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Nishi-Tokyo-shi, Japan

Takahashi H.,Yokohama City University | Hyakusoku H.,Yokohama City University | Horii C.,Yokohama City University | Takahashi M.,Yokohama City University | And 6 more authors.
Head and Neck | Year: 2014

Background. Radioresistance remains a critical issue in the use of radiotherapy for the treatment of head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy of combination treatment with OBP-301, a telomerase-specific replication-selective adenovirus, and radiotherapy in overcoming radioresistance by examining its effect on radiation-resistant HNSCC cells. Methods. Radiation-resistant HNSCC cells were treated with OBP-301 and radiation in vitro and in an orthotopic nude mouse model in vivo and synergism was assessed. Apoptosis and expression of MRN complex, which plays a key role in DNA repair machinery, were also analyzed. Results. Infection with OBP-301 was found to enhance the antitumor efficacy of radiation both in vitro and in vivo by inhibiting MRN complex expression and increasing apoptosis induction. Conclusion. Combined OBP-301 and radiation therapy seems to overcome radioresistance in HNSCC cells by inhibiting DNA repair machinery, and may thus be a novel therapeutic strategy for treating HNSCC. © 2013 Wiley Periodicals, Inc. Source


Lin W.-H.,National Taiwan University | Yeh S.-H.,National Taiwan University | Yang W.-J.,National Taiwan University | Yeh K.-H.,National Taiwan University | And 5 more authors.
International Journal of Cancer | Year: 2013

The telomerase-specific replication-competent oncolytic adenovirus, Telomelysin, was developed for virus-mediated preferential lysis of tumor cells. Its selectivity is derived from a human telomerase reverse transcriptase (hTERT) promoter-driven active viral replication, which occurs in cancer cells with high telomerase activity but not in normal cells lacking such activity. Because the TERT activity is elevated in most cases of hepatocellular carcinoma (HCC), the current study aims to investigate whether Telomelysin can be used for treatment of HCC. The oncolytic effect of Telomelysin has been investigated both in vitro using cell culture and in vivo using an immunocompetent in situ orthotopic HCC model. In this model, HCC developed spontaneously in the liver of HBx transgenic mice, which is pathologically and genetically similar to human HCC. In cell culture assay, Telomelysin lyses HCC cell lines at a low multiplicity of infection (MOI), ranging 0.77-6.35 (MOI [PFU/cell]). In the orthotopic HCC model, Telomelysin showed a potent oncolytic effect on HCC but spared normal liver tissue. Dose escalation analysis identified a safety dose of 1.25 × 108 PFU for this model. The effect of multiple injections of Telomelysin was also evaluated in this immunocompetent HCC model. We found that the virus replicates in HCC after a second intratumoral injection despite an immune response induced by the previous injection. This preclinical study shows that Telomelysin can be used for treatment of human HCC at an appropriate dosage and that its tumor-killing activity persists after multiple injections. What's new? More than 95 percent of hepatocellular carcinomas (HCCs) are associated with telomerase reverse transcriptase (hTERT) activation, which promotes cell immortality. In this study, the adenovirus Telomelysin demonstrated specific oncolytic activity in HCC cells with elevated hTERT. In addition, in mice with orthotopically growing HCC xenografts, the adenovirus slowed tumor growth, despite the generation of an immune response. The results suggest that Telomelysin may be useful in the treatment of HCC. Copyright © 2012 UICC. Source


Nemunaitis J.,Mary Crowley Cancer Research Centers | Nemunaitis J.,Baylor Sammons Cancer Center | Nemunaitis J.,Gradalis, Inc. | Tong A.W.,Baylor Sammons Cancer Center | And 17 more authors.
Molecular Therapy | Year: 2010

A phase I clinical trial was conducted to determine the clinical safety of Telomelysin, a human telomerase reverse transcriptase (hTERT) promoter driven modified oncolytic adenovirus, in patients with advanced solid tumors. A single intratumoral injection (IT) of Telomelysin was administered to three cohorts of patients (1 × 10 10, 1 × 10 11, 1 × 10 12 viral particles). Safety, response and pharmacodynamics were evaluated. Sixteen patients with a variety of solid tumors were enrolled. IT of Telomelysin was well tolerated at all dose levels. Common grade 1 and 2 toxicities included injection site reactions (pain, induration) and systemic reactions (fever, chills). hTERT expression was demonstrated at biopsy in 9 of 12 patients. Viral DNA was transiently detected in plasma in 13 of 16 patients. Viral DNA was detectable in four patients in plasma or sputum at day 7 and 14 post-treatment despite below detectable levels at 24h, suggesting viral replication. One patient had a partial response of the injected malignant lesion. Seven patients fulfilled Response Evaluation Criteria in Solid Tumors (RECIST) definition for stable disease at day 56 after treatment. Telomelysin was well tolerated. Evidence of antitumor activity was suggested. © The American Society of Gene & Cell Therapy. Source


Cotte L.,Service dHepatologie et de Sida | Dellamonica P.,University of Nice Sophia Antipolis | Raffi F.,University of Nantes | Yazdanpanah Y.,Service University des Maladies Infectieuses et du Voyageur | And 9 more authors.
Journal of Acquired Immune Deficiency Syndromes | Year: 2013

Objective: To investigate the safety, tolerability, pharmacokinetics, and antiviral activity of BMS-986001 (a nucleoside reverse transcriptase inhibitor) in treatment-experienced, HIV-1-infected subjects not exposed to antiretroviral treatment in the previous 3 months. Methods: Thirty-two HIV-1-infected subjects were randomized (3:1) to receive BMS-986001 or placebo once daily for 10 days in this double-blind, placebo-controlled, dose-escalating monotherapy phase IIa study. There were 4 treatment groups (100, 200, 300, and 600 mg, all once daily) of 8 subjects each (BMS-986001, n = 6/placebo n = 2). Results: BMS-986001 was generally well tolerated, with no discontinuations due to adverse events and no deaths occurring. Adverse events were experienced by 22 of 24 BMS-986001-treated subjects and did not seem to be dose related. The majority were mild and considered unrelated or unlikely to be related to the study drug. The pharmacokinetics of BMS-986001 were dose proportional. Median decrease in plasma HIV-1 RNA from baseline to day 11 was 0.97, 1.15, 1.28, and 1.15 log10 copies/mL for BMS-986001 at 100, 200, 300, and 600 mg, respectively. Plasma area under the curve correlated with the antiviral activity of BMS-986001, indicating that area under the curves produced by 100-600 mg doses were on the upper end of the exposure-response curve. One subject with a single thymidine analog mutation at baseline responded well to BMS-986001. Conclusions: Administration of BMS-986001 for 10 days resulted in substantial decreases in plasma HIV-1 RNA levels for all dose groups and was generally well tolerated. These data support continued clinical development of BMS-986001 at a dose of 100 mg, once daily or greater. Copyright © 2013 by Lippincott Williams & Wilkins. Source


Urata Y.,Oncolys BioPharma | Paintsil E.,Yale University | Cheng Y.-C.,Yale University | Matsuda T.,Oncolys BioPharma | And 6 more authors.
Journal of Clinical Pharmacology | Year: 2014

The objectives of this study were to evaluate the safety, tolerability and pharmacokinetics (PK) of BMS-986001 as a single oral dose in healthy male subjects. Sixty-four healthy male subjects were randomized to receive a single dose of BMS-986001 or placebo in this single-blind, placebo-controlled, sequential ascending-dose study. There were eight treatment groups (10, 30, 100, 300, 600, and 900mg fed; and 100 and 300mg fasted) of eight subjects each (BMS-986001 n=6/placebo n=2). BMS-986001 was well tolerated, with no serious adverse events (AEs), deaths, or discontinuations due to AEs reported. AEs were experienced by 14.6% of subjects receiving BMS-986001; however, these did not appear to be dose related and were not considered to be related to study drug. BMS-986001 was rapidly absorbed and exhibited a linear dose-exposure relationship across the dose range studied. PK appeared similar whether administered with or without food. Administration of BMS-986001 as a single dose was generally safe and well tolerated. A linear dose-exposure relationship was seen across all doses studied, with no apparent food effect. Further clinical development is warranted. © 2014, The American College of Clinical Pharmacology. Source

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