Efficacy of intraperitoneal adenovirus-mediated p53 gene therapy in ovarian cancer

V. E. Von Gruenigen, J. D. O'Boyle, R. L. Coleman, D. Wilson, D. S. Miller, J. M. Mathis

Research output: Contribution to journalArticle

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Abstract

The purpose of this study was to determine the efficacy of adenovirus- based p53 gene therapy in the treatment of ovarian cancer using an intraperitoneal microscopic tumor animal model system. Adenovirus-mediated wild-type p53 gene was introduced into the NIH:OVCAR-3 human ovarian cancer cell line in vitro and in vivo. In order to study microscopic intraperitoneal tumor, athymic nude mice were inoculated intraperitoneally (i.p.) with 1 x 107 OVCAR-3 cells and observed for tumor growth. Three days after inoculation with OVCAR-3 cells, the mice were divided into 3 treatment groups. One group received three daily i.p. injections of 1 x 108 pfu Ad- CMV-p53, a second group received three daily i.p. injection of 1 x 108 pfu of the control adenovirus construct expressing β galactosidase (Ad-CMV- βgal) and a third group received three daily i.p. injections of normal saline. Adenovirus-mediated introduction of the wild-type p53 gene in the ovarian cancer cell line resulted in transient high levels of p53 protein for 24-48 h. Cell cycle analysis revealed G1 arrest, as well as the appearance of apoptosis. In vitro cell growth assays showed growth inhibition of cancer cells infected with Ad-CMV-p53 compared to cells infected with Ad-CMV-βgal or normal saline. There was a significant increase in survival in the Ad-CMV- p53 adenovirus treated animals compared to the PBS treated animals (P = 0.004). Likewise, the survival in Ad-CMV-p53 treated mice was also significantly greater than mice treated with Ad-CMV-βgal (P < 0.0001). These results demonstrated that Ad-CMV-p53 treatment is effective in inhibiting tumor growth and prolonging survival in this microscopic cancer xenograft model. The results of this study constitute a step in translating promising in vitro and in vivo data from an adenovirus-based gene therapeutic model system into practical and scientifically based human cancer therapeutic trials.

Original languageEnglish
Pages (from-to)365-372
Number of pages8
JournalInternational Journal of Gynecological Cancer
Volume9
Issue number5
DOIs
StatePublished - 1 Jan 1999

Fingerprint

p53 Genes
Adenoviridae
Genetic Therapy
Ovarian Neoplasms
Neoplasms
Growth
Nude Mice
Injections
Survival
Galactosidases
Therapeutics
Cell Line
Heterografts
Cell Cycle
Animal Models
Apoptosis
Genes
In Vitro Techniques
Proteins

Keywords

  • Adenovirus
  • Gene therapy
  • Ovarian cancer
  • p53

Cite this

Von Gruenigen, V. E. ; O'Boyle, J. D. ; Coleman, R. L. ; Wilson, D. ; Miller, D. S. ; Mathis, J. M. / Efficacy of intraperitoneal adenovirus-mediated p53 gene therapy in ovarian cancer. In: International Journal of Gynecological Cancer. 1999 ; Vol. 9, No. 5. pp. 365-372.
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Efficacy of intraperitoneal adenovirus-mediated p53 gene therapy in ovarian cancer. / Von Gruenigen, V. E.; O'Boyle, J. D.; Coleman, R. L.; Wilson, D.; Miller, D. S.; Mathis, J. M.

In: International Journal of Gynecological Cancer, Vol. 9, No. 5, 01.01.1999, p. 365-372.

Research output: Contribution to journalArticle

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AU - Von Gruenigen, V. E.

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AB - The purpose of this study was to determine the efficacy of adenovirus- based p53 gene therapy in the treatment of ovarian cancer using an intraperitoneal microscopic tumor animal model system. Adenovirus-mediated wild-type p53 gene was introduced into the NIH:OVCAR-3 human ovarian cancer cell line in vitro and in vivo. In order to study microscopic intraperitoneal tumor, athymic nude mice were inoculated intraperitoneally (i.p.) with 1 x 107 OVCAR-3 cells and observed for tumor growth. Three days after inoculation with OVCAR-3 cells, the mice were divided into 3 treatment groups. One group received three daily i.p. injections of 1 x 108 pfu Ad- CMV-p53, a second group received three daily i.p. injection of 1 x 108 pfu of the control adenovirus construct expressing β galactosidase (Ad-CMV- βgal) and a third group received three daily i.p. injections of normal saline. Adenovirus-mediated introduction of the wild-type p53 gene in the ovarian cancer cell line resulted in transient high levels of p53 protein for 24-48 h. Cell cycle analysis revealed G1 arrest, as well as the appearance of apoptosis. In vitro cell growth assays showed growth inhibition of cancer cells infected with Ad-CMV-p53 compared to cells infected with Ad-CMV-βgal or normal saline. There was a significant increase in survival in the Ad-CMV- p53 adenovirus treated animals compared to the PBS treated animals (P = 0.004). Likewise, the survival in Ad-CMV-p53 treated mice was also significantly greater than mice treated with Ad-CMV-βgal (P < 0.0001). These results demonstrated that Ad-CMV-p53 treatment is effective in inhibiting tumor growth and prolonging survival in this microscopic cancer xenograft model. The results of this study constitute a step in translating promising in vitro and in vivo data from an adenovirus-based gene therapeutic model system into practical and scientifically based human cancer therapeutic trials.

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