title: Imatinib-resistant CML cells have low ENT activity but maintain sensitivity to gemcitabine.
abstract: Philadelphia chromosome-positive chronic myelogenus leukemia (CML) is widely treated with imatinib mesylate (imatinib), a potent inhibitor of the Bcr-Abl tyrosine kinase. However, resistance to this compound remains a concern. Current treatment approaches include combinations of imatinib with nucleoside analogs such as gemcitabine, which requires equilibrative nucleoside transporters (ENTs) for uptake, to overcome this resistance. Here we report that imatinib treatment decreased ENT1-dependent activity and mRNA expression. Although, imatinib-resistant cells showed decreased levels of both ENT1 and ENT2 activity and expression, these cells remained sensitive to gemcitabine, suggesting that nucleoside analogs can be used as adjunctive therapy.
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
authors.forename: Andrea V
authors.initials: AV
authors.lastname: Leisewitz
authors.forename: Eric I
authors.initials: EI
authors.lastname: Zimmerman
authors.forename: Shannon Z
authors.initials: SZ
authors.lastname: Jones
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Lee M
authors.initials: LM
authors.lastname: Graves
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D001549:Benzamides; D002417:Cattle; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D033705:Equilibrative Nucleoside Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D033721:Equilibrative Nucleoside Transporter 1; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000068877:Imatinib Mesylate; D051379:Mice; D033703:Nucleoside Transport Proteins / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D033705:Equilibrative Nucleoside Transport Proteins; D033721:Equilibrative Nucleoside Transporter 1; D033703:Nucleoside Transport Proteins; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; C498476:SLC29A1 protein, mouse; D003841:Deoxycytidine; D000068877:Imatinib Mesylate; D000093542:Gemcitabine