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Kelly K. Hunt - One of the best experts on this subject based on the ideXlab platform.
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Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53.
Cancer Gene Therapy, 2006Co-Authors: Apar Pataer, Michelle A. Fanale, Stephen G. Swisher, Jack A. Roth, Kelly K. HuntAbstract:Adenoviral delivery of the p53 gene is a potential therapeutic approach for the treatment of lung cancer. Furthermore, amifostine is a Cytoprotective Agent and recent reports have described its potentiation of chemotherapy's antitumor activity in lung cancer. Therefore, we wished to investigate the ability of amifostine both alone and in combination with p53-based therapy to induce apoptosis, and to understand the mechanisms by which this apoptosis occurs. Using p53 null and wild-type p53 human lung cancer cells and normal human bronchial epithelial cells, we evaluated the effects of amifostine on proliferation and apoptosis. We then analyzed Adp53 in combination with amifostine and performed isobologram analysis. Expression of p53, p21WAF1, Bax, Bak, bcl-2, as well as total and phosphorylated Cdc2 in the absence and presence of olomoucine, a phosphorylated Cdc2 kinase inhibitor, was then determined. Amifostine-induced apoptosis in human lung cancer cells in a dose-dependent fashion. The combination of amifostine and Adp53 significantly enhanced, with a supra-additive effect, the inhibition of proliferation of lung cancer cells. This enhancement of apoptosis by amifostine was associated with activation of p53 and dephosphorylation of Cdc2 proteins. Notably, olomoucine effectively prevented amifostine and/or Adp53-induced Cdc2 kinase activation and subsequent apoptosis. Our data shows that amifostine alone can induce apoptosis of human lung cancer cells, and that the combination of Adp53 with amifostine resulted in significantly higher levels of apoptosis. In addition, it appears that Cdc2 kinase plays an important role in the induction of apoptosis by amifostine and Adp53.
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Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53.
Cancer Gene Therapy, 2006Co-Authors: Apar Pataer, Michelle A. Fanale, Stephen G. Swisher, Jack A. Roth, Kelly K. HuntAbstract:Adenoviral delivery of the p53 gene is a potential therapeutic approach for the treatment of lung cancer. Furthermore, amifostine is a Cytoprotective Agent and recent reports have described its potentiation of chemotherapy's antitumor activity in lung cancer. Therefore, we wished to investigate the ability of amifostine both alone and in combination with p53-based therapy to induce apoptosis, and to understand the mechanisms by which this apoptosis occurs. Using p53 null and wild-type p53 human lung cancer cells and normal human bronchial epithelial cells, we evaluated the effects of amifostine on proliferation and apoptosis. We then analyzed Adp53 in combination with amifostine and performed isobologram analysis. Expression of p53, p21WAF1, Bax, Bak, bcl-2, as well as total and phosphorylated Cdc2 in the absence and presence of olomoucine, a phosphorylated Cdc2 kinase inhibitor, was then determined. Amifostine-induced apoptosis in human lung cancer cells in a dose-dependent fashion. The combination of amifostine and Adp53 significantly enhanced, with a supra-additive effect, the inhibition of proliferation of lung cancer cells. This enhancement of apoptosis by amifostine was associated with activation of p53 and dephosphorylation of Cdc2 proteins. Notably, olomoucine effectively prevented amifostine and/or Adp53-induced Cdc2 kinase activation and subsequent apoptosis. Our data shows that amifostine alone can induce apoptosis of human lung cancer cells, and that the combination of Adp53 with amifostine resulted in significantly higher levels of apoptosis. In addition, it appears that Cdc2 kinase plays an important role in the induction of apoptosis by amifostine and Adp53.
Apar Pataer - One of the best experts on this subject based on the ideXlab platform.
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Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53.
Cancer Gene Therapy, 2006Co-Authors: Apar Pataer, Michelle A. Fanale, Stephen G. Swisher, Jack A. Roth, Kelly K. HuntAbstract:Adenoviral delivery of the p53 gene is a potential therapeutic approach for the treatment of lung cancer. Furthermore, amifostine is a Cytoprotective Agent and recent reports have described its potentiation of chemotherapy's antitumor activity in lung cancer. Therefore, we wished to investigate the ability of amifostine both alone and in combination with p53-based therapy to induce apoptosis, and to understand the mechanisms by which this apoptosis occurs. Using p53 null and wild-type p53 human lung cancer cells and normal human bronchial epithelial cells, we evaluated the effects of amifostine on proliferation and apoptosis. We then analyzed Adp53 in combination with amifostine and performed isobologram analysis. Expression of p53, p21WAF1, Bax, Bak, bcl-2, as well as total and phosphorylated Cdc2 in the absence and presence of olomoucine, a phosphorylated Cdc2 kinase inhibitor, was then determined. Amifostine-induced apoptosis in human lung cancer cells in a dose-dependent fashion. The combination of amifostine and Adp53 significantly enhanced, with a supra-additive effect, the inhibition of proliferation of lung cancer cells. This enhancement of apoptosis by amifostine was associated with activation of p53 and dephosphorylation of Cdc2 proteins. Notably, olomoucine effectively prevented amifostine and/or Adp53-induced Cdc2 kinase activation and subsequent apoptosis. Our data shows that amifostine alone can induce apoptosis of human lung cancer cells, and that the combination of Adp53 with amifostine resulted in significantly higher levels of apoptosis. In addition, it appears that Cdc2 kinase plays an important role in the induction of apoptosis by amifostine and Adp53.
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Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53.
Cancer Gene Therapy, 2006Co-Authors: Apar Pataer, Michelle A. Fanale, Stephen G. Swisher, Jack A. Roth, Kelly K. HuntAbstract:Adenoviral delivery of the p53 gene is a potential therapeutic approach for the treatment of lung cancer. Furthermore, amifostine is a Cytoprotective Agent and recent reports have described its potentiation of chemotherapy's antitumor activity in lung cancer. Therefore, we wished to investigate the ability of amifostine both alone and in combination with p53-based therapy to induce apoptosis, and to understand the mechanisms by which this apoptosis occurs. Using p53 null and wild-type p53 human lung cancer cells and normal human bronchial epithelial cells, we evaluated the effects of amifostine on proliferation and apoptosis. We then analyzed Adp53 in combination with amifostine and performed isobologram analysis. Expression of p53, p21WAF1, Bax, Bak, bcl-2, as well as total and phosphorylated Cdc2 in the absence and presence of olomoucine, a phosphorylated Cdc2 kinase inhibitor, was then determined. Amifostine-induced apoptosis in human lung cancer cells in a dose-dependent fashion. The combination of amifostine and Adp53 significantly enhanced, with a supra-additive effect, the inhibition of proliferation of lung cancer cells. This enhancement of apoptosis by amifostine was associated with activation of p53 and dephosphorylation of Cdc2 proteins. Notably, olomoucine effectively prevented amifostine and/or Adp53-induced Cdc2 kinase activation and subsequent apoptosis. Our data shows that amifostine alone can induce apoptosis of human lung cancer cells, and that the combination of Adp53 with amifostine resulted in significantly higher levels of apoptosis. In addition, it appears that Cdc2 kinase plays an important role in the induction of apoptosis by amifostine and Adp53.
Michael I Koukourakis - One of the best experts on this subject based on the ideXlab platform.
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individualization of the subcutaneous amifostine dose during hypofractionated accelerated radiotherapy
Anticancer Research, 2006Co-Authors: Michael I Koukourakis, Ioannis Abatzoglou, Leonidas Sivridis, Maria Tsarkatsi, Helen DelidouAbstract:Background: Individualization of the daily dose of amifostine may prove of value in achieving maximum cytoprotection during radiotherapy. Patients and Methods: Using an algorithm based on: i) the gradual increase of the amifostine dose, ii) an amifostine tolerance-recording scale and iii) the intermittent administration of dexamethasone, the individualization of the subcutaneous amifostine dose was prospectively attempted in a large cohort of 132 cancer patients, treated with 12-15 consecutive fractions of 3.4-3.5 Gy (hypofractionated accelerated radiotherapy with cytoprotection, HypoARC). Results: Using the above algorithm, a daily dose of 1000 mg of amifostine was successfully delivered in 62% of patients. An additional 20% of patients tolerated well a mean daily dose of 750-975 mg. Nausea and fatigue were minimal, while fever/rash enforced amifostine interruption in 7% of cases. Conclusion: Individualization of the amifostine dose allowed an up to two-fold increased daily-dose administration of amifostine and can be tested as a support to aggressive radio-chemotherapy schemes aiming at improving the cure rates of cancer patients, while avoiding excess toxicity. Amifostine is a broad spectrum Cytoprotective Agent that
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Individualization of the subcutaneous amifostine dose during hypofractionated / accelerated radiotherapy.
Anticancer research, 2006Co-Authors: Michael I Koukourakis, Ioannis Abatzoglou, Leonidas Sivridis, Maria Tsarkatsi, Helen DelidouAbstract:Background: Individualization of the daily dose of amifostine may prove of value in achieving maximum cytoprotection during radiotherapy. Patients and Methods: Using an algorithm based on: i) the gradual increase of the amifostine dose, ii) an amifostine tolerance-recording scale and iii) the intermittent administration of dexamethasone, the individualization of the subcutaneous amifostine dose was prospectively attempted in a large cohort of 132 cancer patients, treated with 12-15 consecutive fractions of 3.4-3.5 Gy (hypofractionated accelerated radiotherapy with cytoprotection, HypoARC). Results: Using the above algorithm, a daily dose of 1000 mg of amifostine was successfully delivered in 62% of patients. An additional 20% of patients tolerated well a mean daily dose of 750-975 mg. Nausea and fatigue were minimal, while fever/rash enforced amifostine interruption in 7% of cases. Conclusion: Individualization of the amifostine dose allowed an up to two-fold increased daily-dose administration of amifostine and can be tested as a support to aggressive radio-chemotherapy schemes aiming at improving the cure rates of cancer patients, while avoiding excess toxicity. Amifostine is a broad spectrum Cytoprotective Agent that
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amifostine before chemotherapy improved tolerance profile of the subcutaneous over the intravenous route
Clinical Cancer Research, 2003Co-Authors: Michael I Koukourakis, C Simopoulos, George Minopoulos, George Patlakas, Alexandros Polychronidis, Vassilis Limberis, Kostantinos Romanides, Michael Pitiacoudis, Costantinos ManolasAbstract:Introduction: The i.v. administration of the Cytoprotective Agent amifostine is associated with reversible clinical hypotention, protracted emesis, and malaise in a various percentage of patients. We evaluated, prospectively, whether the s.c. route is a better tolerated alternative to the i.v. route in patients receiving chemotherapy. Patients and Methods: Fifty-nine patients treated with “once every 2 weeks” regimens received 1000 mg of amifostine i.v. before chemotherapy. Patients who developed protracted vomiting and malaise and/or clinical hypotension for two consecutive i.v. administrations received the same dose of amifostine s.c. for the subsequent cycles (i.v./s.c. study). In an additional cohort of 12 patients (s.c. study), 1000 mg of amifostine were given s.c. since the first chemotherapy cycle. Results: In the i.v./s.c. study, 8 (13.5%) patients showed protracted emesis/malaise and/or clinical hypotension during the first two cycles. An additional 4 (6.6%) patients developed similar side effects during the subsequent cycles. Switching to the s.c. route, an improved tolerance was noted. In the s.c. study, a total of 76 injections was administered. Protracted vomiting or clinical hypotension was absent, and this tolerance profile was significantly better than the i.v. one ( P = 0.001). There were no other systemic side effects related to the s.c. administration. Conclusions: Amifostine, at a dose of 1000 mg, is better tolerated when administered s.c. Switching to the s.c. route in patients with poor tolerance using the i.v. administration allows the continuation of cytoprotection with minor side effects. Although preliminary, 1000 mg of amifostine effectively protected against the lower, still more frequently administered doses of chemotherapy given once every 2 weeks.
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subcutaneous administration of amifostine during fractionated radiotherapy a randomized phase ii study
Journal of Clinical Oncology, 2000Co-Authors: Michael I Koukourakis, George Kyrias, Stelios Kakolyris, Charalambos Kouroussis, Chryssi Frangiadaki, Alexandra Giatromanolaki, G Retalis, Vassilios GeorgouliasAbstract:PURPOSE: Amifostine (WR-2721) is an impotant Cytoprotective Agent. Although intravenous administration is the standard route, pharmacokinetic studies have shown acceptable plasma levels of the active metabolite of amifostine (WR-1605) after subcutaneous administration. The subcutaneous route, due to its simplicity, presents multiple advantages over the intravenous route when amifostine is used during fractionated radiotherapy. PATIENTS AND METHODS: Sixty patients with thoracic, 40 with head and neck, and 40 with pelvic tumors who were undergoing radical radiotherapy were enrolled onto a randomized phase II trial to assess the feasibility, tolerance, and Cytoprotective efficacy of amifostine administered subcutaneously. A flat dose of amifostine 500 mg, diluted in 2.5 mL of normal saline, was injected subcutaneously 20 minutes before each radiotherapy fraction. RESULTS: The subcutaneous amifostine regimen was well tolerated by 85% of patients. In approximately 5% of patients, amifostine therapy was interru...
Tadashi Honda - One of the best experts on this subject based on the ideXlab platform.
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an improved synthesis of a hydroxymethyl tricyclic ketone from cyclohexanone the key processes for the synthesis of a highly potent antiinflammatory and Cytoprotective Agent
ChemInform, 2014Co-Authors: Akira Saito, Suqing Zheng, Motohiro Takahashi, Iwao Ojima, Tadashi HondaAbstract:Compound (VI) is a key structure for the synthesis of TBE-31 (VII), which can be obtained after 10 further steps.
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An Improved Synthesis of a Hydroxymethyl Tricyclic Ketone from Cyclohexanone, the Key Processes for the Synthesis of a Highly Potent Anti-inflammatory and Cytoprotective Agent
Synthesis, 2013Co-Authors: Akira Saito, Suqing Zheng, Motohiro Takahashi, Iwao Ojima, Tadashi HondaAbstract:An improved synthesis of hydroxymethyl tricyclic ketone, (±)-(4aS,8aS)-8a-(hydroxymethyl)-1,1,4a-trimethyl-3,4,4a,6,7,8,8a,9,10,10a-decahydrophenanthren-2(1H)-one, in five steps (34% yield) from cyclohexanone has been successfully established. Accordingly, 10 grams of a highly potent anti-inflammatory and Cytoprotective Agent, (±)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3,4b,7,8,8a,9,10,10a-octahydrophenanthrene-2,6-dicarbonitrile (TBE-31), was obtained in 15 steps (9.2% overall yield) via the hydroxymethyl tricyclic ketone from 32 grams of cyclohexanone.
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synthesis and biological evaluation of 1 2 cyano 3 12 dioxooleana 1 9 11 dien 28 oyl 4 ethynylimidazole a novel and highly potent antiinflammatory and Cytoprotective Agent
ChemInform, 2011Co-Authors: Tadashi Honda, Emilie David, Eric M. Padegimas, Chitra Sundararajan, Melean Visnick, Ron Bumeister, Albena T Dinkovakostava, Christian W WigleyAbstract:A small series of new N-acyl(acetylenic)imidazole analogues (I) is synthesized and evaluated for their anti-inflammatory and Cytoprotective activity.
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Synthesis and biological evaluation of 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4-ethynylimidazole. A novel and highly potent anti-inflammatory and Cytoprotective Agent.
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Tadashi Honda, Albena T. Dinkova-kostova, Emilie David, Eric M. Padegimas, Chitra Sundararajan, Melean Visnick, Ron Bumeister, W. Christian WigleyAbstract:To explore more potent N-acylimidazole analogues of CDDO than CDDO-Im, which is one of the most potent compounds in several widely used bioassays related to protection against inflammation and carcinogenesis; we have synthesized and evaluated five new N-acyl(acetylenic)imidazole analogues. Among them, 4-ethynylimidazole 4 is nearly equivalent to CDDO-Im in potency in these bioassays. Remarkably, the solid form of 4 is more stable than that of CDDO-Im. These findings suggest that 4 is a very promising anti-inflammatory and Cytoprotective Agent and its further preclinical evaluation is warranted.
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2 cyano 3 10 dioxooleana 1 9 11 dien 28 oic acid anhydride a novel and highly potent antiinflammatory and Cytoprotective Agent
ChemInform, 2010Co-Authors: Tadashi Honda, Emilie David, Eric M. Padegimas, Chitra Sundararajan, Karen T Liby, Charlotte R Williams, Michael B Sporn, Melean VisnickAbstract:Title compound (I) is easily synthesized as first example of an oleane triterpenoid anhydride.
Mark A. Socinski - One of the best experts on this subject based on the ideXlab platform.
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Does More Aggressive Therapy Improve Outcomes in the Treatment of Unresectable Stage III Non-Small Cell Lung Cancer?
Seminars in Oncology, 2005Co-Authors: Julian G. Rosenman, Mark A. SocinskiAbstract:Concurrent chemotherapy combined with radiation therapy currently offers the best treatment strategy in stage IIIA/IIIB non-small cell lung cancer. However, inadequate radiation dose may be a contributing factor in the resultant lack of adequate control of local disease. Hypothetically, radiation doses that are higher than “standard” (eg, 60 Gy) might increase patient morbidity without improving cure rates, and data from a University of North Carolina phase I/II trial suggested that at least 74 Gy can be given safely to patients receiving cytotoxic chemotherapy, with a trend toward improved survival. Also, clinical data indicate that the Cytoprotective Agent amifostine (Ethyol; MedImmune Inc, Gaithersburg, MD) can be used to reduce esophagitis (and possibly pneumonitis) in patients treated with conventional radiation doses. Finally, a phase III clinical trial is proposed to: (1) test the hypothesis that higher radiation doses lead to a survival advantage in non-small cell lung cancer patients; and (2) discern the value of amifostine as a Cytoprotective Agent in the high-radiation dose range.
