H. Parekh et al., ACQUISITION OF TAXOL RESISTANCE VIA P-GLYCOPROTEIN-MEDIATED AND NON-P-GLYCOPROTEIN-MEDIATED MECHANISMS IN HUMAN OVARIAN-CARCINOMA CELLS, Biochemical pharmacology, 53(4), 1997, pp. 461-470
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.