Oncolytic adenovirus-expressed RNA interference of O(6)-methylguanine DNA methyltransferase activity may enhance the antitumor effects of temozolomide

Temozolomide (TMZ) is an example of an alkylating agent, which are known to be effective anticancer drugs for the treatment of various solid tumors, including glioma and melanoma. TMZ acts predominantly through the mutagenic product O(6)-methylguanine, a cytotoxic DNA lesion. The DNA repair enzyme, O(6)-methylguanine DNA methyltransferase (MGMT), which functions in the resistance of cancers to TMZ, can repair this damage. RNA interference (RNAi) has been previously shown to be a potent tool for the knockdown of genes, and has potential for use in cancer treatment. Oncolytic adenoviruses not only have the ability to destroy cancer cells, but may also be possible vectors for the expression of therapeutic genes. We therefore hypothesized that the oncolytic virus-mediated RNAi of MGMT activity may enhance the antitumor effect of TMZ and provide a promising method for cancer therapy.