¹University of Toronto, Toronto, ON, Canada

Abstract

Background: While ovarian tumors initially appear responsive to chemotherapy, most patients relapse with drug resistant disease. We hypothesized that sustained, local delivery of paclitaxel (PTX) could impact chemo-responsiveness of ovarian tumors by controlling the expression of P-glycoprotein (Pgp)/MDR1.

Methods: Sustained and intermittent administration of PTX using free-PTX or a novel sustained PTX implant system was examined in vitro in SKOV-3 cells and in vivo in an intraperitoneal human ovarian xenograft murine model implanted ip with the sustained release formulation. MDR1/Pgp expression was examined by RT-PCR, flow cytometry and immunohistochemistry.

Results: Equivalent dosing of free-PTX by either sustained or intermittent treatments (5-250 ng/ml) induced MDR1 mRNA levels by 3-4 fold in SKOV-3 cells (P<0.05) without altering Pgp protein levels. On the other hand, similar treatments with PTX-implants did not induce MDR1 or Pgp expression in vitro. Likewise, we did not detect significant changes in the in vivo expression of MDR1/Pgp in xenografts obtained from mice treated for 14 days with sustained PTX-implants which delivered doses of 2.4-240 mg/kg/day of PTX. Basal MDR1/Pgp levels were seen in the highest treatment group.

Conclusions: Overall, localized and sustained administration of PTX does not aggravate MDR1 development thereby demonstrating potential as a novel treatment strategy for ovarian cancer.