A novel approach to overcome temozolomide resistance in glioma and melanoma: Inactivation of MGMT by gene therapy

Malignant glioma is the most common primary brain tumor. Malignant melanoma is the most malignant of skin tumor. The two malignancies are poorly responsive to conventional treatment regimens such as chemotherapy. Temozolomide (TMZ) is a DNA-alkylating agent used for the treatment of glioma, astrocytoma, and melanoma. Resistance to alkylating agents such as TMZ correlates with increased expression of DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Several studies in animal models have demonstrated that decreasing MGMT level with gene therapy could overcome TMZ resistance and enhance tumor cell death. In the present review, we provide an overview of recent advances in this field.

Research highlights
► Resistance glioma and melanoma to alkylating agents such as temozolomide correlates with increased expression of DNA repair protein MGMT.
► Decreasing MGMT level with gene therapy could overcome temozolomide resistance and enhance cancer cell death.
► Conditionally replicating adenoviruses (CRAds) could selectively potentiate the cytotoxicity of temozolomide in cancer cells.
► Inactivation of MGMT by gene therapy may be a novel approach to overcome temozolomide resistance in glioma and melanoma.