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Charles A. Kunos - One of the best experts on this subject based on the ideXlab platform.
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radiochemotherapy plus 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap nsc 663249 in advanced stage cervical and vaginal cancers
Gynecologic Oncology, 2013Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, Nancy Fusco, Ramon Adams, Robert Debernardo, Kimberly Resnick, Raymond W. Redline, Peter FaulhaberAbstract:Abstract Objective Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. Methods We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25mg/m 2 ) co-administered with 1× weekly intravenous cisplatin (40mg/m 2 ) and daily pelvic radiation (45Gy) in women with stage I B2 –IV B cervical (n=22) or stage II–IV vaginal (n=3) cancers. Brachytherapy followed (40Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. Results 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80–99%]) of 25 patients (median follow-up 20months, range 2–35months). 23 (96% [95% confidence interval: 80–99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. Conclusions The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.
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Radiochemotherapy plus 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers ☆ ☆☆
Gynecologic oncology, 2013Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, Nancy Fusco, Ramon Adams, Robert Debernardo, Kimberly Resnick, Raymond W. Redline, Peter FaulhaberAbstract:Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with 1× weekly intravenous cisplatin (40 mg/m(2)) and daily pelvic radiation (45 Gy) in women with stage I(B2)-IV(B) cervical (n=22) or stage II-IV vaginal (n=3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[(18)F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted. Copyright © 2013 Elsevier Inc. All rights reserved.
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a phase i and pharmacokinetic study of oral 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap nsc 663249 in the treatment of advanced stage solid cancers a california cancer consortium study
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Joseph Chao, Charles A. Kunos, Timothy W. Synold, Robert J. Morgan, Jeff Longmate, Heinz-josef Lenz, Dean Lim, Stephen Shibata, Vincent Chung, Ronald G. StollerAbstract:Background 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors.
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management of 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone induced methemoglobinemia
Future Oncology, 2012Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Stephen T Ingalls, Charles L HoppelAbstract:The anticancer agent 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone is a ribonucleotide reductase inhibitor. It inactivates ribonucleotide reductase by disrupting an iron-stabilized radical in ribonucleotide reductase’s small subunits, M2 and M2b (p53R2). Unfortunately, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone also alters iron II (Fe2+) in hemoglobin. This creates Fe3+ methemoglobin that does not deliver oxygen. Fe2+ in hemoglobin normally auto-oxidizes to inactive Fe3+ methemoglobin at a rate of nearly 3% per day and this is counterbalanced by a reductase system that normally limits methemoglobin concentrations to less than 1% of hemoglobin. This balance may be perturbed by symptomatic toxicity levels during 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone therapy. Indications of 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone sequelae attributable to methemoglobinemia include resting dyspnea, headaches and altered cognition. Management of methemoglobinemia includes supplemental oxygen...
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A phase I and pharmacokinetic study of oral 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study
Cancer Chemotherapy and Pharmacology, 2011Co-Authors: Joseph Chao, Charles A. Kunos, Timothy W. Synold, Robert J. Morgan, Jeff Longmate, Heinz-josef Lenz, Dean Lim, Stephen Shibata, Vincent Chung, Ronald G. StollerAbstract:Background 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors.
Steven E Waggoner - One of the best experts on this subject based on the ideXlab platform.
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radiochemotherapy plus 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap nsc 663249 in advanced stage cervical and vaginal cancers
Gynecologic Oncology, 2013Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, Nancy Fusco, Ramon Adams, Robert Debernardo, Kimberly Resnick, Raymond W. Redline, Peter FaulhaberAbstract:Abstract Objective Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. Methods We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25mg/m 2 ) co-administered with 1× weekly intravenous cisplatin (40mg/m 2 ) and daily pelvic radiation (45Gy) in women with stage I B2 –IV B cervical (n=22) or stage II–IV vaginal (n=3) cancers. Brachytherapy followed (40Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. Results 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80–99%]) of 25 patients (median follow-up 20months, range 2–35months). 23 (96% [95% confidence interval: 80–99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. Conclusions The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.
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Radiochemotherapy plus 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers ☆ ☆☆
Gynecologic oncology, 2013Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, Nancy Fusco, Ramon Adams, Robert Debernardo, Kimberly Resnick, Raymond W. Redline, Peter FaulhaberAbstract:Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with 1× weekly intravenous cisplatin (40 mg/m(2)) and daily pelvic radiation (45 Gy) in women with stage I(B2)-IV(B) cervical (n=22) or stage II-IV vaginal (n=3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[(18)F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted. Copyright © 2013 Elsevier Inc. All rights reserved.
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phase ii trial of pelvic radiation weekly cisplatin and 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap nsc 663249 for locally advanced cervical and vaginal cancer
Journal of Clinical Oncology, 2011Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, R Debernardo, Nancy Fusco, A Heugel, J Knazek, Ramon Adams, Afshin DowlatiAbstract:5034 Background: This on-going clinical trial assesses the safety and clinical activity of 3x weekly intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) co-administer...
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phase i trial of pelvic radiation weekly cisplatin and 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap nsc 663249 for locally advanced cervical cancer
Clinical Cancer Research, 2010Co-Authors: Charles A. Kunos, Steven E Waggoner, Afshin Dowlati, Vivian E. Von Gruenigen, Elisa Eldermire, John J. Pink, Timothy J. KinsellaAbstract:Purpose: This study assessed the safety/tolerability, pharmacokinetics, and clinical activity of three times weekly i.v. 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in combination with once-weekly i.v. cisplatin and daily pelvic radiation in patients with gynecologic malignancies. 3-AP is a novel small-molecule inhibitor of ribonucleotide reductase (RNR) and is being tested as a potential radiosensitizer and chemosensitizer. Experimental Design: Patients with stage IB2 to IVB cervical cancer ( n = 10) or recurrent uterine sarcoma ( n = 1) were assigned to dose-finding cohorts of 2-hour 3-AP infusions during 5 weeks of cisplatin chemoradiation. Pharmacokinetic and methemoglobin samples and tumor biopsy for RNR activity were obtained on day 1 and day 10. Clinical response was assessed. Results: The maximum tolerated 3-AP dose was 25 mg/m 2 given three times weekly during cisplatin and pelvic radiation. Two patients experienced manageable 3-AP–related grade 3 or 4 electrolyte abnormalities. 3-AP pharmacokinetics showed a 2-hour half-life, with median peak plasma concentrations of 277 ng/mL (25 mg/m 2 ) and 467 ng/mL (50 mg/m 2 ). Median methemoglobin levels peaked at 1% (25 mg/m 2 ) and 6% (50 mg/m 2 ) at 4 hours after initiating 3-AP infusions. No change in RNR activity was found on day 1 versus day 10 in six early complete responders, whereas elevated RNR activity was seen on day 10 as compared with day 1 in four late complete responders ( P = 0.02). Ten (100%) patients with stage IB2 to IVB cervical cancer achieved complete clinical response and remained without disease relapse with a median 18 months of follow-up (6-32 months). Conclusions: 3-AP was well tolerated at a three times weekly i.v. 25 mg/m 2 dose during cisplatin and pelvic radiation. Clin Cancer Res; 16(4); 1298–306
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Phase I trial of pelvic radiation, weekly cisplatin, and 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) for locally advanced cervical cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2010Co-Authors: Charles A. Kunos, Steven E Waggoner, Afshin Dowlati, Vivian E. Von Gruenigen, Elisa Eldermire, John J. Pink, Timothy J. KinsellaAbstract:Purpose: This study assessed the safety/tolerability, pharmacokinetics, and clinical activity of three times weekly i.v. 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in combination with once-weekly i.v. cisplatin and daily pelvic radiation in patients with gynecologic malignancies. 3-AP is a novel small-molecule inhibitor of ribonucleotide reductase (RNR) and is being tested as a potential radiosensitizer and chemosensitizer. Experimental Design: Patients with stage IB2 to IVB cervical cancer ( n = 10) or recurrent uterine sarcoma ( n = 1) were assigned to dose-finding cohorts of 2-hour 3-AP infusions during 5 weeks of cisplatin chemoradiation. Pharmacokinetic and methemoglobin samples and tumor biopsy for RNR activity were obtained on day 1 and day 10. Clinical response was assessed. Results: The maximum tolerated 3-AP dose was 25 mg/m 2 given three times weekly during cisplatin and pelvic radiation. Two patients experienced manageable 3-AP–related grade 3 or 4 electrolyte abnormalities. 3-AP pharmacokinetics showed a 2-hour half-life, with median peak plasma concentrations of 277 ng/mL (25 mg/m 2 ) and 467 ng/mL (50 mg/m 2 ). Median methemoglobin levels peaked at 1% (25 mg/m 2 ) and 6% (50 mg/m 2 ) at 4 hours after initiating 3-AP infusions. No change in RNR activity was found on day 1 versus day 10 in six early complete responders, whereas elevated RNR activity was seen on day 10 as compared with day 1 in four late complete responders ( P = 0.02). Ten (100%) patients with stage IB2 to IVB cervical cancer achieved complete clinical response and remained without disease relapse with a median 18 months of follow-up (6-32 months). Conclusions: 3-AP was well tolerated at a three times weekly i.v. 25 mg/m 2 dose during cisplatin and pelvic radiation. Clin Cancer Res; 16(4); 1298–306
Tomas Radivoyevitch - One of the best experts on this subject based on the ideXlab platform.
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radiochemotherapy plus 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap nsc 663249 in advanced stage cervical and vaginal cancers
Gynecologic Oncology, 2013Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, Nancy Fusco, Ramon Adams, Robert Debernardo, Kimberly Resnick, Raymond W. Redline, Peter FaulhaberAbstract:Abstract Objective Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. Methods We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25mg/m 2 ) co-administered with 1× weekly intravenous cisplatin (40mg/m 2 ) and daily pelvic radiation (45Gy) in women with stage I B2 –IV B cervical (n=22) or stage II–IV vaginal (n=3) cancers. Brachytherapy followed (40Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. Results 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80–99%]) of 25 patients (median follow-up 20months, range 2–35months). 23 (96% [95% confidence interval: 80–99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. Conclusions The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.
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Radiochemotherapy plus 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers ☆ ☆☆
Gynecologic oncology, 2013Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, Nancy Fusco, Ramon Adams, Robert Debernardo, Kimberly Resnick, Raymond W. Redline, Peter FaulhaberAbstract:Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with 1× weekly intravenous cisplatin (40 mg/m(2)) and daily pelvic radiation (45 Gy) in women with stage I(B2)-IV(B) cervical (n=22) or stage II-IV vaginal (n=3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[(18)F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted. Copyright © 2013 Elsevier Inc. All rights reserved.
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management of 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone induced methemoglobinemia
Future Oncology, 2012Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Stephen T Ingalls, Charles L HoppelAbstract:The anticancer agent 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone is a ribonucleotide reductase inhibitor. It inactivates ribonucleotide reductase by disrupting an iron-stabilized radical in ribonucleotide reductase’s small subunits, M2 and M2b (p53R2). Unfortunately, 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone also alters iron II (Fe2+) in hemoglobin. This creates Fe3+ methemoglobin that does not deliver oxygen. Fe2+ in hemoglobin normally auto-oxidizes to inactive Fe3+ methemoglobin at a rate of nearly 3% per day and this is counterbalanced by a reductase system that normally limits methemoglobin concentrations to less than 1% of hemoglobin. This balance may be perturbed by symptomatic toxicity levels during 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone therapy. Indications of 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone sequelae attributable to methemoglobinemia include resting dyspnea, headaches and altered cognition. Management of methemoglobinemia includes supplemental oxygen...
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phase ii trial of pelvic radiation weekly cisplatin and 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap nsc 663249 for locally advanced cervical and vaginal cancer
Journal of Clinical Oncology, 2011Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, R Debernardo, Nancy Fusco, A Heugel, J Knazek, Ramon Adams, Afshin DowlatiAbstract:5034 Background: This on-going clinical trial assesses the safety and clinical activity of 3x weekly intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) co-administer...
Peter Faulhaber - One of the best experts on this subject based on the ideXlab platform.
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radiochemotherapy plus 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap nsc 663249 in advanced stage cervical and vaginal cancers
Gynecologic Oncology, 2013Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, Nancy Fusco, Ramon Adams, Robert Debernardo, Kimberly Resnick, Raymond W. Redline, Peter FaulhaberAbstract:Abstract Objective Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. Methods We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25mg/m 2 ) co-administered with 1× weekly intravenous cisplatin (40mg/m 2 ) and daily pelvic radiation (45Gy) in women with stage I B2 –IV B cervical (n=22) or stage II–IV vaginal (n=3) cancers. Brachytherapy followed (40Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[ 18 F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. Results 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80–99%]) of 25 patients (median follow-up 20months, range 2–35months). 23 (96% [95% confidence interval: 80–99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. Conclusions The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted.
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Radiochemotherapy plus 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in advanced-stage cervical and vaginal cancers ☆ ☆☆
Gynecologic oncology, 2013Co-Authors: Charles A. Kunos, Tomas Radivoyevitch, Steven E Waggoner, Kristine M Zanotti, Nancy Fusco, Ramon Adams, Robert Debernardo, Kimberly Resnick, Raymond W. Redline, Peter FaulhaberAbstract:Cervical and vaginal cancers have virally-mediated or mutated defects in DNA damage repair responses, making these cancers sensible targets for ribonucleotide reductase inhibition during radiochemotherapy. We conducted a phase II study evaluating 3× weekly 2-hour intravenous 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, 25 mg/m(2)) co-administered with 1× weekly intravenous cisplatin (40 mg/m(2)) and daily pelvic radiation (45 Gy) in women with stage I(B2)-IV(B) cervical (n=22) or stage II-IV vaginal (n=3) cancers. Brachytherapy followed (40 Gy). Toxicity was monitored by common terminology criteria for adverse events (version 3.0). The primary end point of response was assessed by 3-month posttherapy 2-[(18)F] fluoro-2-deoxy-d-glucose positron emission tomography (PET/CT) and clinical examination. 3-AP radiochemotherapy achieved clinical responses in 24 (96% [95% confidence interval: 80-99%]) of 25 patients (median follow-up 20 months, range 2-35 months). 23 (96% [95% confidence interval: 80-99%]) of 24 patients had 3-month posttherapy PET/CT scans that recorded metabolic activity in the cervix or vagina equal or less than that of the cardiac blood pool, suggesting complete metabolic responses. The most frequent 3-AP radiochemotherapy-related adverse events included fatigue, nausea, diarrhea, and reversible hematological and electrolyte abnormalities. The addition of 3-AP to cisplatin radiochemotherapy was tolerable and produced high rates of clinical and metabolic responses in women with cervical and vaginal cancers. Future randomized phase II and III clinical trials of 3-AP radiochemotherapy are warranted. Copyright © 2013 Elsevier Inc. All rights reserved.
Ronald G. Stoller - One of the best experts on this subject based on the ideXlab platform.
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a phase i and pharmacokinetic study of oral 3 Aminopyridine 2 carboxaldehyde thiosemicarbazone 3 ap nsc 663249 in the treatment of advanced stage solid cancers a california cancer consortium study
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Joseph Chao, Charles A. Kunos, Timothy W. Synold, Robert J. Morgan, Jeff Longmate, Heinz-josef Lenz, Dean Lim, Stephen Shibata, Vincent Chung, Ronald G. StollerAbstract:Background 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors.
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A phase I and pharmacokinetic study of oral 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study
Cancer Chemotherapy and Pharmacology, 2011Co-Authors: Joseph Chao, Charles A. Kunos, Timothy W. Synold, Robert J. Morgan, Jeff Longmate, Heinz-josef Lenz, Dean Lim, Stephen Shibata, Vincent Chung, Ronald G. StollerAbstract:Background 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors.
