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

Kaimei Song, Kenneth H Cowan, Birandra K. Sinha

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

We have recently reported that mutations of the tumor suppressor p53 gene are associated with the development of resistance to as-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 râ-diamminedichloroplatinum (II) (CDDP). The purpose of this study was to evaluate whether IP 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 IP 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 IP with a recombinant adenovirus expressing -galactosidase (Ad-gal). Twenty-four hours following IP injection of Ad-gal, tumors were removed and stained for -gal. While tumors showed extensive staining for -gal, indicating internalization of adenovirus and the expression of the transgene in tumors, no expression of -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. Treatment with Adwtp53 (5 x 107 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 × 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 IP dosing with adenovirus-mediated wtp53 gene therapy could be beneficial in combination with CDDP for the treatment of ovarian tumors expressing mutp53.

Original languageEnglish (US)
Pages (from-to)153-159
Number of pages7
JournalOncology Research
Volume11
Issue number3
StatePublished - Dec 1 1999

Fingerprint

p53 Genes
Heterografts
Adenoviridae
Genetic Therapy
Cisplatin
Neoplasms
Galactosidases
Therapeutics
Tumor Burden
Transgenes
Injections
Platinum
Tumor Suppressor Genes
Nude Mice
Ovarian Neoplasms
Cell Death
Staining and Labeling
Mutation
Liver

Keywords

  • Adenovirus
  • Cis-piatinum
  • Combination gene therapy
  • Drug resistance
  • Gene therapy
  • Ovarian carcinoma
  • P53 gene

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

In vivo studies of adenovirus-mediated p53 gene therapy for cis-platinum-resistant human ovarian tumor xenografts. / Song, Kaimei; Cowan, Kenneth H; Sinha, Birandra K.

In: Oncology Research, Vol. 11, No. 3, 01.12.1999, p. 153-159.

Research output: Contribution to journalArticle

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abstract = "We have recently reported that mutations of the tumor suppressor p53 gene are associated with the development of resistance to as-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 r{\^a}-diamminedichloroplatinum (II) (CDDP). The purpose of this study was to evaluate whether IP 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 IP 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 IP with a recombinant adenovirus expressing -galactosidase (Ad-gal). Twenty-four hours following IP injection of Ad-gal, tumors were removed and stained for -gal. While tumors showed extensive staining for -gal, indicating internalization of adenovirus and the expression of the transgene in tumors, no expression of -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. Treatment with Adwtp53 (5 x 107 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 × 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 IP dosing with adenovirus-mediated wtp53 gene therapy could be beneficial in combination with CDDP for the treatment of ovarian tumors expressing mutp53.",
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