Es nucleoside transporter content of acute leukemia cells: role in cell sensitivity to cytarabine (araC).
Nucleoside analogs are important components of treatment regimens for acute leukemia in adults. Plasma membrane permeation of the nucleoside analog molecules, the initial event in the cellular conversion of nucleosides to active agents, is mediated by nucleoside-specific membrane transporters. The widely-expressed es nucleoside transporter accepts as substrates diverse nucleoside analogs, including cytarabine (araC), 2-chlorodeoxyadenosine, and fludarabine. The cellular content of es transporter sites has been measured in blasts from patients with acute lymphoblastic leukemia and acute myelogenous leukemia, by a sensitive, quantitative flow cytometry assay that employs the tightly-bound es ligand, SAENTA fluorescein. Values for es transporter expression varied ten-fold among samples from patients with acute myelogenous leukemia. In this article, we review current findings that document, in confocal fluorescence microscopy images and in flow cytometry assays of SAENTA fluorescein-stained cells, the patient-to-patient variance of es transporter expression in leukemic blasts from patients. Our data show a correlation between the expression of es transporters and the in vitro sensitivity to nucleoside drugs of blasts from acute leukemia patients. These findings show that the flow cytometry assay of es expression provides a facile means of predicting resistance of leukemia cells to the cytotoxicity of araC and other nucleosides.
Gati
W P
WP
Department of Pharmacology, University of Alberta, and Cross Cancer Institute, Edmonton, Canada.
Paterson
A R
AR
Belch
A R
AR
Chlumecky
V
V
Larratt
L M
LM
Mant
M J
MJ
Turner
A R
AR
D000208:Acute Disease; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003561:Cytarabine / Q000493:pharmacokinetics*; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005452:Fluoresceins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D018613:Microscopy, Confocal; D033703:Nucleoside Transport Proteins; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism*; D011684:Purine Nucleosides / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D005452:Fluoresceins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; D011684:Purine Nucleosides; D003561:Cytarabine; C079645:5-(SAENTA-x8)fluorescein