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 thera peutic efficacy. We recently showed a correlation between an increase in in terstitial space and an enhancement of drug delivery in solid tumors. The p resent study evaluated whether this observation can be used to develop a tr eatment strategy, where an apoptosis-inducing pretreatment with paclitaxel is used to enhance its own delivery to solid tumors. In histocultures of hu man pharynx FaDu xenograft tumors, pretreatment with 1 muM nonradiolabeled paclitaxel, which resulted in similar to 25% apoptosis and a 25% reduction in cell density, enhanced the penetration rate of [H-3] paclitaxel. Likewis e, dividing a total drug exposure to two treatments, separated by an interv al to allow apoptosis to occur, resulted in higher drug penetration rate an d accumulation compared with giving the same drug exposure continuously. Si milar results were obtained in rats bearing subcutaneously implanted prosta te MAT-LyLu tumors; fractionation of the dose, to include 1) a pretreatment that yielded sufficient and clinically relevant plasma concentration to in duce 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 dos e but either did not include an apoptosis-inducing pretreatment or did not allow for apoptosis to occur. We conclude that the pharmacological effect o f paclitaxel affects its own delivery to solid tumors and that modification s of the paclitaxel treatment schedule can enhance drug delivery in solid t umors.