The pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice

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 resista nce. To study the importance of these ATP-binding cassette transporters to the toxicity of cancer chemotherapy agents, we have used mice genetically d eficient in both the mdr1a and mdr1b genes [mdr1a/1b(-/-) mice], the mrp1 g ene [mrp1(-/-) mice], and the combined genes mdr1a/1b and mrp1 [mdr1a/1b(-/ -), mrp1(-/-) mice] and embryonic fibroblasts derived from wild-type mice a nd from the three gene knockout animals. The consequences of export pump de ficiencies were evaluated primarily using vincristine and etoposide. Mice d eficient in the three genes, mdr1a/1b and mrp1, exhibited a 128-fold increa se in toxicity to vincristine and a 3-5 fold increase in toxicity to etopos ide; increased toxicity to embryonic fibroblast cells from triple knockout mice also occurred with vincristine and etoposide. Vincristine, which norma lly does not express toxicity to the bone marrow and to the gastrointestina l mucosa when used at therapeutic doses, caused extensive damage to these t issues in mdr1a/1b(-/-), mrp1(-/-) mice. The findings indicate that the P-g lycoprotein and mrp1 are compensatory transporters for vincristine and etop oside in the bone marrow and the gastrointestinal mucosa and emphasize the potential for increased toxicities by the combined inhibition of these effl ux pumps.