This Article Full Text 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 Johnson, D. R. Articles by Sartorelli, A. C. Search for Related Content PubMed PubMed Citation Articles by Johnson, D. R. Articles by Sartorelli, A. C.

The Pharmacological Phenotype of Combined Multidrug-Resistance mdr1a/1b- and mrp1-deficient Mice

Department of Pharmacology and Developmental Therapeutics Program, Cancer Center and Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520

Two major classes of plasma membrane proteins that actively extrude a wide range of structurally diverse hydrophobic amphipathic antineoplastic agents from cells, with different mechanisms of action, lead to multidrug resistance. To study the importance of these ATP-binding cassette transporters to the toxicity of cancer chemotherapy agents, we have used mice genetically deficient in both the mdr1a and mdr1b genes [mdr1a/1b(-/-) mice], the mrp1 gene [mrp1(-/-) mice], and the combined genes mdr1a/1b and mrp1 [mdr1a/1b(-/-), mrp1(-/-) mice] and embryonic fibroblasts derived from wild-type mice and from the three gene knockout animals. The consequences of export pump deficiencies were evaluated primarily using vincristine and etoposide. Mice deficient in the three genes, mdr1a/1b and mrp1, exhibited a 128-fold increase in toxicity to vincristine and a 3–5-fold increase in toxicity to etoposide; increased toxicity to embryonic fibroblast cells from triple knockout mice also occurred with vincristine and etoposide. Vincristine, which normally does not express toxicity to the bone marrow and to the gastrointestinal mucosa when used at therapeutic doses, caused extensive damage to these tissues in mdr1a/1b(-/-), mrp1(-/-) mice. The findings indicate that the P-glycoprotein and mrp1 are compensatory transporters for vincristine and etoposide in the bone marrow and the gastrointestinal mucosa and emphasize the potential for increased toxicities by the combined inhibition of these efflux pumps.

This article has been cited by other articles:

				J. S. Lagas, M. L.H. Vlaming, and A. H. Schinkel Pharmacokinetic Assessment of Multiple ATP-binding Cassette Transporters: The Power of Combination Knockout Mice Mol. Interv., June 1, 2009; 9(3): 136 - 145. [Abstract] [Full Text] [PDF]

				E. Hopper-Borge, X. Xu, T. Shen, Z. Shi, Z.-S. Chen, and G. D. Kruh Human Multidrug Resistance Protein 7 (ABCC10) Is a Resistance Factor for Nucleoside Analogues and Epothilone B Cancer Res., January 1, 2009; 69(1): 178 - 184. [Abstract] [Full Text] [PDF]

				K. B. Goralski, P. D. Acott, A. D. Fraser, D. Worth, and C. J. Sinal BRAIN CYCLOSPORIN A LEVELS ARE DETERMINED BY ONTOGENIC REGULATION OF MDR1A EXPRESSION Drug Metab. Dispos., February 1, 2006; 34(2): 288 - 295. [Abstract] [Full Text] [PDF]

				M. G. Belinsky, P. A. Dawson, I. Shchaveleva, L. J. Bain, R. Wang, V. Ling, Z.-S. Chen, A. Grinberg, H. Westphal, A. Klein-Szanto, et al. Analysis of the In Vivo Functions of Mrp3 Mol. Pharmacol., July 1, 2005; 68(1): 160 - 168. [Abstract] [Full Text] [PDF]

				D. Mahadevan and A. F. List Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies Blood, October 1, 2004; 104(7): 1940 - 1951. [Abstract] [Full Text] [PDF]

				M. F. De Rosa, D. Sillence, C. Ackerley, and C. Lingwood Role of Multiple Drug Resistance Protein 1 in Neutral but Not Acidic Glycosphingolipid Biosynthesis J. Biol. Chem., February 27, 2004; 279(9): 7867 - 7876. [Abstract] [Full Text] [PDF]

				Y. Mochida, K.-i. Taguchi, S. Taniguchi, M. Tsuneyoshi, H. Kuwano, T. Tsuzuki, M. Kuwano, and M. Wada The role of P-glycoprotein in intestinal tumorigenesis: disruption of mdr1a suppresses polyp formation in ApcMin/+ mice Carcinogenesis, July 1, 2003; 24(7): 1219 - 1224. [Abstract] [Full Text] [PDF]

				D. Burg, P. Wielinga, N. Zelcer, T. Saeki, G. J. Mulder, and P. Borst Inhibition of the Multidrug Resistance Protein 1 (MRP1) by Peptidomimetic Glutathione-Conjugate Analogs Mol. Pharmacol., November 1, 2002; 62(5): 1160 - 1166. [Abstract] [Full Text] [PDF]

				Z. P. Lin, D. R. Johnson, R. A. Finch, M. G. Belinsky, G. D. Kruh, and A. C. Sartorelli Comparative Study of the Importance of Multidrug Resistance-associated Protein 1 and P-Glycoprotein to Drug Sensitivity in Immortalized Mouse Embryonic Fibroblasts Mol. Cancer Ther., October 1, 2002; 1(12): 1105 - 1114. [Abstract] [Full Text] [PDF]

				N. Zelcer, T. Saeki, G. Reid, J. H. Beijnen, and P. Borst Characterization of Drug Transport by the Human Multidrug Resistance Protein 3 (ABCC3) J. Biol. Chem., November 30, 2001; 276(49): 46400 - 46407. [Abstract] [Full Text] [PDF]