Tumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib.
Authors
Watson, Amanda JSabharwal, Ami
Thorncroft, Mary R
McGown, Gail
Kerr, Richard
Bojanic, Stana
Soonawalla, Zahir
King, Alexandra
Miller, Andrea
Waller, Sue
Leung, Hing
Margison, Geoffrey P
Middleton, Mark R
Affiliation
Cancer Research UK Carcinogenesis Group, University of Manchester, Paterson Institute for Cancer Research, Manchester, United Kingdom.Issue Date
2010-01-15
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PURPOSE: 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.Citation
Tumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib. 2010, 16 (2):743-9 Clin. Cancer Res.Journal
Clinical Cancer ResearchDOI
10.1158/1078-0432.CCR-09-1389PubMed ID
20068091Type
ArticleLanguage
enISSN
1078-0432ae974a485f413a2113503eed53cd6c53
10.1158/1078-0432.CCR-09-1389
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