In vivo studies of adenovirus-based p53 gene therapy for ovarian cancer.

OBJECTIVES

To test the safety, efficacy, and toxicity of gene therapy using wild-type p53-expressing adenovirus (Ad-CMV-p53) in a nude mouse model with intraperitoneal (i.p.) 2774 human ovarian cancer cell line that contains a p53 mutation.

STUDY DESIGN

An initial study of adenovirus tolerance was determined in nude mice by a single i.p. injection of increasing doses of Ad-CMV-p53. Nude mice were implanted with an LD100 dose of 1 x 10(7) cells. To study the efficacy and specificity of Ad-CMV-p53 treatment, the mice received treatment with different adenovirus constructs. One group received Ad-CMV-p53 and another group received a control adenovirus construct, Ad-CMV-beta gal. To study the treatment response to Ad-CMV-p53, the mice were divided into groups and received various treatment schedules of 1 x 10(8) pfu of Ad-CMV-p53.

RESULTS

The mice tolerated Ad-CMV-p53 without adverse effects at doses of 1 x 10(8) pfu. The response to Ad-CMV-p53 showed significant survival duration in each dose regimen, with a survival time greater than that of untreated animals (P = 0.0173). However, no statistically significant survival advantage was observed between Ad-CMV-p53- and Ad-CMV-beta gal-treated mice.

CONCLUSIONS

These studies show that at the adenovirus dose and administration regimen used, there is effective but not specific 2774 tumor growth inhibition in vivo. Efficient introduction of biologically active genes into tumor cells would greatly facilitate cancer therapy. Thus, although promising, these results caution that much effort will be required to realize the potential for clinical application of adenovirus-based ovarian cancer gene therapy.