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Clinical Cancer Research Vol. 6, 250-259, January 2000
© 2000 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

E1A-mediated Paclitaxel Sensitization in HER-2/neu-overexpressing Ovarian Cancer SKOV3.ip1 through Apoptosis Involving the Caspase-3 Pathway1

Naoto T. Ueno, Chandra Bartholomeusz, John L. Herrmann, Zeev Estrov, Ruping Shao, Michael Andreeff, Janet Price, Ralph W. Paul, Pervin Anklesaria, Dihua Yu and Mien-Chie Hung2

Departments of Blood and Marrow Transplantation [N. T. U., C. B., M. A.], Leukemia [Z. E.], Genitourinary Medical Oncology [J. L. H.], Surgical Oncology [D. Y., M-C. H.], and Cancer Biology [N. T. U., C. B., R. S., J. P., M-C. H.] and Breast Cancer Basic Research Program [N. T. U., C. B., R. S., M-C. H.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, and Targeted Genetics Co., Seattle, Washington 98101 [R. W. P., P. A.]

HER-2/neu-overexpressing breast cancer cells are more resistant to the chemotherapeutic agent paclitaxel (Taxol) than low-HER-2/neu-expressing breast cancer cells, and the adenoviral type 5 E1A can down-regulate HER-2/neu overexpression. Therefore, in this study, we asked (a) whether E1A might sensitize response to paclitaxel in human HER-2/neu-overexpressing ovarian cancer cells, and, if so, what is the mechanism responsible; and (b) whether this enhanced chemosensitivity would translate into a therapeutic effect in an ovarian cancer xenograft model. Consequently, we demonstrated that: (a) adenovirus type 5 E1A could enhance the sensitivity of paclitaxel in paclitaxel-resistant HER-2/neu-overexpressing human ovarian cancer cells in vitro by inducing apoptosis, (b) this induction was heavily dependent on activation of the caspase-3 pathway, and (c) nude mice bearing i.p. HER-2/neu-overexpressing human ovarian cancer cells and treated with both paclitaxel and E1A gene therapy survived significantly longer than did mice treated only with paclitaxel or E1A gene therapy. Thus, we concluded that the E1A gene enhanced 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-regulation has recently been completed, the current study also provided a scientific basis to further develop a novel therapy that combines paclitaxel and E1A gene therapy and its testing in a Phase II trial.




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