Adenoviral-mediated delivery of herpes simplex virus thymidine kinase results 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 utilized toxin for selective killing of carcinoma cells. Expression of the viral thymidine kinase gene renders cells sensitive to the toxic effects of nucleoside analogs such as ganciclovir. An advantage of this system is the "bystander effect" whereby thymidine kinase transduced tumor cells elicit a toxic effect on surrounding nontransduced tumor cells. Ovarian carcinoma appears to be an ideal candidate for gene therapy as the majority of women present with advanced stage disease, have poor prognosis for long-term survival and have the disease confined within the peritoneal cavity. Therefore the utility of an adenoviral vector 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 effects and that preimmunization had no effects on subsequent challenge. SCID mice were orthotopically transplanted with human ovarian carcinoma cells and, after establishment of tumor, given a recombinant adenovirus expressing either the herpes simplex virus thymidine kinase or the 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 reduction. The remaining animals were followed daily for survival. The animals treated with the recombinant adenovirus expressing the herpes simplex virus thymidine kinase gene and ganciclovir had significant reduction in overall tumor burden and demonstrated statistically significant prolongation in overall survival.
Rosenfeld
M E
ME
Department of Medical Genetics, University of Alabama, Birmingham 35294, USA.
Wang
M
M
Siegal
G P
GP
Alvarez
R D
RD
Mikheeva
G
G
Krasnykh
V
V
Curiel
D T
DT
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase; D015774:Ganciclovir