Exploring the unique mechanisms of anticancer drugs can provide the opportunity to identify novel targets for future drug development. Suicide gene therapy with the herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) is a selective approach for the treatment of cancer. Only the cells containing HSV-TK can activate GCV to a toxic metabolite, thus sparing normal dividing tissues. Upon activation by HSV-TK and further metabolism by host cell enzymes, GCV becomes incorporated into the DNA of dividing tumor cells resulting in cell death by a unique mechanism compared to other HSV-TK substrates. However, the underlying mechanistic differences that confer high anticancer activity for GCV are still unknown. The studies described in this dissertation identify differences in the magnitude of DNA damage and the DNA repair pathways activated by GCV and a less toxic HSV-TK substrate, 1-β-D-arabinofuranosylthymine. Furthermore, the DNA repair pathway of homologous recombination (HR) is identified as a critical repair mechanism to survive GCV exposure.These observations suggest that inhibition of HR will improve GCV mediated tumor cell kill. While there are no inhibitors specific for HR, this dissertation demonstrates that the lysine deacetylase inhibitor Vorinostat (SAHA) inhibits HR in response to GCV resulting in synergistic tumor cell kill. Importantly, this synergy occurs only in cells proficient in HR demonstrating that the mechanism of synergy between GCV and SAHA is specifically due to inhibition of HR after GCV induced DNA damage. Collectively, these studies reveal that tumor cells activate the DNA repair pathway of HR in response to GCV and identify SAHA as a novel, mechanism based drug to enhance HSV-TK/GCV gene therapy.
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Exploring and Exploiting DNA Repair Mechanisms to Improve Suicide Gene Therapy with Ganciclovir.
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