Inactivation of the DNA-Repair Gene MGMT and the Clinical Response of Gliomas to Alkylating Agents

Alkylating agents are highly reactive molecules that cause cell death by binding to DNA. 1 , 2 The most frequent site of alkylation in DNA is the O 6 position of guanine. Alkylation here forms cross-links between adjacent strands of DNA, 1 which explains how the nitrosoureas, tetrazines, and procarbazine kill cells. The cross-linking of double-stranded DNA by alkylating agents is inhibited by the cellular DNA-repair protein O 6 -methylguanine-DNA methyltransferase (MGMT), also known as O 6 -alkylguanine-DNA alkyltransferase. The MGMT protein rapidly reverses alkylation at the O 6 position of guanine, 3 , 4 thereby averting the formation of lethal cross-links. Through this mechanism, MGMT causes resistance to . . .