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J P Daures - One of the best experts on this subject based on the ideXlab platform.
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is there a case for cisplatin in the treatment of small cell lung cancer a meta analysis of randomized trials of a cisplatin containing regimen versus a regimen without this Alkylating Agent
British Journal of Cancer, 2000Co-Authors: J L Pujol, J P DauresAbstract:Chemotherapy is the backbone of small-cell lung cancer therapy. However, optimal drug combinations and schedules remain to be defined and there is hitherto no world-wide accepted standard regimen. Cisplatin, an Alkylating Agent with high putative toxicity is currently widely used although its effectiveness in this disease has not been established firmly. We conducted a meta-analysis of published data reporting trials randomizing a cisplatin-containing regimen versus a regimen without this Alkylating Agent in order to determine possible differences in survival response and toxicity. Nineteen trials have been identified in medical literature (4054 evaluable patients). Ten trials randomized patients to receive a cisplatin-etoposide regimen versus a regimen without any of these two drugs. A subgroup analysis was, therefore, carried out in the nine remaining trials that randomly allocated patients between two regimens differing in the absence or presence of cisplatin, whereas etoposide was given (or not given) in both arms (1579 evaluable patients). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death and the increase in probability of being responders to chemotherapy. There was no significant difference between the cisplatin-containing regimen and the regimen without this drug when the risk of toxic-death was taken into account with respective probabilities of 3.1 and 2.7% (NS). Patients randomized in a cisplatin-containing regimen had an increase in probability of being responders with an OR of 1.35, 95% confidence interval (CI) of 1.18–1.55;P < 10–5 corresponding to an increase of objective (partial plus complete) response rate from 0.62 to 0.69 (a result taking into account a significant heterogeneity). Patients treated with a cisplatin-containing regimen benefited from a significant reduction of risk of death at 6 months and 1 year with respective OR 0.87, 95% CI 0.75–0.98, P = 0.03, and or 0.80, 95% CI 0.69–0.93, P = 0.002 (no statistical heterogeneity). This corresponded to a significant increase in the probability of survival of 2.6% and 4.4% at 6 months and 1 year respectively. The meta-analysis restricted to the subset of nine trials without etoposide treatment imbalance reached similar conclusions. A cisplatin-containing regimen yields a higher response rate and probability of survival than does a chemotherapy containing others Alkylating Agents without a perceptible increase in risk of toxic-death. © 2000 Cancer Research Campaign
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is there a case for cisplatin in the treatment of small cell lung cancer a meta analysis of randomized trials of a cisplatin containing regimen versus a regimen without this Alkylating Agent
British Journal of Cancer, 2000Co-Authors: J L Pujol, J P DauresAbstract:Chemotherapy is the backbone of small-cell lung cancer therapy. However, optimal drug combinations and schedules remain to be defined and there is hitherto no world-wide accepted standard regimen. Cisplatin, an Alkylating Agent with high putative toxicity is currently widely used although its effectiveness in this disease has not been established firmly. We conducted a meta-analysis of published data reporting trials randomizing a cisplatin-containing regimen versus a regimen without this Alkylating Agent in order to determine possible differences in survival response and toxicity. Nineteen trials have been identified in medical literature (4054 evaluable patients). Ten trials randomized patients to receive a cisplatin-etoposide regimen versus a regimen without any of these two drugs. A subgroup analysis was, therefore, carried out in the nine remaining trials that randomly allocated patients between two regimens differing in the absence or presence of cisplatin, whereas etoposide was given (or not given) in both arms (1579 evaluable patients). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death and the increase in probability of being responders to chemotherapy. There was no significant difference between the cisplatin-containing regimen and the regimen without this drug when the risk of toxic-death was taken into account with respective probabilities of 3.1 and 2.7% (NS). Patients randomized in a cisplatin-containing regimen had an increase in probability of being responders with an OR of 1.35, 95% confidence interval (CI) of 1.18-1.55; P < 10(-5) corresponding to an increase of objective (partial plus complete) response rate from 0.62 to 0.69 (a result taking into account a significant heterogeneity). Patients treated with a cisplatin-containing regimen benefited from a significant reduction of risk of death at 6 months and 1 year with respective OR 0.87, 95% CI 0.75-0.98, P = 0.03, and or 0.80, 95% CI 0.69-0.93, P = 0.002 (no statistical heterogeneity). This corresponded to a significant increase in the probability of survival of 2.6% and 4.4% at 6 months and 1 year respectively. The meta-analysis restricted to the subset of nine trials without etoposide treatment imbalance reached similar conclusions. A cisplatin-containing regimen yields a higher response rate and probability of survival than does a chemotherapy containing others Alkylating Agents without a perceptible increase in risk of toxic-death.
J L Pujol - One of the best experts on this subject based on the ideXlab platform.
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is there a case for cisplatin in the treatment of small cell lung cancer a meta analysis of randomized trials of a cisplatin containing regimen versus a regimen without this Alkylating Agent
British Journal of Cancer, 2000Co-Authors: J L Pujol, J P DauresAbstract:Chemotherapy is the backbone of small-cell lung cancer therapy. However, optimal drug combinations and schedules remain to be defined and there is hitherto no world-wide accepted standard regimen. Cisplatin, an Alkylating Agent with high putative toxicity is currently widely used although its effectiveness in this disease has not been established firmly. We conducted a meta-analysis of published data reporting trials randomizing a cisplatin-containing regimen versus a regimen without this Alkylating Agent in order to determine possible differences in survival response and toxicity. Nineteen trials have been identified in medical literature (4054 evaluable patients). Ten trials randomized patients to receive a cisplatin-etoposide regimen versus a regimen without any of these two drugs. A subgroup analysis was, therefore, carried out in the nine remaining trials that randomly allocated patients between two regimens differing in the absence or presence of cisplatin, whereas etoposide was given (or not given) in both arms (1579 evaluable patients). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death and the increase in probability of being responders to chemotherapy. There was no significant difference between the cisplatin-containing regimen and the regimen without this drug when the risk of toxic-death was taken into account with respective probabilities of 3.1 and 2.7% (NS). Patients randomized in a cisplatin-containing regimen had an increase in probability of being responders with an OR of 1.35, 95% confidence interval (CI) of 1.18–1.55;P < 10–5 corresponding to an increase of objective (partial plus complete) response rate from 0.62 to 0.69 (a result taking into account a significant heterogeneity). Patients treated with a cisplatin-containing regimen benefited from a significant reduction of risk of death at 6 months and 1 year with respective OR 0.87, 95% CI 0.75–0.98, P = 0.03, and or 0.80, 95% CI 0.69–0.93, P = 0.002 (no statistical heterogeneity). This corresponded to a significant increase in the probability of survival of 2.6% and 4.4% at 6 months and 1 year respectively. The meta-analysis restricted to the subset of nine trials without etoposide treatment imbalance reached similar conclusions. A cisplatin-containing regimen yields a higher response rate and probability of survival than does a chemotherapy containing others Alkylating Agents without a perceptible increase in risk of toxic-death. © 2000 Cancer Research Campaign
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is there a case for cisplatin in the treatment of small cell lung cancer a meta analysis of randomized trials of a cisplatin containing regimen versus a regimen without this Alkylating Agent
British Journal of Cancer, 2000Co-Authors: J L Pujol, J P DauresAbstract:Chemotherapy is the backbone of small-cell lung cancer therapy. However, optimal drug combinations and schedules remain to be defined and there is hitherto no world-wide accepted standard regimen. Cisplatin, an Alkylating Agent with high putative toxicity is currently widely used although its effectiveness in this disease has not been established firmly. We conducted a meta-analysis of published data reporting trials randomizing a cisplatin-containing regimen versus a regimen without this Alkylating Agent in order to determine possible differences in survival response and toxicity. Nineteen trials have been identified in medical literature (4054 evaluable patients). Ten trials randomized patients to receive a cisplatin-etoposide regimen versus a regimen without any of these two drugs. A subgroup analysis was, therefore, carried out in the nine remaining trials that randomly allocated patients between two regimens differing in the absence or presence of cisplatin, whereas etoposide was given (or not given) in both arms (1579 evaluable patients). The DerSimonian and Laird method was used to estimate the size effects and the Peto and Yusuf method was used in order to generate the odds ratios (OR) of reduction in risk of death and the increase in probability of being responders to chemotherapy. There was no significant difference between the cisplatin-containing regimen and the regimen without this drug when the risk of toxic-death was taken into account with respective probabilities of 3.1 and 2.7% (NS). Patients randomized in a cisplatin-containing regimen had an increase in probability of being responders with an OR of 1.35, 95% confidence interval (CI) of 1.18-1.55; P < 10(-5) corresponding to an increase of objective (partial plus complete) response rate from 0.62 to 0.69 (a result taking into account a significant heterogeneity). Patients treated with a cisplatin-containing regimen benefited from a significant reduction of risk of death at 6 months and 1 year with respective OR 0.87, 95% CI 0.75-0.98, P = 0.03, and or 0.80, 95% CI 0.69-0.93, P = 0.002 (no statistical heterogeneity). This corresponded to a significant increase in the probability of survival of 2.6% and 4.4% at 6 months and 1 year respectively. The meta-analysis restricted to the subset of nine trials without etoposide treatment imbalance reached similar conclusions. A cisplatin-containing regimen yields a higher response rate and probability of survival than does a chemotherapy containing others Alkylating Agents without a perceptible increase in risk of toxic-death.
Francis J Giles - One of the best experts on this subject based on the ideXlab platform.
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a phase ii study of cloretazine vnp40101m a novel sulfonylhydrazine Alkylating Agent in patients with very high risk relapsed acute myeloid leukemia
Leukemia Research, 2006Co-Authors: Francis J Giles, Norbert Vey, Srdan Verstovsek, Stefan Faderl, J Karp, Gail J Roboz, Khuda Dan Khan, Maureen Cooper, Syed Fazl Ali Bilgrami, Augustin FerrantAbstract:Cloretazine (VNP40101M) is a sulfonylhydrazine Alkylating Agent with significant anti-leukemia activity. A multicenter phase II study of cloretazine was conducted in patients with first relapse of acute myeloid leukemia (AML) following an initial complete remission (CR) of less than 12 months. Cloretazine was given as a single intravenous infusion at a dose of 600 mg/m(2). Fifty-three patients (median age 62 years (18-84), 41 of 44 (93%) evaluable with intermediate or high risk cytogenetics, 32 (60%) with initial CR durations < or =6 months) were treated on study. Two patients (4%) achieved a second CR. Five (9%) patients died within 30 days of receiving cloretazine therapy. Median overall survival (2.3 months) in the study cohort was directly comparable to that of 233 matched patients treated with other single Agents. The study cloretazine regimen had minimal activity in a very high risk subset of patients with relapsed AML.
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cloretazine vnp40101m a novel sulfonylhydrazine Alkylating Agent in patients age 60 years or older with previously untreated acute myeloid leukemia
Journal of Clinical Oncology, 2006Co-Authors: Francis J Giles, Norbert Vey, Stefan Faderl, Farhad Ravandi, David A Rizzieri, Judith E Karp, Khuda Khan, Gregor Verhoef, Pierre W Wijermans, Anjali S AdvaniAbstract:PURPOSE: Cloretazine (VNP40101M) is a sulfonylhydrazine Alkylating Agent with significant antileukemia activity. A multicenter phase II study of cloretazine was conducted in patients 60 years of age or older with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Cloretazine 600 mg/m2 was administered as a single intravenous infusion. Patients were stratified by age, performance score, cytogenetic risk category, type of AML, and comorbidity. RESULTS: One hundred four patients, median age 72 years (range, 60 to 84 years), were treated on study. Performance status was 2 in 31 patients (30%) and no patient had a favorable karyotype. Forty-seven patients (45%) had cardiac disease, 25 patients (24%) had hepatic disease, and 19 patients (18%) had pulmonary disease, defined as per the Hematopoietic Cell Transplantation-Specific Comorbidity Index, at study entry. The overall response rate was 32%, with 29 patients (28%) achieving complete response (CR) and four patients (4%) achieving CR with incomplete platelet recovery. Response rates in 44 de novo AML patients, 45 secondary AML patients, and 15 high-risk MDS patients were 50%, 11%, and 40%, respectively. Response by cytogenetic risk category was 39% in 56 patients with intermediate cytogenetic risk and 24% in 46 patients with unfavorable cytogenetic risk. Nineteen (18%) patients died within 30 days of receiving cloretazine therapy. Median overall survival was 94 days, with a 1-year survival of 14%; the median duration of survival was 147 days, with a 1-year survival of 28% for those who achieved CR. CONCLUSION: Cloretazine has significant activity and modest extramedullary toxicity in elderly patients with AML or high-risk MDS. Response rates remain consistent despite increasing age and comorbidity.
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phase i study of cloretazine vnp40101m a novel sulfonylhydrazine Alkylating Agent combined with cytarabine in patients with refractory leukemia
Clinical Cancer Research, 2005Co-Authors: Francis J Giles, Srdan Verstovsek, Stefan Faderl, Deborah A Thomas, Jorge E Cortes, Alessandra Ferrajoli, Stanton L Gerson, Farhad Ravandi, Steven M Kornblau, Guillermo GarciamaneroAbstract:Purpose: Cloretazine (VNP40101M) is a novel sulfonylhydrazine Alkylating Agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-β-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease. Design: Ara-C was given i.v. at a fixed dose of 1.5 gm/m2/d by continuous infusion for 4 days (patients ages <65 years at time of diagnosis) or 3 days (patients ages ≥65 years). Cloretazine was given i.v. over 15 to 60 minutes on day 2 at a starting dose of 200 mg/m2, with escalation in 100 mg/m2 increments in cohorts of three to six patients until a maximum tolerated dose was established. The DNA repair enzyme O 6-alkylguanine DNA alkyltransferase (AGT) was measured at baseline. Results: Forty patients, including 32 with acute myeloid leukemia, received 47 courses of treatment. Complete responses were seen at cloretazine dose levels of ≥400 mg/m2 in 10 of 37 (27%) evaluable patients, and in this patient subset, AGT activity was significantly lower in patients that responded to treatment than in patients who did not ( P ≤ 0.027). Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen with 500 and 600 mg/m2 of cloretazine combined with the 4-day ara-C schedule but not seen with the 3-day schedule. Conclusion: The recommended cloretazine dose schedule for future studies is 600 mg/m2 combined with 1.5 gm/m2/d continuous infusion of ara-C for 3 days. The cloretazine and ara-C regimen has significant antileukemic activity. AGT activity may be a predictor of response to cloretazine.
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a phase i and pharmacokinetic study of vnp40101m a novel sulfonylhydrazine Alkylating Agent in patients with refractory leukemia
Clinical Cancer Research, 2004Co-Authors: Francis J Giles, Srdan Verstovsek, Stefan Faderl, Deborah A Thomas, Guillermo Garciamanero, Jorge E Cortes, Alessandra Ferrajoli, Sima Jeha, Miloslav Beran, Charles KollerAbstract:Purpose: VNP40101M is a novel sulfonylhydrazine Alkylating Agent with broad antitumor activity in animal models. As Alkylating Agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS). Experimental Design: VNP40101M was given as a single i.v. infusion over 15–70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m 2 was escalated by ∼33% in cohorts of 3–6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8. Results: Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m 2 for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m 2 was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m 2 and 1 with acute myeloid leukemia treated with 600 mg/m 2 , achieved complete remission. Conclusions: VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.
Michael S Bobola - One of the best experts on this subject based on the ideXlab platform.
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o 6 methylguanine dna methyltransferase activity is associated with response to Alkylating Agent therapy and with mgmt promoter methylation in glioblastoma and anaplastic glioma
BBA clinical, 2015Co-Authors: Michael S Bobola, A Blank, Douglas D Kolstoe, Mohammad Alnoor, John Y S Chen, Daniel L Silbergeld, Robert C Rostomily, Marc C Chamberlain, John R SilberAbstract:Background CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following Alkylating Agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies.
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human glioma cell sensitivity to the sequence specific Alkylating Agent methyl lexitropsin
Clinical Cancer Research, 2007Co-Authors: Michael S Bobola, A Blank, Douglas D Kolstoe, Sridhar Varadarajan, Nolan W Smith, Ryan D Goff, Barry Gold, John R SilberAbstract:Purpose: Defining the cytotoxicity of individual adducts in DNA is necessary for mechanistic understanding of human brain tumor resistance to therapeutic Alkylating Agents and for design of DNA repair-related antiresistance strategies. Our purpose is to characterize the sensitivity of human glioma cells to methyl-lexitropsin (Me-lex), a sequence-specific alkylator that produces 3-methyladenine (3-meA) as the predominant (>90%) DNA lesion. Experimental Design: We quantitated the Me-lex cytotoxicity of 10 human glioma cell lines that differ in O 6 -methylguanine ( O 6 -meG)-DNA methyltransferase (MGMT) and mismatch repair activity. We used antisense suppression of alkyladenine DNA glycosylase (AAG) and Ape1 to assess the contribution of 3-meA and abasic sites to lethality and measured abasic sites. Results: ( a ) The LD 10 for Me-lex varied widely among the cell lines. ( b ) MGMT-proficient lines were more resistant than MGMT-deficient lines, an unexpected finding because Me-lex produces very little O 6 -meG. ( c ) Suppression of AAG increased Me-lex killing and reduced abasic site content. ( d ) Suppression of Ape1 increased Me-lex killing and increased abasic site content. ( e ) Ablation of MGMT had no effect on Me-lex cytotoxicity. Conclusions: ( a ) Me-lex is cytotoxic in human glioma cells and AAG promotes resistance, indicating that 3-meA is a lethal lesion in these cells. ( b ) Abasic sites resulting from 3-meA repair are cytotoxic and Ape1 promotes resistance to these derivative lesions. ( c ) A factor(s) associated with MGMT expression, other than repair of O 6 -meG, contributes to Me-lex resistance. ( d ) Me-lex may have clinical utility in the adjuvant therapy of gliomas. ( e ) AAG and Ape1 inhibitors may be useful in targeting Alkylating Agent resistance.
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apurinic endonuclease activity in adult gliomas and time to tumor progression after Alkylating Agent based chemotherapy and after radiotherapy
Clinical Cancer Research, 2004Co-Authors: A Blank, Michael S Bobola, Douglas D Kolstoe, Mitchel S Berger, Daniel L Silbergeld, Robert C Rostomily, Mary J Emond, Elizabeth H Meade, Alexander M SpenceAbstract:Purpose: Apurinic/apyrimidinic endonuclease (Ap endo) is a key DNA repair enzyme that cleaves DNA at cytotoxic abasic sites caused by Alkylating Agents and radiation. We have observed that human glioma cells deficient in Ap endo activity are hypersensitive to clinically used alkylators (Silber et al. , Clin Cancer Res 2002;8:3008.). Here we examine the association of glioma Ap endo activity with clinical response after Alkylating Agent-based chemotherapy or after radiotherapy. Experimental Design: Cox proportional hazards regression models were used to analyze the relationship of Ap endo activity with time to tumor progression (TTP). Results: In a univariate model with Ap endo activity entered as a continuous variable, the hazard ratio (HR) for progression after alkylator therapy in 30 grade III gliomas increased by a factor of 1.061 for every 0.01 increase in activity ( P = 0.013). Adjusting for age, gender, extent of resection, and prior treatment strengthened slightly the association (HR = 1.094; P = 0.003). Similarly, the HR for progression after radiotherapy in 44 grade II and III tumors increased by a factor of 1.069 ( P = 0.008). Adjusting for the aforementioned variables had little effect on the association. In contrast, we observed no association between activity and TTP in grade IV gliomas after either alkylator therapy in 34 tumors or radiotherapy in 26 tumors. Conclusions: Our data suggest that Ap endo activity mediates resistance to Alkylating Agents and radiation and may be a useful predictor of progression after adjuvant therapy in a subset of gliomas.
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o6 methylguanine dna methyltransferase deficient phenotype in human gliomas frequency and time to tumor progression after Alkylating Agent based chemotherapy
Clinical Cancer Research, 1999Co-Authors: John R Silber, A Blank, Michael S Bobola, Saadi Ghatan, Douglas D Kolstoe, Mitchel S BergerAbstract:The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) contributes to the resistance of human brain tumor cell lines and xenografts to methylating and chloroethylating Agents. We assayed MGMT in 174 newly diagnosed or recurrent gliomas to ( a ) quantitate changes in MGMT activity associated with Alkylating Agent-based chemotherapy; and ( b ) assess the contribution of MGMT to clinical outcome. Glioma MGMT activity ranged 300-fold, averaging 3,800 ± 7,200 molecules/cell. Twenty-four percent of tumors lacked detectable activity [Methyl repair-deficient (Mer − ) phenotype, defined here as 6 cells]. Tumors treated with surgery alone and tumors recurring after surgery and radiotherapy did not differ significantly in frequency of the Mer − phenotype (29% versus 24%). However, the frequency of the Mer − phenotype among tumors recurring after surgery, radiation, and Alkylating Agent-based chemotherapy was 7-fold lower than in tumors treated with surgery alone (4.3% versus 29%; P ≤ 0.02) and 6-fold lower than in tumors recurring after surgery and radiation (4.3% versus 24%; P ≤ 0.05). In contrast to gliomas, there was no relationship of Alkylating Agent-based therapy with the frequency of the Mer − phenotype in paired histologically normal brain. These data suggest that Alkylating Agents, either alone or synergistically with radiotherapy, selectively kill Mer − glioma cells in situ. Importantly, Mer − and Mer + tumors did not differ in time to tumor progression following treatment with Alkylating Agents, indicating that although Mer − glioma cells may be differentially killed by alkylators, factors other than Mer phenotype were the principal determinants of time to clinical progression. Nonetheless, our results support the possibility that complete ablation of glioma MGMT with substrate analogue inhibitors could improve the efficacy of Alkylating Agent-based chemotherapy.
John R Silber - One of the best experts on this subject based on the ideXlab platform.
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o 6 methylguanine dna methyltransferase activity is associated with response to Alkylating Agent therapy and with mgmt promoter methylation in glioblastoma and anaplastic glioma
BBA clinical, 2015Co-Authors: Michael S Bobola, A Blank, Douglas D Kolstoe, Mohammad Alnoor, John Y S Chen, Daniel L Silbergeld, Robert C Rostomily, Marc C Chamberlain, John R SilberAbstract:Background CpG methylation in the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with better outcome following Alkylating Agent chemotherapy in glioblastoma (GBM) and anaplastic glioma (AG). To what extent improved response reflects low or absent MGMT activity in glioma tissue has not been unequivocally assessed. This information is central to developing anti-resistance therapies.
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human glioma cell sensitivity to the sequence specific Alkylating Agent methyl lexitropsin
Clinical Cancer Research, 2007Co-Authors: Michael S Bobola, A Blank, Douglas D Kolstoe, Sridhar Varadarajan, Nolan W Smith, Ryan D Goff, Barry Gold, John R SilberAbstract:Purpose: Defining the cytotoxicity of individual adducts in DNA is necessary for mechanistic understanding of human brain tumor resistance to therapeutic Alkylating Agents and for design of DNA repair-related antiresistance strategies. Our purpose is to characterize the sensitivity of human glioma cells to methyl-lexitropsin (Me-lex), a sequence-specific alkylator that produces 3-methyladenine (3-meA) as the predominant (>90%) DNA lesion. Experimental Design: We quantitated the Me-lex cytotoxicity of 10 human glioma cell lines that differ in O 6 -methylguanine ( O 6 -meG)-DNA methyltransferase (MGMT) and mismatch repair activity. We used antisense suppression of alkyladenine DNA glycosylase (AAG) and Ape1 to assess the contribution of 3-meA and abasic sites to lethality and measured abasic sites. Results: ( a ) The LD 10 for Me-lex varied widely among the cell lines. ( b ) MGMT-proficient lines were more resistant than MGMT-deficient lines, an unexpected finding because Me-lex produces very little O 6 -meG. ( c ) Suppression of AAG increased Me-lex killing and reduced abasic site content. ( d ) Suppression of Ape1 increased Me-lex killing and increased abasic site content. ( e ) Ablation of MGMT had no effect on Me-lex cytotoxicity. Conclusions: ( a ) Me-lex is cytotoxic in human glioma cells and AAG promotes resistance, indicating that 3-meA is a lethal lesion in these cells. ( b ) Abasic sites resulting from 3-meA repair are cytotoxic and Ape1 promotes resistance to these derivative lesions. ( c ) A factor(s) associated with MGMT expression, other than repair of O 6 -meG, contributes to Me-lex resistance. ( d ) Me-lex may have clinical utility in the adjuvant therapy of gliomas. ( e ) AAG and Ape1 inhibitors may be useful in targeting Alkylating Agent resistance.
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o6 methylguanine dna methyltransferase deficient phenotype in human gliomas frequency and time to tumor progression after Alkylating Agent based chemotherapy
Clinical Cancer Research, 1999Co-Authors: John R Silber, A Blank, Michael S Bobola, Saadi Ghatan, Douglas D Kolstoe, Mitchel S BergerAbstract:The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) contributes to the resistance of human brain tumor cell lines and xenografts to methylating and chloroethylating Agents. We assayed MGMT in 174 newly diagnosed or recurrent gliomas to ( a ) quantitate changes in MGMT activity associated with Alkylating Agent-based chemotherapy; and ( b ) assess the contribution of MGMT to clinical outcome. Glioma MGMT activity ranged 300-fold, averaging 3,800 ± 7,200 molecules/cell. Twenty-four percent of tumors lacked detectable activity [Methyl repair-deficient (Mer − ) phenotype, defined here as 6 cells]. Tumors treated with surgery alone and tumors recurring after surgery and radiotherapy did not differ significantly in frequency of the Mer − phenotype (29% versus 24%). However, the frequency of the Mer − phenotype among tumors recurring after surgery, radiation, and Alkylating Agent-based chemotherapy was 7-fold lower than in tumors treated with surgery alone (4.3% versus 29%; P ≤ 0.02) and 6-fold lower than in tumors recurring after surgery and radiation (4.3% versus 24%; P ≤ 0.05). In contrast to gliomas, there was no relationship of Alkylating Agent-based therapy with the frequency of the Mer − phenotype in paired histologically normal brain. These data suggest that Alkylating Agents, either alone or synergistically with radiotherapy, selectively kill Mer − glioma cells in situ. Importantly, Mer − and Mer + tumors did not differ in time to tumor progression following treatment with Alkylating Agents, indicating that although Mer − glioma cells may be differentially killed by alkylators, factors other than Mer phenotype were the principal determinants of time to clinical progression. Nonetheless, our results support the possibility that complete ablation of glioma MGMT with substrate analogue inhibitors could improve the efficacy of Alkylating Agent-based chemotherapy.
