Paclitaxel (Taxol) Resistance in Breast Cancer Cells.

Abstract : A paclitaxel resistant cell line, KPTA5, was established by co-selecting the parental cell line K562 with step-wise increased concentrations of paclitaxel (Taxol%) in the presence of the cyclosporin D analogue PSC 833 (2 %M), a potent modulator of the multidrug resistance phenotype. KPTA5 cells are 9-fold resistant to paclitaxel and taxotere, but do not exhibit significant resistance to vinca alkaloids, etoposide, anthracyclines, anti-metabolites, or alkylating agents. Doubling time and morphology were similar to the parental K562 cells. rt-PCR analysis revealed no alterations in the expression of the mdrl and MRP genes. Cellular paclitaxel accumulation was unchanged. Cell cycle analyses showed a significantly higher proportion of K562 cells blocked in G2/M, in comparison with KPTA5 cells. In both cases, disruption of the mitotic spindles and the presence of multiple mitotic asters were comparable but occurred at lower paclitaxel concentrations in K562 cells than in KPTA5 cells. KPTA5 cells have a 2-fold increase both in 5%-tubulin mRNA expression and in the corresponding tubulin protein Class W isotype content, as evaluated by rt-PCR and immunostaining. These cells display a novel phenotype of resistance to paclitaxel which suggests that alterations in expression of the 5(3-tubulin gene may be involved in resistance to this drug.