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Research Articles: Therapeutics, Targets, and Development

Effects of sustained and intermittent paclitaxel therapy on tumor repopulation in ovarian cancer

Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Micheline Piquette-Miller, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, Canada M5G 3M2. Phone: 416-946-3057; Fax: 416-978-8511. E-mail: m.piquette.miller{at}utoronto.ca

Abstract

Tumor repopulation between cycles of chemotherapy likely has a negative effect on clinical outcome in ovarian cancer patients. Thus, avoiding treatment-free periods when tumor cells proliferate by providing sustained chemotherapy regimens may improve clinical response. We investigated the effect of sustained versus intermittent paclitaxel administration on tumor repopulation in ovarian cancer. Growth, clonogenic survival, and apoptosis were followed in SKOV3 and A2780 cells after equivalent exposure to intermittent and sustained levels of paclitaxel. In vivo tumor repopulation in response to sustained and intermittent paclitaxel therapy was investigated in an i.p. xenograft model of human ovarian cancer. Tumor growth, proliferation, and apoptosis were evaluated at different intervals during and after the course of treatment using 5-bromo-2-deoxyuridine uptake, caspase-3, and terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling immunoassays. Sustained treatment significantly reduced survival in vitro in both cell lines, whereas an increase in clonogenic survival was observed in the intermittent group with each treatment gap, indicating a gradual acceleration in repopulation rates. Similarly, in vivo, sustained therapy resulted in a significant reduction of tumor growth and proliferation. Intermittent therapy resulted in increased tumor proliferation and no efficacy. The percentage of apoptotic tumor cells significantly increased in the sustained group, whereas no significant changes were seen in the control and intermittent groups. Intermittent administration of paclitaxel significantly augmented both in vitro and in vivo tumor repopulation rates, whereas sustained delivery inhibited tumor growth and repopulation. Sustained administration of paclitaxel may increase chemoresponsiveness and clinical response in ovarian cancer by attenuating tumor repopulation. [Mol Cancer Ther 2008;7(3):630–7]

Grant support: Ontario Cancer Research Network and National Cancer Institute of Canada (Canadian Cancer Society).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 9/19/07; revised 11/ 6/07; accepted 12/13/07.