P-glycoprotein and Mrp1 collectively protect the bone marrow from vincristine-induced toxicity in vivo.

Abstract

ABC transporter proteins may protect haematopoietic progenitor cells from chemotherapy-induced toxicity. By using an in vitro colony-forming assay, we found that bone marrow of Mdr1ab, Mrp1, Mdr1ab/Mrp1 knockout (KO) mice was two-, five- to 10- and 25-fold, respectively, more sensitive to vincristine than wild-type mice bone marrow. To study the impact of ABC transporters on in vivo bone marrow sensitivity without the added complication of altered pharmacokinetics, we created chimeras of wild-type mice transplanted with bone marrow from wild-type, Mrp1, Mdr1ab or Mdr1ab/Mrp1 KO donor mice. Following a single bolus injection of vincristine, the chimeras transplanted with wild-type or Mdr1ab KO marrow cells showed no reductions in WBC. A significant reduction was observed in Mrp1 KO chimeras, but the most pronounced effect was observed in mice receiving bone marrow from Mdr1ab/Mrp1 KO mice. A pharmacokinetic analysis in wild-type and KO mice showed that the absence of P-gp reduced the body clearance of vincristine, but that no further reduction occurred when Mrp1 was also absent. However, the tissue accumulation of vincristine in tissues of these Mdr1ab/Mrp1 KO mice was further increased. This study demonstrates that the presence of multiple drug transporters protects the bone marrow, and probably other tissues as well, against chemotherapeutic insults.