Effect of Nucleoside Transport Inhibitors on Thymidine Salvage and the Toxicity of Nucleoside Analogs in Mouse Bone Marrow Granulocyte-Macrophage Progenitor Cells

Abstract

In an attempt to elucidate the types of nucleoside transporters present in bone marrow stem cells, thisstudy examined the effect of nucleoside transport inhibitors on the toxicity of nucleoside analogs and on the salvageof thymidine by mouse bone marrow granulocyte and macrophage progenitor cells using the CFU-GMassay. Concentrations of NBMPR (nitrobenzylmercaptopurine riboside) as low as 10 nM protected these cellsfrom the toxicity of the adenosine analog tubercidin and provided a partial block of thymidine-rescue of thegranulocyte-macrophage progenitor cells from methotrexate toxicity. Dipyridamole had similar effects but generallyrequired higher concentrations. These results suggested that the major nucleoside transporter in these cellsis 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 μM NBMPR. These results suggested that the bonemarrow granulocyte-macrophage progenitor cells also have a concentrative nucleoside transporter that is capableof pumping 2-chlorodeoxyadenosine into the cells while efflux of the nucleoside via es is blocked by NBMPR.