This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mickisch, G. H. Articles by Pastan, I. Search for Related Content PubMed PubMed Citation Articles by Mickisch, G. H. Articles by Pastan, I.

Monoclonal Antibody MRK16 Reverses the Multidrug Resistance of Multidrug-resistant Transgenic Mice

Laboratories of Molecular Biology [G. H. M., L. H. P., I. P.] and Cell Biology [M. M. G.], Division of Cancer Biology, Diagnosis and Centers, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Using multidrug-resistant (MDR)-transgenic mice, whose bone marrow cells express the human MDR1 gene at a level approximately equal to that found in many human cancers, we determined the efficacy of human-specific anti-P-glycoprotein monoclonal antibody MRK16 in overcoming multidrug resistance in an intact animal. MRK16 alone (2 mg) did not significantly affect the WBC counts of the MDR-transgenic mice, but MRK16, as well as the F(ab')₂ fragments of MRK16, led to a dose-dependent circumvention of bone marrow resistance against daunomycin, doxorubicin, vincristine, vinblastine, etoposide, and taxol. This sensitizing effect could not be enhanced by combining MRK16 with low molecular weight chemosensitizing agents such as verapamil, quinine, quinidine, or cyclosporin A. We also investigated the concept of specifically targeting and killing multidrug-resistant cells by using MRK16 coupled to Pseudomonas exotoxin (PE). MRK16-PE resulted in a dose-dependent killing of bone marrow cells in MDR-transgenic mice, whereas no bone marrow toxicity was observed in normal control mice. Administration of excess MRK16 prior to injection of MRK16-PE successfully blocked the effect of MRK16-PE. MOPC-PE, a non-MDR-related control monoclonal antibody conjugate, did not target and kill multidrug-resistant bone marrow cells in MDR-transgenic mice. Thus, these immunological approaches to reversing multidrug resistance appear to be both specific and effective.

¹ G. H. M. is supported by Deutsche Forschungsgemeinschaft (DFG-Mi 334/1-1) and by Boehringer Mannheim Foundation.

² To whom requests for reprints should be addressed, at Building 37, Boom 4E 16, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.

Received 1/27/92. Accepted 6/ 4/92.

This article has been cited by other articles:

				S.-J. Kim, H. Uehara, S. Yazici, J. E. Busby, T. Nakamura, J. He, M. Maya, C. Logothetis, P. Mathew, X. Wang, et al. Targeting platelet-derived growth factor receptor on endothelial cells of multidrug-resistant prostate cancer. J Natl Cancer Inst, June 7, 2006; 98(11): 783 - 793. [Abstract] [Full Text] [PDF]

				W. Pfutzner, A. Terunuma, C. L. Tock, E. K. Snead, T. M. Kolodka, M. M. Gottesman, L. Taichman, and J. C. Vogel Topical colchicine selection of keratinocytes transduced with the multidrug resistance gene (MDR1) can sustain and enhance transgene expression in vivo PNAS, October 1, 2002; 99(20): 13096 - 13101. [Abstract] [Full Text] [PDF]

				V. V. Rao, J. L. Dahlheimer, M. E. Bardgett, A. Z. Snyder, R. A. Finch, A. C. Sartorelli, and D. Piwnica-Worms Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier PNAS, March 30, 1999; 96(7): 3900 - 3905. [Abstract] [Full Text] [PDF]