OVERLAPPING PHENOTYPES OF MULTIDRUG-RESISTANCE AMONG PANELS OF HUMAN CANCER-CELL LINES

In addition to P-glycoprotein (Pgp), 2 proteins related to multidrug r esistance (MDR) have recently been described. The Multidrug-Resistance -associated protein (MRP) is one of the ATP-binding-cassette (ABC) tra nsporters. The Lung-Resistance Protein (LRP) is the major component of human vaults, which are newly described cellular organelles and thoug ht to mediate intracellular transport processes. Using immunocytochemi cal methods, we have examined the expression of MRP and LRP among pane ls of human cancer-cell lines not selected for drug resistance which h ave been previously characterized for expression of Pgp, and in vitro response to a variety of anti-cancer drugs. Expression of MRP and LRP was observed in 47/55 (87%) and 46/59 (78%) cell lines, respectively. Statistically significant correlations were observed between expressio n of each of these 3 proteins and in vitro sensitivity to at least one drug classically associated with MDR. LRP showed the greatest individ ual predictive value, which also applied to several nonclassical MDR d rugs. Co expression of 2-3 MDR-related proteins was observed in 64% of the lines and was, in general, associated with high relative levels o f drug resistance. Previously identified ''classic'' MDR lines as well as ''pan-resistant'' lines concurrently expressed all 3 MDR-related p roteins. Some highly drug-resistant cell lines without detectable MDRI /Pgp were found to express relatively high levels of MRP and LRP. The high prevalence of MRP and LRP expression observed in this large set o f cell lines, which have not been subjected to laboratory drug selecti on, suggests that MDR mechanisms associated with these proteins may be widespread in human malignancies. Moreover, the overlapping of these more recently recognized MDR phenotypes with Pgp-type MDR results in a complex phenotype, the understanding of which may be of importance in the development of new drugs and design of clinical treatment protoco ls, particularly those seeking to employ strategies to reverse the MDR phenotype. (C) 1996 Wiley-Liss, Inc.