Multidrug resistance phenotype and paclitaxel (Taxol (R)) sensitivity in human renal carcinoma cell lines of different histologic types

We compared the effects of paclitaxel (Taxol(R)) in human renal cell carcin oma (RCC) of different histologic types. The growth inhibitory effects of p aclitaxel on 34 human RCC cell lines of strictly defined different histolog ic types were determined by 3-[4,5-dimethylthiazolyl]-2,5-diphenyltetrazoli umbromide (MTT) assays. Paclitaxel-induced morphologic alterations were vis ualized by light and immunofluorescence and by transmission electron micros copy. The expression and function of P-glycoprotein and multidrug resistanc e-associated protein (MRP) were defined by reverse transcriptase polymerase chain reaction and fluorescence-activated cell sorting (FACS) analysis, re spectively. Modulation of P-glycoprotein function was performed by verapami l or Cremophor(R) EL. A significant (p < 0.05) dose-dependent paclitaxel-in duced growth inhibition could be demonstrated in all cell lines, with the e ffects of paclitaxel dissolved in Cremophor(R) EL/ethanol (= Taxol(R)) exce eding the effects of paclitaxel dissolved in dimethyl sulfoxide. The extent of response markedly varied between the different cell lines, although chr omophilic RCCs exhibited a more pronounced response to Taxol (IC50: 0.03-0. 38 mu M) than clear cell RCCs (IC50: 0.01-36.69 mu M). Exposure to paclitax el/Taxol(R) induced an increase of microtubule bundles in the clear cell an d the chromophobe RCCs but not in the chromophilic RCCs. The expressions of the MRP was low in RCC cell lines and was not found to be related to pacli taxel/Taxol(R) sensitivity. In contrast, the expression level of P-glycopro tein was much more pronounced and showed a positive correlation (p < 0.05) with the response to paclitaxel. Reversal of P-glycoprotein function by ver apamil or Cremophor(R) EL enhanced the growth inhibitory effects of paclita xel and further supported the role P-glycoprotein for paclitaxel sensitivit y of human RCCs. Paclitaxel/Taxol(R) effectively inhibits proliferation of human RCCs in vitro, irrespective of their histologic types. Moreover, expr ession and function of P-glycoprotein markedly contribute to paclitaxel res ponsiveness, although other as yet undefined drug resistance mechanisms are effective in human RCCs as well.