Multidrug resistance phenotype and paclitaxel (Taxol) sensitivity in human renal carcinoma cell lines of different histologic types.
We compared the effects of paclitaxel (Taxol) in human renal cell carcinoma (RCC) of different histologic types. The growth inhibitory effects of paclitaxel on 34 human RCC cell lines of strictly defined different histologic types were determined by 3-[4,5-dimethylthiazolyl]-2,5-diphenyltetrazoliumbromide (MTT) assays. Paclitaxel-induced morphologic alterations were visualized by light and immunofluorescence and by transmission electron microscopy. The expression and function of P-glycoprotein and multidrug resistance-associated protein (MRP) were defined by reverse transcriptase polymerase chain reaction and fluorescence-activated cell sorting (FACS) analysis, respectively. Modulation of P-glycoprotein function was performed by verapamil or Cremophor EL. A significant (p < 0.05) dose-dependent paclitaxel-induced growth inhibition could be demonstrated in all cell lines, with the effects of paclitaxel dissolved in Cremophor EL/ethanol (= Taxol) exceeding the effects of paclitaxel dissolved in dimethyl sulfoxide. The extent of response markedly varied between the different cell lines, although chromophilic RCCs exhibited a more pronounced response to Taxol (IC50: 0.03-0.38 microM) than clear cell RCCs (IC50: 0.01-36.69 microM). Exposure to paclitaxel/Taxol induced an increase of microtubule bundles in the clear cell and the chromophobe RCCs but not in the chromophilic RCCs. The expression of the MRP was low in RCC cell lines and was not found to be related to paclitaxel/Taxol sensitivity. In contrast, the expression level of P-glycoprotein was much more pronounced and showed a positive correlation (p < 0.05) with the response to paclitaxel. Reversal of P-glycoprotein function by verapamil or Cremophor EL enhanced the growth inhibitory effects of paclitaxel and further supported the role of P-glycoprotein for paclitaxel sensitivity of human RCCs. Paclitaxel/Taxol effectively inhibits proliferation of human RCCs in vitro, irrespective of their histologic types. Moreover, expression and function of P-glycoprotein markedly contribute to paclitaxel responsiveness, although other as yet undefined drug resistance mechanisms are effective in human RCCs as well.
Reinecke
P
P
Institute of Pathology, University Hospital of Düsseldorf, Germany.
Schmitz
M
M
Schneider
E M
EM
Gabbert
H E
HE
Gerharz
C D
CD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000502:physiology; D018528:ATP-Binding Cassette Transporters / Q000032:analysis / Q000502:physiology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel / Q000494:pharmacology*; D010641:Phenotype; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel