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[Cancer Research 60, 5269-5277, September 15, 2000]
© 2000 American Association for Cancer Research

Tumor Biology

Specific Detection of Multidrug Resistance Proteins MRP1, MRP2, MRP3, MRP5, and MDR3 P-Glycoprotein with a Panel of Monoclonal Antibodies1

George L. Scheffer, Marcel Kool, Marc Heijn, Marcel de Haas, Adriana C. L. M. Pijnenborg, Jan Wijnholds, Ardy van Helvoort, Mariska C. de Jong, Jan H. Hooijberg, Carla A. A. M. Mol, Marcel van der Linden, J. Marleen L. de Vree, Paul van der Valk, Ronald P. J. Oude Elferink, Piet Borst and Rik J. Scheper2

Departments of Pathology [G. L. S., A. C. L. M. P., M. C. d. J., P. v. d. V., R. J. S.] and Oncology [M. H., J. H. H.], Free University Hospital, 1081 HV Amsterdam; Division of Molecular Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam [M. K., M. d. H., J. W., A. v. H., C. A. A. M. M., M. v. d. L., P. B.]; and Department of Gastrointestinal and Liver Diseases, Academic Medical Center, 1105 AZ Amsterdam [J. M. L. d. V., R. P. J. O. E.], the Netherlands

Tumor cells may display a multidrug resistance phenotype by overexpression of ATP binding cassette transporter genes such as multidrug resistance (MDR) 1 P-glycoprotein (P-gp) or the multidrug resistance protein 1 (MRP1). MDR3 P-gp is a close homologue of MDR1 P-gp, but its role in MDR is probably minor and remains to be established. The MRP1 protein belongs to a family of at least six members. Three of these, i.e., MRP1, MRP2, and MRP3, can transport MDR drugs and could be involved in MDR. The substrate specificity of the other family members remains to be defined. Specific monoclonal antibodies are required for wide-scale studies on the putative contribution of these closely related transporter proteins to MDR.

In this report, we describe the extensive characterization of a panel of monoclonal antibodies (Mabs) detecting several MDR-related transporter proteins in both human and animal tissues. The panel consists of P3II-1 and P3II-26 for MDR3 P-gp; MRPr1, MRPm6, MRPm5, and MIB6 for MRP1; M2I-4, M2II-12, M2III-5 and M2III-6 for MRP2; M3II-9 and M3II-21 for MRP3; and M5I-1 and M5II-54 for MRP5. All Mabs in the panel appeared to be fully specific for their cognate antigens, both in Western blots and cytospin preparations, as revealed by lack of cross-reactivity with any of the other family members. Indeed, all Mabs were very effective in detecting their respective antigens in cytospins of transfected cell lines, whereas in flow cytometric and immunohistochemical analyses, distinct differences in reactivity and suitability were noted. These Mabs should become valuable tools in studying the physiological functions of these transporter proteins, in screening procedures for the absence of these proteins in hereditary metabolic (liver) diseases, and in studying the possible contributions of these molecules to MDR in cancer patients.




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