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 mous e model with intraperitoneal (ip) 2774 human ovarian cancer cell line that contains a p53 mutation. Study design. An initial study of adenov irus tolerance was determined in nude mice by a single ip injection of increasing doses of Ad-CMV-p53. Nude mice were implanted with an LD10 0 dose of 1 x 10(7) cells. To study the efficacy and specificity of Ad -CMV-p53 treatment, the mice received treatment with different adenovi rus constructs. One group received Ad-CMV-p53 and another group receiv ed a control adenovirus construct, Ad-CMV-beta gal. To study the treat ment response to Ad-CMV-p53, the mice were divided into groups and rec eived various treatment schedules of 1 x 10(8) pfu of Ad-CMV-p53. Resu lts. 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 signific ant survival advantage was observed between Ad-CMV-p53- and Ad-CMV-bet a gal-treated mice. Conclusions. These studies show that at the adenov irus 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 app lication of adenovirus-based ovarian cancer gene therapy. (C) 1998 Aca demic Press.