Inducible expression of herpes simplex virus thymidine kinase increases sensitivity to ganciclovir but does not enhance bystander effect in breast cancer cells

Delivery of cancer chemotherapy directly to the cancer cell has great appea l. Previous studies using adenoviral transfer of the herpes simplex virus t hymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) in an ascites m odel of breast cancer was successful in reducing tumor burden and prolongin g life. However, increasing the viral dose resulted in increased toxicity a nd host mortality emphasizing the need for an improved therapeutic ratio. T o test the hypothesis that enhancement of HSV-tk gene expression would lead to increased sensitivity to GCV and improved bystander effect, we created breast cancer cells expressing HSV-tk under the control of the inducible te tracycline promoter. Using this system, we could inducibly increase gene ex pression and biochemical activation of HSV-tk. These increased levels of HS V-tk decreased the IC50 to GCV nearly 50-fold. However, the bystander effec t was not enhanced by increasing HSV-tk gene expression. We conclude that i ncreased HSV-tk gene expression improves sensitivity to CCV. However, addit ional measures, such as increased gap junction communication, will likely b e needed to enhance the bystander effect and the therapeutic efficacy of th is strategy.