Enhancement of paclitaxel delivery to solid tumors by apoptosis-inducing pretreatment: effect of treatment schedule.

The limited penetration of paclitaxel into solid tumors may limit its therapeutic efficacy. We recently showed a correlation between an increase in interstitial space and an enhancement of drug delivery in solid tumors. The present study evaluated whether this observation can be used to develop a treatment strategy, where an apoptosis-inducing pretreatment with paclitaxel is used to enhance its own delivery to solid tumors. In histocultures of human pharynx FaDu xenograft tumors, pretreatment with 1 microM nonradiolabeled paclitaxel, which resulted in approximately 25% apoptosis and a 25% reduction in cell density, enhanced the penetration rate of [(3)H]paclitaxel. Likewise, dividing a total drug exposure to two treatments, separated by an interval to allow apoptosis to occur, resulted in higher drug penetration rate and accumulation compared with giving the same drug exposure continuously. Similar results were obtained in rats bearing subcutaneously implanted prostate MAT-LyLu tumors; fractionation of the dose, to include 1) a pretreatment that yielded sufficient and clinically relevant plasma concentration to induce apoptosis and 2) a second dose given at an interval selected to allow apoptosis and reduction in tumor cell density to occur, resulted in higher tumor concentration compared with other treatments using the same total dose but either did not include an apoptosis-inducing pretreatment or did not allow for apoptosis to occur. We conclude that the pharmacological effect of paclitaxel affects its own delivery to solid tumors and that modifications of the paclitaxel treatment schedule can enhance drug delivery in solid tumors.