Intrinsic drug resistance in primary and metastatic renal cell carcinoma.
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.
Gamelin
E
E
Medicinal Oncology, Laboratory of Pathology, and Urologic Oncology Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mertins
S D
SD
Regis
J T
JT
Mickley
L
L
Abati
A
A
Worrell
R A
RA
Linehan
W M
WM
Bates
S E
SE
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005456:Fluorescent Dyes; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D019450:Genes, MDR / Q000235:genetics*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014407:Tumor Cells, Cultured
D018528:ATP-Binding Cassette Transporters; D066246:ErbB Receptors; D005456:Fluorescent Dyes; D007381:Intermediate Filament Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins