In vivo studies of adenovirus-mediated p53 gene therapy for cis-platinum-resistant human ovarian tumor xenografts

We have recently reported that mutations of the tumor suppressor p53 gene a re associated with the development of resistance to cis-platinum in human o varian cancer cells. and that adenovirus-mediated reintroduction of the wil d-type p53 (wtp53) gene in ovarian tumor cells resulted in the sensitizatio n of tumor cells to cis-diamminedichloroplatinum (II) (CDDP). The purpose o f this study was to evaluate whether IP treatment of CDDP-resistant tumor c ells expressing mutant p53 (mutp53) with a recombinant adenovirus expressin g wtp53 (Adwtp53) would result in the sensitization of resistant cells to C DDP. In order to determine whether IP injection of a recombinant adenovirus would result in expression of the transgene in tumor cells growing intrape ritoneally. we first injected A2780/CP cells in nude mice and 10 days later the mice were injected IP with a recombinant adenovirus expressing beta-ga lactosidase (Adp-gal). Twenty-four hours following IP injection of Adp-gal, tumors were removed and stained for beta-gal. While tumors showed extensiv e staining for beta-gal, indicating internalization of adenovirus and the e xpression of the transgene in tumors, no expression of beta-gal protein was detected in liver. IP treatment of A2780/CP tumor xenografts with Adwtp53 caused extensive tumor cell death, which was further enhanced by CDDP. Trea tment with Adwtp53 (5 x 10(7) pfu/day. 3-5 treatments) resulted in a signif icant decrease in tumor volume and increase in animal survival compared to either no treatment or treatment with vector alone without p53 gene. Additi onal therapy with CDDP (1 mg/kg/day x 3-4) further reduced tumor volume and increased survival (30-40%), suggesting that combination therapy of Adwtp5 3 and CDDP was better than single agents alone. Our results indicate that I P dosing with adenovirus-mediated wtp53 gene therapy could be beneficial in combination with CDDP for the treatment of ovarian tumors expressing mutp5 3.