Effect of nucleoside transport inhibitors on thymidine salvage and the toxicity of nucleoside analogs in mouse bone marrow granulocyte-macrophage progenitor cells.
In an attempt to elucidate the types of nucleoside transporters present in bone marrow stem cells, this study examined the effect of nucleoside transport inhibitors on the toxicity of nucleoside analogs and on the salvage of thymidine by mouse bone marrow granulocyte and macrophage progenitor cells using the CFU-GM assay. Concentrations of NBMPR (nitrobenzylmercaptopurine riboside) as low as 10 nM protected these cells from the toxicity of the adenosine analog tubercidin and provided a partial block of thymidine-rescue of the granulocyte-macrophage progenitor cells from methotrexate toxicity. Dipyridamole had similar effects but generally required higher concentrations. These results suggested that the major nucleoside transporter in these cells is the NBMPR-sensitive equilibrative carrier, es. In contrast to the results with tubercidin, the toxicity of 2-chlorodeoxyadenosine was increased 8- to 10-fold by 1 microM NBMPR. These results suggested that the bone marrow granulocyte-macrophage progenitor cells also have a concentrative nucleoside transporter that is capable of pumping 2-chlorodeoxyadenosine into the cells while efflux of the nucleoside via es is blocked by NBMPR.
Marina
N M
NM
Department of Hematology and Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101, USA.
Belt
J A
JA
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000633:toxicity; D001692:Biological Transport; D001854:Bone Marrow Cells / Q000187:drug effects; D002478:Cells, Cultured; D017338:Cladribine / Q000633:toxicity; D005260:Female; D006098:Granulocytes / Q000187:drug effects* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008727:Methotrexate / Q000633:toxicity; D051379:Mice; D008808:Mice, Inbred CBA; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors*; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism*; D014372:Tubercidin / Q000633:toxicity
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D033703:Nucleoside Transport Proteins; D013868:Thioinosine; D017338:Cladribine; C001789:4-nitrobenzylthioinosine; D014372:Tubercidin; D013936:Thymidine; D008727:Methotrexate