Tumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib.
AuthorsWatson, Amanda J
Thorncroft, Mary R
Margison, Geoffrey P
Middleton, Mark R
AffiliationCancer Research UK Carcinogenesis Group, University of Manchester, Paterson Institute for Cancer Research, Manchester, United Kingdom.
MetadataShow full item record
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.
CitationTumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib. 2010, 16 (2):743-9 Clin. Cancer Res.
JournalClinical Cancer Research
- A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer.
- Authors: Sabharwal A, Corrie PG, Midgley RS, Palmer C, Brady J, Mortimer P, Watson AJ, Margison GP, Middleton MR
- Issue date: 2010 Oct
- Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours.
- Authors: Tawbi HA, Villaruz L, Tarhini A, Moschos S, Sulecki M, Viverette F, Shipe-Spotloe J, Radkowski R, Kirkwood JM
- Issue date: 2011 Sep 6
- Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors.
- Authors: Ranson M, Middleton MR, Bridgewater J, Lee SM, Dawson M, Jowle D, Halbert G, Waller S, McGrath H, Gumbrell L, McElhinney RS, Donnelly D, McMurry TB, Margison GP
- Issue date: 2006 Mar 1
- Chemotherapeutic resistance in anaplastic astrocytoma cell lines treated with a temozolomide-lomeguatrib combination.
- Authors: Ugur HC, Taspinar M, Ilgaz S, Sert F, Canpinar H, Rey JA, Castresana JS, Sunguroglu A
- Issue date: 2014 Feb
- Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis.
- Authors: Esteller M, Risques RA, Toyota M, Capella G, Moreno V, Peinado MA, Baylin SB, Herman JG
- Issue date: 2001 Jun 15