Targeting O⁶-methylguanine-DNA methyltransferase with specific inhibitors as a strategy in cancer therapy

Cell Mol Life Sci. 2010 Nov;67(21):3663-81. doi: 10.1007/s00018-010-0491-7. Epub 2010 Aug 18.

Abstract

O (6)-methylguanine-DNA methyltransferase (MGMT) repairs the cancer chemotherapy-relevant DNA adducts, O (6)-methylguanine and O (6)-chloroethylguanine, induced by methylating and chloroethylating anticancer drugs, respectively. These adducts are cytotoxic, and given the overwhelming evidence that MGMT is a key factor in resistance, strategies for inactivating MGMT have been pursued. A number of drugs have been shown to inactivate MGMT in cells, human tumour models and cancer patients, and O (6)-benzylguanine and O (6)-[4-bromothenyl]guanine have been used in clinical trials. While these agents show no side effects per se, they also inactivate MGMT in normal tissues and hence exacerbate the toxic side effects of the alkylating drugs, requiring dose reduction. This might explain why, in any of the reported trials, the outcome has not been improved by their inclusion. It is, however, anticipated that, with the availability of tumour targeting strategies and hematopoetic stem cell protection, MGMT inactivators hold promise for enhancing the effectiveness of alkylating agent chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / therapeutic use*
  • Clinical Trials as Topic
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology*
  • O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors*
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism*

Substances

  • Antineoplastic Agents, Alkylating
  • Enzyme Inhibitors
  • O(6)-Methylguanine-DNA Methyltransferase