Anumber of
DNA-damaging chemotherapeutic agents attack the O(6) position on
guanine, forming the most potent cytotoxic
DNA adducts known. The
DNA repair enzyme O(6)-alkylguanine
DNA alkyltransferase (AGT), encoded by the gene MGMT, repairs alkylation at this site and is responsible for protecting both
tumor and normal cells from these agents. Cells and tissues vary greatly in AGT expression, not only between tissues but also between individuals. AGT activity correlates inversely with sensitivity to agents that form O(6)-alkylguanine
DNA adducts, such as
carmustine (
BCNU),
temozolomide,
streptozotocin, and
dacarbazine. The one exception is those
tumors lacking mismatch repair, which renders them resistant to methylating agents. A recent study in patients with
gliomas confirmed the correlation between low-level expression of the MGMT gene and response and survival after
BCNU. An inhibitor to AGT,
O(6)-benzylguanine (BG), depletes AGT in human
tumors without associated toxicity and is now in phase II clinical trials. Finally, mutations within the active site region of the MGMT gene render the AGT
protein resistant to BG inactivation. As a result, mutant MGMT gene transfer into hematopoietic stem cells has been shown to selectively protect the marrow from the combination of an
alkylating agent and BG, while at the same time sensitizing
tumor cells. MGMT remains a paradigm for development of new agents that modulate known mechanisms of drug resistance in
cancer cells and raise the spectra of combinatorial
therapies that encompass known drug resistance mechanisms.