Transport of topoisomerase I inhibitors by the breast cancer resistance protein. Potential clinical implications.
The multidrug resistance protein BCRP (breast cancer resistance protein) is a member of the ATP-binding cassette family of drug transporters. Overexpression of BCRP caused by exposure of cells to mitoxantrone (MX) or doxorubicin/verapamil resulted in a resistance pattern that is different from what is generally seen in the case of P-glycoprotein and MRP1 overexpression. Recently, the BCRP gene has been described in ovarian, breast, colon, and gastric cancer and fibrosarcoma cell lines. Our human tumor cells T8 and MX3, derived from the ovarian cancer cell line IGROV1 by stepwise increased exposure to topotecan and MX, are resistant to topotecan, CPT11, SN38, and 9-aminocamptothecin as well as MX. Increased energy-dependent efflux of affected drugs was noted. BCRP is a very efficient transporter of topotecan. Our recent studies, using the monoclonal antibody (mAb) BXP34, revealed that BCRP is located in the plasma membrane of the T8 and MX3 cell lines. Preliminary results of staining of human tumor cells showed low or absent levels of BCRP in a panel of solid tumors and acute myeloid leukemia cells.
Schellens
J H
JH
The Netherlands Cancer Institute, Department of Medical Oncology and Experimental Therapy, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. jhm@nki.nl
Maliepaard
M
M
Scheper
R J
RJ
Scheffer
G L
GL
Jonker
J W
JW
Smit
J W
JW
Beijnen
J H
JH
Schinkel
A H
AH
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology; D009363:Neoplasm Proteins; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000493:pharmacokinetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D059004:Topoisomerase I Inhibitors; C080125:9-aminocamptothecin; D000077146:Irinotecan; D019772:Topotecan; D008942:Mitoxantrone; D002166:Camptothecin