PROSTATE-CANCER GENE-THERAPY - HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE TRANSDUCTION FOLLOWED BY GANCICLOVIR IN MOUSE AND HUMAN PROSTATE-CANCER MODELS

Prostate cancer is the most common internal malignancy in men in the U nited States. Most cancers are diagnosed when they are locally advance d or metastatic and there is no effective treatment. In this study we evaluated the effectiveness of cytotoxic gene therapy in human PC-3 an d DU145 prostate cancer cell lines and in a rodent cell line, RM-1, de rived from the mouse prostate reconstitution model system. The tell li nes were efficiently transduced in vitro by a replicative-defective re combinant adenovirus (ADV) carrying the herpes simplex virus thymidine kinase gene (HSV-tk). A virus titer-dependent sensitivity to ganciclo vir (GCV) was observed. To determine a target therapeutic viral dose i n vivo, subcutaneous tumors were generated by injection of RM-1 cells in syngeneic male hosts and injected with escalating doses of HSV-tk v irus (5 x 10(7) to 1x10(9) pfu). The mice received GCV twice daily for 6 days and were sacrificed when tumor volumes exceeded 2.5 cm(3) or w hen they appeared to be in distress. Because the two highest doses wer e equally as effective, further controlled studies were performed with the lower dose of 5 x 10(8) pfu with ADV/RSV-tk or a control virus co ntaing the beta-galactosidase gene (ADV/RSV-beta-Gal) and treated with GCV or saline (PBS). The mean tumor volume in the treated animals was 16% that of control animals at 13 days. Histologically, treated tumor s demonstrated necrosis and had a significantly higher apoptotic index . Survival data indicated that the treatment animals lived 7 days (21 in total) longer than the control animals, with 1 treatment animal bei ng totally free of tumor. These results demonstrate that HSV-tk + GCV cytotoxic gene therapy can inhibit the growth of mouse and human prost ate cancer cells in vitro and interrupt tumor growth of an aggressive mouse prostate cancer cell line in vivo.