Up-regulation of Mismatch Repair Pathway by Suicide Gene Therapy: Implications on the use of Temozolomide Treatment in Malignant Glioma

Abstract

Objective: The dependency of the efficacy of temozolomide (TMZ) on cellular DNA repair activities makes it therapeutically effective in approximately half of malignant glioma (MG) patient population with a dysfunctional DNA repair system. Adenovirus-mediated Herpes simplex virus thymidine kinase and ganciclovir (AdHSV-tk/GCV) suicide gene therapy is effective in those as well as in MG patients with a functional DNA repair system. When administered together, these two therapies show evidence of synergistic cytotoxicity. However, the validity of such claims has been questioned as the exact mechanism has been unknown. Methods: The underlying mechanism was studied in rat and human MG cell lines and in an immunocompetent, orthotopic, syngeneic rat MG model. Results: The results, for the first time, revealed an up-regulation of mismatch repair (MMR) pathway in MG cells by AdHSV-tk/GCV therapy, an adjunct effect to AdHSV-tk/GCV’s pro-apoptotic therapeutic mode of action that enhanced the cytotoxicity of TMZ. When combined with AdHSV-tk/GCV therapy, initially resistant MG cells were sensitized to TMZ treatment. The enhancement of TMZ’s efficacy was also seen in vivo as a significant increase in survival and a reduction in tumor growth rate, without affecting the adverse effect profile. Conclusion: This study demonstrates a synergistic outcome of AdHSV-tk/GCV and TMZ treatment combination, underlying mechanism for the synergy and a possible improved therapeutic protocol for enhanced efficacy. The findings may have an impact on future clinical use of this treatment combination, as well as benefit other chemotherapies, which depend on MMR pathway for action.