Increased endothelial uptake of paclitaxel as a potential mechanism for its antiangiogenic effects: potentiation by Cox-2 inhibition.

Paclitaxel has antiangiogenic properties, but the mechanisms for the enhanced sensitivity of endothelial cells (ECs) to this drug are not established. The aims of our study were to compare the distribution of paclitaxel into ECs with other cell types, to assess the effects of low doses of paclitaxel on Cox-2 expression and to determine the combined effects of paclitaxel and Cox-2 inhibitors on angiogenesis in vitro and in patients with cancer. Upon exposure to low (5 nM) concentrations of [3H]-paclitaxel, uptake of radioactivity was more than 5 times higher in ECs than other cell types. Exposing human umbilical vein ECs to low nanomolar (1-50 nM) concentrations of paclitaxel enhanced Cox-2 expression more than 2-fold, as measured by ELISA. Combined treatment with paclitaxel and the Cox-2 inhibitor NS-398 resulted in increased antiendothelial effects as compared to each agent alone. To assess the biologic effects of the combined treatment in vivo, 4 cancer patients were treated with a prolonged intravenous infusion of paclitaxel (10 mg/m2/day) and the Cox-2 inhibitor celecoxib (400 mg p.o. BID), and plasma angiogenic activity and drug levels were measured. The treatment was well tolerated, providing steady-state concentrations of paclitaxel in plasma near 10 nM and potent plasma antiendothelial effects were observed. These findings suggest that antiangiogenic effects of paclitaxel may be due its preferential accumulation in ECs. Low dose paclitaxel in combination with a Cox-2 inhibitor is an attractive antiangiogenic and antitumor strategy that deserves further evaluation in clinical trials.