Intrinsic drug resistance in primary and metastatic renal cell carcinoma

J Urol. 1999 Jul;162(1):217-24. doi: 10.1097/00005392-199907000-00071.


Much remains to be learned about drug resistance in the biology of RCC and its metastases. We measured MDR-1/P-glycoprotein expression in 19 tumor samples from patients with metastatic RCC by RNase protection and quantitative PCR assays. The median level of the 16 tumor metastases was 4.9 (range: 0.10 to 156.2) relative to the level of 10 assigned to a reference cell line, SW620, which has been characterized as expressing a minimum level of MDR-1. Since these levels were lower than expected for RCC, we asked whether the metastases possessed a phenotype different from primary RCC and examined MDR-1 expression in 5 paired cell lines derived from primary and metastatic RCC. In 8/10 lines, MDR-1 expression was >10. Relative to the level in the primary line, MDR-1 expression was decreased (3 to 50-fold) in 3 metastatic lines, was increased in 1, and unchanged in 1. MRP mRNA expression was lower in the metastatic lines while EGFR expression was variable. IC50 values for 6 compounds (including 4 standard agents and one new Phase 1 agent) were determined for the paired lines. Rhodamine and calcein efflux assays were performed as measures of P-glycoprotein and MRP function. Rhodamine efflux correlated with MDR-1 mRNA expression (r = 0.87) and with the IC50s (r = 0.60) for paclitaxel in the paired cell lines. In contrast, calcein efflux did not correlate with MRP expression. Lastly, MDR-1 expression correlated with cytokeratin 8 (CK8) protein levels, a measure of cellular differentiation. In sum, these data suggest renal cell carcinoma (RCC) metastases have altered MDR-1 expression potentially due to altered differentiation relative to the primary tumor. Thus, the drug resistance phenotype of primary RCC tumors may not reflect that of their metastases.

MeSH terms

  • ATP-Binding Cassette Transporters / biosynthesis
  • ATP-Binding Cassette Transporters / genetics
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / secondary
  • Drug Resistance, Neoplasm
  • ErbB Receptors / biosynthesis
  • ErbB Receptors / genetics
  • Fluorescent Dyes
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genes, MDR / genetics*
  • Humans
  • Intermediate Filament Proteins / biosynthesis
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / genetics*
  • Multidrug Resistance-Associated Proteins
  • Tumor Cells, Cultured


  • ATP-Binding Cassette Transporters
  • Fluorescent Dyes
  • Intermediate Filament Proteins
  • Multidrug Resistance-Associated Proteins
  • ErbB Receptors