP) level of chronic hepatitis C patients. A total of 210 patients with chronic hepatitis C genotype 1 of high viral load (baseline serum hepatitis C virus RNA > 5.0 log10 IU/mL) were divided into two groups by type of treatment: triple therapy with telaprevir, pegylated-interferon-α (PEG-IFNα), and ribavirin (RBV) for 24 wk (n = 88), or dual therapy with PEG-IFNα and RBV for 48 wk (n = 122). The relationship between virological response and the change in the serum AFP level from baseline to 24 wk after the end of treatment was examined. No significant difference in mean baseline AFP level was found between the triple and dual therapy groups (8.8 ng/mL vs 7.8 ng/mL). Triple therapy produced significant declines in the AFP level in sustained virological response (SVR) and non-SVR patients (7.8 ng/mL at baseline to 3.5 ng/mL at 24 wk after the end of treatment, P < 0.001 and 14.3 ng/mL to 9.5 ng/mL, P = 0.004, respectively). In contrast, dual therapy resulted in a significant decline in AFP level only in SVR patients (4.7 ng/mL to 2.8 ng/mL, P < 0.001), but not in non-SVR patients (10.2 ng/mL to 10.1 ng/mL). Among patients with a high-baseline AFP level (≥ 10 ng/mL), the decline in the AFP level was significantly higher in the triple therapy than in the dual therapy group (15.9 ng/mL vs 1.6 ng/mL, P = 0.037). Regardless of virological response, telaprevir-based triple therapy reduced the serum AFP level.

  1. Effectiveness of Targeted Musical Therapy on Sleep Quality and Overcoming Insomnia in Seniors

    Directory of Open Access Journals (Sweden)

    Reza Mottaghi

    2016-07-01

    Conclusion: The present study showed that targeted music therapy can lead to the improvement in the overall sleep quality, daily functioning, and subjective sleep quality thereby resulting in a sharp decline in the number of sleep drugs in seniors with primary insomnia disorder. Therefore, it is highly recommended by the music therapy and mental health experts for overcoming the sleep problems in older adults.

  2. Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly & Cushing Disease Paradigms

    Directory of Open Access Journals (Sweden)

    Michael Anthony Mooney

    2016-07-01

    Full Text Available The current treatment of pituitary adenomas requires a balance of conservative management, surgical resection, and in select tumor types, molecular therapy. Acromegaly treatment is an evolving field where our understanding of molecular targets and drug therapies has improved treatment options for patients with excess growth hormone levels. We highlight the use of molecular therapies in this disease process and advances in this field, which may represent a paradigm shift for the future of pituitary adenoma treatment.

  3. Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly and Cushing Disease Paradigms.

    Science.gov (United States)

    Mooney, Michael A; Simon, Elias D; Little, Andrew S

    2016-01-01

    The current treatment of pituitary adenomas requires a balance of conservative management, surgical resection, and in select tumor types, molecular therapy. Acromegaly treatment is an evolving field where our understanding of molecular targets and drug therapies has improved treatment options for patients with excess growth hormone levels. We highlight the use of molecular therapies in this disease process and advances in this field, which may represent a paradigm shift for the future of pituitary adenoma treatment.

  4. Companion diagnostics for the targeted therapy of gastric cancer.

    Science.gov (United States)

    Yoo, Changhoon; Park, Young Soo

    2015-10-21

    Gastric cancer is the fourth most common type of cancer and represents a major cause of cancer-related deaths worldwide. With recent biomedical advances in our understanding of the molecular characteristics of gastric cancer, many genetic alterations have been identified as potential targets for its treatment. Multiple novel agents are currently under development as the demand for active agents that improve the survival of gastric cancer patients constantly increases. Based on lessons from previous trials of targeted agents, it is now widely accepted that the establishment of an optimal diagnostic test to select molecularly defined patients is of equal importance to the development of active agents against targetable genetic alterations. Herein, we highlight the current status and future perspectives of companion diagnostics in the treatment of gastric cancer.

  5. Cannabinoid Receptors: A Novel Target for Therapy of Prostate Cancer

    Science.gov (United States)

    2007-02-01

    study could be to develop nonhabit-forming cannabi - noid agonist (s) for the management of prostate cancer . REFERENCES 1. Jemal, A., Siegel, R.W...for Therapy of Prostate Cancer PRINCIPAL INVESTIGATOR: Prof. Hasan Mukhtar, Ph.D (PI) Dr. Farrukh Afaq, Ph.D (Co-Investigator...REPORT DATE: February 2007 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command

  6. Targeting dendritic cells in vivo for cancer therapy

    Directory of Open Access Journals (Sweden)

    Irina eCaminschi

    2012-02-01

    Full Text Available Monoclonal antibodies that recognise cell surface molecules have been used deliver antigenic cargo to dendritic cells (DC for induction of immune responses. The encouraging anti-tumour immunity elicited using this immunisation strategy suggests its suitability for clinical trials. This review discusses the complex network of DC, the functional specialisation of DC-subsets, the immunological outcomes of targeting different DC-subsets and their cell surface receptors, and the requirements for the induction of effective anti-tumour immunity. Finally, we review preclinical experiments and the progress towards targeting human DC in vivo.

  7. Targeting post-translational modifications of histones for cancer therapy.

    Science.gov (United States)

    Hsu, Y-C; Hsieh, Y-H; Liao, C-C; Chong, L-W; Lee, C-Y; Yu, Y-L; Chou, R-H

    2015-10-30

    Post-translational modifications (PTMs) on histones including acetylation, methylation, phosphorylation, citrullination, ubiquitination, ADP ribosylation, and sumoylation, play important roles in different biological events including chromatin dynamics, DNA replication, and transcriptional regulation. Aberrant histones PTMs leads to abnormal gene expression and uncontrolled cell proliferation, followed by development of cancers. Therefore, targeting the enzymes required for specific histone PTMs holds a lot of potential for cancer treatment. In this review article, we retrospect the latest studies in the regulations of acetylation, methylation, and phosphorylation of histones. We also summarize inhibitors/drugs that target these modifications for cancer treatment.

  8. Alpha-spectrometry and fractal analysis of surface micro-images for characterisation of porous materials used in manufacture of targets for laser plasma experiments

    Energy Technology Data Exchange (ETDEWEB)

    Aushev, A A; Barinov, S P; Vasin, M G; Drozdov, Yu M; Ignat' ev, Yu V; Izgorodin, V M; Kovshov, D K; Lakhtikov, A E; Lukovkina, D D; Markelov, V V; Morovov, A P; Shishlov, V V [Russian Federal Nuclear Center ' All-Russian Research Institute of Experimental Physics' , Sarov, Nizhnii Novgorod region (Russian Federation)

    2015-06-30

    We present the results of employing the alpha-spectrometry method to determine the characteristics of porous materials used in targets for laser plasma experiments. It is shown that the energy spectrum of alpha-particles, after their passage through porous samples, allows one to determine the distribution of their path length in the foam skeleton. We describe the procedure of deriving such a distribution, excluding both the distribution broadening due to statistical nature of the alpha-particle interaction with an atomic structure (straggling) and hardware effects. The fractal analysis of micro-images is applied to the same porous surface samples that have been studied by alpha-spectrometry. The fractal dimension and size distribution of the number of the foam skeleton grains are obtained. Using the data obtained, a distribution of the total foam skeleton thickness along a chosen direction is constructed. It roughly coincides with the path length distribution of alpha-particles within a range of larger path lengths. It is concluded that the combined use of the alpha-spectrometry method and fractal analysis of images will make it possible to determine the size distribution of foam skeleton grains (or pores). The results can be used as initial data in theoretical studies on propagation of the laser and X-ray radiation in specific porous samples. (laser plasma)

  9. Targeted gene therapy and cell reprogramming in Fanconi anemia

    Science.gov (United States)

    Rio, Paula; Baños, Rocio; Lombardo, Angelo; Quintana-Bustamante, Oscar; Alvarez, Lara; Garate, Zita; Genovese, Pietro; Almarza, Elena; Valeri, Antonio; Díez, Begoña; Navarro, Susana; Torres, Yaima; Trujillo, Juan P; Murillas, Rodolfo; Segovia, Jose C; Samper, Enrique; Surralles, Jordi; Gregory, Philip D; Holmes, Michael C; Naldini, Luigi; Bueren, Juan A

    2014-01-01

    Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective lentiviral vectors to demonstrate for the first time that FANCA can be efficiently and specifically targeted into the AAVS1 safe harbor locus in fibroblasts from FA-A patients. Strikingly, up to 40% of FA fibroblasts showed gene targeting 42 days after gene editing. Given the low number of hematopoietic precursors in the bone marrow of FA patients, gene-edited FA fibroblasts were then reprogrammed and re-differentiated toward the hematopoietic lineage. Analyses of gene-edited FA-iPSCs confirmed the specific integration of FANCA in the AAVS1 locus in all tested clones. Moreover, the hematopoietic differentiation of these iPSCs efficiently generated disease-free hematopoietic progenitors. Taken together, our results demonstrate for the first time the feasibility of correcting the phenotype of a DNA repair deficiency syndrome using gene-targeting and cell reprogramming strategies. PMID:24859981

  10. Sphingolipid metabolism enzymes as targets for anticancer therapy

    NARCIS (Netherlands)

    Kok, JW; Sietsma, H

    Treatment with anti-cancer agents in most cases ultimately results in apoptotic cell death of the target tumour cells. Unfortunately, tumour cells can develop multidrug resistance, e.g., by a reduced propensity to engage in apoptosis by which they become insensitive to multiple chemotherapeutics.

  11. Targeted gene therapy and cell reprogramming in Fanconi anemia.

    Science.gov (United States)

    Rio, Paula; Baños, Rocio; Lombardo, Angelo; Quintana-Bustamante, Oscar; Alvarez, Lara; Garate, Zita; Genovese, Pietro; Almarza, Elena; Valeri, Antonio; Díez, Begoña; Navarro, Susana; Torres, Yaima; Trujillo, Juan P; Murillas, Rodolfo; Segovia, Jose C; Samper, Enrique; Surralles, Jordi; Gregory, Philip D; Holmes, Michael C; Naldini, Luigi; Bueren, Juan A

    2014-06-01

    Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective lentiviral vectors to demonstrate for the first time that FANCA can be efficiently and specifically targeted into the AAVS1 safe harbor locus in fibroblasts from FA-A patients. Strikingly, up to 40% of FA fibroblasts showed gene targeting 42 days after gene editing. Given the low number of hematopoietic precursors in the bone marrow of FA patients, gene-edited FA fibroblasts were then reprogrammed and re-differentiated toward the hematopoietic lineage. Analyses of gene-edited FA-iPSCs confirmed the specific integration of FANCA in the AAVS1 locus in all tested clones. Moreover, the hematopoietic differentiation of these iPSCs efficiently generated disease-free hematopoietic progenitors. Taken together, our results demonstrate for the first time the feasibility of correcting the phenotype of a DNA repair deficiency syndrome using gene-targeting and cell reprogramming strategies. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

  12. Small molecules and targeted therapies in distant metastatic disease

    DEFF Research Database (Denmark)

    Hersey, P; Bastholt, L; Chiarion-Sileni, V

    2009-01-01

    with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib...

  13. Choline kinase-alpha by regulating cell aggressiveness and drug sensitivity is a potential druggable target for ovarian cancer

    OpenAIRE

    Granata, A; Nicoletti, R; Tinaglia, V; De Cecco, L; Pisanu, M E; Ricci, A; Podo, F; Canevari, S; Iorio, E; Bagnoli, M; Mezzanzanica, D

    2013-01-01

    Background: Aberrant choline metabolism has been proposed as a novel cancer hallmark. We recently showed that epithelial ovarian cancer (EOC) possesses an altered MRS-choline profile, characterised by increased phosphocholine (PCho) content to which mainly contribute over-expression and activation of choline kinase-alpha (ChoK-alpha). Methods: To assess its biological relevance, ChoK-alpha expression was downmodulated by transient RNA interference in EOC in vitro models. Gene expression profi...

  14. Pegylated interferon alpha-2a and ribavirin combination therapy in HCV liver transplant recipients. Experience of 7 cases.

    Science.gov (United States)

    Iacob, Speranta; Gheorghe, Liana; Hrehoret, Doina; Becheanu, Gabriel; Herlea, Vlad; Popescu, Irinel

    2008-06-01

    Hepatitis C virus (HCV) related cirrhosis represents the leading indication for liver transplantation (LT) worldwide and HCV reinfection is the rule among transplant recipients. Combination therapy with interferon and ribavirin is the treatment of choice for established recurrent hepatitis C. To evaluate the efficacy and safety of the combination of pegylated interferon alpha-2a and ribavirin in LT recipients with histological recurrence of hepatitis C. Seven LT recipients with chronic hepatitis C recurrence were treated with peginterferon alpha-2a with an initial intended dose of 180 microg/week and an intended dose of ribavirin 800-1000 mg/day for at least 12 months and followed-up for at least 24 weeks. Early virological response rate was 57.1%. Three patients (42.8%) had end of treatment virological response and all had also sustained viral response (SVR). Five patients had end of treatment biological response, out of which 4 had also sustained biochemical response. Three patients had both SVR and sustained biochemical response. Four patients had end of treatment histological response, out of which 3 patients had also SVR. Cytopenia was the most common adverse event: anemia (57.1%), leucopenia/neutropenia (71.4%), thrombocytopenia (42.8%). Combination of pegylated interferon and ribavirin can be safely and successfully used in liver transplant recipients.

  15. Combined adjuvant radiation and interferon-alpha 2B therapy in high-risk melanoma patients: the potential for increased radiation toxicity

    International Nuclear Information System (INIS)

    Hazard, Lisa J.; Sause, William T.; Noyes, R. Dirk

    2002-01-01

    Purpose: Surgically resected melanoma patients with high-risk features commonly receive adjuvant therapy with interferon-alpha 2b combined with radiation therapy; the purpose of our study was to evaluate the potential enhancement of radiation toxicity by interferon. Methods and Materials: Patients at LDS Hospital and the University of Utah Medical Center in Salt Lake City treated with interferon during radiotherapy or within 1 month of its completion were retrospectively identified, and their charts were reviewed. If possible, the patients were asked to return to the LDS Hospital radiation therapy department for follow-up. Results: Five of 10 patients receiving interferon-alpha 2b therapy during radiation therapy or within 1 month of its completion experienced severe subacute/late complications of therapy. Severe subacute/late complications included two patients with peripheral neuropathy, one patient with radiation necrosis in the brain, and two patients with radiation necrosis in the s.c. tissue. One patient with peripheral neuropathy and one patient with radiation necrosis also developed lymphedema. Conclusions: In vitro studies have identified a radiosensitizing effect by interferon-alpha on certain cell lines, which suggests the possibility that patients treated with interferon and radiation therapy may experience more severe radiation toxicities. We have observed severe subacute/late complications in five of 10 patients treated with interferon-alpha 2b during radiation therapy or within 1 month of its completion. Although an observational study of 10 patients lacks the statistic power to reach conclusions regarding the safety and complication rates of combined interferon and radiation therapy, it is sufficient to raise concerns and suggest the need for prospective studies

  16. Reimbursement of targeted cancer therapies within 3 different European health care systems

    NARCIS (Netherlands)

    Mihajlović, Jovan; Dolk, Christiaan; Tolley, Keith; Simoens, Steven; Postma, Maarten J.

    2015-01-01

    PURPOSE: Targeted cancer therapies (TCTs) are drugs that specifically act on molecular targets within the cancer cell, causing its regression and/or destruction. Although TCTs offer clinically important gains in survival in one of the most challenging therapeutic areas, these gains are followed by

  17. mTOR in squamous cell carcinoma of the oesophagus: a potential target for molecular therapy?

    NARCIS (Netherlands)

    Boone, J.; ten Kate, F. J. W.; Offerhaus, G. J. A.; van Diest, P. J.; Borel Rinkes, I. H. M.; van Hillegersberg, R.

    2008-01-01

    AIMS: The mammalian target of rapamycin (mTOR), an important regulator of protein translation and cell proliferation, is activated in various malignancies. In a randomised controlled trial of advanced renal cell carcinoma patients, targeted therapy to mTOR by means of rapamycin analogues has been

  18. [With alpha blockers, finasteride and nettle root against benign prostatic hyperplasia. Which patients are helped by conservative therapy?].

    Science.gov (United States)

    Vahlensieck, W

    2002-04-18

    Symptomatic benign prostatic hyperplasia (BPH), which a man has a 50% chance of developing during the course of his lifetime, should receive stage-related treatment. While Vahlensieck stage I disease requires no therapy, stages II and III are indications for medication. Established medications for the treatment of BPH in current use are alpha-blockers, finasteride, and the phytotherapeutic agents pumpkin seed (cucurbitae semen), nettle root (urticae radix), the phytosterols contained in Hypoxis rooperi, rye pollen and the fruits of saw palmetto (sabalis serrulati fructus). If the patient responds, these medicaments can be given life-long, or intermittently. The hard criterion for the rational use of drug treatment of BPH is, over the long term, the reduction in the number of prostate operations. In stage IV disease surgical measures--after prior compensation of renal function--are to the fore.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    International Nuclear Information System (INIS)

    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

  1. Molecular targets in cancer therapy: the Ron approach

    Directory of Open Access Journals (Sweden)

    Serena Germano

    2011-12-01

    Full Text Available The receptor tyrosine kinase Ron and its ligand, Macrophage Stimulating Protein (MSP, mediate multiple processes involved in the control of cell proliferation, migration and protection from apoptosis. Dysregulated signaling of Ron, due to hyperactivation or loss of negative regulation, is involved in tumor progression and metastasis. Growing evidence indicates that Ron is abnormally expressed and activated in certain types of primary epithelial cancers (i.e. breast, colon, lung, pancreas, bladder and thyroid, where it critically contributes to the maintenance of tumorigenic and invasive phenotype. Furthermore, a positive association between aberrant Ron expression and aggressive biological indicators as well as a worse clinical outcome have been reported in breast, bladder and thyroid carcinomas. Different approaches have proved effective in targeting receptor activation/expression both in vitro and in animal models, leading to reversion of the tumorigenic phenotype. Altogether these results show that Ron is an attractive molecular target for clinical intervention.

  2. Molecular targeting of angiogenesis for imaging and therapy

    International Nuclear Information System (INIS)

    Brack, Simon S.; Neri, Dario; Dinkelborg, Ludger M.

    2004-01-01

    Angiogenesis, i.e. the proliferation of new blood vessels from pre-existing ones, is an underlying process in many human diseases, including cancer, blinding ocular disorders and rheumatoid arthritis. The ability to selectively target and interfere with neovascularisation would potentially be useful in the diagnosis and treatment of angiogenesis-related diseases. This review presents the authors' views on some of the most relevant markers of angiogenesis described to date, as well as on specific ligands which have been characterised in pre-clinical animal models and/or clinical studies. Furthermore, we present an overview on technologies which are likely to have an impact on the way molecular targeting of angiogenesis is performed in the future. (orig.)

  3. Adverse Renal Effects of Novel Molecular Oncologic Targeted Therapies: A Narrative Review

    Directory of Open Access Journals (Sweden)

    Kenar D. Jhaveri

    2017-01-01

    Full Text Available Novel targeted anti-cancer therapies have resulted in improvement in patient survival compared to standard chemotherapy. Renal toxicities of targeted agents are increasingly being recognized. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here we review the adverse renal effects associated with a selection of currently approved targeted cancer therapies, directed to EGFR, HER2, BRAF, MEK, ALK, PD1/PDL1, CTLA-4, and novel agents targeted to VEGF/R and TKIs. In summary, electrolyte disorders, renal impairment and hypertension are the most commonly reported events. Of the novel targeted agents, ipilumumab and cetuximab have the most nephrotoxic events reported. The early diagnosis and prompt recognition of these renal adverse events are essential for the general nephrologist taking care of these patients.

  4. Catching moving targets: cancer stem cell hierarchies, therapy-resistance & considerations for clinical intervention.

    LENUS (Irish Health Repository)

    Gasch, Claudia

    2017-01-01

    It is widely believed that targeting the tumour-initiating cancer stem cell (CSC) component of malignancy has great therapeutic potential, particularly in therapy-resistant disease. However, despite concerted efforts, CSC-targeting strategies have not been efficiently translated to the clinic. This is partly due to our incomplete understanding of the mechanisms underlying CSC therapy-resistance. In particular, the relationship between therapy-resistance and the organisation of CSCs as Stem-Progenitor-Differentiated cell hierarchies has not been widely studied. In this review we argue that modern clinical strategies should appreciate that the CSC hierarchy is a dynamic target that contains sensitive and resistant components and expresses a collection of therapy-resisting mechanisms. We propose that the CSC hierarchy at primary presentation changes in response to clinical intervention, resulting in a recurrent malignancy that should be targeted differently. As such, addressing the hierarchical organisation of CSCs into our bench-side theory should expedite translation of CSC-targeting to bed-side practice. In conclusion, we discuss strategies through which we can catch these moving clinical targets to specifically compromise therapy-resistant disease.

  5. Advances in targeting strategies for nanoparticles in cancer imaging and therapy.

    Science.gov (United States)

    Yhee, Ji Young; Lee, Sangmin; Kim, Kwangmeyung

    2014-11-21

    In the last decade, nanoparticles have offered great advances in diagnostic imaging and targeted drug delivery. In particular, nanoparticles have provided remarkable progress in cancer imaging and therapy based on materials science and biochemical engineering technology. Researchers constantly attempted to develop the nanoparticles which can deliver drugs more specifically to cancer cells, and these efforts brought the advances in the targeting strategy of nanoparticles. This minireview will discuss the progress in targeting strategies for nanoparticles focused on the recent innovative work for nanomedicine.

  6. Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

    Directory of Open Access Journals (Sweden)

    Han-Chung Wu

    2010-01-01

    Full Text Available Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

  7. Nonalcoholic steatohepatitis: emerging targeted therapies to optimize treatment options

    Directory of Open Access Journals (Sweden)

    Milic S

    2015-08-01

    Full Text Available Sandra Milic,1 Ivana Mikolasevic,1,2 Irena Krznaric-Zrnic,1 Marija Stanic,3 Goran Poropat,1 Davor Stimac,1 Vera Vlahovic-Palcevski,4 Lidija Orlic2 1Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia; 2Department of Nephrology, Dialysis and Kidney Transplantation, UHC Rijeka, Rijeka, Croatia; 3Department of Hematology, UHC Rijeka, Rijeka, Croatia; 4Department for Clinical Pharmacology, University of Rijeka Medical School, UHC Rijeka, Rijeka, Croatia Abstract: Diet and lifestyle changes have led to worldwide increases in the prevalences of obesity and metabolic syndrome, resulting in substantially greater incidence of nonalcoholic fatty liver disease (NAFLD. NAFLD is considered a hepatic manifestation of metabolic syndrome and is related to diabetes, insulin resistance, central obesity, hyperlipidemia, and hypertension. Nonalcoholic steatohepatitis (NASH is an entity that describes liver inflammation due to NAFLD. Growing evidence suggests that NAFLD is a multisystem disease with a clinical burden that is not only confined to liver-related morbidity and mortality, but that also affects several extra-hepatic organs and regulatory pathways. Thus, NAFLD is considered an important public health issue, but there is currently no effective therapy for all NAFLD patients in the general population. Studies seeking optimal therapy for NAFLD and NASH have not yet led to development of a universal protocol for treating this growing problem. Several pharmacological agents have been studied in an effort to improve insulin resistance and the proinflammatory mediators that may be responsible for NASH progression. Cardiovascular risk factors are highly prevalent among NASH patients, and the backbone of treatment regimens for these patients still comprises general lifestyle interventions, including dietary changes and increased physical activity. Vitamin E and thiazolidinedione derivatives are currently the most evidence-based therapeutic options, but only

  8. Interferon Alpha-2a Therapy in Patients with Refractory Behçet Uveitis.

    Science.gov (United States)

    Hasanreisoglu, Murat; Cubuk, Mehmet Ozgur; Ozdek, Sengul; Gurelik, Gokhan; Aktas, Zeynep; Hasanreisoglu, Berati

    2017-02-01

    To report the results of IFNα2a therapy in patients with Behçet uveitis refractory to azathioprine-cyclosporine combination treatment. In a retrospective study, 39 patients treated with either azathioprine-cyclosporine combination treatment (group 1, n = 23) or IFNα2a (group 2, n = 16) with a diagnosis of ocular Behçet disease (BD), were included in the study. Group 2 consisted of patients who did not respond to conventional combination therapy, and were therefore treated with IFNα2a. Clinical response and relapse rates were recorded for each group. The mean number of uveitis attacks/year per patient was 0.8 ± 1.6 in Group 1. In Group 2, a significant decrease in the mean number of uveitis attacks/year per patient was observed after initiation of IFNα2a (2.4 ± 1.8 vs 1.3 ± 2.0) (puveitis attack/year and attack-free intervals, with a partial response to both treatments. IFNα2a therapy is an effective alternative for Behçet uveitis patients where conventional combination therapy fails.

  9. Influence of Interferon-Alpha Combined with Chemo (Radio Therapy on Immunological Parameters in Pancreatic Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Svetlana Karakhanova

    2014-03-01

    Full Text Available Prognosis of patients with carcinoma of the exocrine pancreas is particularly poor. A combination of chemotherapy with immunotherapy could be an option for treatment of pancreatic cancer. The aim of this study was to perform an immunomonitoring of 17 patients with pancreatic cancer from the CapRI-2 study, and tumor-bearing mice treated with combination of chemo (radio therapies with interferon-2α. Low doses of interferon-2α led to a decrease in total leukocyte and an increase in monocyte counts. Furthermore, we observed a positive effect of interferon-2α therapy on the dendritic cells and NK (natural killer cell activation immediately after the first injection. In addition, we recorded an increased amount of interferon-γ and IL-10 in the serum following the interferon-2α therapy. These data clearly demonstrate that pancreatic carcinoma patients also show an immunomodulatory response to interferon-2α therapy. Analysis of immunosuppressive cells in the Panc02 orthotopic mouse model of pancreatic cancer revealed an accumulation of the myeloid-derived suppressor cells in spleens and tumors of the mice treated with interferon-2α and 5-fluorouracil. The direct effect of the drugs on myeloid-derived suppressor cells was also registered in vitro. These data expose the importance of immunosuppressive mechanisms induced by combined chemo-immunotherapy.

  10. Complement, a target for therapy in inflammatory and degenerative diseases.

    Science.gov (United States)

    Morgan, B Paul; Harris, Claire L

    2015-12-01

    The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.

  11. GPNMB expression in uveal melanoma: a potential for targeted therapy.

    Science.gov (United States)

    Williams, Michelle D; Esmaeli, Bita; Soheili, Aydin; Simantov, Ronit; Gombos, Dan S; Bedikian, Agop Y; Hwu, Patrick

    2010-06-01

    Uveal melanoma is an aggressive disease without effective adjuvant therapy for metastases. Despite genomic differences between cutaneous and uveal melanomas, therapies based on shared biological factors could be effective against both tumor types. High expression of glycoprotein-NMB (GPNMB) in cutaneous melanomas led to the development of CDX-011 (glembatumumab vedotin), a fully human monoclonal antibody against the extracellular domain of GPNMB conjugated to the cytotoxic microtubule toxin monomethylauristatin E. Ongoing phase II trials suggest that CDX-011 has activity against advanced cutaneous melanomas. To determine the potential role of CDX-011 in uveal melanomas, we studied their GPNMB expression. Paraffin-embedded tissues from 22 uveal melanomas treated by enucleation from 2004-2007 at one institution were evaluated immunohistochemically for expression of GPNMB using biotinylated CDX-011 (unconjugated) antibody. Melanoma cells were evaluated for percentage and intensity of expression. Spectral imaging was used in one case with high melanin content. Clinical data were reviewed. Twelve women and 10 men with a median age of 58.7 years (range: 28-83 years) were included. Eighteen of 21 tumors evaluated immunohistochemically (85.7%) expressed GPNMB in 10-90% of tumor cells with variable intensity (5 tumors, 1+; 11, 2+; and 2, 3+). Eleven of 18 tumors (61.1%) expressed GPNMB in >or=50% of cells. Spectral imaging showed diffuse CDX-011 (unconjugated) reactivity in the remaining case. Uveal melanoma, like cutaneous melanoma, commonly expresses GPNMB. Ongoing clinical trials of CDX-011 should be extended to patients with metastatic uveal melanoma to determine potential efficacy in this subset of patients with melanoma.

  12. Delineation of Supraclavicular Target Volumes in Breast Cancer Radiation Therapy

    International Nuclear Information System (INIS)

    Brown, Lindsay C.; Diehn, Felix E.; Boughey, Judy C.; Childs, Stephanie K.; Park, Sean S.; Yan, Elizabeth S.; Petersen, Ivy A.; Mutter, Robert W.

    2015-01-01

    Purpose: To map the location of gross supraclavicular metastases in patients with breast cancer, in order to determine areas at highest risk of harboring subclinical disease. Methods and Materials: Patients with axial imaging of gross supraclavicular disease were identified from an institutional breast cancer registry. Locations of the metastatic lymph nodes were transferred onto representative axial computed tomography images of the supraclavicular region and compared with the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. Results: Sixty-two patients with 161 supraclavicular nodal metastases were eligible for study inclusion. At the time of diagnosis, 117 nodal metastases were present in 44 patients. Forty-four nodal metastases in 18 patients were detected at disease recurrence, 4 of whom had received prior radiation to the supraclavicular fossa. Of the 161 nodal metastases, 95 (59%) were within the RTOG consensus volume, 4 nodal metastases (2%) in 3 patients were marginally within the volume, and 62 nodal metastases (39%) in 30 patients were outside the volume. Supraclavicular disease outside the RTOG consensus volume was located in 3 regions: at the level of the cricoid and thyroid cartilage (superior to the RTOG volume), in the posterolateral supraclavicular fossa (posterolateral to the RTOG volume), and in the lateral low supraclavicular fossa (lateral to the RTOG volume). Only women with multiple supraclavicular metastases had nodal disease that extended superiorly to the level of the thyroid cartilage. Conclusions: For women with risk of harboring subclinical supraclavicular disease warranting the addition of supraclavicular radiation, coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted

  13. Delineation of Supraclavicular Target Volumes in Breast Cancer Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Brown, Lindsay C. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Diehn, Felix E. [Department of Radiology, Mayo Clinic, Rochester, Minnesota (United States); Boughey, Judy C. [Department of Surgery, Mayo Clinic, Rochester, Minnesota (United States); Childs, Stephanie K.; Park, Sean S.; Yan, Elizabeth S.; Petersen, Ivy A. [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States); Mutter, Robert W., E-mail: mutter.robert@mayo.edu [Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota (United States)

    2015-07-01

    Purpose: To map the location of gross supraclavicular metastases in patients with breast cancer, in order to determine areas at highest risk of harboring subclinical disease. Methods and Materials: Patients with axial imaging of gross supraclavicular disease were identified from an institutional breast cancer registry. Locations of the metastatic lymph nodes were transferred onto representative axial computed tomography images of the supraclavicular region and compared with the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. Results: Sixty-two patients with 161 supraclavicular nodal metastases were eligible for study inclusion. At the time of diagnosis, 117 nodal metastases were present in 44 patients. Forty-four nodal metastases in 18 patients were detected at disease recurrence, 4 of whom had received prior radiation to the supraclavicular fossa. Of the 161 nodal metastases, 95 (59%) were within the RTOG consensus volume, 4 nodal metastases (2%) in 3 patients were marginally within the volume, and 62 nodal metastases (39%) in 30 patients were outside the volume. Supraclavicular disease outside the RTOG consensus volume was located in 3 regions: at the level of the cricoid and thyroid cartilage (superior to the RTOG volume), in the posterolateral supraclavicular fossa (posterolateral to the RTOG volume), and in the lateral low supraclavicular fossa (lateral to the RTOG volume). Only women with multiple supraclavicular metastases had nodal disease that extended superiorly to the level of the thyroid cartilage. Conclusions: For women with risk of harboring subclinical supraclavicular disease warranting the addition of supraclavicular radiation, coverage of the posterior triangle and the lateral low supraclavicular region should be considered. For women with known supraclavicular disease, extension of neck coverage superior to the cricoid cartilage may be warranted.

  14. Vinculin but not alpha-actinin is a target of PKC phosphorylation during junctional assembly induced by calcium

    DEFF Research Database (Denmark)

    Perez-Moreno, M; Avila, A; Islas, S

    1998-01-01

    and alpha-actinin, two actin binding proteins of the adherent junctions. We found that during the junctional sealing induced by Ca2+, both proteins move towards the cell periphery and, while there is a significant increase in the phosphorylation of vinculin, alpha-actinin remains unchanged. The increased...

  15. Tumor targeting with radiolabeled alpha(v)beta(3) integrin binding peptides in a nude mouse model.

    NARCIS (Netherlands)

    Janssen, M.L.H.; Oyen, W.J.G.; Dijkgraaf, I.; Massuger, L.F.A.G.; Frielink, C.; Edwards, D.S.; Rajopadhye, M.; Boonstra, H.; Corstens, F.H.M.; Boerman, O.C.

    2002-01-01

    The alpha(v)beta(3) integrin is expressed on proliferating endothelial cells such as those present in growing tumors, as well as on tumor cells of various origin. Tumor-induced angiogenesis can be blocked in vivo by antagonizing the alpha(v)beta(3) integrin with small peptides containing the

  16. Adult soft tissue sarcomas: conventional therapies and molecularly targeted approaches.

    Science.gov (United States)

    Mocellin, Simone; Rossi, Carlo R; Brandes, Alba; Nitti, Donato

    2006-02-01

    The therapeutic approach to soft tissue sarcomas (STS) has evolved over the past two decades based on the results from randomized controlled trials, which are guiding physicians in the treatment decision-making process. Despite significant improvements in the control of local disease, a significant number of patients ultimately die of recurrent/metastatic disease following radical surgery due to a lack of effective adjuvant treatments. In addition, the characteristic chemoresistance of STS has compromised the therapeutic value of conventional antineoplastic agents in cases of unresectable advanced/metastatic disease. Therefore, novel therapeutic strategies are urgently needed to improve the prognosis of patients with STS. Recent advances in STS biology are paving the way to the development of molecularly targeted therapeutic strategies, the efficacy of which relies not only on the knowledge of the molecular mechanisms underlying cancer development/progression but also on the personalization of the therapeutic regimen according to the molecular features of individual tumours. In this work, we review the state-of-the-art of conventional treatments for STS and summarize the most promising findings in the development of molecularly targeted therapeutic approaches.

  17. Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy

    Directory of Open Access Journals (Sweden)

    Wiebke Sihver

    2014-03-01

    Full Text Available The epidermal growth factor receptor (EGFR has evolved over years into a main molecular target for the treatment of different cancer entities. In this regard, the anti-EGFR antibody cetuximab has been approved alone or in combination with: (a chemotherapy for treatment of colorectal and head and neck squamous cell carcinoma and (b with external radiotherapy for treatment of head and neck squamous cell carcinoma. The conjugation of radionuclides to cetuximab in combination with the specific targeting properties of this antibody might increase its therapeutic efficiency. This review article gives an overview of the preclinical studies that have been performed with radiolabeled cetuximab for imaging and/or treatment of different tumor models. A particularly promising approach seems to be the treatment with therapeutic radionuclide-labeled cetuximab in combination with external radiotherapy. Present data support an important impact of the tumor micromilieu on treatment response that needs to be further validated in patients. Another important challenge is the reduction of nonspecific uptake of the radioactive substance in metabolic organs like liver and radiosensitive organs like bone marrow and kidneys. Overall, the integration of diagnosis, treatment and monitoring as a theranostic approach appears to be a promising strategy for improvement of individualized cancer treatment.

  18. SKIN TOXICITY OF TARGETED THERAPY: VEMURAFENIB, FIRST EXPERIENCES FROM MONTENEGRO

    Directory of Open Access Journals (Sweden)

    Todorović Vladimir

    2015-07-01

    Full Text Available Introduction: Data on melanoma incidence and mortality in Montenegro is only partially complete. GLOBOCAN and EUCAN reports estimate melanoma incidence in Montenegro to be between 4.6-7.3 cases/100 000. At least 50% of all metastatic melanoma cell lines carry an activating mutation in the BRAF oncogene. The treatment of advanced melanoma with the selective BRAF inhibitors, such as vemurafenib demonstrated improvement in progression free interval and overall survival when compared to conventional chemotherapy treatment. Up to 95% of patients treated with vemurafenib experience skin toxicity. Material and methods: Five patients with metastatic melanoma have been treated with vemurafenib at the Clinic for Oncology and Radiotherapy Podgorica, Montenegro, during the period 2013-2014. They were treated with standard dose (960 mg twice a day, per os. Data about the occurrence and management of skin side-effects in these patients were retrospectively collected from medical charts. Severity of side-effects was graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. Results: In 2013, 41 new cases of melanoma were registered in Montenegro, 20 (48.7% male and 21 (51.3% female. In 2014, 49 new cases of melanoma were registered, 27 (55.1% male and 22 (44.9% female. Two out of five (40% vemurafenib treated patients experienced photosensitivity, three (60% had rash eruptions, four (80% developed alopecia, and two (40% had dry skin problems. Alteration in nevus color and size occurred in one (20% patient, and two (40% patients developed new pigmented lesions. Conclusion: Skin side effects associated with vemurafenib are plentiful, but generally manageable with supportive care measures. In our experience, majority of described side-effects were of grade 1 or 2, and none required dose modifications, or discontinuation of the therapy. Our experience suggests that patients taking BRAF inhibitors should have regular

  19. Dose Dependent Survival Response in Chronic Myeloid Leukemia under Continuous and Pulsed Targeted Therapy

    International Nuclear Information System (INIS)

    Pizzolato, N.; Valenti, D.; Spagnolo, B.; Persano Adorno, D.

    2010-01-01

    A simulative study of cancer growth dynamics in patients affected by Chronic Myeloid Leukemia (CML), under the effect of a targeted dose dependent continuous or pulsed therapy, is presented. We have developed a model for the dynamics of CML in which the stochastic evolution of white blood cell populations are simulated by adopting a Monte Carlo approach. Several scenarios in the evolutionary dynamics of white blood cells, as a consequence of the efficacy of the different modelled therapies, pulsed or continuous, are described. The best results, in terms of a permanent disappearance of the leukemic phenotype, are achieved with a continuous therapy and higher dosage. However, our findings demonstrate that an intermittent therapy could represent a valid choice in patients with high risk of toxicity, when a long-term therapy is considered. A suitably tuned pulsed therapy can enhance the treatment efficacy and reduce the percentage of patients developing resistance. (authors)

  20. Targeting HIF-2α as therapy for advanced cancers.

    Science.gov (United States)

    Murugesan, Thanabal; Rajajeyabalachandran, Gurukumari; Kumar, Swetha; Nagaraju, Shruthi; Kumar, Sooriya

    2018-05-14

    Hypoxia-inducible factors (HIF-1α, -2α -3α, and -β) are key factors that control hypoxia-induced carcinogenic pathways. HIF-1α is predominantly involved in the early stages of cancer, whereas HIF-2α is actively involved in the later stages; in addition, chronic (prolonged) rather than acute (short) hypoxia is a feature of metastasis and chemoresistance that occur during the later stages of cancer. Oncometabolites, onco-miRNAs, glucose deprivation, pseudohypoxia, cytokine/chemokine secretion, and some unique upstream proteins are involved in the signaling switch from HIF-1α to HIF-2α; thus, understanding this signaling switch is critical for the treatment of advanced cancer. In this review, we highlight data relating to HIF-2α rather than HIF-1α signaling in cancer pathways and discuss prospective drugs that target this important factor. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. Muscarinic receptors as targets for anti-inflammatory therapy.

    Science.gov (United States)

    Sales, María Elena

    2010-11-01

    ACh, the main neurotransmitter in the neuronal cholinergic system, is synthesized by pre-ganglionic fibers of the sympathetic and parasympathetic autonomic nervous system and by post-ganglionic parasympathetic fibers. There is increasing experimental evidence that ACh is widely expressed in prokaryotic and eukaryotic non-neuronal cells. The neuronal and non-neuronal cholinergic systems comprise ACh, choline acetyltransferase and cholinesterase, enzymes that synthesize and catabolize ACh, and the nicotinic and muscarinic ACh receptors (nAChRs and mAChRs, respectively), which are the targets for ACh action. This review analyzes the participation of the cholinergic system, particularly through mAChRs, in inflammation, and discusses the role of the different mAChR antagonists that have been used to treat skin inflammatory disorders, asthma and COPD, as well as intestinal inflammation and systemic inflammatory diseases, to assess the potential application of these compounds as therapeutic tools.

  2. Effect of antitumour necrosis factor-alpha therapy on bone turnover in patients with active Crohn's disease: a prospective study.

    Science.gov (United States)

    Ryan, B M; Russel, M G V M; Schurgers, L; Wichers, M; Sijbrandij, J; Stockbrugger, R W; Schoon, E

    2004-10-15

    Patients with Crohn's disease are at increased risk of osteoporosis. Disease activity and circulating proinflammatory cytokines are thought to play a role in this process. Infliximab, a chimaeric antitumour necrosis factor-alpha antibody is effective in the treatment of Crohn's disease. The aim of this study was to investigate the impact of treatment with infliximab on bone turnover in Crohn's disease patients. This was a prospective trial. Twenty-four patients with active Crohn's disease were treated with infliximab (5 mg/kg). Bone markers were assayed pre- and post-treatment. Bone formation was measured using serum bone-specific alkaline phosphatase and total osteocalcin and bone resorption using serum N-telopeptide cross-linked type 1 collagen. Infliximab therapy caused a significant increase in both markers of bone formation in patients with active Crohn's disease. No significant change in the bone resorption marker serum N-telopeptide cross-linked type 1 was found. Infliximab therapy had a significant beneficial effect on bone metabolism in patients with active Crohn's disease. These findings further support the theory that active ongoing inflammation and high levels of circulating cytokines play a pivotal role in the pathogenesis of bone loss in patients with Crohn's disease.

  3. Evaluation of laser therapy and alpha-lipoic acid for the treatment of burning mouth syndrome: a randomized clinical trial.

    Science.gov (United States)

    Barbosa, Natália Guimarães; Gonzaga, Amanda Katarinny Goes; de Sena Fernandes, Luzia Leiros; da Fonseca, Aldilane Gonçalves; Queiroz, Salomão Israel Monteiro Lourenço; Lemos, Telma Maria Araújo Moura; da Silveira, Éricka Janine Dantas; de Medeiros, Ana Miryam Costa

    2018-03-03

    The aim of this study was to evaluate the efficacy of low-level laser therapy (LLLT) and alpha-lipoic acid (ALA) in the treatment of burning mouth syndrome (BMS) and secondary oral burning (SOB) by unstimulated sialometry, symptom assessment, and measurement of salivary TNF-α levels. Forty-four patients were randomized into four treatment groups: BMS/laser (n = 10), BMS/ALA (n = 5), SOB/laser (n = 15), and SOB/ALA (n = 14). The control group consisted of eight healthy female subjects. Unstimulated salivary flow was measured before and after treatment, and the collected saliva was stored at - 20 °C for the analysis of TNF-α. Symptoms were evaluated before and after treatment using a pain visual analog scale. Most patients were women (81.8%) during menopause (72.2%). LLLT and ALA were efficient in increasing salivary flow only in BMS but provided symptom relief in both conditions. TNF-α levels did not differ between patients with BMS and SOB or between those patients and the control group. No differences were observed in posttreatment TNF-α levels in either condition. The results of this study suggest that LLLT and ALA are efficient therapies in reducing burning mouth symptoms, with LLLT being more efficient than ALA.

  4. NIR and MR imaging supported hydrogel based delivery system for anti-TNF alpha probiotic therapy of IBD

    Science.gov (United States)

    Janjic, Jelena M.; Berlec, Ales; Bagia, Christina; Liu, Lu S.; Jeric, Irenej; Gach, Michael; Janjic, Bratislav M.; Strukelj, Borut

    2016-03-01

    Current treatment of inflammatory bowel disease (IBD) is largely symptomatic and consists of anti-inflammatory agents, immune-suppressives or antibiotics, whereby local luminal action is preferred to minimize systemic side-effects. Recently, anti-TNFα therapy has shown considerable success and is now being routinely used. Here we present a novel approach of using perfluorocarbon (PFC) nanoemulsion containing hydrogels (nanoemulgels) as imaging supported delivery systems for anti-TNF alpha probiotic delivery in IBD. To further facilitate image-guided therapy a food-grade lactic acid bacterium Lactococcus lactis capable of TNFα-binding was engineered to incorporate infrared fluorescent protein (IRFP). This modified bacteria was then incorporated into novel PFC nanoemulgels. The nanoemulgels presented here are designed to deliver locally anti-TNFα probiotic in the lower colon and rectum and provide dual imaging signature of gel delivery (MRI) across the rectum and lower colon and bacteria release (NIR). NIR imaging data in vitro demonstrates high IRFP expressing and TNFα-binding bacteria loading in the hydrogel and complete release in 3 hours. Stability tests indicate that gels remain stable for at least 14 days showing no significant change in droplet size, zeta potential and pH. Flow cytometry analyses demonstrate the NIRF expressing bacteria L. lactis binds TNFα in vitro upon release from the gels. Magnetic resonance and near-infrared imaging in vitro demonstrates homogeneity of hydrogels and the imaging capacity of the overall formulation.

  5. Anti-Tumor Necrosis Factor-alpha in therapy of severe alcoholic hepatitis: a case report

    Directory of Open Access Journals (Sweden)

    M. Romano

    2013-05-01

    Full Text Available AIM OF THE STUDY The aim of this study is to evaluate the tolerance and effects of a single dose of infliximab combined with steroid therapy. PATIENTS AND METHODS A 44-years old man patient with chronic alcohol abuse, obesity, dyslipidemia and diabetes with AH (Maddrey’s score 32 received an association of prednisolone (80 mg/day ev and infliximab (5 mg/kg once. RESULTS At 2 weeks bilirubin decreased from 18.1 mg/dL to 6 mg/dL. At 4 weeks AST decreased from 1042 U/L to 154 U/L, ALT from 1112 U/L to 151 U/L, Maddrey’s score decreased to 17.4. Infliximab was well tolerated, but after 5 weeks the patient suffered an adverse event characterized by fever, panniculitis, septicaemia of Staphylococcus aureus treated with specific therapy. At 60 days the patient was asymptomatic and the liver function tests were normal (Maddrey’s score 10. At 6 months of follow-up: Maddrey’s score 6. CONCLUSIONS In AH, infliximab was well tolerated and associated with significant improvement in LFTs and Maddrey’s score, but these promising results should encourage large trials assessing better the strategy of therapy and criteria for enrolment of the patients.

  6. Epigenetics in Medullary Thyroid Cancer: From Pathogenesis to Targeted Therapy.

    Science.gov (United States)

    Vitale, Giovanni; Dicitore, Alessandra; Messina, Erika; Sciammarella, Concetta; Faggiano, Antongiulio; Colao, Annamaria

    2016-01-01

    Medullary thyroid carcinoma (MTC) originates from the parafollicular C cells of the thyroid gland. Mutations of the RET proto-oncogene are implicated in the pathogenesis of MTC. Germline activating mutations of this gene have been reported in about 88-98% of familial MTCs, while somatic mutations of RET gene have been detected in about 23-70% of sporadic forms. Although these genetic events are well characterized, much less is known about the role of epigenetic abnormalities in MTC. The present review reports a detailed description of epigenetic abnormalities (DNA methylation, histone modifications and miRNA profile), probably involved in the pathogenesis and progression of MTC. A systematic review was performed using Pubmed and Google patents databases. We report the current understanding of epigenetic patterns in MTC and discuss the potential use of current knowledge in designing novel therapeutic strategies through epigenetic drugs, focusing on recent patents in this field. Taking into account the reversibility of epigenetic alterations and the recent development in this field, epigenetic therapy may emerge for clinical use in the near future for patients with advanced MTC.

  7. Beyond typing and grading: target analysis in individualized therapy as a new challenge for tumour pathology.

    Science.gov (United States)

    Kreipe, Hans H; von Wasielewski, Reinhard

    2007-01-01

    In order to bring about its beneficial effects in oncology, targeted therapy depends on accurate target analysis. Whether cells of a tumour will be sensitive to a specific treatment is predicted by the detection of appropriate targets in cancer tissue by immunohistochemistry or molecular methods. In most instances this is performed by histopathologists. Reliability and reproducibility of tissue-based target analysis in histopathology require novel measures of quality assurance by internal and external controls. As a model for external quality assurance in targeted therapy an annual inter-laboratory trial has been set up in Germany applying tissue arrays with up to 60 mammary cancer samples which are tested by participants for expression of HER2/neu and steroid hormone receptors.

  8. A dual-targeting upconversion nanoplatform for two-color fluorescence imaging-guided photodynamic therapy.

    Science.gov (United States)

    Wang, Xu; Yang, Cheng-Xiong; Chen, Jia-Tong; Yan, Xiu-Ping

    2014-04-01

    The targetability of a theranostic probe is one of the keys to assuring its theranostic efficiency. Here we show the design and fabrication of a dual-targeting upconversion nanoplatform for two-color fluorescence imaging-guided photodynamic therapy (PDT). The nanoplatform was prepared from 3-aminophenylboronic acid functionalized upconversion nanocrystals (APBA-UCNPs) and hyaluronated fullerene (HAC60) via a specific diol-borate condensation. The two specific ligands of aminophenylboronic acid and hyaluronic acid provide synergistic targeting effects, high targetability, and hence a dramatically elevated uptake of the nanoplatform by cancer cells. The high generation yield of (1)O2 due to multiplexed Förster resonance energy transfer between APBA-UCNPs (donor) and HAC60 (acceptor) allows effective therapy. The present nanoplatform shows great potential for highly selective tumor-targeted imaging-guided PDT.

  9. Hypoxia inducible factor-1 alpha stabilization for regenerative therapy in traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Mushfiquddin Khan

    2017-01-01

    Full Text Available Mild traumatic brain injury (TBI, also called concussion, initiates sequelae leading to motor deficits, cognitive impairments and subtly compromised neurobehaviors. While the acute phase of TBI is associated with neuroinflammation and nitroxidative burst, the chronic phase shows a lack of stimulation of the neurorepair process and regeneration. The deficiency of nitric oxide (NO, the consequent disturbed NO metabolome, and imbalanced mechanisms of S-nitrosylation are implicated in blocking the mechanisms of neurorepair processes and functional recovery in the both phases. Hypoxia inducible factor-1 alpha (HIF-1α, a master regulator of hypoxia/ischemia, stimulates the process of neurorepair and thus aids in functional recovery after brain trauma. The activity of HIF-1α is regulated by NO via the mechanism of S-nitrosylation of HIF-1α. S-nitrosylation is dynamically regulated by NO metabolites such as S-nitrosoglutathione (GSNO and peroxynitrite. GSNO stabilizes, and peroxynitrite destabilizes HIF-1α. Exogenously administered GSNO was found not only to stabilize HIF-1α and to induce HIF-1α-dependent genes but also to stimulate the regeneration process and to aid in functional recovery in TBI animals.

  10. Erythrocyte membrane-coated gold nanocages for targeted photothermal and chemical cancer therapy

    Science.gov (United States)

    Zhu, Dao-Ming; Xie, Wei; Xiao, Yu-Sha; Suo, Meng; Zan, Ming-Hui; Liao, Qing-Quan; Hu, Xue-Jia; Chen, Li-Ben; Chen, Bei; Wu, Wen-Tao; Ji, Li-Wei; Huang, Hui-Ming; Guo, Shi-Shang; Zhao, Xing-Zhong; Liu, Quan-Yan; Liu, Wei

    2018-02-01

    Recently, red blood cell (RBC) membrane-coated nanoparticles have attracted much attention because of their excellent immune escapability; meanwhile, gold nanocages (AuNs) have been extensively used for cancer therapy due to their photothermal effect and drug delivery capability. The combination of the RBC membrane coating and AuNs may provide an effective approach for targeted cancer therapy. However, few reports have shown the utilization of combining these two technologies. Here, we design erythrocyte membrane-coated gold nanocages for targeted photothermal and chemical cancer therapy. First, anti-EpCam antibodies were used to modify the RBC membranes to target 4T1 cancer cells. Second, the antitumor drug paclitaxel (PTX) was encapsulated into AuNs. Then, the AuNs were coated with the modified RBC membranes. These new nanoparticles were termed EpCam-RPAuNs. We characterized the capability of the EpCam-RPAuNs for selective tumor targeting via exposure to near-infrared irradiation. The experimental results demonstrate that EpCam-RPAuNs can effectively generate hyperthermia and precisely deliver the antitumor drug PTX to targeted cells. We also validated the biocompatibility of the EpCam-RAuNs in vitro. By combining the molecularly modified targeting RBC membrane and AuNs, our approach provides a new way to design biomimetic nanoparticles to enhance the surface functionality of nanoparticles. We believe that EpCam-RPAuNs can be potentially applied for cancer diagnoses and therapies.

  11. Targeted cancer gene therapy : the flexibility of adenoviral gene therapy vectors

    NARCIS (Netherlands)

    Rots, MG; Curiel, DT; Gerritsen, WR; Haisma, HJ

    2003-01-01

    Recombinant adenoviral vectors are promising reagents for therapeutic interventions in humans, including gene therapy for biologically complex diseases like cancer and cardiovascular diseases. In this regard, the major advantage of adenoviral vectors is their superior in vivo gene transfer

  12. Understanding the molecular target therapy and it's approved synchronous use with radiation therapy in current Indian oncology practice

    International Nuclear Information System (INIS)

    Gupta, Puneet; Dohhen, Umesh Kumar; Romana; Srivastava, Priyanka

    2012-01-01

    The molecular targeted drugs (MTD) are of two types; large and small. The large molecular targeted drugs (LMTD) cannot cross the cancer cell membrane whereas those that cross the cancer cell membrane are nicknamed small molecular target drugs (SMTD). India has availability of almost all MTD originals approved by USA Food and Drug administration. However a few LMTD like inj vectibix, inj Zevalin, Inj Bexar etc.; and SMTD like cap Tipifarnib approved for AML, are not available in India currently although approved and available in USA. The MTD may he used alone as singlet; along with chemotherapy as doublet or triplet; or along with radiation and chemotherapy combo (nicknamed chemo-radiation-bio therapy). The molecular target therapy approved by USA and/or European FDA and currently available in India and used along with radiation therapy with or without chemotherapy, indication wise are; Brain Tumor Inj Nimotuzumab (LMTD) and Inj bevacizumab (LMTD) in Glioblasoma Multiforme; for Carcinoma Head and neck Inj Cetuximab and Inj Nimotuzumab (LMTT), Tab Geftinib (SMTD). (author)

  13. Thrombotic Management of Antiphospholipid Syndrome: Towards Novel Targeted Therapies.

    Science.gov (United States)

    Islam, Md Asiful; Alam, Fahmida; Wong, Kah Keng; Kamal, Mohammad Amjad; Gan, Siew Hua

    2017-01-01

    Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or pregnancy morbidity with persistent levels of antiphospholipid antibodies (aPLs). The development of thrombosis in APS is mediated by aPLs and contributes to the high mortality rate in APS patients. However, although APS has been reported for more than 30 years, there has been no optimal regimen for its prevention or for the management of thrombosis, mainly because the mainstay treatment strategies for managing APS are not targeted towards aPL-mediated thrombotic pathophysiology. Instead, the treatments commonly used are aimed at general thrombotic disorders. Warfarin is the most commonly used vitamin K antagonist (VKA), in addition to anti-platelet medications, such as aspirin and clopidogrel. Over the last decade, novel non-VKA oral anticoagulants, including rivaroxaban, apixaban and dabigatran, as well as immunomodulatory agents, such as rituximab, eculizumab, hydroxychloroquine, statins and sirolimus, have also been used. In this review, we discuss the current treatment strategies and future treatment outlook for thrombotic APS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  14. Targeting gut microbiome: A novel and potential therapy for autism.

    Science.gov (United States)

    Yang, Yongshou; Tian, Jinhu; Yang, Bo

    2018-02-01

    Autism spectrum disorder (ASD) is a severely neurodevelopmental disorder that impairs a child's ability to communicate and interact with others. Children with neurodevelopmental disorder, including ASD, are regularly affected by gastrointestinal problems and dysbiosis of gut microbiota. On the other hand, humans live in a co-evolutionary association with plenty of microorganisms that resident on the exposed and internal surfaces of our bodies. The microbiome, refers to the collection of microbes and their genetic material, confers a variety of physiologic benefits to the host in many key aspects of life as well as being responsible for some diseases. A large body of preclinical literature indicates that gut microbiome plays an important role in the bidirectional gut-brain axis that communicates between the gut and central nervous system. Moreover, accumulating evidences suggest that the gut microbiome is involved in the pathogenesis of ASD. The present review introduces the increasing evidence suggesting the reciprocal interaction network among microbiome, gut and brain. It also discusses the possible mechanisms by which gut microbiome influences the etiology of ASD via altering gut-brain axis. Most importantly, it highlights the new findings of targeting gut microbiome, including probiotic treatment and fecal microbiota transplant, as novel and potential therapeutics for ASD diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. A new target concept for proton accelerator driven boron neutron capture therapy applications

    International Nuclear Information System (INIS)

    Powell, J.R.; Ludewig, H.; Todosow, M.; Reich, M.

    1998-01-01

    A new target concept termed Discs Incorporating Sector Configured Orbiting Sources (DISCOS), is proposed for spallation applications, including BNCT (Boron Neutron Capture Therapy). In the BNCT application a proton beam impacts a sequence of ultra thin lithium DISCOS targets to generate neutrons by the 7 Li(p,n) 7 Be reaction. The proton beam loses only a few keV of its ∼MeV energy as it passes through a given target, and is re-accelerated to its initial energy, by a DC electric field between the targets

  16. Emerging hematological targets and therapy for cardiovascular disease: From bench to bedside

    Directory of Open Access Journals (Sweden)

    Ana Villegas

    2008-09-01

    Full Text Available Ana Villegas, Fernando A Gonzalez, Leopoldo Llorente, Santiago RedondoService of Hematology and Hemotherapy, Hospital Clinico Universitario San Carlos, Madrid, SpainAbstract: Atherosclerotic cardiovascular disease is the leading cause of death and a major part of its pathophysiology remains obscure. Some hematological targets have been related to the development and clinical outcome of this disease, especially soluble cytokines, leukocytes, red blood cells, hemostatic factors and platelets, and bone-marrow vascular progenitors. These emerging factors may be modulated by current antiatherosclerotic pharmacotherapy, target-designed novel drugs or progenitor cell therapy. The aim of current review article is to comprehensively review the role of these antiatherosclerotic targets and therapy.Keywords: atherosclerosis, blood, progenitor cells, cytokines, therapy

  17. [Management of side effects of targeted therapies in renal cancer: stomatological side effects (mucositis, epistaxis)].

    Science.gov (United States)

    Agbo-Godeau, Scarlette; Nicolas-Virelizier, Emmanuelle; Scotté, Florian

    2011-01-01

    The advent of targeted therapies in the treatment of renal cancer has shown different types of lesions of the oral cavity, which appear to be specific to the drug classes used (mTOR inhibitors, anti-angiogenic agents and conventional cytotoxic drugs). Before starting treatment with targeted therapy, it is essential to have an oral and a dental examination. The treatment of mucositis induced by targeted therapies is based on bicarbonate-based mouthwash, with the optional addition of an antifungal or a local antiseptic. It is possible to use topical or systemic analgesics for the pain. Dietary advice for patients is also useful. Most cases of epistaxis caused by anti-angiogenics stop spontaneously and require no medical intervention. Regular application of an emollient can be used to prevent the formation of scabs. Copyright © 2011 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  18. Imaging and Targeted Therapy of Multidrug Resistance. Final Report

    International Nuclear Information System (INIS)

    Piwnica-Worms, David

    2009-01-01

    One focus area of DOE Office of Science was the Imaging of Gene Expression in Health and Disease in real time in tissue culture, whole animals and ultimately patients. Investigators of the Molecular Imaging Group, Washington University Medical School, ascribed to this objective and a major focus of this group directly tied into the DOE program through their efforts targeting the multidrug resistance gene (MDR1). Our plans for continuation of the program were to extend and build on this line of investigation, incorporating new molecular tools into our methodology to selectively inhibit MDR1 gene expression with novel modulation strategies. Two approaches were to be pursued: (1) high throughput screening of compounds that disrupted mutant p53 transactivation of the MDR1 promoter, and (2) knockdown of MDR1 messenger RNA with retroviral-mediated delivery of small interfering RNA constructs. These would be combined with our continuing effort to synthesize ligands and examine structure-activity relationships of bis-salicylaldehydes labeled with gallium-68 to generate PET agents for imaging MDR1 P-glycoprotein function. We would be uniquely positioned to correlate therapeutic modulation of MDR1 gene expression and protein function in the same systems in vivo using PET and bioluminescence reporters. Use of animal models such as the mdr1a/1b(-/-) gene deleted mice would also have enabled refined analysis of modulation and tracer pharmacokinetics in vivo. Overall, this DOE program and resultant tools would enable direct monitoring of novel therapeutic strategies and the MDR phenotype in relation to gene expression and protein function in vivo.

  19. Utility of Normal Tissue-to-Tumor {alpha}/{beta} Ratio When Evaluating Isodoses of Isoeffective Radiation Therapy Treatment Plans

    Energy Technology Data Exchange (ETDEWEB)

    Gay, Hiram A., E-mail: hgay@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri (United States); Jin Jianyue [Department of Radiation Oncology, Henry Ford Hospital, Detroit, Michigan (United States); Chang, Albert J. [Department of Radiation Oncology, University of California, San Francisco, California (United States); Ten Haken, Randall K. [Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan (United States)

    2013-01-01

    Purpose: To achieve a better understanding of the effect of the number of fractions on normal tissue sparing for equivalent tumor control in radiation therapy plans by using equivalent biologically effective dose (BED) isoeffect calculations. Methods and Materials: The simple linear quadratic (LQ) model was assumed to be valid up to 10 Gy per fraction. Using the model, we formulated a well-known mathematical equality for the tumor prescription dose and probed and solved a second mathematical problem for normal tissue isoeffect. That is, for a given arbitrary relative isodose distribution (treatment plan in percentages), 2 isoeffective tumor treatment regimens (N fractions of the dose D and n fractions of the dose d) were denoted, which resulted in the same BED (corresponding to 100% prescription isodose). Given these situations, the LQ model was further exploited to mathematically establish a unique relative isodose level, z (%), for the same arbitrary treatment plan, where the BED to normal tissues was also isoeffective for both fractionation regimens. Results: For the previously stated problem, the relative isodose level z (%), where the BEDs to the normal tissue were also equal, was defined by the normal tissue {alpha}/{beta} ratio divided by the tumor {alpha}/{beta} times 100%. Fewer fractions offers a therapeutic advantage for those portions of the normal tissue located outside the isodose surface, z, whereas more fractions offer a therapeutic advantage for those portions of the normal tissue within the isodose surface, z. Conclusions: Relative isodose-based treatment plan evaluations may be useful for comparing isoeffective tumor regimens in terms of normal tissue effects. Regions of tissues that would benefit from hypofractionation or standard fractionation can be identified.

  20. Serum alpha-fetoprotein response can predict prognosis in hepatocellular carcinoma patients undergoing radiofrequency ablation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Kao, W.-Y. [Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan (China); Chiou, Y.-Y., E-mail: yychiou@vghtpe.gov.tw [Department of Radiology, Taipei Veterans General Hospital, Taiwan (China); Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Hung, H.-H. [Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan (China); Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Su, C.-W., E-mail: cwsu2@vghtpe.gov.tw [Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan (China); Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Chou, Y.-H. [Department of Radiology, Taipei Veterans General Hospital, Taiwan (China); Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Wu, J.-C. [Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Department of Medical Research and Education, Taipei Veterans General Hospital, Taiwan (China); Huo, T.-I. [Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan (China); Institute of Pharmacology, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Huang, Y.-H. [Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan (China); Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Wu, W.-C. [Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taiwan (China)

    2012-05-15

    Aims: To evaluate the clinical inference of serum alpha-fetoprotein (AFP) response in hepatocellular carcinoma (HCC) patients undergoing percutaneous radiofrequency ablation (RFA). Materials and methods: Three hundred and thirteen previously untreated HCC patients were enrolled in the study. The optimal AFP response was defined as >20% decrease from baseline after 1 month of RFA for those with a baseline AFP level of {>=}100 ng/ml. The impact of AFP response on prognosis was analysed and prognostic factors were assessed. Results: After a median follow-up of 26.7 {+-} 19.1 months, 49 patients died and 264 patients were alive. The cumulative 5 year survival rates were 75.3 and 57.4% in patients with an initial AFP of <100 ng/ml and {>=}100 ng/ml, respectively (p = 0.003). In the 58 patients with a baseline AFP of {>=}100 ng/ml and initial completed tumour necrosis after RFA, the cumulative 5 year survival rates were 62.4 and 25.7% in optimal and non-optimal AFP responders, respectively (p = 0.001). By multivariate analysis, the prothrombin time international normalized ratio >1.1 (p = 0.009), non-optimal AFP response (p = 0.023), and creatinine >1.5 mg/dl (p = 0.021) were independent risk factors predictive of poor overall survival. Besides, the cumulative 5 year recurrence rates were 83.4 and 100% in optimal and non-optimal AFP responders, respectively (p < 0.001). Multivariate analysis demonstrated platelet count {<=}10{sup 5}/mm{sup 3} (p = 0.048), tumour size >2 cm (p = 0.027), and non-optimal AFP response (p < 0.001) were independent risk factors associated with tumour recurrence after RFA. Conclusions: Serum AFP response may be a useful marker for predicting prognosis in HCC patients undergoing RFA.

  1. Impact on estrogen receptor binding and target tissue uptake of [{sup 18}F]fluorine substitution at the 16{alpha}-position of fulvestrant (faslodex; ICI 182,780)

    Energy Technology Data Exchange (ETDEWEB)

    Seimbille, Yann; Benard, Francois E-mail: francois.benard@USherbrooke.ca; Rousseau, Jacques; Pepin, Emilie; Aliaga, Antonio; Tessier, Guillaume; Lier, Johan E. van

    2004-08-01

    Fulvestrant (Faslodex; ICI 182,780) is a pure estrogen receptor (ER) antagonist recently approved for the treatment of hormone-sensitive breast cancer in post-menopausal women with disease progression following antiestrogen therapy. Fulvestrant strongly binds to the ER and its mode of action consists of inhibition of ER dimerization leading to a down regulation of ER protein cellular levels. With the aim to develop a probe for positron emission tomography (PET) imaging capable of predicting the potential therapeutic efficacy of selective ER modulators (SERM), we prepared three new 16{alpha}-[{sup 18}F]fluoro-fulvestrant derivatives. These new radiopharmaceuticals were evaluated for their binding affinity to the human ER{alpha} and for their target tissue uptake in immature female rats. Substitution of one of the side-chain F-atoms of fulvestrant for {sup 18}F would have led to a product of low specific activity; instead we selected the 16{alpha}-position for {sup 18}F-labeling, which at least in the case of estradiol (ES) is well tolerated by the ER. Radiochemical synthesis proceeds by stereoselective introduction of the [{sup 18}F]fluoride at the 16-{sup 18}F-position of fulvestrant via opening of an intermediate O-cyclic sulfate followed by hydrolysis of the protecting methoxymethyl (MOM) ether and sulfate groups. Three analogs with different oxidation states of the side chain sulfur, i.e. sulfide, sulfone or sulfoxide (fulvestrant) were prepared. Introduction of the 16{sup 18}F-fluorine led to a dramatic decrease of the apparent binding affinity for ER, as reported by Wakeling et al. (Cancer Res. 1991;51:3867-73). Likewise, in vivo ER-mediated uterus uptake values in immature female rats were disappointing. Overall, our findings suggest that these new PET radiopharmaceuticals are not suitable as tracers to predict ER(+) breast cancer response to hormonal therapy with selective ER modulators.

  2. Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

    OpenAIRE

    Bao, Qi; Zhao, Yue; Niess, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl-Walter; Huss, Ralf; Nelson, Peter J.; Bruns, Christiane J.

    2012-01-01

    Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associa...

  3. Adaptive Radiation Therapy for Postprostatectomy Patients Using Real-Time Electromagnetic Target Motion Tracking During External Beam Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Mingyao [Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri (United States); Bharat, Shyam [Philips Research North America, Briarcliff Manor, New York (United States); Michalski, Jeff M.; Gay, Hiram A. [Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri (United States); Hou, Wei-Hsien [St Louis University School of Medicine, St Louis, Missouri (United States); Parikh, Parag J., E-mail: pparikh@radonc.wustl.edu [Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri (United States)

    2013-03-15

    Purpose: Using real-time electromagnetic (EM) transponder tracking data recorded by the Calypso 4D Localization System, we report inter- and intrafractional target motion of the prostate bed, describe a strategy to evaluate treatment adequacy in postprostatectomy patients receiving intensity modulated radiation therapy (IMRT), and propose an adaptive workflow. Methods and Materials: Tracking data recorded by Calypso EM transponders was analyzed for postprostatectomy patients that underwent step-and-shoot IMRT. Rigid target motion parameters during beam delivery were calculated from recorded transponder positions in 16 patients with rigid transponder geometry. The delivered doses to the clinical target volume (CTV) were estimated from the planned dose matrix and the target motion for the first 3, 5, 10, and all fractions. Treatment adequacy was determined by comparing the delivered minimum dose (D{sub min}) with the planned D{sub min} to the CTV. Treatments were considered adequate if the delivered CTV D{sub min} is at least 95% of the planned CTV D{sub min}. Results: Translational target motion was minimal for all 16 patients (mean: 0.02 cm; range: −0.12 cm to 0.07 cm). Rotational motion was patient-specific, and maximum pitch, yaw, and roll were 12.2, 4.1, and 10.5°, respectively. We observed inadequate treatments in 5 patients. In these treatments, we observed greater target rotations along with large distances between the CTV centroid and transponder centroid. The treatment adequacy from the initial 10 fractions successfully predicted the overall adequacy in 4 of 5 inadequate treatments and 10 of 11 adequate treatments. Conclusion: Target rotational motion could cause underdosage to partial volume of the postprostatectomy targets. Our adaptive treatment strategy is applicable to post-prostatectomy patients receiving IMRT to evaluate and improve radiation therapy delivery.

  4. Immuno-Oncology-The Translational Runway for Gene Therapy: Gene Therapeutics to Address Multiple Immune Targets.

    Science.gov (United States)

    Weß, Ludger; Schnieders, Frank

    2017-12-01

    Cancer therapy is once again experiencing a paradigm shift. This shift is based on extensive clinical experience demonstrating that cancer cannot be successfully fought by addressing only single targets or pathways. Even the combination of several neo-antigens in cancer vaccines is not sufficient for successful, lasting tumor eradication. The focus has therefore shifted to the immune system's role in cancer and the striking abilities of cancer cells to manipulate and/or deactivate the immune system. Researchers and pharma companies have started to target the processes and cells known to support immune surveillance and the elimination of tumor cells. Immune processes, however, require novel concepts beyond the traditional "single-target-single drug" paradigm and need parallel targeting of diverse cells and mechanisms. This review gives a perspective on the role of gene therapy technologies in the evolving immuno-oncology space and identifies gene therapy as a major driver in the development and regulation of effective cancer immunotherapy. Present challenges and breakthroughs ranging from chimeric antigen receptor T-cell therapy, gene-modified oncolytic viruses, combination cancer vaccines, to RNA therapeutics are spotlighted. Gene therapy is recognized as the most prominent technology enabling effective immuno-oncology strategies.

  5. Targeted Therapy of Cancer Using Photodynamic Therapy in Combination with Multi-faceted Anti-Tumor Modalities

    Directory of Open Access Journals (Sweden)

    Malini Olivo

    2010-05-01

    Full Text Available Photodynamic therapy (PDT has emerged as one of the important therapeutic options in the management of cancer and other diseases. PDT involves a tumor-localized photosensitizer (PS, which when appropriately illuminated by visible light converts oxygen into cytotoxic reactive oxygen species (ROS, that attack key structural entities within the targeted cells, ultimately resulting in necrosis or apoptosis. Though PDT is a selective modality, it can be further enhanced by combining other targeted therapeutic strategies that include the use of synthetic peptides and nanoparticles for selective delivery of photosensitizers. Another potentially promising strategy is the application of targeted therapeutics that exploit a myriad of critical pathways involved in tumorigenesis and metastasis. Vascular disrupting agents that eradicate tumor vasculature during PDT and anti-angiogenic agents that targets specific molecular pathways and prevent the formation of new blood vessels are novel therapeutic approaches that have been shown to improve treatment outcome. In addition to the well-documented mechanisms of direct cell killing and damage to the tumor vasculature, PDT can also activate the body’s immune response against tumors. Numerous pre-clinical studies and clinical observations have demonstrated the immuno-stimulatory capability of PDT. Herein, we aim to integrate the most important findings with regard to the combination of PDT and other novel targeted therapy approaches, detailing its potential in cancer photomedicine.

  6. A Knock-in Reporter for a Novel AR-Targeted Therapy

    Science.gov (United States)

    2016-05-01

    AWARD NUMBER: W81XWH-15-1-0049 TITLE: A Knock -in Reporter for a Novel AR-Targeted Therapy PRINCIPAL INVESTIGATOR: Chunhong Yan, Ph.D...5a. CONTRACT NUMBER A Knock -in Reporter for a Novel AR-Targeted Therapy 5b. GRANT NUMBER W81XWH-15-1-0049 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...enhancer. While the knock -in reporter is expected to faithfully reproduce chemical responses of the endogenous AR gene, we carried out a pilot screen

  7. Human alpha-enolase from endothelial cells as a target antigen of anti-endothelial cell antibody in Behçet's disease.

    Science.gov (United States)

    Lee, Kwang Hoon; Chung, Hae-Shin; Kim, Hyoung Sup; Oh, Sang-Ho; Ha, Moon-Kyung; Baik, Ja-Hyun; Lee, Sungnack; Bang, Dongsik

    2003-07-01

    To identify and recombine a protein of the human dermal microvascular endothelial cell (HDMEC) that specifically reacts with anti-endothelial cell antibody (AECA) in the serum of patients with Behçet's disease (BD), and to evaluate the usefulness of this protein in BD. The proteomics technique, with 2-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry, was used to identify and recombine HDMEC antigen. Western blotting and enzyme-linked immunosorbent assay (ELISA) of recombinant protein isolated by gene cloning were performed on serum from healthy controls, patients with BD, and patients with other rheumatic diseases (rheumatoid arthritis, systemic lupus erythematosus, and Wegener's granulomatosis). Eighteen of 40 BD patients had serum IgM antibody to HDMEC antigen. The purified protein that reacted with AECA in BD patient sera was found to be alpha-enolase by 2-dimensional gel electrophoresis followed by immunoblotting and MALDI-TOF mass spectrometry. Recombinant alpha-enolase protein was isolated and refined by gene cloning. On Western blots, AECA-positive IgM from the sera of patients with active BD reacted strongly with recombinant human alpha-enolase. BD patient sera positive for anti-alpha-enolase did not react with human gamma-enolase. On dot-blotting, reactivity to human alpha-enolase was detected only in the IgM-positive group. Fifteen of the 18 AECA-positive sera that were positive for the HDMEC antigen showed reactivity to recombinant alpha-enolase IgM antibody by ELISA. The alpha-enolase protein is the target protein of serum AECA in BD patients. This is the first report of the presence of IgM antibodies to alpha-enolase in endothelial cells from the serum of BD patients. Although further studies relating this protein to the pathogenesis of BD will be necessary, alpha-enolase and its antibody may prove useful in the development of new diagnostic and treatment modalities in BD.

  8. The roles of pathology in targeted therapy of women with gynecologic cancers.

    Science.gov (United States)

    Murali, Rajmohan; Grisham, Rachel N; Soslow, Robert A

    2018-01-01

    The role of the pathologist in the multidisciplinary management of women with gynecologic cancer has evolved substantially over the past decade. Pathologists' evaluation of parameters such as pathologic stage, histologic subtype, grade and microsatellite instability, and their identification of patients at risk for Lynch syndrome have become essential components of diagnosis, prognostic assessment and determination of optimal treatment of affected women. Despite the use of multimodality treatment and combination cytotoxic chemotherapy, the prognosis of women with advanced-stage gynecologic cancer is often poor. Therefore, expanding the arsenal of available systemic therapies with targeted therapeutic agents is appealing. Anti-angiogenic therapies, immunotherapy and poly ADP ribose polymerase (PARP) inhibitors are now routinely used for the treatment of advanced gynecologic cancer, and many more are under investigation. Pathologists remain important in the clinical management of patients with targeted therapy, by identifying potentially targetable tumors on the basis of their pathologic phenotype, by assessing biomarkers that are predictive of response to targeted therapy (e.g. microsatellite instability, PD1/PDL1 expression), and by monitoring treatment response and resistance. Pathologists are also vital to research efforts exploring novel targeted therapies by identifying homogenous subsets of tumors for more reliable and meaningful analyses, and by confirming expression in tumor tissues of novel targets identified in genomic, epigenetic or other screening studies. In the era of precision gynecologic oncology, the roles of pathologists in the discovery, development and implementation of targeted therapeutic strategies remain as central as they are for traditional (surgery-chemotherapy-radiotherapy) management of women with gynecologic cancers. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. The Role of High Dose Interleukin-2 in the Era of Targeted Therapy.

    Science.gov (United States)

    Gills, Jessie; Parker, William P; Pate, Scott; Niu, Sida; Van Veldhuizen, Peter; Mirza, Moben; Holzbeierlein, Jeffery M; Lee, Eugene K

    2017-09-01

    We assessed survival outcomes following high dose interleukin-2 in a contemporary cohort of patients during the era of targeted agents. We retrospectively reviewed the records of patients with metastatic renal cell carcinoma treated with high dose interleukin-2 between July 2007 and September 2014. Clinicopathological data were abstracted and patient response to therapy was based on RECIST (Response Evaluation Criteria In Solid Tumors), version 1.1 criteria. The Kaplan-Meier method was used to estimate progression-free and overall survival in the entire cohort, the response to high dose interleukin-2 in regard to previous targeted agent therapy and the response to the targeted agent in relation to the response to high dose interleukin-2. We identified 92 patients, of whom 87 had documentation of a response to high dose interleukin-2. Median overall survival was 34.4 months from the initiation of high dose interleukin-2 therapy in the entire cohort. Patients who received targeted therapy before high dose interleukin-2 had overall survival (median 34.4 and 30.0 months, p = 0.88) and progression-free survival (median 1.5 and 1.7 months, p = 0.8) similar to those in patients who received no prior therapy, respectively. Additionally, patients with a complete or partial response to high dose interleukin-2 had similar outcomes for subsequent targeted agents compared to patients whose best response was stable or progressive disease (median overall survival 30.1 vs 25.4 months, p = 0.4). Our data demonstrate that patient responses to high dose interleukin-2 and to targeted agents before and after receiving high dose interleukin-2 are independent. As such, carefully selected patients should be offered high dose interleukin-2 for the possibility of a complete and durable response without the fear of limiting the treatment benefit of targeted agents. Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  10. Palliative chemotherapy and targeted therapies for esophageal and gastroesophageal junction cancer.

    Science.gov (United States)

    Janmaat, Vincent T; Steyerberg, Ewout W; van der Gaast, Ate; Mathijssen, Ron Hj; Bruno, Marco J; Peppelenbosch, Maikel P; Kuipers, Ernst J; Spaander, Manon Cw

    2017-11-28

    Almost half of people with esophageal or gastroesophageal junction cancer have metastatic disease at the time of diagnosis. Chemotherapy and targeted therapies are increasingly used with a palliative intent to control tumor growth, improve quality of life, and prolong survival. To date, and with the exception of ramucirumab, evidence for the efficacy of palliative treatments for esophageal and gastroesophageal cancer is lacking. To assess the effects of cytostatic or targeted therapy for treating esophageal or gastroesophageal junction cancer with palliative intent. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Web of Science, PubMed Publisher, Google Scholar, and trial registries up to 13 May 2015, and we handsearched the reference lists of studies. We did not restrict the search to publications in English. Additional searches were run in September 2017 prior to publication, and they are listed in the 'Studies awaiting assessment' section. We included randomized controlled trials (RCTs) on palliative chemotherapy and/or targeted therapy versus best supportive care or control in people with esophageal or gastroesophageal junction cancer. Two authors independently extracted data. We assessed the quality and risk of bias of eligible studies according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated pooled estimates of effect using an inverse variance random-effects model for meta-analysis. We identified 41 RCTs with 11,853 participants for inclusion in the review as well as 49 ongoing studies. For the main comparison of adding a cytostatic and/or targeted agent to a control arm, we included 11 studies with 1347 participants. This analysis demonstrated an increase in overall survival in favor of the arm with an additional cytostatic or targeted therapeutic agent with a hazard ratio (HR) of 0.75 (95% confidence interval (CI) 0.68 to 0.84, high-quality evidence). The median increased

  11. Oligoclonal CD8+ T-cell expansion in patients with chronic hepatitis C is associated with liver pathology and poor response to interferon-alpha therapy.

    Science.gov (United States)

    Manfras, Burkhard J; Weidenbach, Hans; Beckh, Karl-Heinz; Kern, Peter; Möller, Peter; Adler, Guido; Mertens, Thomas; Boehm, Bernhard O

    2004-05-01

    The role of CD8(+) T lymphocytes in chronic hepatitis C virus (HCV) infection and in liver injury with subsequent development of fibrosis and cirrhosis is poorly understood. To address this question, we performed a follow-up study including 27 chronically HCV-infected individuals. We determined clonality and phenotypes of circulating CD8(+) T cells employing TCRBV spectratyping. Antigen specificity was tested by rMHC-peptide tetramer staining and stimulation with recombinant HCV antigens. In addition, T-cell clonality and phenotypes were followed during the variable clinical response of interferon- (IFN) alpha treatment. We could demonstrate that CD8(+) T-cell expansions were significantly associated with liver fibrosis and cirrhosis. Likewise, increased oligoclonality of circulating CD8(+) T cells in chronic HCV infection was identified as an indicator for poor clinical response to IFN-alpha therapy. Moreover, we also found that IFN-alpha therapy enhanced the differentiation of CD8(+) T cells towards a late differentiation phenotype (CD28(-) CD57(+)). In cases of virus elimination the disappearance of expanded terminally differentiated CD8(+) cells was observed. Thus, this study identifies an association of clonal expansions of circulating CD8(+) T cells with liver pathology and provides a possible explanation for the fact that response to IFN-alpha therapy diminishes with the duration of infection.

  12. Magnetic chitosan nanoparticles as a drug delivery system for targeting photodynamic therapy

    International Nuclear Information System (INIS)

    Sun Yun; Chen Zhilong; Yang Xiaoxia; Huang Peng; Zhou Xinping; Du Xiaoxia

    2009-01-01

    Photodynamic therapy (PDT) has become an increasingly recognized alternative to cancer treatment in clinic. However, PDT therapy agents, namely photosensitizer (PS), are limited in application as a result of prolonged cutaneous photosensitivity, poor water solubility and inadequate selectivity, which are encountered by numerous chemical therapies. Magnetic chitosan nanoparticles provide excellent biocompatibility, biodegradability, non-toxicity and water solubility without compromising their magnetic targeting. Nevertheless, no previous attempt has been reported to develop an in vivo magnetic drug delivery system with chitosan nanoparticles for magnetic resonance imaging (MRI) monitored targeting photodynamic therapy. In this study, magnetic targeting chitosan nanoparticles (MTCNPs) were prepared and tailored as a drug delivery system and imaging agents for PS, designated as PHPP. Results showed that PHPP-MTCNPs could be used in MRI monitored targeting PDT with excellent targeting and imaging ability. Non-toxicity and high photodynamic efficacy on SW480 carcinoma cells both in vitro and in vivo were achieved with this method at the level of 0-100 μM. Notably, localization of nanoparticles in skin and hepatic tissue was significantly less than in tumor tissue, therefore photosensitivity and hepatotoxicity can be attenuated.

  13. Mesenchymal Stem Cell-Based Tumor-Targeted Gene Therapy in Gastrointestinal Cancer

    Science.gov (United States)

    Bao, Qi; Zhao, Yue; Niess, Hanno; Conrad, Claudius; Schwarz, Bettina; Jauch, Karl-Walter; Huss, Ralf; Nelson, Peter J.

    2012-01-01

    Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host. PMID:22530882

  14. Target volume delineation and treatment planning for particle therapy a practical guide

    CERN Document Server

    Leeman, Jonathan E; Cahlon, Oren; Sine, Kevin; Jiang, Guoliang; Lu, Jiade J; Both, Stefan

    2018-01-01

    This handbook is designed to enable radiation oncologists to treat patients appropriately and confidently by means of particle therapy. The orientation and purpose are entirely practical, in that the focus is on the physics essentials of delivery and treatment planning , illustration of the clinical target volume (CTV) and associated treatment planning for each major malignancy when using particle therapy, proton therapy in particular. Disease-specific chapters provide guidelines and concise knowledge on CTV selection and delineation and identify aspects that require the exercise of caution during treatment planning. The treatment planning techniques unique to proton therapy for each disease site are clearly described, covering beam orientation, matching/patching field techniques, robustness planning, robustness plan evaluation, etc. The published data on the use of particle therapy for a given disease site are also concisely reported. In addition to fully meeting the needs of radiation oncologists, this "kn...

  15. Glutamate metabotropic receptors as targets for drug therapy in epilepsy.

    Science.gov (United States)

    Moldrich, Randal X; Chapman, Astrid G; De Sarro, Giovambattista; Meldrum, Brian S

    2003-08-22

    Metabotropic glutamate (mGlu) receptors have multiple actions on neuronal excitability through G-protein-linked modifications of enzymes and ion channels. They act presynaptically to modify glutamatergic and gamma-aminobutyric acid (GABA)-ergic transmission and can contribute to long-term changes in synaptic function. The recent identification of subtype-selective agonists and antagonists has permitted evaluation of mGlu receptors as potential targets in the treatment of epilepsy. Agonists acting on group I mGlu receptors (mGlu1 and mGlu5) are convulsant. Antagonists acting on mGlu1 or mGlu5 receptors are anticonvulsant against 3,5-dihydroxyphenylglycine (DHPG)-induced seizures and in mouse models of generalized motor seizures and absence seizures. The competitive, phenylglycine mGlu1/5 receptor antagonists generally require intracerebroventricular administration for potent anticonvulsant efficacy but noncompetitive antagonists, e.g., (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydrocyclopenta[c]furan-1-on (BAY36-7620), 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) block generalized seizures with systemic administration. Agonists acting on group II mGlu receptors (mGlu2, mGlu3) to reduce glutamate release are anticonvulsant, e.g., 2R,4R-aminopyrrolidine-2,4-dicarboxylate [(2R,4R)-APDC], (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268). The classical agonists acting on group III mGlu receptors such as L-(+)-2-amino-4-phosphonobutyric acid, and L-serine-O-phosphate are acutely proconvulsant with some anticonvulsant activity. The more recently identified agonists (R,S)-4-phosphonophenylglycine [(R,S)-PPG] and (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG] and (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid [ACPT-1] are all anticonvulsant without proconvulsant effects. Studies in animal models of kindling

  16. From Single Target to Multitarget/Network Therapeutics in Alzheimer’s Therapy

    Directory of Open Access Journals (Sweden)

    Hailin Zheng

    2014-01-01

    Full Text Available Brain network dysfunction in Alzheimer’s disease (AD involves many proteins (enzymes, processes and pathways, which overlap and influence one another in AD pathogenesis. This complexity challenges the dominant paradigm in drug discovery or a single-target drug for a single mechanism. Although this paradigm has achieved considerable success in some particular diseases, it has failed to provide effective approaches to AD therapy. Network medicines may offer alternative hope for effective treatment of AD and other complex diseases. In contrast to the single-target drug approach, network medicines employ a holistic approach to restore network dysfunction by simultaneously targeting key components in disease networks. In this paper, we explore several drugs either in the clinic or under development for AD therapy in term of their design strategies, diverse mechanisms of action and disease-modifying potential. These drugs act as multi-target ligands and may serve as leads for further development as network medicines.

  17. Targeting cellular adhesion molecules, chemokines and chemokine receptors in rheumatoid arthritis

    NARCIS (Netherlands)

    Haringman, Jasper J.; Oostendorp, Roos L.; Tak, Paul P.

    2005-01-01

    The development of specific targeted therapies, such as anti-TNF-alpha treatment, for chronic inflammatory disorders such as rheumatoid arthritis, has significantly improved treatment, although not all patients respond. Targeting cellular adhesion molecules and chemokines/chemokine receptors as

  18. Aptamer conjugated paclitaxel and magnetic fluid loaded fluorescently tagged PLGA nanoparticles for targeted cancer therapy

    Energy Technology Data Exchange (ETDEWEB)

    Aravind, Athulya; Nair, Remya; Raveendran, Sreejith; Veeranarayanan, Srivani; Nagaoka, Yutaka; Fukuda, Takahiro; Hasumura, Takahashi; Morimoto, Hisao; Yoshida, Yasuhiko; Maekawa, Toru; Sakthi Kumar, D., E-mail: sakthi@toyo.jp

    2013-10-15

    Controlled and targeted drug delivery is an essential criterion in cancer therapy to reduce the side effects caused by non-specific drug release and toxicity. Targeted chemotherapy, sustained drug release and optical imaging have been achieved using a multifunctional nanocarrier constructed from poly (D, L-lactide-co-glycolide) nanoparticles (PLGA NPs), an anticancer drug paclitaxel (PTX), a fluorescent dye Nile red (NR), magnetic fluid (MF) and aptamers (Apt, AS1411, anti-nucleolin aptamer). The magnetic fluid and paclitaxel loaded fluorescently labeled PLGA NPs (MF-PTX-NR-PLGA NPs) were synthesized by a single-emulsion technique/solvent evaporation method using a chemical cross linker bis (sulfosuccinimidyl) suberate (BS3) to enable binding of aptamer on to the surface of the nanoparticles. Targeting aptamers were then introduced to the particles through the reaction with the cross linker to target the nucleolin receptors over expressed on the cancer cell surface. Specific binding and uptake of the aptamer conjugated magnetic fluid loaded fluorescently tagged PLGA NPs (Apt-MF-NR-PLGA NPs) to the target cancer cells induced by aptamers was observed using confocal microscopy. Cytotoxicity assay conducted in two cell lines (L929 and MCF-7) confirmed that targeted MCF-7 cancer cells were killed while control cells were unharmed. In addition, aptamer mediated delivery resulting in enhanced binding and uptake to the target cancer cells exhibited increased therapeutic effect of the drug. Moreover, these aptamer conjugated magnetic polymer vehicles apart from actively transporting drugs into specifically targeted tumor regions can also be used to induce hyperthermia or for facilitating magnetic guiding of particles to the tumor regions. - Highlights: • Aptamer escorted, theranostic biodegradable PLGA carriers were developed. • Can target cancer cells, control drug release, image and magnetically guide. • Highly specific to the targeted cancer cells thus delivering

  19. A possible usage of a CDK4 inhibitor for breast cancer stem cell-targeted therapy

    International Nuclear Information System (INIS)

    Han, Yu Kyeong; Lee, Jae Ho; Park, Ga-Young; Chun, Sung Hak; Han, Jeong Yun; Kim, Sung Dae; Lee, Janet; Lee, Chang-Woo; Yang, Kwangmo; Lee, Chang Geun

    2013-01-01

    Highlights: ► A CDK4 inhibitor may be used for breast cancer stem cell-targeted therapy. ► The CDK4 inhibitor differentiated the cancer stem cell population (CD24 − /CD44 + ) of MDA-MB-231. ► The differentiation of the cancer stem cells by the CDK4 inhibitor radiosensitized MDA-MB-231. -- Abstract: Cancer stem cells (CSCs) are one of the main reasons behind cancer recurrence due to their resistance to conventional anti-cancer therapies. Thus, many efforts are being devoted to developing CSC-targeted therapies to overcome the resistance of CSCs to conventional anti-cancer therapies and decrease cancer recurrence. Differentiation therapy is one potential approach to achieve CSC-targeted therapies. This method involves inducing immature cancer cells with stem cell characteristics into more mature or differentiated cancer cells. In this study, we found that a CDK4 inhibitor sensitized MDA-MB-231 cells but not MCF7 cells to irradiation. This difference appeared to be associated with the relative percentage of CSC-population between the two breast cancer cells. The CDK4 inhibitor induced differentiation and reduced the cancer stem cell activity of MDA-MB-231 cells, which are shown by multiple marker or phenotypes of CSCs. Thus, these results suggest that radiosensitization effects may be caused by reducing the CSC-population of MDA-MB-231 through the use of the CDK4 inhibitor. Thus, further investigations into the possible application of the CDK4 inhibitor for CSC-targeted therapy should be performed to enhance the efficacy of radiotherapy for breast cancer

  20. Influence of androgen deprivation therapy on the uptake of PSMA-targeted agents: Emerging opportunities challenges

    Energy Technology Data Exchange (ETDEWEB)

    Bakht, Martin K.; Oh, So Won; Youn, Hye Won; Cheon, Gi Jeong; Kwak, Cheol; Kang, Keon Wook [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2017-09-15

    Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgen-deprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer.

  1. Influence of androgen deprivation therapy on the uptake of PSMA-targeted agents: Emerging opportunities challenges

    International Nuclear Information System (INIS)

    Bakht, Martin K.; Oh, So Won; Youn, Hye Won; Cheon, Gi Jeong; Kwak, Cheol; Kang, Keon Wook

    2017-01-01

    Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgen-deprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer

  2. Translational research: precision medicine, personalized medicine, targeted therapies: marketing or science?

    Science.gov (United States)

    Marquet, Pierre; Longeray, Pierre-Henry; Barlesi, Fabrice; Ameye, Véronique; Augé, Pascale; Cazeneuve, Béatrice; Chatelut, Etienne; Diaz, Isabelle; Diviné, Marine; Froguel, Philippe; Goni, Sylvia; Gueyffier, François; Hoog-Labouret, Natalie; Mourah, Samia; Morin-Surroca, Michèle; Perche, Olivier; Perin-Dureau, Florent; Pigeon, Martine; Tisseau, Anne; Verstuyft, Céline

    2015-01-01

    Personalized medicine is based on: 1) improved clinical or non-clinical methods (including biomarkers) for a more discriminating and precise diagnosis of diseases; 2) targeted therapies of the choice or the best drug for each patient among those available; 3) dose adjustment methods to optimize the benefit-risk ratio of the drugs chosen; 4) biomarkers of efficacy, toxicity, treatment discontinuation, relapse, etc. Unfortunately, it is still too often a theoretical concept because of the lack of convenient diagnostic methods or treatments, particularly of drugs corresponding to each subtype of pathology, hence to each patient. Stratified medicine is a component of personalized medicine employing biomarkers and companion diagnostics to target the patients likely to present the best benefit-risk balance for a given active compound. The concept of targeted therapy, mostly used in cancer treatment, relies on the existence of a defined molecular target, involved or not in the pathological process, and/or on the existence of a biomarker able to identify the target population, which should logically be small as compared to the population presenting the disease considered. Targeted therapies and biomarkers represent important stakes for the pharmaceutical industry, in terms of market access, of return on investment and of image among the prescribers. At the same time, they probably represent only the first generation of products resulting from the combination of clinical, pathophysiological and molecular research, i.e. of translational research. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  3. Comparative effectiveness and adverse effects of interferon alpha-2b plus ribavirin therapy in hepatitis 'C' for 26 weeks

    International Nuclear Information System (INIS)

    Ali, S.

    2009-01-01

    Hepatitis C is major emerging challenge for pathologists and treating physicians all over the world. Already 10 million Pakistani population has become anti-HCV positive. It is not only affecting hepatobiliary system but with passage of time research is revealing that Hepatitis C is going to involve almost every organ of the body. With timely diagnosis and treatment, millions of patients can be saved from morbidity and mortality. The nation has to sacrifice initial economic allocations to avoid later millions of mortalities and greater economic losses on affected patients and to support their families. The objective of this study was to evaluate effectiveness of combine therapy of Hepatitis C in local population of Pakistan. This case series study was done at CMH Okara, Kohat, Abbottabad, and PAF Hospital, Shorkot from August 2000 to August 2009. All 1,000 patients from 10 to 60 years of age, confirmed anti-HCV Positive by ELISA and PCR Positive for HCV RNA, were subjected to Interferon alpha-2b and Ribavirin therapy for similar period of time. Response and adverse affects were observed by clinical examination, blood complete picture including platelet count and ALT fortnightly. PCR for HCV RNA and ultrasound abdomen (hepatobiliary system) was done quarterly during treatment and 6 monthly for 2 years after treatment to review the sustained response and relapse. Over all cure rate after 2 years was 855 (85.5%) excluding the 50 (5%) of initial resistant to one year treatment and 95 (9.5%) re-treated relapse cases. One hundred and forty-five (14.5%) patients were found to be resistant to treatment. Hepatitis C must be treated timely after proper diagnosis. Interferon and Ribavirin combination have shown high 'cure' rate in Hepatitis C. In spite of high cure rate of 85.5% with timely and proper treatment, low socio-economic status is a major problem for poor individuals to get treatment. Preventive aspect must be strictly followed and implemented. (author)

  4. Comparative effectiveness and adverse effects of interferon alpha-2b plus ribavirin therapy in hepatitis 'C' for 26 weeks.

    Science.gov (United States)

    Ali, Shafqut; Iram, Samia

    2009-01-01

    Hepatitis C is major emerging challenge for pathologists and treating physicians all over the world. Already 10 million Pakistani population has become anti-HCV positive. It is not only affecting hepatobiliary system but with passage of time research is revealing that Hepatitis C is going to involve almost every organ of the body. With timely diagnosis and treatment, millions of patients can be saved from morbidity and mortality. The nation has to sacrifice initial economic allocations to avoid later millions of mortalities and greater economic losses on affected patients and to support their families. The objective of this study was to evaluate effectiveness of combine therapy of Hepatitis C in local population of Pakistan. This case series study was done at CMH Okara, Kohat, Abbottabad, and PAF Hospital, Shorkot from August 2000 to August 2009. All 1,000 patients from 10 to 60 years of age, confirmed anti-HCV Positive by ELISA and PCR Positive for HCV RNA, were subjected to Interferon alpha-2b and Ribavirin therapy for similar period of time. Response and adverse affects were observed by clinical examination, blood complete picture including platelet count and ALT fortnightly. PCR for HCV RNA and ultrasound abdomen (hepatobilliary system) was done quarterly during treatment and 6 monthly for 2 years after treatment to review the sustained response and relapse. Over all cure rate after 2 years was 855 (85.5%) excluding the 50 (5%) of initial resistant to one year treatment and 95 (9.5%) re-treated relapse cases. One hundred and forty-five (14.5%) patients were found to be resistant to treatment. Hepatitis C must be treated timely after proper diagnosis. Interferon and Ribavirin combination have shown high 'cure' rate in Hepatitis C. In spite of high cure rate of 85.5% with timely and proper treatment, low socio-economic status is a major problem for poor individuals to get treatment. Preventive aspect must be strictly followed and implemented.

  5. Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-alpha, Oncostatin M and response to biologic therapies.

    LENUS (Irish Health Repository)

    Moran, Ellen M

    2009-01-01

    INTRODUCTION: The aim of this study was to examine IL-17A in patients, following anti-TNF-alpha therapy and the effect of IL-17A on matrix turnover and cartilage degradation. METHODS: IL-17A expression was examined by ELISA and immunohistology in the rheumatoid arthritis (RA) joints. RA whole synovial tissue explant (RA ST), primary synovial fibroblasts (RASFC), human cartilage and chondrocyte cultures were stimulated with IL-17A +\\/- TNF-alpha and Oncostatin M (OSM). Matrix metalloproteinase (MMP) and tissue inhibitor (TIMP-1) were assessed by ELISA and zymography. Cartilage proteoglycan release was assessed histologically by Safranin-O staining. Clinical parameters, IL-17A, MMP\\/TIMP were assessed in patients pre\\/post biologic therapy. RESULTS: IL-17A levels were higher in RA vs osteoarthritis (OA)\\/normal joints (P < 0.05). IL-17A up-regulated MMP-1, -2, -9, and -13 in RA ST, RASFC, cartilage and chondrocyte cultures (P < 0.05). In combination with TNF-alpha and OSM, IL-17A shifted the MMP:TIMP-1 ratio in favor of matrix degradation (all P < 0.05). Cartilage proteoglycan depletion in response to IL-17A was mild; however, in combination with TNF-alpha or OSM showed almost complete proteoglycan depletion. Serum IL-17A was detected in 28% of patients commencing biologic therapy. IL-17A negative patients demonstrated reductions post therapy in serum MMP1\\/TIMP4, MMP3\\/TIMP1 and MMP3\\/TIMP4 ratios and an increase in CS846 (all P < 0.05). No significant changes were observed in IL-17A positive patients. CONCLUSIONS: IL-17A is produced locally in the inflamed RA joint. IL-17A promotes matrix turnover and cartilage destruction, especially in the presence of other cytokines, mimicking the joint environment. IL-17A levels are modulated in vivo, following anti-TNF therapy, and may reflect changes in matrix turnover.

  6. Discontinuing VEGF-targeted Therapy for Progression Versus Toxicity Affects Outcomes of Second-line Therapies in Metastatic Renal Cell Carcinoma

    DEFF Research Database (Denmark)

    De Velasco, Guillermo; Xie, Wanling; Donskov, Frede

    2017-01-01

    BACKGROUND: A significant subgroup of metastatic renal cell carcinoma (mRCC) patients discontinue vascular endothelial growth factor-targeted therapies (VEGF-TT) because of toxicity. Whether clinical outcomes differ in patients who receive second-line (2L) targeted therapy on the basis of reason ...

  7. Computational design and application of endogenous promoters for transcriptionally targeted gene therapy for rheumatoid arthritis.

    NARCIS (Netherlands)

    Geurts, J.; Joosten, L.A.B.; Takahashi, N.; Arntz, O.J.; Gluck, A.; Bennink, M.B.; Berg, W.B. van den; Loo, F.A.J. van de

    2009-01-01

    The promoter regions of genes that are differentially regulated in the synovial membrane during the course of rheumatoid arthritis (RA) represent attractive candidates for application in transcriptionally targeted gene therapy. In this study, we applied an unbiased computational approach to define

  8. Overcoming resistance and restoring sensitivity to HER2-targeted therapies in breast cancer.

    LENUS (Irish Health Repository)

    Mohd Sharial, M S N

    2012-12-01

    Approximately 15%-23% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2), which leads to the activation of signaling pathways that stimulate cell proliferation and survival. HER2-targeted therapy has substantially improved outcomes in patients with HER2-positive breast cancer. However, both de novo and acquired resistance are observed.

  9. Reimbursement of targeted cancer therapies within three different European health care systems

    NARCIS (Netherlands)

    Mihajlovic, Jovan; Dolk, C.; Postma, Maarten

    2014-01-01

    Objectives: To identify differences in the recommendations for targeted cancer therapies (TCT) in three distinctive European health care systems: Serbian, Scottish and Dutch, and to examine the role of cost effectiveness analyses (CEA) in such recommendations. Methods: A list of currently approved

  10. Targeting the EGFR pathway for cancer therapy

    DEFF Research Database (Denmark)

    Johnston, JB; Navaratnam, S; Pitz, MW

    2006-01-01

    .g.: Trastuzumab/Herceptin, Pertuzumab/Omnitarg/rhuMab-2C4, Cetuximab/Erbitux/IMC-C225, Panitumumab/Abenix/ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background...

  11. Molecular alterations as target for therapy in metastatic osteosarcoma: a review of literature

    NARCIS (Netherlands)

    Posthuma de Boer, J.; Witlox, M.A.; Kaspers, G.J.L.; van Royen, B.J.

    2011-01-01

    Treating metastatic osteosarcoma (OS) remains a challenge in oncology. Current treatment strategies target the primary tumour rather than metastases and have a limited efficacy in the treatment of metastatic disease. Metastatic cells have specific features that render them less sensitive to therapy

  12. Phenotype switching : tumor cell plasticity as a resistance mechanism and target for therapy

    NARCIS (Netherlands)

    Kemper, K.; de Goeje, P.L.; Peeper, D.S.; van Amerongen, R.

    2014-01-01

    Mutations in BRAF are present in the majority of patients with melanoma, rendering these tumors sensitive to targeted therapy with BRAF and MEK inhibitors. Unfortunately, resistance almost invariably develops. Recently, a phenomenon called "phenotype switching" has been identified as an escape

  13. Intermittent targeted therapies and stochastic evolution in patients affected by chronic myeloid leukemia

    Science.gov (United States)

    Pizzolato, N.; Persano Adorno, D.; Valenti, D.; Spagnolo, B.

    2016-05-01

    Front line therapy for the treatment of patients affected by chronic myeloid leukemia (CML) is based on the administration of tyrosine kinase inhibitors, namely imatinib or, more recently, axitinib. Although imatinib is highly effective and represents an example of a successful molecular targeted therapy, the appearance of resistance is observed in a proportion of patients, especially those in advanced stages. In this work, we investigate the appearance of resistance in patients affected by CML, by modeling the evolutionary dynamics of cancerous cell populations in a simulated patient treated by an intermittent targeted therapy. We simulate, with the Monte Carlo method, the stochastic evolution of initially healthy cells to leukemic clones, due to genetic mutations and changes in their reproductive behavior. We first present the model and its validation with experimental data by considering a continuous therapy. Then, we investigate how fluctuations in the number of leukemic cells affect patient response to the therapy when the drug is administered with an intermittent time scheduling. Here we show that an intermittent therapy (IT) represents a valid choice in patients with high risk of toxicity, despite an associated delay to the complete restoration of healthy cells. Moreover, a suitably tuned IT can reduce the probability of developing resistance.

  14. Internal and External Triggering Mechanism of "Smart" Nanoparticle-Based DDSs in Targeted Tumor Therapy.

    Science.gov (United States)

    Qiana, Xian-Ling; Li, Jun; Wei, Ran; Lin, Hui; Xiong, Li-Xia

    2018-05-09

    Anticancer chemotherapeutics have a lot of problems via conventional drug delivery systems (DDSs), including non-specificity, burst release, severe side-effects, and damage to normal cells. Owing to its potential to circumventing these problems, nanotechnology has gained increasing attention in targeted tumor therapy. Chemotherapeutic drugs or genes encapsulated in nanoparticles could be used to target therapies to the tumor site in three ways: "passive", "active", and "smart" targeting. To summarize the mechanisms of various internal and external "smart" stimulating factors on the basis of findings from in vivo and in vitro studies. A thorough search of PubMed was conducted in order to identify the majority of trials, studies and novel articles related to the subject. Activated by internal triggering factors (pH, redox, enzyme, hypoxia, etc.) or external triggering factors (temperature, light of different wavelengths, ultrasound, magnetic fields, etc.), "smart" DDSs exhibit targeted delivery to the tumor site, and controlled release of chemotherapeutic drugs or genes. In this review article, we summarize and classify the internal and external triggering mechanism of "smart" nanoparticle-based DDSs in targeted tumor therapy, and the most recent research advances are illustrated for better understanding. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. Multistage Targeting Strategy Using Magnetic Composite Nanoparticles for Synergism of Photothermal Therapy and Chemotherapy.

    Science.gov (United States)

    Wang, Yi; Wei, Guoqing; Zhang, Xiaobin; Huang, Xuehui; Zhao, Jingya; Guo, Xing; Zhou, Shaobing

    2018-03-01

    Mitochondrial-targeting therapy is an emerging strategy for enhanced cancer treatment. In the present study, a multistage targeting strategy using doxorubicin-loaded magnetic composite nanoparticles is developed for enhanced efficacy of photothermal and chemical therapy. The nanoparticles with a core-shell-SS-shell architecture are composed of a core of Fe 3 O 4 colloidal nanocrystal clusters, an inner shell of polydopamine (PDA) functionalized with triphenylphosphonium (TPP), and an outer shell of methoxy poly(ethylene glycol) linked to the PDA by disulfide bonds. The magnetic core can increase the accumulation of nanoparticles at the tumor site for the first stage of tumor tissue targeting. After the nanoparticles enter the tumor cells, the second stage of mitochondrial targeting is realized as the mPEG shell is detached from the nanoparticles by redox responsiveness to expose the TPP. Using near-infrared light irradiation at the tumor site, a photothermal effect is generated from the PDA photosensitizer, leading to a dramatic decrease in mitochondrial membrane potential. Simultaneously, the loaded doxorubicin can rapidly enter the mitochondria and subsequently damage the mitochondrial DNA, resulting in cell apoptosis. Thus, the synergism of photothermal therapy and chemotherapy targeting the mitochondria significantly enhances the cancer treatment. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Individualization of anticancer therapy; molecular targets of novel drugs in oncology

    Directory of Open Access Journals (Sweden)

    Katarzyna Regulska

    2012-11-01

    Full Text Available Deregulation of cellular signal transduction, caused by gene mutations, has been recognized as a basic factor of cancer initiation, promotion and progression. Thus, the ability to control the activity of overstimulated signal molecules by the use of appropriate inhibitors became the idea of targeted cancer therapy, which has provided an effective tool to normalize the molecular disorders in malignant cells and to treat certain types of cancer. The molecularly targeted drugs are divided into two major pharmaceutical classes: monoclonal antibodies and small-molecule kinase inhibitors. This review presents a summary of their characteristics, analyzing their chemical structures, specified molecular targets, mechanisms of action and indications for use. Also the molecules subjected to preclinical trials or phase I, II and III clinical trials evaluating their efficiency and safety are presented. Moreover, the article discusses further perspectives for development of targeted therapies focusing on three major directions: systematic searching and discovery of new targets that are oncogenic drivers, improving the pharmacological properties of currently known drugs, and developing strategies to overcome drug resistance. Finally, the role of proper pharmacodiagnostics as a key to rational anticancer therapy has been emphasized since the verification of reliable predictive biomarkers is a basis of individualized medicine in oncology. 

  17. Systemic sclerosis and localized scleroderma--current concepts and novel targets for therapy.

    Science.gov (United States)

    Distler, Oliver; Cozzio, Antonio

    2016-01-01

    Systemic sclerosis (SSc) is a chronic autoimmune disease with a high morbidity and mortality. Skin and organ fibrosis are key manifestations of SSc, for which no generally accepted therapy is available. Thus, there is a high unmet need for novel anti-fibrotic therapeutic strategies in SSc. At the same time, important progress has been made in the identification and characterization of potential molecular targets in fibrotic diseases over the recent years. In this review, we have selected four targeted therapies, which are tested in clinical trials in SSc, for in depths discussion of their preclinical characterization. Soluble guanylate cyclase (sGC) stimulators such as riociguat might target both vascular remodeling and tissue fibrosis. Blockade of interleukin-6 might be particularly promising for early inflammatory stages of SSc. Inhibition of serotonin receptor 2b signaling links platelet activation to tissue fibrosis. Targeting simultaneously multiple key molecules with the multityrosine kinase-inhibitor nintedanib might be a promising approach in complex fibrotic diseases such as SSc, in which many partially independent pathways are activated. Herein, we also give a state of the art overview of the current classification, clinical presentation, diagnostic approach, and treatment options of localized scleroderma. Finally, we discuss whether the novel targeted therapies currently tested in SSc could be used for localized scleroderma.

  18. Cure of human ovarian carcinoma solid xenografts by fractionated [211At] alpha-radioimmunotherapy

    DEFF Research Database (Denmark)

    Bäck, Tom A; Chouin, Nicolas; Lindegren, Sture

    2017-01-01

    The goal of this study was to investigate if targeted alpha therapy (TAT) could be used to successfully treat also macro tumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous (i.v.) fractionated regimen of alpha-radioimmunotherapy (α-...

  19. Targeting chemotherapy-resistant leukemia by combining DNT cellular therapy with conventional chemotherapy.

    Science.gov (United States)

    Chen, Branson; Lee, Jong Bok; Kang, Hyeonjeong; Minden, Mark D; Zhang, Li

    2018-04-24

    While conventional chemotherapy is effective at eliminating the bulk of leukemic cells, chemotherapy resistance in acute myeloid leukemia (AML) is a prevalent problem that hinders conventional therapies and contributes to disease relapse, and ultimately patient death. We have recently shown that allogeneic double negative T cells (DNTs) are able to target the majority of primary AML blasts in vitro and in patient-derived xenograft models. However, some primary AML blast samples are resistant to DNT cell therapy. Given the differences in the modes of action of DNTs and chemotherapy, we hypothesize that DNT therapy can be used in combination with conventional chemotherapy to further improve their anti-leukemic effects and to target chemotherapy-resistant disease. Drug titration assays and flow-based cytotoxicity assays using ex vivo expanded allogeneic DNTs were performed on multiple AML cell lines to identify therapy-resistance. Primary AML samples were also tested to validate our in vitro findings. Further, a xenograft model was employed to demonstrate the feasibility of combining conventional chemotherapy and adoptive DNT therapy to target therapy-resistant AML. Lastly, blocking assays with neutralizing antibodies were employed to determine the mechanism by which chemotherapy increases the susceptibility of AML to DNT-mediated cytotoxicity. Here, we demonstrate that KG1a, a stem-like AML cell line that is resistant to DNTs and chemotherapy, and chemotherapy-resistant primary AML samples both became more susceptible to DNT-mediated cytotoxicity in vitro following pre-treatment with daunorubicin. Moreover, chemotherapy treatment followed by adoptive DNT cell therapy significantly decreased bone marrow engraftment of KG1a in a xenograft model. Mechanistically, daunorubicin increased the expression of NKG2D and DNAM-1 ligands on KG1a; blocking of these pathways attenuated DNT-mediated cytotoxicity. Our results demonstrate the feasibility and benefit of using DNTs as

  20. Clinical proteomics-driven precision medicine for targeted cancer therapy: current overview and future perspectives.

    Science.gov (United States)

    Zhou, Li; Wang, Kui; Li, Qifu; Nice, Edouard C; Zhang, Haiyuan; Huang, Canhua

    2016-01-01

    Cancer is a common disease that is a leading cause of death worldwide. Currently, early detection and novel therapeutic strategies are urgently needed for more effective management of cancer. Importantly, protein profiling using clinical proteomic strategies, with spectacular sensitivity and precision, offer excellent promise for the identification of potential biomarkers that would direct the development of targeted therapeutic anticancer drugs for precision medicine. In particular, clinical sample sources, including tumor tissues and body fluids (blood, feces, urine and saliva), have been widely investigated using modern high-throughput mass spectrometry-based proteomic approaches combined with bioinformatic analysis, to pursue the possibilities of precision medicine for targeted cancer therapy. Discussed in this review are the current advantages and limitations of clinical proteomics, the available strategies of clinical proteomics for the management of precision medicine, as well as the challenges and future perspectives of clinical proteomics-driven precision medicine for targeted cancer therapy.

  1. Tabletted guar gum microspheres of piroxicam for targeted adjuvant therapy for colonic adenocarcinomas.

    Science.gov (United States)

    Vats, Anima; Pathak, Kamla

    2012-11-01

    In recent years, nonsteroidal anti-inflammatory drugs have been found to be cogent as an adjuvant therapeutic agent in mitigating colorectal cancer. Thus, this present investigation was aimed to formulate an oral, targeted tablet of piroxicam microspheres for sustained and targeted adjuvant therapy for colonic adenocarcinomas. Crosslinked guar gum microspheres of piroxicam were directly compressed into matrix tablet and coated with Eudragit S100. The optimized tablet that displayed 0% release in simulated gastric fluid, 15% in simulated intestinal fluid and 97.1% in simulated colonic fluid underwent roentgenographic study in rabbits to check its safe transit to the colon. x-ray images revealed intactness of the tablet until it reached the colon where the tablet matrix eroded. The designed, conceptual formulation emerged as potential carrier for targeted adjuvant therapy of piroxicam.

  2. The development of molecularly targeted anticancer therapies: an Eli Lilly and Company perspective.

    Science.gov (United States)

    Perry, William L; Weitzman, Aaron

    2005-03-01

    The ability to identify activated pathways that drive the growth and progression of cancer and to develop specific and potent inhibitors of key proteins in these pathways promises to dramatically change the treatment of cancer: A patient's cancer could be characterized at the molecular level and the information used to select the best treatment options. The development of successful therapies not only requires extensive target validation, but also new approaches to evaluating drug efficacy in animal models and in the clinic compared to the development of traditional cytotoxic agents. This article highlights Eli Lilly and Company's approach to developing targeted therapies, from target identification and validation through evaluation in the clinic. A selection of drugs in the Lilly Oncology pipeline is also discussed.

  3. Viral Response to Specifically Targeted Antiviral Therapy for Hepatitis C and the Implications for Treatment Success

    Directory of Open Access Journals (Sweden)

    Curtis L Cooper

    2010-01-01

    Full Text Available Currently, hepatitis C virus (HCV antiviral therapy is characterized by long duration, a multitude of side effects, difficult administration and suboptimal success; clearly, alternatives are needed. Collectively, specifically targeted antiviral therapy for HCV (STAT-C molecules achieve rapid viral suppression and very high rapid virological response rates, and improve sustained virological response rates. The attrition rate of agents within this class has been high due to various toxicities. Regardless, several STAT-C molecules are poised to become the standard of care for HCV treatment in the foreseeable future. Optimism must be tempered with concerns related to the rapid development of drug resistance with resulting HCV rebound. Strategies including induction dosing with interferon and ribavirin, use of combination high-potency STAT-C molecules and an intensive emphasis on adherence to HCV antiviral therapy will be critical to the success of this promising advance in HCV therapy.

  4. Elective Clinical Target Volumes for Conformal Therapy in Anorectal Cancer: A Radiation Therapy Oncology Group Consensus Panel Contouring Atlas

    International Nuclear Information System (INIS)

    Myerson, Robert J.; Garofalo, Michael C.; El Naqa, Issam; Abrams, Ross A.; Apte, Aditya; Bosch, Walter R.; Das, Prajnan; Gunderson, Leonard L.; Hong, Theodore S.; Kim, J.J. John; Willett, Christopher G.; Kachnic, Lisa A.

    2009-01-01

    Purpose: To develop a Radiation Therapy Oncology Group (RTOG) atlas of the elective clinical target volume (CTV) definitions to be used for planning pelvic intensity-modulated radiotherapy (IMRT) for anal and rectal cancers. Methods and Materials: The Gastrointestinal Committee of the RTOG established a task group (the nine physician co-authors) to develop this atlas. They responded to a questionnaire concerning three elective CTVs (CTVA: internal iliac, presacral, and perirectal nodal regions for both anal and rectal case planning; CTVB: external iliac nodal region for anal case planning and for selected rectal cases; CTVC: inguinal nodal region for anal case planning and for select rectal cases), and to outline these areas on individual computed tomographic images. The imaging files were shared via the Advanced Technology Consortium. A program developed by one of the co-authors (I.E.N.) used binomial maximum-likelihood estimates to generate a 95% group consensus contour. The computer-estimated consensus contours were then reviewed by the group and modified to provide a final contouring consensus atlas. Results: The panel achieved consensus CTV definitions to be used as guidelines for the adjuvant therapy of rectal cancer and definitive therapy for anal cancer. The most important difference from similar atlases for gynecologic or genitourinary cancer is mesorectal coverage. Detailed target volume contouring guidelines and images are discussed. Conclusion: This report serves as a template for the definition of the elective CTVs to be used in IMRT planning for anal and rectal cancers, as part of prospective RTOG trials.

  5. Symptomatic benign prostatic hyperplasia: the role of 5-alpha-reductase inhibitors in the prevention of acute urinary retention and surgical therapy

    Directory of Open Access Journals (Sweden)

    Norma Marigliano

    2012-01-01

    Full Text Available Benign prostatic hyperplasia (BPH is a disease that affects over 50% of males aged 50 years or older. In men aged >80 years, the incidence is 90%. BPH occurs in 9-25% of males aged 40 to 79 years. Fifty percent of patients with BPH are symptomatic. The symptoms include reduced urinary flow, nocturia, defective bladder emptying, urinary hesitancy, and dysuria. Disease progression can be associated with acute urinary retention (AUR. Prostatic obstruction includes mechanical and dynamic components, the latter mediated by alpha-muscarinic receptors. Treatment with alpha-1-blockers (alfuzosin, doxazosin, tamsulosin, and terazosin leads to rapid amelioration of symptoms and urinary flow, usually within one or two weeks. The 5-alpha reductase inhibitors (5-ARIs are “disease-modifying drugs.” They control the growth of the prostate by blocking the conversion of testosterone into dihydrotestosterone (DHT. Finasteride is a 5–ARI that is selective for type 2 receptors. Dutasteride is a powerful inhibitor of both 5- alpha reductase isoforms (type 1 and 2 and produces more complete suppression of DHT synthesis than finasteride. Dutasteride also has a much longer half-life than finasteride (five weeks versus five to six hours. The authors review the results of clinical trials involving finasteride and dutasteride, with and without alpha-1-blockers, highlighting the important role of dutasteride in improving acute urinary retention and eliminating the need for surgical therapy.

  6. New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Abhijit M. Godbole

    2011-01-01

    Full Text Available Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The androgen receptor (AR, a receptor of nuclear family and a transcription factor, is the most important target in this disease. While most efforts in the clinic are currently directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops. Most prostate cancer deaths are attributable to this castration-resistant form of prostate cancer (CRPC. Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes, posttranslational modifications of AR such as sumoylation. Herein, we provide an overview of the structure of human AR and its key structural domains that can be used as targets to develop novel antiandrogens. We also summarize recent findings about the antiandrogens and the epigenetic factors that modulate the action of AR.

  7. Divergent clinical outcomes of alpha-glucosidase enzyme replacement therapy in two siblings with infantile-onset Pompe disease treated in the symptomatic or pre-symptomatic state

    OpenAIRE

    Matsuoka, Takashi; Miwa, Yoshiyuki; Tajika, Makiko; Sawada, Madoka; Fujimaki, Koichiro; Soga, Takashi; Tomita, Hideshi; Uemura, Shigeru; Nishino, Ichizo; Fukuda, Tokiko; Sugie, Hideo; Kosuga, Motomichi; Okuyama, Torayuki; Umeda, Yoh

    2016-01-01

    Pompe disease is an autosomal recessive, lysosomal glycogen storage disease caused by acid ?-glucosidase deficiency. Infantile-onset Pompe disease (IOPD) is the most severe form and is characterized by cardiomyopathy, respiratory distress, hepatomegaly, and skeletal muscle weakness. Untreated, IOPD generally results in death within the first year of life. Enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rhGAA) has been shown to markedly improve the life expectan...

  8. Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for In Vivo Gene Therapy of Uterine Leiomyoma.

    Science.gov (United States)

    Abdelaziz, Mohamed; Sherif, Lotfy; ElKhiary, Mostafa; Nair, Sanjeeta; Shalaby, Shahinaz; Mohamed, Sara; Eziba, Noura; El-Lakany, Mohamed; Curiel, David; Ismail, Nahed; Diamond, Michael P; Al-Hendy, Ayman

    2016-04-01

    Gene therapy is a potentially effective non-surgical approach for the treatment of uterine leiomyoma. We demonstrated that targeted adenovirus vector, Ad-SSTR-RGD-TK/GCV, was highly effective in selectively inducing apoptosis and inhibiting proliferation of human leiomyoma cells in vitro while sparing normal myometrial cells. An in-vivo study, to compare efficacy and safety of modified adenovirus vector Ad-SSTR-RGD-TK/GCV versus untargeted vector for treatment of leiomyoma. Female nude mice were implanted with rat leiomyoma cells subcutaneously. Then mice were randomized into three groups. Group 1 received Ad-LacZ (marker gene), Group 2 received untargeted Ad-TK, and Group 3 received the targeted Ad-SSTR-RGD-TK. Tumors were measured weekly for 4 weeks. Then mice were sacrificed and tissue samples were collected. Evaluation of markers of apoptosis, proliferation, extracellular matrix, and angiogenesis was performed using Western Blot & Immunohistochemistry. Statistical analysis was done using ANOVA. Dissemination of adenovirus was assessed by PCR. In comparison with the untargeted vector, the targeted adenoviral vector significantly shrank leiomyoma size (P leiomyoma lesions with both targeted and untargeted adenovirus. Targeted adenovirus, effectively reduces tumor size in leiomyoma without dissemination to other organs. Further evaluation of this localized targeted strategy for gene therapy is needed in appropriate preclinical humanoid animal models in preparation for a future pilot human trial. © The Author(s) 2016.

  9. Mitochondria and Mitochondrial ROS in Cancer: Novel Targets for Anticancer Therapy.

    Science.gov (United States)

    Yang, Yuhui; Karakhanova, Svetlana; Hartwig, Werner; D'Haese, Jan G; Philippov, Pavel P; Werner, Jens; Bazhin, Alexandr V

    2016-12-01

    Mitochondria are indispensable for energy metabolism, apoptosis regulation, and cell signaling. Mitochondria in malignant cells differ structurally and functionally from those in normal cells and participate actively in metabolic reprogramming. Mitochondria in cancer cells are characterized by reactive oxygen species (ROS) overproduction, which promotes cancer development by inducing genomic instability, modifying gene expression, and participating in signaling pathways. Mitochondrial and nuclear DNA mutations caused by oxidative damage that impair the oxidative phosphorylation process will result in further mitochondrial ROS production, completing the "vicious cycle" between mitochondria, ROS, genomic instability, and cancer development. The multiple essential roles of mitochondria have been utilized for designing novel mitochondria-targeted anticancer agents. Selective drug delivery to mitochondria helps to increase specificity and reduce toxicity of these agents. In order to reduce mitochondrial ROS production, mitochondria-targeted antioxidants can specifically accumulate in mitochondria by affiliating to a lipophilic penetrating cation and prevent mitochondria from oxidative damage. In consistence with the oncogenic role of ROS, mitochondria-targeted antioxidants are found to be effective in cancer prevention and anticancer therapy. A better understanding of the role played by mitochondria in cancer development will help to reveal more therapeutic targets, and will help to increase the activity and selectivity of mitochondria-targeted anticancer drugs. In this review we summarized the impact of mitochondria on cancer and gave summary about the possibilities to target mitochondria for anticancer therapies. J. Cell. Physiol. 231: 2570-2581, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  10. Role of chemotherapy and targeted therapy in early-stage non-small cell lung cancer.

    Science.gov (United States)

    Nagasaka, Misako; Gadgeel, Shirish M

    2018-01-01

    Adjuvant platinum based chemotherapy is accepted as standard of care in stage II and III non-small cell lung cancer (NSCLC) patients and is often considered in patients with stage IB disease who have tumors ≥ 4 cm. The survival advantage is modest with approximately 5% at 5 years. Areas covered: This review article presents relevant data regarding chemotherapy use in the perioperative setting for early stage NSCLC. A literature search was performed utilizing PubMed as well as clinical trial.gov. Randomized phase III studies in this setting including adjuvant and neoadjuvant use of chemotherapy as well as ongoing trials on targeted therapy and immunotherapy are also discussed. Expert commentary: With increasing utilization of screening computed tomography scans, it is possible that the percentage of early stage NSCLC patients will increase in the coming years. Benefits of adjuvant chemotherapy in early stage NSCLC patients remain modest. There is a need to better define patients most likely to derive survival benefit from adjuvant therapy and spare patients who do not need adjuvant chemotherapy due to the toxicity of such therapy. Trials for adjuvant targeted therapy, including adjuvant EGFR-TKI trials and trials of immunotherapy drugs are ongoing and will define the role of these agents as adjuvant therapy.

  11. A view on EGFR-targeted therapies from the oncogene-addiction perspective.

    Science.gov (United States)

    Perez, Rolando; Crombet, Tania; de Leon, Joel; Moreno, Ernesto

    2013-01-01

    Tumor cell growth and survival can often be impaired by inactivating a single oncogen- a phenomenon that has been called as "oncogene addiction." It is in such scenarios that molecular targeted therapies may succeed. among known oncogenes, the epidermal growth factor receptor (EGFR) has become the target of different cancer therapies. So far, however, the clinical benefit from EGFR-targeted therapies has been rather limited. a critical review of the large amount of clinical data obtained with anti-EGFR agents, carried out from the perspective of the oncogene addiction concept, may help to understand the causes of the unsatisfactory results. In this article we intend to do such an exercise taking as basis for the analysis a few case studies of anti-EGFR agents that are currently in the clinic. There, the "EGFR addiction" phenomenon becomes apparent in high-responder patients. We further discuss how the concept of oncogene addiction needs to be interpreted on the light of emerging experimental evidences and ideas; in particular, that EGFR addiction may reflect the interconnection of several cellular pathways. In this regard we set forth several hypotheses; namely, that requirement of higher glucose uptake by hypoxic tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted antibodies in EGFR-addicted tumors would induce stable disease by reversing the malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T cell response. Finally, we discuss possible reasons for the failure of certain combinatorial therapies involving anti-EGFR agents, arguing that some of these agents might produce either a negative or a positive trans-modulation effect on other oncogenes. It becomes evident that we need operational definitions of EGFR addiction in order to determine which patient populations may benefit from treatment with anti-EGFR drugs, and to improve the design of these therapies.

  12. A view on EGFR-targeted therapies from the oncogene-addiction perspective

    Directory of Open Access Journals (Sweden)

    Rolando ePerez

    2013-04-01

    Full Text Available Tumor cell growth and survival can often be impaired by inactivating a single oncogen – a phenomenon that has been called as 'oncogene addiction'. It is in such scenarios that molecular targeted therapies may succeed. Among known oncogenes, the epidermal growth factor receptor (EGFR has become the target of different cancer therapies. So far, however, the clinical benefit from EGFR-targeted therapies has been rather limited. A critical review of the large amount of clinical data obtained with anti-EGFR agents, carried out from the perspective of the oncogene addiction concept, may help to understand the causes of the unsatisfactory results. In this article we intend to do such an exercise taking as basis for the analysis a few case studies of anti-EGFR agents that are currently in the clinic. There, the 'EGFR addiction' phenomenon becomes apparent in high-responder patients. We further discuss how the concept of oncogene addiction needs to be interpreted on the light of emerging experimental evidences and ideas; in particular, that EGFR addiction may reflect the interconnection of several cellular pathways. In this regard we set forth several hypotheses; namely, that requirement of higher glucose uptake by hypoxic tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted antibodies in EGFR-addicted tumors would induce stable disease by reversing the malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T cell response. Finally, we discuss possible reasons for the failure of certain combinatorial therapies involving anti-EGFR agents, arguing that some of these agents might produce either a negative or a positive trans-modulation effect on other oncogenes. It becomes evident that we need operational definitions of EGFR addiction in order to determine which patient populations may benefit from treatment with anti-EGFR drugs, and to improve the design of these therapies.

  13. Assessing the response to targeted therapies in renal cell carcinoma: technical insights and practical considerations.

    Science.gov (United States)

    Bex, Axel; Fournier, Laure; Lassau, Nathalie; Mulders, Peter; Nathan, Paul; Oyen, Wim J G; Powles, Thomas

    2014-04-01

    The introduction of targeted agents for the treatment of renal cell carcinoma (RCC) has resulted in new challenges for assessing response to therapy, and conventional response criteria using computed tomography (CT) are limited. It is widely recognised that targeted therapies may lead to significant necrosis without significant reduction in tumour size. In addition, the vascular effects of antiangiogenic therapy may occur long before there is any reduction in tumour size. To perform a systematic review of conventional and novel imaging methods for the assessment of response to targeted agents in RCC and to discuss their use from a clinical perspective. Relevant databases covering the period January 2006 to April 2013 were searched for studies reporting on the use of anatomic and functional imaging techniques to predict response to targeted therapy in RCC. Inclusion criteria were randomised trials, nonrandomised controlled studies, retrospective case series, and cohort studies. Reviews, animal and preclinical studies, case reports, and commentaries were excluded. A narrative synthesis of the evidence is presented. A total of 331 abstracts and 76 full-text articles were assessed; 34 studies met the inclusion criteria. Current methods of response assessment in RCC include anatomic methods--based on various criteria including Choi, size and attenuation CT, and morphology, attenuation, size, and structure--and functional techniques including dynamic contrast-enhanced (DCE) CT, DCE-magnetic resonance imaging, DCE-ultrasonography, positron emission tomography, and approaches utilising radiolabelled monoclonal antibodies. Functional imaging techniques are promising surrogate biomarkers of response in RCC and may be more appropriate than anatomic CT-based methods. By enabling quantification of tumour vascularisation, functional techniques can directly and rapidly detect the biologic effects of antiangiogenic therapies compared with the indirect detection of belated effects

  14. Nanobody-Based Delivery Systems for Diagnosis and Targeted Tumor Therapy

    Directory of Open Access Journals (Sweden)

    Yaozhong Hu

    2017-11-01

    Full Text Available The development of innovative targeted therapeutic approaches are expected to surpass the efficacy of current forms of treatments and cause less damage to healthy cells surrounding the tumor site. Since the first development of targeting agents from hybridoma’s, monoclonal antibodies (mAbs have been employed to inhibit tumor growth and proliferation directly or to deliver effector molecules to tumor cells. However, the full potential of such a delivery strategy is hampered by the size of mAbs, which will obstruct the targeted delivery system to access the tumor tissue. By serendipity, a new kind of functional homodimeric antibody format was discovered in camelidae, known as heavy-chain antibodies (HCAbs. The cloning of the variable domain of HCAbs produces an attractive minimal-sized alternative for mAbs, referred to as VHH or nanobodies (Nbs. Apart from their dimensions in the single digit nanometer range, the unique characteristics of Nbs combine a high stability and solubility, low immunogenicity and excellent affinity and specificity against all possible targets including tumor markers. This stimulated the development of tumor-targeted therapeutic strategies. Some autonomous Nbs have been shown to act as antagonistic drugs, but more importantly, the targeting capacity of Nbs has been exploited to create drug delivery systems. Obviously, Nb-based targeted cancer therapy is mainly focused toward extracellular tumor markers, since the membrane barrier prevents antibodies to reach the most promising intracellular tumor markers. Potential strategies, such as lentiviral vectors and bacterial type 3 secretion system, are proposed to deliver target-specific Nbs into tumor cells and to block tumor markers intracellularly. Simultaneously, Nbs have also been employed for in vivo molecular imaging to diagnose diseased tissues and to monitor the treatment effects. Here, we review the state of the art and focus on recent developments with Nbs as

  15. Potential efficacy of therapies targeting intrahepatic lesions after sorafenib treatment of patients with hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Terashima, Takeshi; Yamashita, Tatsuya; Horii, Rika; Arai, Kuniaki; Kawaguchi, Kazunori; Kitamura, Kazuya; Yamashita, Taro; Sakai, Yoshio; Mizukoshi, Eishiro; Honda, Masao; Kaneko, Shuichi

    2016-01-01

    We investigated the contribution of subsequent therapy for advanced hepatocellular carcinoma refractory or intolerant to sorafenib. Further, we investigated the impact of sorafenib on overall survival using individual data. We reviewed the medical records of patients with advanced hepatocellular carcinoma treated with sorafenib. Survival after sorafenib treatment and overall survival were defined as the time when we discovered that patients were either refractory or intolerant to sorafenib and the period from the start of sorafenib treatment, respectively, until death during the study. We compared patients’ prognoses according to their subsequent treatment as follows: group A, therapies targeting intrahepatic lesions; group B, systemic therapies alone; group C, no subsequent therapy. We used linear regression analysis to determine whether there was an association with survival after sorafenib treatment and with overall survival. Of 79 patients, 63 (79.7 %) received one or more subsequent therapies (44 and 19 patients in groups A and B, respectively). The five patients who survived more than two years after sorafenib treatment was discontinued responded to therapies targeting intrahepatic lesions. The median survival times of groups A, B, and C were 11.9 months, 5.8 months, and 3.6 months, respectively. Multivariate analysis revealed that group A, Child-Pugh score, serum α-fetoprotein level, and cause of failure of sorafenib treatment were independent prognostic factors for survival after sorafenib treatment. Individual survival after sorafenib treatment correlated highly with overall survival. Targeting intrahepatic lesions may be useful for treating patients with advanced hepatocellular carcinoma patients after sorafenib treatment is discontinued. The online version of this article (doi:10.1186/s12885-016-2380-4) contains supplementary material, which is available to authorized users

  16. Ovarian cancer and the immune system - The role of targeted therapies.

    Science.gov (United States)

    Turner, Taylor B; Buchsbaum, Donald J; Straughn, J Michael; Randall, Troy D; Arend, Rebecca C

    2016-08-01

    The majority of patients with epithelial ovarian cancer are diagnosed with advanced disease. While many of these patients will respond initially to chemotherapy, the majority will relapse and die of their disease. Targeted therapies that block or activate specific intracellular signaling pathways have been disappointing. In the past 15years, the role of the immune system in ovarian cancer has been investigated. Patients with a more robust immune response, as documented by the presence of lymphocytes infiltrating within their tumor, have increased survival and better response to chemotherapy. In addition, a strong immunosuppressive environment often accompanies ovarian cancer. Recent research has identified potential therapies that leverage the immune system to identify and destroy tumor cells that previously evaded immunosurveillance mechanisms. In this review, we discuss the role of the immune system in ovarian cancer and focus on specific pathways and molecules that show a potential for targeted therapy. We also review the ongoing clinical trials using targeted immunotherapy in ovarian cancer. The role of targeted immunotherapy in patients with ovarian cancer represents a field of growing research and clinical importance. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Chemoradiotherapy in head and neck squamous cell carcinoma: focus on targeted therapies

    International Nuclear Information System (INIS)

    Bozec, A.; Thariat, J.; Bensadoun, R.J.; Milano, G.

    2008-01-01

    Radiotherapy is an essential treatment for many patients with head and neck squamous cell carcinoma. Its association with molecular targeted therapies represents a real progress. Among the recent advances in the molecular targeted therapy of cancer, the applications centred on E.G.F.R. are currently the most promising and the most advanced at clinical level. Considering the set of therapeutic tools targeting E.G.F.R., there are at present two well-identified emerging categories of drugs with monoclonal antibodies, on the one hand, and tyrosine kinase inhibitors, on the other. In many preclinical studies, the combination of anti-E.G.F.R. drugs with irradiation has led to additive or supra-additive cytotoxic effects. Furthermore, anti-angiogenic agents have shown promising results in association with anti-E.G.F.R. drugs and radiotherapy. This research effort has recently produced encouraging clinical results in advanced head and neck cancer with combination of cetuximab (an anti-E.G.F.R. monoclonal antibody) with irradiation with a significant impact on patient survival. Active and efficient clinical research is currently ongoing to determine the place of molecular targeted therapies in the treatment of head and neck cancer, particularly in association with radiotherapy. (authors)

  18. Targeted therapy of advanced non-small cell lung cancer: the role of bevacizumab.

    Science.gov (United States)

    Stinchcombe, Thomas E

    2007-09-01

    Lung cancer is the leading cause of cancer death in the United States. The majority of patients present with advanced stage disease, and treatment with standard cytotoxic chemotherapy agents have been shown to provide a modest improvement in survival, reduce disease-related symptoms, and improve quality of life. However, with standard chemotherapy treatments the prognosis is poor with the majority of patients dying in less than a year from diagnosis. Treatment with standard chemotherapy agents has reached a therapeutic plateau, and recent investigations have focused on therapies that target a specific pathway within the malignant cell or related to angiogenesis. The most promising of the targeted therapies are agents that target the process of angiogenesis. Bevacizuamab is a monoclonal antibody that binds to circulating vascular endotheli