Effects of nucleoside transport inhibitors on the salvage and toxicity of adenosine and deoxyadenosine in L1210 and P388 mouse leukemia cells

Abstract

Incubation of deoxycoformycin-treated L1210 leukemia cells with dipyridamole or nitrobenzylthioinosine, inhibitors of nucleoside transport, enhanced the long-term incorporation of 2'-deoxyadenosine and adenosine into the nucleotide pool and the toxicity of 2'-deoxyadenosine for the cells. In contrast, 2'-deoxyadenosine uptake in deoxycoformycin-treated P388 leukemia cells, which was about 10 times greater than that in L1210 cells, was inhibited by dipyridamole and nitrobenzylthioinosine, and 2'-deoxyadenosine toxicity was not significantly affected by the transport inhibitors. P388 cells also were about 6 times more resistant to 2'-deoxyadenosine than were L1210 cells, in spite of the greater uptake of the nucleoside. We found that purine nucleoside transport in L1210 and P388 cells exhibited similar kinetic properties and sensitivity to dipyridamole and nitrobenzylthioinosine (both influx and efflux) and that the stimulation of 2'-deoxyadenosine uptake by the inhibitors in L1210 cells is not mediated at the level of its transport into the cells but rather reflects an enhanced intracellular net accumulation of deoxyadenosine nucleotides.