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Kent S. Gates - One of the best experts on this subject based on the ideXlab platform.
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Toward Hypoxia-Selective DNA-Alkylating Agents Built by Grafting Nitrogen Mustards onto the Bioreductively Activated, Hypoxia-Selective DNA-Oxidizing Agent 3‑Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)
2015Co-Authors: Kevin M. Johnson, Zachary D. Parsons, Charles L. Barnes, Kent S. GatesAbstract:Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of Tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, Tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the Tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells
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toward hypoxia selective dna alkylating agents built by grafting nitrogen mustards onto the bioreductively activated hypoxia selective dna oxidizing agent 3 amino 1 2 4 benzotriazine 1 4 dioxide Tirapazamine
Journal of Organic Chemistry, 2014Co-Authors: Kevin M Johnson, Zachary D. Parsons, Charles L. Barnes, Kent S. GatesAbstract:Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of Tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, Tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the Tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1...
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toward hypoxia selective dna alkylating agents built by grafting nitrogen mustards onto the bioreductively activated hypoxia selective dna oxidizing agent 3 amino 1 2 4 benzotriazine 1 4 dioxide Tirapazamine
Journal of Organic Chemistry, 2014Co-Authors: Kevin M Johnson, Zachary D. Parsons, Charles L. Barnes, Kent S. GatesAbstract:Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of Tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, Tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the Tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells.
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Electron and Spin-Density Analysis of Tirapazamine Reduction Chemistry
2012Co-Authors: Jian Yin, Rainer Glaser, Kent S. GatesAbstract:Tirapazamine (TPZ, 1, 3-amino-1,2,4-benzotriazine 1,4-N,N-dioxide), the radical anion 2 formed by one-electron reduction of 1, and neutral radicals 3 and 4 formed by protonation of 2 at O(N4) or O(N1), respectively, and their N–OH homolyses 3 → 5 + ·OH and 4 → 6 + ·OH have been studied with configuration interaction theory, perturbation theory, and density functional theory. A comprehensive comparative analysis is presented of structures and electronic structures and with focus on the development of an understanding of the spin-density distributions of the radical species. The skeletons of radicals 3 and 4 are distinctly nonplanar, several stereoisomeric structures are discussed, and there exists an intrinsic preference for 3 over 4. The N-oxides 1, 5, and 6 have closed-shell singlet ground states and low-lying, singlet biradical (SP-1, SP-6) or biradicaloid (SP-5) excited states. The doublet radicals 2, 3, and 4 are heavily spin-polarized. Most of the spin density of the doublet radicals 2, 3, and 4 is located in one (N,O)-region, and in particular, 3 and 4 are not C3-centered radicals. Significant amounts of spin density occur in both rings in the singlet biradical(oid) excited states of 1, 5, and 6. The dipole moment of the N2–C3(X) bond is large, and the nature of X provides a powerful handle to modulate the N2–C3 bond polarity with opposite effects on the two NO regions. Our studies show very low proton affinities of radical anion 2 and suggest that the pKa of radical [2+H] might be lower than 6. Implications are discussed regarding the formation of hydroxyl from 3 and/or 4, regarding the ability of 5 and 6 to react with carbon-centered radicals in a manner that ultimately leads to oxygen transfer, and regarding the interpretation of the EPR spectra of reduced TPZ species and of their spin-trap adducts
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dna base damage by the antitumor agent 3 amino 1 2 4 benzotriazine 1 4 dioxide Tirapazamine
Journal of the American Chemical Society, 2003Co-Authors: Mustafa Birincioglu, Goutam Chowdhury, Pawel Jaruga, Henry Rodriguez, Miral Dizdaroglu, Kent S. GatesAbstract:Tirapazamine is a bioreductively activated DNA-damaging agent that selectively kills the hypoxic cells found in solid tumors. This compound shows clinical promise and is currently being examined in a variety of clinical trials, including several phase III studies. It is well established that DNA is an important cellular target for Tirapazamine; however, the structural nature of the DNA damage inflicted by this drug remains poorly understood. As part of an effort to understand the chemical events responsible for the hypoxia-selective cytotoxicity of this drug, the studies reported here are designed to characterize Tirapazamine-mediated damage to the genetic information stored in the heterocyclic base residues of double-stranded DNA. Here, we used gas chromatography/mass spectrometry and liquid chromatography/mass spectrometry to characterize and quantify oxidative DNA base damage mediated by Tirapazamine. A multiplicity of modified bases including 8,5'-cyclopurine-2'-deoxynucleoside tandem lesions were identified and quantified. The results provide the first detailed insight regarding the structural identity of the DNA base lesions caused by this drug. Interestingly, it appears that the hypoxic conditions under which Tirapazamine operates, along with the unique chemical properties of the drug, yield a unique variety of DNA base damage that is dominated by formamidopyrimidine and 5-hydroxy-6-hydropyrimidine lesions. Importantly, the results suggest that Tirapazamine may generate a set of poorly repaired, potentially cytotoxic DNA base lesions that block DNA transcription and replication. Overall, the results indicate that DNA base damage may contribute to the biological effects of Tirapazamine in vivo.
Danny Rischin - One of the best experts on this subject based on the ideXlab platform.
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phase 1 study of Tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer
International Journal of Gynecological Cancer, 2010Co-Authors: Danny Rischin, Kailash Narayan, Amit Oza, Linda Mileshkin, David Bernshaw, Jimin Choi, Rodney J HicksAbstract:Introduction: Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. The aim of this phase I study was to develop a well-tolerated regimen that added Tirapazamine to the standard regimen of radiation and weekly low-dose cisplatin. Methods: Eligible patients had previously untreated carcinoma of the cervix, stages IB2 to IVA. The starting schedule was radiotherapy (45-50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly intravenous cisplatin, 40 mg/m2 on weeks 1 to 6 and weekly intravenous Tirapazamine, 290 mg/m2 in weeks 1 to 5. Results: Eleven patients were enrolled. The median age was 52 years (range, 31-65 years). Ten patients had squamous cell carcinoma and 1 patient had adenocarcinoma; 5 patients had stage 1B2 disease, 1 had stage IIA, 3 had stage IIB-3, 1 had stage IIIB, and 1 had stage IVA. The first 2 patients on dose level 1 experienced a dose-limiting toxicity (DLT): 1 experienced grade 3 alanine amino transferase elevation and grade 4 pulmonary embolism, and 1 experienced grade 3 ototoxicity. Doses were decreased to dose level −1 with a 30-mg/m2 dose of cisplatin and a 260-mg/m2 dose of Tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level −1a: a 35-mg/m2 dose of cisplatin and a 260-mg/m2 doses of Tirapazamine with 2 DLTs-grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. Three of 10 evaluable patients have experienced locoregional failure. Conclusions: The combination of weekly Tirapazamine and cisplatin with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being Tirapazamine 260 mg/m2 and cisplatin 30 mg/m2. Further study of this weekly schedule is not warranted.
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Phase III study of Tirapazamine, cisplatin and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck
Journal of Clinical Oncology, 2008Co-Authors: Danny Rischin, Jordi Giralt, Kally Yuen, Jacques Bernier, Brian Sullivan, Andy Trotti, Jean-henri Bourhis, Lester J Peters, Michael Henke, Richard FisherAbstract:LBA6008 Background: Promising results in a randomized phase II trial with the hypoxic cytotoxin, Tirapazamine combined with cisplatin and radiation led to this phase III trial known as HeadSTART. M...
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prognostic significance of 18f misonidazole positron emission tomography detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without Tirapazamine a substudy of trans tasman radiation oncology group study 98 02
Journal of Clinical Oncology, 2006Co-Authors: Danny Rischin, David Binns, Richard Fisher, June Corry, Sandro V Porceddu, Rodney J Hicks, Lester J PetersAbstract:Purpose To determine the association between tumor hypoxia, treatment regimen, and locoregional failure (LRF) in patients with stage III or IV squamous cell carcinoma of the head and neck randomly assigned to radiotherapy (70 Gy in 35 fractions over 7 weeks) plus either Tirapazamine and cisplatin in weeks 1, 4, and 7 and Tirapazamine alone in weeks 2 and 3 (TPZ/CIS) or cisplatin and infusional fluorouracil during weeks 6 and 7 (chemoboost). Patients and Methods Forty-five patients were enrolled onto a hypoxic imaging substudy of a larger randomized trial. Pretreatment and midtreatment [18F]-fluoromisonidazole positron emission tomography scans (FMISO-PET) were performed 2 hours after tracer administration, with qualitative scoring of uptake in both primary tumors and nodes. Results Thirty-two patients (71%) had detectable hypoxia in either or both primary and nodal disease. In patients who received chemoboost, one of 10 patients without hypoxia had LRF compared with eight of 13 patients with hypoxia; the ...
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Tirapazamine cisplatin and radiation versus fluorouracil cisplatin and radiation in patients with locally advanced head and neck cancer a randomized phase ii trial of the trans tasman radiation oncology group trog 98 02
Journal of Clinical Oncology, 2005Co-Authors: Danny Rischin, Richard Fisher, Lester J Peters, Andrew Macann, James W Denham, Michael Poulsen, Michael Jackson, Lizbeth Kenny, Michael Penniment, June CorryAbstract:Purpose To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma (SCC) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial. Patients and Methods One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were randomized to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either cisplatin (75 mg/m2) plus Tirapazamine (290 mg/m2/d) on day 2 of weeks 1, 4, and 7, and Tirapazamine alone (160 mg/m2/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS), or cisplatin (50 mg/m2) on day 1 and infusional fluorouracil (360 mg/m2/d) on days 1 through 5 of weeks 6 and 7 (chemoboost). Results Three-year failure-free survival rates were 55% with TPZ/CIS (95% CI, 39% to 70%) and 44% with chemoboost (95% CI, 30% to 60%; log-rank P = .16). Three-year locoregional failure-free rates were 84% in the TPZ/CIS arm (95% CI, 71% to 92%) and 66% in the chemoboost arm (95% CI, 51% to 7...
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Superiority of Tirapazamine-containing chemoradiation in head and neck cancers showing evidence of hypoxia on 18F-misonidazole (FMISO) pet scanning
Journal of Clinical Oncology, 2004Co-Authors: Rod Hicks, Danny Rischin, David Binns, Richard Fisher, June Corry, C. Kane, Sandro V Porceddu, M. Grossi, Lester J PetersAbstract:5520 Background: 45 patients were enrolled on a hypoxic imaging sub-study of a larger TROG trial in which patients with Stage III or IV SCC of the head and neck were randomized to radiotherapy (70Gy/35fx/7weeks) plus either cisplatin and infusional 5FU during weeks 6 and 7 (CIS/5FU) or the hypoxic cytotoxin, Tirapazamine and cisplatin in weeks 1, 4 and 7 and Tirapazamine alone in weeks 2 and 3 (CIS/TPZ) (Proc ASCO 22: 495, 2003). The objective was to determine the association between tumor hypoxia, treatment regimen and local-regional failure (LRF). Methods: Pretreatment FMISO PET was performed 2 hours after tracer administration with qualitative scoring of uptake in both primary tumours and nodes. Scores of 2 (mild) or grade 3 (moderate-high) were deemed positive for the presence of hypoxia. Results: 32 (71%) patients had detectable hypoxia in either or both primary and nodal disease. Hypoxia was present in the primary tumours of 17 of 45 (38%) patients and in the nodes of 21 of 35 (60%) node positive pa...
Lester J Peters - One of the best experts on this subject based on the ideXlab platform.
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Phase III study of Tirapazamine, cisplatin and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck
Journal of Clinical Oncology, 2008Co-Authors: Danny Rischin, Jordi Giralt, Kally Yuen, Jacques Bernier, Brian Sullivan, Andy Trotti, Jean-henri Bourhis, Lester J Peters, Michael Henke, Richard FisherAbstract:LBA6008 Background: Promising results in a randomized phase II trial with the hypoxic cytotoxin, Tirapazamine combined with cisplatin and radiation led to this phase III trial known as HeadSTART. M...
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prognostic significance of 18f misonidazole positron emission tomography detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without Tirapazamine a substudy of trans tasman radiation oncology group study 98 02
Journal of Clinical Oncology, 2006Co-Authors: Danny Rischin, David Binns, Richard Fisher, June Corry, Sandro V Porceddu, Rodney J Hicks, Lester J PetersAbstract:Purpose To determine the association between tumor hypoxia, treatment regimen, and locoregional failure (LRF) in patients with stage III or IV squamous cell carcinoma of the head and neck randomly assigned to radiotherapy (70 Gy in 35 fractions over 7 weeks) plus either Tirapazamine and cisplatin in weeks 1, 4, and 7 and Tirapazamine alone in weeks 2 and 3 (TPZ/CIS) or cisplatin and infusional fluorouracil during weeks 6 and 7 (chemoboost). Patients and Methods Forty-five patients were enrolled onto a hypoxic imaging substudy of a larger randomized trial. Pretreatment and midtreatment [18F]-fluoromisonidazole positron emission tomography scans (FMISO-PET) were performed 2 hours after tracer administration, with qualitative scoring of uptake in both primary tumors and nodes. Results Thirty-two patients (71%) had detectable hypoxia in either or both primary and nodal disease. In patients who received chemoboost, one of 10 patients without hypoxia had LRF compared with eight of 13 patients with hypoxia; the ...
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Tirapazamine cisplatin and radiation versus fluorouracil cisplatin and radiation in patients with locally advanced head and neck cancer a randomized phase ii trial of the trans tasman radiation oncology group trog 98 02
Journal of Clinical Oncology, 2005Co-Authors: Danny Rischin, Richard Fisher, Lester J Peters, Andrew Macann, James W Denham, Michael Poulsen, Michael Jackson, Lizbeth Kenny, Michael Penniment, June CorryAbstract:Purpose To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma (SCC) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial. Patients and Methods One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were randomized to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either cisplatin (75 mg/m2) plus Tirapazamine (290 mg/m2/d) on day 2 of weeks 1, 4, and 7, and Tirapazamine alone (160 mg/m2/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS), or cisplatin (50 mg/m2) on day 1 and infusional fluorouracil (360 mg/m2/d) on days 1 through 5 of weeks 6 and 7 (chemoboost). Results Three-year failure-free survival rates were 55% with TPZ/CIS (95% CI, 39% to 70%) and 44% with chemoboost (95% CI, 30% to 60%; log-rank P = .16). Three-year locoregional failure-free rates were 84% in the TPZ/CIS arm (95% CI, 71% to 92%) and 66% in the chemoboost arm (95% CI, 51% to 7...
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Superiority of Tirapazamine-containing chemoradiation in head and neck cancers showing evidence of hypoxia on 18F-misonidazole (FMISO) pet scanning
Journal of Clinical Oncology, 2004Co-Authors: Rod Hicks, Danny Rischin, David Binns, Richard Fisher, June Corry, C. Kane, Sandro V Porceddu, M. Grossi, Lester J PetersAbstract:5520 Background: 45 patients were enrolled on a hypoxic imaging sub-study of a larger TROG trial in which patients with Stage III or IV SCC of the head and neck were randomized to radiotherapy (70Gy/35fx/7weeks) plus either cisplatin and infusional 5FU during weeks 6 and 7 (CIS/5FU) or the hypoxic cytotoxin, Tirapazamine and cisplatin in weeks 1, 4 and 7 and Tirapazamine alone in weeks 2 and 3 (CIS/TPZ) (Proc ASCO 22: 495, 2003). The objective was to determine the association between tumor hypoxia, treatment regimen and local-regional failure (LRF). Methods: Pretreatment FMISO PET was performed 2 hours after tracer administration with qualitative scoring of uptake in both primary tumours and nodes. Scores of 2 (mild) or grade 3 (moderate-high) were deemed positive for the presence of hypoxia. Results: 32 (71%) patients had detectable hypoxia in either or both primary and nodal disease. Hypoxia was present in the primary tumours of 17 of 45 (38%) patients and in the nodes of 21 of 35 (60%) node positive pa...
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phase i trial of concurrent Tirapazamine cisplatin and radiotherapy in patients with advanced head and neck cancer
Journal of Clinical Oncology, 2001Co-Authors: Danny Rischin, Richard Fisher, Lester J Peters, Rodney J Hicks, Peter Hughes, Rosetta Hart, Maree Sexton, Ieta Dcosta, Reinhard Von RoemelingAbstract:PURPOSE: To determine the maximum-tolerated dose of Tirapazamine when combined with cisplatin and radiation in patients with T3/4 and/or N2/3 squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: The starting schedule was conventionally fractionated radiotherapy (70 Gy in 7 weeks) with concomitant cisplatin 75 mg/m2 and Tirapazamine 290 mg/m2 (before cisplatin) in weeks 1, 4, and 7 and Tirapazamine alone 160 mg/m2 three times a week in weeks 2, 3, 5, and 6. Positron emission tomography scans for tumor hypoxia (18F misonidazole) were performed before and during radiotherapy. RESULTS: We treated 16 patients with predominantly oropharyngeal primary tumors, including 10 patients with T4 or N3 disease. Febrile neutropenia occurred toward the end of radiotherapy in three out of six patients treated on the initial dose level. Two of these patients also developed grade 4 acute radiation reactions. Another 10 patients were treated with the same doses, but the week 5 and week 6 Tirapazamine doses were...
Richard Fisher - One of the best experts on this subject based on the ideXlab platform.
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Phase III study of Tirapazamine, cisplatin and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck
Journal of Clinical Oncology, 2008Co-Authors: Danny Rischin, Jordi Giralt, Kally Yuen, Jacques Bernier, Brian Sullivan, Andy Trotti, Jean-henri Bourhis, Lester J Peters, Michael Henke, Richard FisherAbstract:LBA6008 Background: Promising results in a randomized phase II trial with the hypoxic cytotoxin, Tirapazamine combined with cisplatin and radiation led to this phase III trial known as HeadSTART. M...
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prognostic significance of 18f misonidazole positron emission tomography detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without Tirapazamine a substudy of trans tasman radiation oncology group study 98 02
Journal of Clinical Oncology, 2006Co-Authors: Danny Rischin, David Binns, Richard Fisher, June Corry, Sandro V Porceddu, Rodney J Hicks, Lester J PetersAbstract:Purpose To determine the association between tumor hypoxia, treatment regimen, and locoregional failure (LRF) in patients with stage III or IV squamous cell carcinoma of the head and neck randomly assigned to radiotherapy (70 Gy in 35 fractions over 7 weeks) plus either Tirapazamine and cisplatin in weeks 1, 4, and 7 and Tirapazamine alone in weeks 2 and 3 (TPZ/CIS) or cisplatin and infusional fluorouracil during weeks 6 and 7 (chemoboost). Patients and Methods Forty-five patients were enrolled onto a hypoxic imaging substudy of a larger randomized trial. Pretreatment and midtreatment [18F]-fluoromisonidazole positron emission tomography scans (FMISO-PET) were performed 2 hours after tracer administration, with qualitative scoring of uptake in both primary tumors and nodes. Results Thirty-two patients (71%) had detectable hypoxia in either or both primary and nodal disease. In patients who received chemoboost, one of 10 patients without hypoxia had LRF compared with eight of 13 patients with hypoxia; the ...
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Tirapazamine cisplatin and radiation versus fluorouracil cisplatin and radiation in patients with locally advanced head and neck cancer a randomized phase ii trial of the trans tasman radiation oncology group trog 98 02
Journal of Clinical Oncology, 2005Co-Authors: Danny Rischin, Richard Fisher, Lester J Peters, Andrew Macann, James W Denham, Michael Poulsen, Michael Jackson, Lizbeth Kenny, Michael Penniment, June CorryAbstract:Purpose To select one of two chemoradiotherapy regimens for locally advanced squamous cell carcinoma (SCC) of the head and neck as the experimental arm for the next Trans-Tasman Radiation Oncology Group phase III trial. Patients and Methods One hundred twenty-two previously untreated patients with stage III/IV SCC of the head and neck were randomized to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either cisplatin (75 mg/m2) plus Tirapazamine (290 mg/m2/d) on day 2 of weeks 1, 4, and 7, and Tirapazamine alone (160 mg/m2/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS), or cisplatin (50 mg/m2) on day 1 and infusional fluorouracil (360 mg/m2/d) on days 1 through 5 of weeks 6 and 7 (chemoboost). Results Three-year failure-free survival rates were 55% with TPZ/CIS (95% CI, 39% to 70%) and 44% with chemoboost (95% CI, 30% to 60%; log-rank P = .16). Three-year locoregional failure-free rates were 84% in the TPZ/CIS arm (95% CI, 71% to 92%) and 66% in the chemoboost arm (95% CI, 51% to 7...
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Superiority of Tirapazamine-containing chemoradiation in head and neck cancers showing evidence of hypoxia on 18F-misonidazole (FMISO) pet scanning
Journal of Clinical Oncology, 2004Co-Authors: Rod Hicks, Danny Rischin, David Binns, Richard Fisher, June Corry, C. Kane, Sandro V Porceddu, M. Grossi, Lester J PetersAbstract:5520 Background: 45 patients were enrolled on a hypoxic imaging sub-study of a larger TROG trial in which patients with Stage III or IV SCC of the head and neck were randomized to radiotherapy (70Gy/35fx/7weeks) plus either cisplatin and infusional 5FU during weeks 6 and 7 (CIS/5FU) or the hypoxic cytotoxin, Tirapazamine and cisplatin in weeks 1, 4 and 7 and Tirapazamine alone in weeks 2 and 3 (CIS/TPZ) (Proc ASCO 22: 495, 2003). The objective was to determine the association between tumor hypoxia, treatment regimen and local-regional failure (LRF). Methods: Pretreatment FMISO PET was performed 2 hours after tracer administration with qualitative scoring of uptake in both primary tumours and nodes. Scores of 2 (mild) or grade 3 (moderate-high) were deemed positive for the presence of hypoxia. Results: 32 (71%) patients had detectable hypoxia in either or both primary and nodal disease. Hypoxia was present in the primary tumours of 17 of 45 (38%) patients and in the nodes of 21 of 35 (60%) node positive pa...
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phase i trial of concurrent Tirapazamine cisplatin and radiotherapy in patients with advanced head and neck cancer
Journal of Clinical Oncology, 2001Co-Authors: Danny Rischin, Richard Fisher, Lester J Peters, Rodney J Hicks, Peter Hughes, Rosetta Hart, Maree Sexton, Ieta Dcosta, Reinhard Von RoemelingAbstract:PURPOSE: To determine the maximum-tolerated dose of Tirapazamine when combined with cisplatin and radiation in patients with T3/4 and/or N2/3 squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: The starting schedule was conventionally fractionated radiotherapy (70 Gy in 7 weeks) with concomitant cisplatin 75 mg/m2 and Tirapazamine 290 mg/m2 (before cisplatin) in weeks 1, 4, and 7 and Tirapazamine alone 160 mg/m2 three times a week in weeks 2, 3, 5, and 6. Positron emission tomography scans for tumor hypoxia (18F misonidazole) were performed before and during radiotherapy. RESULTS: We treated 16 patients with predominantly oropharyngeal primary tumors, including 10 patients with T4 or N3 disease. Febrile neutropenia occurred toward the end of radiotherapy in three out of six patients treated on the initial dose level. Two of these patients also developed grade 4 acute radiation reactions. Another 10 patients were treated with the same doses, but the week 5 and week 6 Tirapazamine doses were...
David R Gandara - One of the best experts on this subject based on the ideXlab platform.
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phase iii trial of paclitaxel plus carboplatin with or without Tirapazamine in advanced non small cell lung cancer southwest oncology group trial s0003
Journal of Clinical Oncology, 2005Co-Authors: Stephen K Williamson, Jason Mccoy, John Crowley, Primo N Lara, Derick H Lau, Robert W Tucker, Glenn Mills, David R GandaraAbstract:Purpose Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells. We conducted a phase III clinical trial to determine whether the addition of Tirapazamine to paclitaxel and carboplatin offered a survival advantage when used in the treatment of patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Of 396 patients registered, 367 eligible patients were randomly assigned to either arm 1 (n = 181), which consisted of treatment every 21 days with paclitaxel 225 mg/m2/3 h, carboplatin (area under the curve = 6), and Tirapazamine 260 mg/m2 in cycle 1 (which was escalated, if tolerable, to 330 mg/m2 in cycle 2), or arm 2 (n = 186), which consisted of paclitaxel and carboplatin as in arm 1 with no Tirapazamine. Results Patient characteristics were similar between the two arms. There were no statistically significant differences in response rates, progression-free survival, or overall survival. Patients on arm 1 had significantly (P...
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phase i study of Tirapazamine plus cisplatin etoposide and concurrent thoracic radiotherapy in limited stage small cell lung cancer s0004 a southwest oncology group study
Clinical Cancer Research, 2004Co-Authors: Jason Mccoy, Stephen K Williamson, J Ryu, Laurie E Gaspar, Martin J Edelman, Shaker R Dakhil, Stanley D Sides, John Crowley, David R GandaraAbstract:Purpose: To determine the feasibility and a recommended phase II dose of Tirapazamine when combined with chemoradiotherapy in limited-stage small cell lung cancer (LSCLC). Experimental Design: Concurrent chemoradiotherapy consisted of two cycles of cisplatin, etoposide, and once-daily radiation to 61 Gy. Tirapazamine (260 mg/m 2 ) was given 1 h before cisplatin with planned dose escalation to 330 mg/m 2 in the absence of dose-limiting toxicity, defined as ≥33% esophagitis (grade 3 or above). Consolidation therapy consisted of two cycles of Tirapazamine (330 mg/m 2 ), cisplatin, and etoposide. Complete responders received prophylactic cranial irradiation. Results: Thirty patients were enrolled at the 260 mg/m 2 Tirapazamine dose. All had performance status of 0–1. By comparison with S9713, a predecessor Southwest Oncology Group study in LSCLC that used the same concurrent chemoradiotherapy without Tirapazamine, the present trial showed a higher rate of grade 3–4 esophagitis (34% versus 22%), vomiting (34% versus 23%), and febrile neutropenia (7% versus 2%). The consolidation phase was relatively well tolerated, with grade 4 neutropenia in 44% and febrile neutropenia in 5% of patients. There were two treatment-related deaths: one from neutropenic fever and one from respiratory infection. The overall response rate was 80%, and the median survival was 22 months. Conclusions: Protocol-defined dose-limiting toxicity was observed at the initial Tirapazamine dose, precluding dose escalation. Compared with S9713, the addition of Tirapazamine increased the incidence of vomiting, neutropenia, and febrile neutropenia, although the overall toxicity profile remained acceptable. In view of the observed favorable survival, further study of Tirapazamine in LSCLC is warranted.
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Tirapazamine prototype for a novel class of therapeutic agents targeting tumor hypoxia
Seminars in Oncology, 2002Co-Authors: David R Gandara, Primo N Lara, Derick H Lau, Zelanna Goldberg, P C Mack, Paul H GumerlockAbstract:Preclinical models in vitro and in vivo have shown that tumor hypoxia alters the malignant cell phenotype, selecting for p53 mutations, stimulating angiogenesis and metastasis, and markedly reducing the efficacy of both radiotherapy and chemotherapy. Similarly, clinical studies measuring pretreatment tumor oxygen status confirm that the presence of hypoxia confers a negative impact on local control, disease-free survival, and overall survival. Despite these data and extensive past research efforts, the promise of developing selective hypoxic-cell sensitizers has been largely unfulfilled. In contrast, Tirapazamine is the rationally designed prototype for a new class of therapeutic agents targeting tumor hypoxia: hypoxic cytotoxins. Tirapazamine is bioreductively activated in hypoxic cells and has been shown to potentiate the cytotoxicity of radiation and a number of chemotherapeutic drug classes, in particular platinum compounds and taxanes. This article reviews the preclinical and clinical development of Tirapazamine, as well as current trials in non-small cell lung cancer designed to provide proof of principle for this new category of cancer therapeutics.