281. Modulating the Immune Response to Oncolytic Measles Viruses

Abstract

Top of pageAbstract In an effort to improve the efficacy of cancer chemotherapy by intervening into the cellular responses to chemotherapeutic change, we have used adenoviral overexpression of N-methylpurine DNA glycosylase (MPG, ANPG or AAG) in breast cancer cells, to study its ability to imbalance base excision repair (BER) and sensitize cancer cells to alkylating agents. Our results demonstrate that MPG overexpressing cells are significantly more sensitive to the alkylating agents methyl methanesulfonate (MMS), N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), methyl nitrosourea (MNU), dimethyl sulfate (DMS) and the clinical chemotherapeutic temozolomide (TMZ). Sensitivity is further increased through co-administration of the BER inhibitor methoxyamine (MX), which covalently binds abasic (AP) sites and makes them refractory to subsequent repair. MX reduction of cell survival is significantly greater in cells overexpressing MPG than in control cells, suggesting a heightened production of AP sites that if made persistent, results in increased cellular toxicity. We further explored the mechanism of MPG-induced sensitivity, and found that sensitivity was associated with a significant increase in the number of AP sites and/or single strand breaks in overexpressing cells, confirming an MPG-driven accumulation of toxic BER intermediates. This data establishes transient MPG overexpression as a potential therapeutic approach for increasing cellular sensitivity to alkylating agent chemotherapy.