Studies on the molecular mechanism of growth inhibition with p53 adenoviral construct in human ovarian cancer

Abstract

Mujoo K, Catino JJ, Maneval DC, Gutterman JU. Studies on the molecular mechanism of growth inhibition with p53 adenoviral construct in human ovarian cancer. Int J Gynecol Cancer 1998; 8: 233–241. Advanced stage human ovarian cancer exhibits 50–60% mutation of the p53 tumor suppressor gene. We introduced the wild-type p53 gene into the cells using a replication deficient recombinant adenovirus for p53 gene therapy. p53-adenovirus (rAd-p53) inhibited the growth of a number of ovarian cancer cells, which correlated well with the transduction of adenovirus containing β-galactosidase reporter gene in the tested cell lines. Results presented herein demonstrate that p53 induced the expression of CDK inhibitor WAF1/CIP1/p21 in human ovarian cancer cells with null or mutant p53. p53 incorporation also induced the expression of mdm-2 and bax proteins in human ovarian cancer cells. In contrast, we were unable to detect the expression of bcl-2 protein in the tested cells, and the expression bcl-xL in the tested human ovarian cells was not altered post-infection of cells with rAd-p53. Cell cycle analysis revealed pronounced G1 arrest 24 h post-infection with rAd-p53 in human ovarian cancer cells with only a small percentage of cells (−2%) undergoing apoptosis. rAd-p53 (p53-adenovirus) inhibited the growth of established subcutaneous xenograft tumors (OVCAR-3) of human ovarian carcinoma and completely regressed the tumors in 5/8 mice, indicating a potential for p53 tumor suppressor gene therapy in human ovarian cancer.