DIFFERENTIAL MODULATION OF CISPLATIN ACCUMULATION IN LEUKOCYTES AND TUMOR-CELL LINES BY THE PACLITAXEL VEHICLE CREMOPHOR EL

Background. Several clinical studies have shown that polychemotherapy with the taxanes paclitaxel or docetaxel preceded or followed by cispl atin is associated with important schedule-dependent differences in to xicities, such as leukocytopenia. In general, the pharmacokinetics of both drugs during the combined treatment are unaltered, suggesting tha t a pharmacodynamic interaction might have occurred. Materials and met hods: In order to gain insight into this pharmacologic interaction, we performed in vitro drug accumulation studies using peripheral blood l eukocytes and a panel of tumor and non-malignant cell lines with pacli taxel and docetaxel, as wel as with their respective formulation vehic les Cremophor EL and Tween 80. Results: Our results show a significant reduction in the intracellular cisplatin concentration in leukocytes of up to 42% in the presence of Cremophor EL and Tween 80 as compared to the control. This pharmacodynamic interaction of these surfactants with cisplatin seems to be specific for haematopoietic cells, and does not occur in solid tumor cells. Conclusion: The present data suggest that the pharmaceutical vehicles Cremophor EL and Tween 80 might contr ibute to the reduced cisplatin-associated myelotoxicity observed in th e clinical combination chemotherapy studies with paclitaxel and doceta xel.