ADENOVIRAL-MEDIATED P53 TUMOR-SUPPRESSOR GENE-THERAPY OF HUMAN OVARIAN-CARCINOMA

Mutations of p53 gene are reported in 50-60% of human cancers and rein troduction of wild-type p53 can suppress cell proliferation, In this s tudy, replication deficient recombinant adenovirus encoding wild-type p53 (ACN53) under the control of the human cytomegalovirus (CMV) promo ter was constructed. A specific incorporation of the p53 gene with ACN 53 in SK-OV-3 (deleted p53 gene) cells was observed, ACN53 reduced the colony-forming ability of SK-OV-3 cells thereby supporting that 95-98 % of cells are susceptible to infection by recombinant adenovirus. ACN 53 inhibited the growth of 71-98% of SK-OV-3 cells 72-216 h after sing le infection, A highly aggressive ovarian xenograft model was establis hed in which animals die between 25-45 days, A localization study with the adenovirus-containing beta galactosidase reporter gene showed eff ective gene transfer in the tumor tissues, Ex vivo treatment of SK-OV- 3 cells with ACN53 followed by injection into nude mice, increased the survival of the p53 treated mice by more than 50% compared with contr ol animals, Gene therapy with ACN53 in intraperitoneal model of SK-OV- 3 cells in two independent experiments revealed that there were some l ong-term survivors in the group of mice [2/5 (66 and 120 days) and [2/ 8 (166 and 423 days)] treated with ACN53. These findings demonstrate t he potential of the p53 tumor suppressor gene therapy in human ovarian carcinoma.