EXPRESSION OF THE MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN (MRP) AND CHEMORESISTANCE OF HUMAN NON-SMALL-CELL LUNG-CANCER CELLS

Human non-small-cell lung cancer (NSCLC) is considered to he a chemoth erapy-refractory malignancy. The underlying mechanisms remain rather o bscure, The multidrug resistance-associated protein (MRP), mediating a multidrug resistance (MDR) phenotype, has been reported to be overexp ressed in several drug-selected lung cancer cell lines, A few previous studies have described intrinsic MRP expression in both NSCLC and nor mal lung tissues, However, the drug-transporting activity as well as t he correlation with chemoresistance is unclear, Using 15 unselected ce ll lines, we show that MRP (mRNA and protein as detected by reverse tr anscriptase polymerase chain reaction and immunoblot) is frequently ex pressed intrinsically, with markedly varying intensity, in NSCLC, Two cell lines expressed high MRP levels, one comparable to the drug-selec ted controls (GLC4/ADR, HL-60/AR) without, however, amplification of t he MRP gene (Southern hybridization), Using H-3-daunomycin (H-3-DM) an d calcein as MRP substrates and probenecid (PRO), genistein (GEN), ben zbromarone (BB), N-ethylmaleimide (NEM) and verapamil (VP) as MRP modu lators, drug accumulation studies revealed a transporting activity of MRP that correlated significantly with the gene expression data, Moreo ver, a significant correlation between MRP expression and chemoresista nce against daunomycin (DM), doxorubicin (DOX), etoposide (VP-16) and vinblastine (VBL), but not cisplatin (CDDP) and bleomycin (Bleo) (MTT- based survival assay), was detected, Correlations mainly rested on the pronounced chemoresistance of 2 highly MRP-expressing cell lines and did not reach significance when these cell lines were excluded. (C) 19 97 Wiley-Liss, Inc.