ADENOVIRAL-MEDIATED DELIVERY OF HERPES-SIMPLEX VIRUS THYMIDINE KINASERESULTS IN TUMOR REDUCTION AND PROLONGED SURVIVAL IN A SCID MOUSE MODEL OF HUMAN OVARIAN-CARCINOMA

The herpes simplex virus thymidine kinase gene is the most widely util ized toxin for selective killing of carcinoma cells. Expression of the viral thymidine kinase gene renders cells sensitive to the toxic effe cts of nucleoside analogs such as ganciclovir. An advantage of this sy stem is the ''bystander effect'' whereby thymidine kinase transduced t umor cells elicit a toxic effect on surrounding nontransduced tumor ce lls. Ovarian carcinoma appears to be an ideal candidate for gene thera py as the majority of women present with advanced stage disease, have poor prognosis for long-term survival and have the disease confined wi thin the peritoneal cavity, Therefore the utility of an adenoviral vec tor to elicit an in vitro bystander effect in ovarian carcinoma cells and the therapeutic efficacy of such a system in vivo was undertaken. Immunocompetent animals were utilized to determine the maximum dose of adenovirus that could be administered without any undesirable side ef fects and that preimmunization had no effects on subsequent challenge. SCID mice were orthotopically transplanted with human ovarian carcino ma cells and, after establishment of tumor, given a recombinant adenov irus expressing either the herpes simplex virus thymidine kinase or th e Escherichia coli beta-galactosidase gene. Half the animals from each viral group were treated with either a ganciclovir regiment (50 mg/kg daily for 14 days) or an equal volume, of serum-free media. A subset of mice were killed following drug treatment and analyzed for tumor re duction. The remaining animals were followed daily for survival. The a nimals treated with the recombinant adenovirus expressing the herpes s implex virus thymidine kinase gene and ganciclovir had significant red uction in overall tumor burden and demonstrated statistically signific ant prolongation in overall survival.