The novel nucleoside transport system exhibited by NB4 cells, csg, transports deoxyguanosine analogues, including ara-G.
We studied acceptance of various deoxyguanosine analogues by the unique guanosine preferring nucleoside transport system exhibited by NB4 cells, csg. Indirect assessment of acceptance using transport inhibition assays revealed that both 1-beta-D-arabinofuranosylguanine (ara-G) and 4'-thio-beta-D-xylofuranosylguanine (thio-xyl-G) compete with guanosine for the csg system, inhibiting guanosine flux by approximately 50%. Direct examination of [3H]-ara-G transport revealed total transport was equally allocated to csg, and es systems and a total transport rate similar to that determined for guanosine [Flanagan and Meckling-Gill, J Biol Chem 1997;272:18026-32]. Cytotoxicity assays revealed that although both ara-G and thio-xyl-G were capable of competing with guanosine for the csg system, neither analogue elicited cytotoxic effects at physiologically relevant concentrations. The analog, 4'-thio-beta-D-arabinofuranosylguanine does not gain entry to NB4 cells via the csg transport system. Competition assays revealed that this analogue potentiated the inward flux of guanosine and was capable of killing NB4 cells with potency similar to the conventional leukemia drug, ara-C.
Flanagan
Sheryl A
SA
Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ont., Canada N1G 2W1.
Gandhi
Varsha
V
Secrist
John A
JA
Meckling
Kelly A
KA
D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001087:Arabinonucleosides / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D003849:Deoxyguanosine / Q000493:pharmacokinetics* / Q000494:pharmacology; D006151:Guanosine / Q000378:metabolism; D006801:Humans; D014316:Tritium; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D014316:Tritium; D006151:Guanosine; C028771:9-arabinofuranosylguanine; D003849:Deoxyguanosine