P-glycoprotein and Mrp1 collectively protect the bone marrow from vincristine-induced toxicity in vivo.
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.
Department of Clinical Chemistry, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. o.v.tellingen@nki.nl
O
O
van Tellingen
T
T
Buckle
J W
JW
Jonker
M A
MA
van der Valk
J H
JH
Beijnen
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D016026:Bone Marrow Transplantation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D014018:Tissue Distribution; D018183:Transplantation Chimera; D014750:Vincristine / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014750:Vincristine