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Tumor O-6-methylguanine-DNA Methyltransferase Inactivation by Oral Lomeguatrib

Lookup NU author(s): Professor Hing Leung

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Abstract

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) similar to 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. Clin Cancer Res; 16(2); 743-9. (C) 2010 AACR.

Publication metadata

Author(s): Watson AJ, Sabharwal A, Thorncroft M, McGown G, Kerr R, Bojanic S, Soonawalla Z, King A, Miller A, Waller S, Leung H, Margison GP, Middleton MR

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2010

Volume: 16

Issue: 2

Pages: 743

Print publication date: 15/01/2010

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1078-0432.CCR-09-1389

DOI: 10.1158/1078-0432.CCR-09-1389

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