Acquisition of taxol resistance via P-glycoprotein- 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 microM (2008/13) or 0.5 microM (2008/17) taxol. Thereafter, a series of clones with increasing taxol resistance were derived from the 2008/17 and 2008/13 cells by stepwise sequential exposure to increasing concentrations of taxol. The 2008/17 clones displayed a classical P-glycoprotein-mediated drug-resistance phenotype. In contrast, the 2008/13 clones followed the classical P-glycoprotein-mediated resistance phenotype until a 245-fold taxol-resistant clone (2008/13/2) was obtained, which was followed by a further 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-associated protein and taxol resistance was observed. Verapamil increased the sensitivity of all drug-resistant clones to taxol, and this was probably related to the ability of verapamil to increase the intracellular concentration of taxol (except in the case of 2008/13/4 cells). The 2008/17 clones were highly cross-resistant to Adriamycin, etoposide, and vincristine. They also displayed a low level of cross-resistance to camptothecin but were not cross-resistant to cisplatin. The taxol-resistant 2008/13 clones displayed a similar pattern of cross-resistance for all drugs (except Adriamycin). The 2008/13 clones were only 2-to 4-fold cross-resistant 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 [3H]taxol to semipurified microtubule preparations 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 ovarian carcinoma cells resistance to taxol can be acquired via as yet undescribed mechanisms.