Differential inactivation of polymorphic variants of human O6-alkylguanine-DNA alkyltransferase

Qingming Fang, Natalia A. Loktionova, Robert C. Moschel, Sahar Javanmard, Gary T. Pauly, Anthony Pegg

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The human DNA repair protein O6-alkylguanine-DNA alkyltransferase (hAGT) is an important source of resistance to some therapeutic alkylating agents and attempts to circumvent this resistance by the use of hAGT inhibitors have reached clinical trials. Several human polymorphisms in the MGMT gene that encodes hAGT have been described including L84F and the linked double alteration I143V/K178R. We have investigated the inactivation of these variants and the much rarer variant W65C by O6-benzylguanine, which is currently in clinical trials, and a number of other second generation hAGT inhibitors that contain folate derivatives (O4-benzylfolic acid, the 3′ and 5′ folate esters of O6-benzyl-2′-deoxyguanosine and the folic acid γ ester of O6-(p-hydroxymethyl)benzylguanine). The I143V/K178R variant was resistant to all of these compounds. The resistance was due solely to the I143V change. These results suggest that the frequency of the I143V/K178R variant among patients in the clinical trials with hAGT inhibitors and the correlation with response should be considered.

Original languageEnglish (US)
Pages (from-to)618-626
Number of pages9
JournalBiochemical Pharmacology
Volume75
Issue number3
DOIs
StatePublished - Feb 1 2008

All Science Journal Classification (ASJC) codes

  • Pharmacology

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