Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy

Cara A. Rabik, Maria Chidiamara Njoku, M. Eileen Dolan

Research output: Contribution to journalReview articlepeer-review

Abstract

DNA adducts at the O6-position of guanine are a result of the carcinogenic, mutagenic and cytotoxic actions of methylating and chloroethylating agents. The presence of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) renders cells resistant to the biological effects induced by agents that attack at this position. O6-Benzylguanine (O6-BG) is a low molecular weight substrate of AGT and therefore, results in sensitizing cells and tumors to alkylating agent-induced cytotoxicity and antitumor activity. Presently, chemotherapy regimens of O6-BG in combination with BCNU, temozolomide and Gliadel are in clinical development. Other ongoing clinical trials include expression of mutant AGT proteins that confer resistance to O6-BG in bone marrow stem cells, in an effort to reduce the potential enhanced toxicity and mutagenicity of alkylating agents in the bone marrow. O6-BG has also been found to enhance the cytotoxicity of agents that do not form adducts at the O6-position of DNA, including platinating agents. O6-BG's mechanism of action with these agents is not fully understood; however, it is independent of AGT activity or AGT inactivation. A better understanding of the effects of this agent will contribute to its clinical usefulness and the design of better analogs to further improve cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)261-276
Number of pages16
JournalCancer Treatment Reviews
Volume32
Issue number4
DOIs
StatePublished - Jun 1 2006
Externally publishedYes

Keywords

  • Alkylation
  • Alkyltransferase
  • Chemotherapy
  • DNA repair
  • O-benzylguanine
  • Platination

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

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