Cooperative effect of adenoviral p53 gene therapy and standard chemotherapy in ovarian cancer cells independent of the endogenous p53 status

Abstract

Clinical adenoviral p53 gene therapy has been shown by us and others to inhibit tumor growth of ovarian cancer with endogenous mutant p53. This study was designed to test the cooperative antitumor effect of standard combination chemotherapy using paclitaxel and carboplatin together with adenoviral p53 gene transfer in the presence of wild-type and mutant p53. Seven ovarian cancer cell lines with mutant p53 and seven ovarian cancer cell lines with wild-type p53 were tested. An E1-deleted adenovirus type 5 expressing p53 (ACNp53) was used for p53 gene transfer. p53 gene transfer at 50% transduction efficiency significantly reduced IC 50 of carboplatin chemotherapy up to 49-fold, of paclitaxel chemotherapy up to six-fold, and of paclitaxel/carboplatin chemotherapy up to 19-fold in the wild-type p53 cell line OV-MZ-5. Synergism between ACNp53 and chemotherapy calculated by median-effect analysis was found at low drug concentrations in all cell lines independent of the p53 mutational status. In conclusion, adenoviral p53 gene transfer significantly increased the sensitivity of ovarian tumor cells to paclitaxel, to carboplatin and/or to the combination of both.

The cooperative effect of p53 and Rb in local nanotherapy in a rabbit VX2 model of hepatocellular carcinoma

“…45 Moreover, this cooperative effect of p53 gene therapy and chemotherapy is independent of the endogenous p53 status. 46 These data reinforce the notion that the cytotoxicity of many anticancer agents may act in part through the wt-p53. …”

In vivo restoration of RhoB expression leads to ovarian tumor regression

“…Promising preclinical data on the in vitro transfection of wild-type p53 into ovarian cancer cells bearing p53 mutations and into xenograft models, coupled with evidence from phase I trials, led to the introduction of this innovative and encouraging technique for front-line treatment of patients with advanced ovarian cancer. 18,24,25 However, dominantnegative crosstalk between ectopic wild-type p53 and recently identified dominant p53 mutants as well as splice variants of p63 and p73 (frequently overexpressed in ovarian cancers) could seriously compromise the effectiveness of p53 gene therapy.…”

Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed

“…20 This study firstly demonstrated in p53-wild-type mesothelioma cells that augmented p53 ) were injected into the intrapleural cavity of nude mice (n ¼ 6) (day 1) and they were treated as indicated on day 3. Ad-p53 with chemotherapy for mesothelioma Q Li et al expressions produced synergistic anti-tumor effects with CDDP or PEM in most of the cases and even in an orthotopic animal model.…”