Transduction of the Herpes Thymidine Kinase Gene into Premalignant Murine Mammary Epithelial Cells Renders Subsequent Breast Cancers Responsive to Ganciclovir Therapy

Abstract

Drug sensitivity (“suicide”) genes can sensitize cancer cells to chemotherapy, but therapeutic use of these genes is limited by difficulties in delivering them to all areas of established cancers. An alternative strategy entails preemptive introduction of suicide genes into tissues at risk for cancer, thereby imparting drug sensitivity as a clonal property to cancers arising from sensitized cells. To test the preemptive approach, a retroviral vector was used to transduce the herpes thymidine kinase gene into the TM4 line of preneoplastic murine mammary epithelial cells to yield a clonal subline sensitized to the guanosine analog ganciclovir. Ganciclovir therapy of tumors that arose from the transduced cells retarded tumor growth and induced durable regressions in 7/20 mice; ganciclovir was ineffective against control tumors. The results imply the possibility of reducing cancer lethality by actions taken before cancers arise.

Overview summary

When used therapeutically, the efficacy of the herpes thymidine kinase “suicide gene” as a means of sensitizing cancer cells to ganciclovir is impaired by the difficulty of delivering the gene quantitatively to all areas of a cancer in vivo. This paper demonstrates that when the same gene is transduced preemptively into target cells—in this case premalignant murine mammary epithelium—subsequent cancers respond well to ganciclovir, and are sometimes eradicated. These results suggest that the obstacle of inadequate gene delivery might be overcome by exploiting a unique property of preemptively transduced cells—their potential, if they later spawn cancers, to ensure the presence of a suicide gene in every cancer cell.