title: Multidrug resistance protein attenuates gemtuzumab ozogamicin-induced cytotoxicity in acute myeloid leukemia cells.
abstract: Gemtuzumab ozogamicin (GO) is a novel immunoconjugate therapy for acute myeloid leukemia (AML). P-glycoprotein (Pgp) confers resistance to GO and is associated with a worse clinical response. To address whether multidrug resistance protein (MRP) affects GO susceptibility, we characterized Pgp, MRP1, and MRP2 expression in CD33+ cell lines and CD33+ AML samples and analyzed the effect of the Pgp inhibitor cyclosporine (CSA) and the MRP inhibitor MK-571 on GO-induced cytotoxicity. MRP1, but not MRP2, expression correlated with MRP activity. MK-571 enhanced GO-induced cytotoxicity in Pgp-negative/MRP-positive NB4 and HL-60 cells. CSA, but not MK-571 alone, restored GO susceptibility in Pgp-positive/MRP-positive TF1 cells; however, MK-571 enhanced cytotoxicity in the presence of CSA. All patient samples exhibited MRP activity, and 17 of 23 exhibited Pgp activity. CSA increased GO-induced cytotoxicity in 12 Pgp-positive samples, whereas MK-571 alone was effective in only one sample with minimal Pgp activity. In 3 Pgp-positive/MRP-positive samples, MK-571 enhanced GO-induced cytotoxicity in the presence of CSA. Thus, MRP1 may attenuate susceptibility to GO. This effect was comparatively less than that for Pgp and required the inhibition of Pgp for detection in cells that coexpressed both transporters. Because MK-571 and CSA failed to affect cytotoxicity in a portion of Pgp-positive/MRP-positive AML samples, additional resistance mechanisms are likely important.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. rwalter@fhcrc.org
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
authors.forename: Brian W
authors.initials: BW
authors.lastname: Raden
authors.forename: Tom C
authors.initials: TC
authors.lastname: Hong
authors.forename: David A
authors.initials: DA
authors.lastname: Flowers
authors.forename: Irwin D
authors.initials: ID
authors.lastname: Bernstein
authors.forename: Michael L
authors.initials: ML
authors.lastname: Linenberger
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D000079982:Gemtuzumab; D018922:HL-60 Cells; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D063268:Sialic Acid Binding Ig-like Lectin 3; D014407:Tumor Cells, Cultured
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; D003524:Cyclosporins; D000922:Immunotoxins; D011422:Propionates; D011804:Quinolines; D012333:RNA, Messenger; D063268:Sialic Acid Binding Ig-like Lectin 3; C059141:verlukast; D000079982:Gemtuzumab