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Mechanisms of carcinogenicity/chemotherapy by O(6)-methylguanine

Item Type:Article
Title:Mechanisms of carcinogenicity/chemotherapy by O(6)-methylguanine
Creators Name:Margison, G.P. and Santibanez-Koref, M.F. and Povey, A.C.
Abstract:Alkylating agents are a structurally diverse group of compounds that cause a wide range of biological effects, including cell death, mutation and cancer. DNA damaged by these agents contains widely different amounts of 12 alkylated purines/pyrimidines and two phosphotriester isomers. The biological effects appear to be mediated predominantly by attack at the O(6) position of guanine. DNA extracted from various normal human tissues contains detectable levels of O(6)-alkylguanine, the source of which has not been defined. Given that, following DNA replication, this lesion cannot only generate point mutations but can also initiate mismatch repair-mediated DNA recombination and cell death, it seems worthwhile to consider the possible contribution of these events and cell killing to the aetiology of human cancer. There is increasing evidence that point mutations are not the only mechanism involved in malignant transformation by alkylating agents. Some cancer chemotherapeutic agents exploit the cytotoxic effects of O6-alkylguanine and an understanding of the processing of this lesion has allowed strategies to be developed that should increase the effectiveness of such agents.
Keywords:Alkylating Agents, DNA, DNA Adducts, DNA Damage, DNA Methylation, Guanine, Neoplasms, Point Mutation, Genetic Recombination, Animals
Publisher:Oxford University Press
Page Range:483-487
Date:November 2002
Official Publication:https://doi.org/10.1093/mutage/17.6.483
PubMed:View item in PubMed

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