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 language | English (US) |
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Pages (from-to) | 261-276 |
Number of pages | 16 |
Journal | Cancer Treatment Reviews |
Volume | 32 |
Issue number | 4 |
DOIs | |
State | Published - Jun 2006 |
Externally published | Yes |
Keywords
- Alkylation
- Alkyltransferase
- Chemotherapy
- DNA repair
- O-benzylguanine
- Platination
ASJC Scopus subject areas
- Oncology
- Radiology Nuclear Medicine and imaging