CURATIVE POTENTIAL OF HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE-TRANSFER IN RATS WITH 9L GLIOSARCOMA

The transfer of the gene coding for the thymidine kinase of the herpes simplex virus (HSV-tk), followed by ganciclovir (GCV) administration, has been described for the treatment of several types of cancer, espe cially brain tumors. We further studied the efficacy of this approach by using the 9L rat gliosarcoma model, and cells producing 5 X 10(3), 9 X 10(4), 3 X 10(5) HSV-tk retroviral particles per milliliter. Their stereotactic injection in 9L brain tumors and GCV treatment did not r esult in any increase of survival. To study a model of optimal in vivo transduction, we examined the survival of rats with tumors growing fr om 9L cells that had been previously transduced in vitro with the HSV- tk vectors (9LTk cells). We observed that GCV administration cured 26% (n = 42) of the animals with 9LTk brain tumors, with most of the rela psing tumors remaining HSV-tk positive. The increase of either the dos e or the duration of GCV treatment did not improve the survival rate. But the cerebral localization of the tumor played an important role, b ecause this survival rate reached 67% (n = 12) when similar tumors wer e growing subcutaneously. No or only marginal antitumoral responses we re induced by the presence of a selectable marker gene in the HSV-tk v ectors. These results demonstrate that in vitro HSV-tk gene transfer i n 9L tumor cells, but not in vivo gene transfer, followed by GCV treat ment, is able to cure rats at a rate that is higher for subcutaneous t han for intracerebral tumors.