Role of MGMT in tumor development, progression, diagnosis, treatment and prognosis.

Abstract

O(6)-Methylguanine-DNA-methyltransferase (MGMT) is a unique protein, which both repairs O(6)-alkylguanine lesions stoichiometrically without a multi-enzymatic pathway and self-inactivates. It has recently been linked to the therapeutic success of alkylating agent chemotherapy, specifically temozolomide treatment. This drug affects the MGMT pathway to induce cell death in tumor tissue. Low levels of functional MGMT have been correlated with success of treatment, while high levels bring about failure of therapy. Expression of MGMT protein varies in normal and tumoral tissue. Furthermore, its epigenetic silencing due to promoter methylation has been linked to its lack of expression in many types of tumor, including gliomas. Great enthusiasm surrounds the utility of this protein in cancer treatment. Not only has there been success in manipulating MGMT levels to enhance alkylating agent therapy, but studies also suggest a possible role of MGMT in protecting hematopoietic cells from the myelosuppressive effects of high-dose chemotherapy. Innovative research into this protein will no doubt be rewarding. This review presents a summary of what is known about this unique protein, including its structure, function in its pathway, polymorphisms, expression in normal and tumoral tissue, relation to alkylating agent therapy, and possible future applications.