ACQUISITION OF TAXOL RESISTANCE VIA P-GLYCOPROTEIN-MEDIATED AND NON-P-GLYCOPROTEIN-MEDIATED MECHANISMS IN HUMAN OVARIAN-CARCINOMA CELLS

Taxol-resistant clones from a human ovarian carcinoma cell line (2008) were selected by an initial exposure to 0.05 mu M (2008/13) or 0.5 mu M (2008/17) taxol. Thereafter, a series of clones with increasing tax ol resistance were derived from the 2008/17 and 2008/13 cells by stepw ise sequential exposure to increasing concentrations of taxol. The 200 8/17 clones displayed a classical P-glycoprotein-mediated drug-resista nce phenotype. In contrast, the 2008/13 clones followed the classical P-glycoprotein-mediated resistance phenotype until a 245-fold taxol-re sistant clone (2008/13/2) was obtained, which was followed by a furthe r increase in the degree of resistance but significant down-regulation of P-glycoprotein expression in the 252-fold taxol-resistant 2008/13/ 4 cells. This clone (2008/13/4) also accumulated significantly higher intracellular levels of taxol than those expressing the P-glycoprotein . No correlation between the expression of the multidrug resistance-as sociated protein and taxol resistance was observed. Verapamil increase d the sensitivity of all drug-resistant clones to taxol, and this was probably related to the ability of verapamil to increase the intracell ular concentration of taxol (except in the case of 2008/13/4 cells). T he 2008/17 clones were highly cross-resistant to Adriamycin(R), etopos ide, and vincristine. They also displayed a low level of cross-resista nce to camptothecin but were not cross-resistant to cisplatin. The tax ol-resistant 2008/13 clones were only 2- to 4-fold cross-resistant to Adriamycin. The levels of alpha tubulin and beta-tubulin were similar in the parental 2008 and taxol-resistant 2008/13/4 cells. Furthermore, the in vitro binding of [H-3]taxol to semipurified microtubule prepar ations derived from the parental 2008 and the taxol-resistant 2008/13/ 2 and 2008/13/4 cells was similar. These results show that in human ov arian carcinoma cells resistance to taxol can be acquired via as yet u ndescribed mechanisms. (C) 1996 Elsevier Science Inc.