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dc.contributor.authorWatson, Amanda J
dc.contributor.authorSabharwal, Ami
dc.contributor.authorThorncroft, Mary R
dc.contributor.authorMcGown, Gail
dc.contributor.authorKerr, Richard
dc.contributor.authorBojanic, Stana
dc.contributor.authorSoonawalla, Zahir
dc.contributor.authorKing, Alexandra
dc.contributor.authorMiller, Andrea
dc.contributor.authorWaller, Sue
dc.contributor.authorLeung, Hing
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorMiddleton, Mark R
dc.date.accessioned2010-08-09T15:52:50Z
dc.date.available2010-08-09T15:52:50Z
dc.date.issued2010-01-15
dc.identifier.citationTumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib. 2010, 16 (2):743-9 Clin. Cancer Res.en
dc.identifier.issn1078-0432
dc.identifier.pmid20068091
dc.identifier.doi10.1158/1078-0432.CCR-09-1389
dc.identifier.urihttp://hdl.handle.net/10541/109343
dc.description.abstractPURPOSE: A major mechanism of resistance to chlorethylnitrosureas and methylating agents involves the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT). We sought to determine the dose of oral 6-(4-bromo-2-thienyl) methoxy purin-2-amine (lomeguatrib), a pseudosubstrate inactivator of MGMT, required to render active protein undetectable 12 hours after dosing in prostate, primary central nervous system (CNS), and colorectal cancer patients. EXPERIMENTAL DESIGN: Lomeguatrib was administered orally as a single dose (20-160 mg) approximately 12 hours before tumor resection. Dose escalation was projected to continue until grade 2 toxicity or until complete inactivation of tumor MGMT was encountered. Total MGMT protein levels were quantified by ELISA, and active protein levels were quantified by biochemical assay. MGMT promoter methylation was determined in glioblastoma DNA by methylation-specific PCR. RESULTS: Thirty-seven patients were dosed with lomeguatrib, and 32 informative tumor samples were obtained. Mean total MGMT level varied between tumor types: 554 +/- 404 fmol/mg protein (+/-SD) for prostate cancer, 87.4 +/- 40.3 fmol/mg protein for CNS tumors, and 244 +/- 181 fmol/mg protein for colorectal cancer. MGMT promoter hypermethylation did not correlate with total protein expression. Consistent total MGMT inactivation required 120 mg of lomeguatrib in prostate and colorectal cancers. Complete consistent inactivation in CNS tumors was observed only at the highest dose of lomeguatrib (160 mg). CONCLUSIONS: Total MGMT inactivation can be achieved in prostate, primary CNS, and colorectal cancers with a single administration of 120 or 160 mg lomeguatrib. The dose needed did not correlate with mean total MGMT protein concentrations. One hundred twenty to 160 mg/d of lomeguatrib should be administered to achieve total MGMT inactivation in future studies.
dc.language.isoenen
dc.subjectAnticancerous Agentsen
dc.subjectCancerous Gene Expression Regulationen
dc.subjectCanceren
dc.subject.meshAdministration, Oral
dc.subject.meshAdolescent
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAged, 80 and over
dc.subject.meshAntineoplastic Agents
dc.subject.meshBiomarkers, Pharmacological
dc.subject.meshCombined Modality Therapy
dc.subject.meshDNA Methylation
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshFemale
dc.subject.meshGene Expression Regulation, Enzymologic
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshGene Silencing
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshNeoplasms
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase
dc.subject.meshPurines
dc.subject.meshYoung Adult
dc.titleTumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib.en
dc.typeArticleen
dc.contributor.departmentCancer Research UK Carcinogenesis Group, University of Manchester, Paterson Institute for Cancer Research, Manchester, United Kingdom.en
dc.identifier.journalClinical Cancer Researchen
html.description.abstractPURPOSE: A major mechanism of resistance to chlorethylnitrosureas and methylating agents involves the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT). We sought to determine the dose of oral 6-(4-bromo-2-thienyl) methoxy purin-2-amine (lomeguatrib), a pseudosubstrate inactivator of MGMT, required to render active protein undetectable 12 hours after dosing in prostate, primary central nervous system (CNS), and colorectal cancer patients. EXPERIMENTAL DESIGN: Lomeguatrib was administered orally as a single dose (20-160 mg) approximately 12 hours before tumor resection. Dose escalation was projected to continue until grade 2 toxicity or until complete inactivation of tumor MGMT was encountered. Total MGMT protein levels were quantified by ELISA, and active protein levels were quantified by biochemical assay. MGMT promoter methylation was determined in glioblastoma DNA by methylation-specific PCR. RESULTS: Thirty-seven patients were dosed with lomeguatrib, and 32 informative tumor samples were obtained. Mean total MGMT level varied between tumor types: 554 +/- 404 fmol/mg protein (+/-SD) for prostate cancer, 87.4 +/- 40.3 fmol/mg protein for CNS tumors, and 244 +/- 181 fmol/mg protein for colorectal cancer. MGMT promoter hypermethylation did not correlate with total protein expression. Consistent total MGMT inactivation required 120 mg of lomeguatrib in prostate and colorectal cancers. Complete consistent inactivation in CNS tumors was observed only at the highest dose of lomeguatrib (160 mg). CONCLUSIONS: Total MGMT inactivation can be achieved in prostate, primary CNS, and colorectal cancers with a single administration of 120 or 160 mg lomeguatrib. The dose needed did not correlate with mean total MGMT protein concentrations. One hundred twenty to 160 mg/d of lomeguatrib should be administered to achieve total MGMT inactivation in future studies.


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