SPECIES-SPECIFIC DIFFERENCES IN TAXOL TRANSPORT AND CYTOTOXICITY AGAINST HUMAN AND RODENT TUMOR-CELLS - EVIDENCE FOR AN ALTERNATE TRANSPORT-SYSTEM

The efficacy of taxol against a wide range of sensitive and refractory solid tumors has prompted extensive investigation into the factors th at influence its cytotoxicity. Our preliminary observations indicated that taxol had a superior antitumor effect against human cells (Daudi, K562, 2008, 2008/C13, 2780 and C70) compared with its effect against rodent cells (WS, WR, NIH3T3, and CHO). Although verapamil, an inhibi tor of P-glycoprotein function, markedly increased the efficacy of tax ol against the rodent cells (WS, WR, and CHO), the expression of P-gly coprotein was found only at low levels in the WR cells. In addition, l evels of the multidrug resistance-associated protein (MRP), as assesse d by reverse transcriptase-polymerase chain reaction analysis, were fo und to be higher in the human than in the rodent cells, although MRP m RNA was not detected by northern blotting. Transport studies indicated that the reduced sensitivity of the rodent cells to taxol was due to decreased intracellular taxol levels and reduced intracellular binding . However, no correlation was found between the intracellular binding of taxol and the intracellular levels of alpha- and beta-tubulin, or t he intracellular concentration of polymerized tubulin. These studies w ere extended further by assessing the binding of taxol to semi-purifie d microtubule proteins from WS, CHO and 2008/C13 cells in vitro. The microtubule protein preparations from WS, CHO and 2008/C13 cells, whi ch have a 50-fold difference in their sensitivity to taxol, were found to bind equal amounts of radiolabeled taxol, and this binding was inh ibited (80%) in the presence of unlabeled taxol. These results lead us to propose the presence in the rodent cells of an alternative taxol t ransport system that is distinct from the P-glycoprotein and MRP syste ms.