Efficient inhibition of P-glycoprotein-mediated multidrug resistance with a monoclonal antibody.
P-glycoprotein (Pgp), encoded by the MDR1 gene, is an active efflux pump for many structurally diverse lipophilic compounds. Cellular expression of Pgp results in multidrug resistance (MDR) in vitro and is believed to be a clinically relevant mechanism for tumor resistance to chemotherapy. We have developed a mouse monoclonal antibody, UIC2, that recognizes an extracellular epitope of human Pgp. UIC2 inhibited the efflux of Pgp substrates from MDR cells and significantly increased the cytotoxicity of Pgp-transported drugs, under the conditions where no effect was detectable with other anti-Pgp antibodies. Potentiation of cytotoxicity by UIC2 was observed with all the tested drugs associated with MDR (vinblastine, vincristine, colchicine, taxol, doxorubicin, etoposide, actinomycin D, puromycin, and gramicidin D) but not with any of the drugs to which MDR cells are not cross-resistant (methotrexate, 5-fluorouracil, cis-platinum, G418, and gentamicin). The inhibitory effect of UIC2 in vitro was as strong as that of verapamil (a widely used Pgp inhibitor) at its highest clinically achievable concentrations. Our results suggest that UIC2 or its derivatives provide an alternative or supplement to chemical agents for the reversal of MDR in clinical cancer.
Mechetner
E B
EB
Department of Genetics, University of Illinois, Chicago, IL 60612.
Roninson
I B
IB
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D000937:Antigen-Antibody Reactions; D000954:Antigens, Surface / Q000276:immunology; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D014747:Vinblastine / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D008562:Membrane Glycoproteins; D014747:Vinblastine