Perspectives for the gene therapy of malignant gliomas by suicide gene transfer

A promising strategy in the treatment of malignant gliomas involves the creation of Herpes Simplex Virus-thymidine kinase (HSV-tk) modified tumor cells. Some authors have observed complete tumor regression after ganciclovir (GCV) treatment of established gliomas transduced in vivo by the HSV-tk gene. Yet, further investigations did not confirm completely these results, even if confirmed the therapeutic potential of such a therapy. Using the rat C6 glioblastoma as a model of malignant brain tumor, we investigated the efficacy of in vivo and in vitro transduction of growing brain tumors with the HSV-tk gene, followed by GCV administration. The stereotactic injection into the left striatum of C6 cells mixed with retroviral producer cells and GCV treatment did not improve significantly the animal survival compared to controls. On the contrary, there was a significant prolongation of the survival of rats inoculated with C6 cells engineered in vitro to express the HSV-tk gene. Nevertheless, complete eradication of the tumors was not achieved. We also injected a group of six rats with a mixture of cells expressing the murine Interleukin-4 (IL-4) gene and C6 cells. IL-4 has been shown to produce the regression of experimental brain tumors. Our preliminary experience seems to confirm that hypothesis. Our results indicate that the outcome of HSV-tk gene therapy can be limited not only by low gene transfer but also by insufficient delivery of GCV to tumor cells. Combined strategies, based on contemporary transduction of HSV-tk and IL-4, may enhance the therapeutic perspectives of such a therapy.