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Monoclonal Antibody to an External Epitope of the Human mdr1 P-Glycoprotein¹

Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and The Children's Hospital, Boston, Massachusetts 02115 [R. J. A., K. S., J. C.], and the Netherlands Cancer Institute, Amsterdam [A. S.], the Department of Neurology, [E B.], and the Department of Pathology, Academic Medical Center, University of Amsterdam [J. B.], the Netherlands

² To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, Pediatric Hematology/Oncology, 44 Binney Street, Boston, MA 02115.

A membrane glycoprotein, termed P-glycoprotein, has been shown to be responsible for cross-resistance to a broad range of structurally and functionally distinct cytotoxic agents. P-glycoprotein, encoded in humans by the mdr1 gene, functions as an energy-dependent efflux pump to exclude these cytotoxic agents from the resistant cell. In order to study the phenomenon of multidrug resistance in both normal and neoplastic cells, we have generated a mouse monoclonal antibody directed to an external epitope of the human P-glycoprotein. This monoclonal antibody, 4E3, is an IgG2a class antibody which specifically recognizes the human mdr1 P-glycoprotein but not the mdr3 gene product. The 4E3 monoclonal antibody immunoprecipitates both the glycosylated and nonglycosylated forms of P-glycoprotein under mild denaturation conditions. In addition, 4E3 can detect P-glycoprotein in immunocytochemical analysis of fixed tissue-cultured cells and in analysis of frozen sections of human tissue. Binding of the monoclonal antibody to multidrug-resistant cells does not significantly affect the intracellular accumulation or potentiate the cytotoxicity of daunomycin in multidrug-resistant cells. However, at high concentrations of antibody, 4E3 produces a mild potentiation of vinblastine and actinomycin cytotoxicity in multidrug-resistant cells. This monoclonal antibody will be useful both for analyzing P-glycoprotein expression in normal and neoplastic cells and for isolating live cells expressing the P-glycoprotein without significantly affecting the efflux functions of the transporter.

¹ This work was supported by NIH Grant CA48162 and the Gaffney Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/ 1/92. Accepted 11/ 4/92.

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