E1A-mediated paclitaxel sensitization in HER-2/neu-overexpressing ovarian cancer SKOV3.ip1 through apoptosis involving the caspase-3 pathway

HER-2/neu-overexpressing breast cancer cells are more resistant to the chem otherapeutic agent paclitaxel (Taxol) than low-HER-2/neu-expressing breast cancer cells, and the adenoviral type 5 E1A can down-regulate HER-2/neu ove rexpression. Therefore, in this study, we asked (a) whether E1A might sensi tize response to paclitaxel in human HER-2/neu-overexpressing ovarian cance r cells, and, if so, what is the mechanism responsible; and (b) whether thi s enhanced chemosensitivity would translate into a therapeutic effect in an ovarian cancer xenograft model, Consequently, we demonstrated that: (a) ad enovirus type 5 E1A could enhance the sensitivity of paclitaxel in paclitax el-resistant HER-2/neu-overexpressing human ovarian cancer cells in vitro b y inducing apoptosis, (b) this induction was heavily dependent on activatio n of the caspase-3 pathway, and (c) nude mice bearing i.p. HER-2/neu-overex pressing human ovarian cancer cells and treated with both paclitaxel and E1 A gene therapy survived significantly longer than did mice treated only wit h paclitaxel or E1A gene therapy. Thus, we concluded that the E1A gene enha nced both the in vitro and in vivo sensitivity of paclitaxel in paclitaxel- resistant HER-2/neu-overexpressing ovarian cancer SKOV3.ip1 cells. Because a Phase I clinical trial using E1A gene targeted to HER-2/neu down-regulati on has recently been completed, the current study also provided a scientifi c basis to further develop a novel therapy that combines paclitaxel and E1A gene therapy and its testing in a Phase II trial.