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 are associated with the development of resistance to cis-platinum in human ovarian cancer cells, and that adenovirus-mediated reintroduction of the wild-type p53 (wtp53) gene in ovarian tumor cells resulted in the sensitization of tumor cells to cis-diamminedichloroplatinum (II) (CDDP). The purpose of this study was to evaluate whether i.p. treatment of CDDP-resistant tumor cells expressing mutant p53 (mutp53) with a recombinant adenovirus expressing wtp53 (Adwtp53) would result in the sensitization of resistant cells to CDDP. In order to determine whether i.p. injection of a recombinant adenovirus would result in expression of the transgene in tumor cells growing intraperitoneally, we first injected A2780/CP cells in nude mice and 10 days later the mice were injected i.p. with a recombinant adenovirus expressing beta-galactosidase (Ad beta-gal). Twenty-four hours following i.p. injection of Ad beta-gal, tumors were removed and stained for beta-gal. While tumors showed extensive staining for beta-gal, indicating internalization of adenovirus and the expression of the transgene in tumors, no expression of beta-gal protein was detected in liver. I.p. treatment of A2780/CP tumor xenografts with Adwtp53 caused extensive tumor cell death, which was further enhanced by CDDP. Treatment with Adwtp53 (5 x 10(7) pfu/day, 3-5 treatments) resulted in a significant decrease in tumor volume and increase in animal survival compared to either no treatment or treatment with vector alone without p53 gene. Additional therapy with CDDP (1 mg/kg/day x 3-4) further reduced tumor volume and increased survival (30-40%), suggesting that combination therapy of Adwtp53 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 mutp53.
Song
K
K
Medicine Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, MD, USA.
Cowan
K H
KH
Sinha
B K
BK
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D015996:Survival Rate; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin