formycin-b and 5-hexyl-2--deoxyuridine

Previous studies have shown that 5-hexyl-2'-deoxyuridine (HdUrd) blocked the cytotoxic effects of 5-fluorodeoxyuridine and deoxyadenosine in L1210 cells. HdUrd had no effect in preventing the inhibitory effects of 5-fluorouracil. These data suggested that HdUrd was an inhibitor of nucleoside transport in L1210 cells (Cory, J. G.; Halley, M. C.; Janey, A.; Lapis, K. Cancer Res. 50:4552-4556; 1990). Studies have now been carried out which show that HdUrd inhibits nucleoside transport as measured by [3H]uridine or [3H]formycin B transport into L1210 cells in culture. The IC50 for HdUrd inhibition of total [3H]uridine uptake was approximately 20 microM in wild-type L1210 cells. Since wild-type L1210 cells have three distinct nucleoside transporters, the effect of HdUrd on each transporter was examined using the non-metabolized nucleoside analog, formycin B. The nitrobenzylmercaptopurine riboside (NBMPR)-sensitive transporter, es, was most sensitive to HdUrd with an IC50 of 1.0 +/- 0.1 microM; the NBMPR-insensitive transporter, ei, was much less sensitive to HdUrd with an IC50 of 32 +/- 2 microM; the sodium ion-dependent transporter, cif, was the least sensitive transporter to HdUrd with an IC50 of 130 +/- 5 microM. These data support the concept that HdUrd, a relatively non-cytotoxic agent, could be useful in increasing the potency of antitumor inhibitors directed at the de novo pathways for nucleotide synthesis through the blockage of the salvage pathways for nucleosides.

Topics: Animals; Antimetabolites, Antineoplastic; Biological Transport; Carrier Proteins; Deoxyuridine; Formycins; Kinetics; Leukemia L1210; Membrane Proteins; Nucleoside Transport Proteins; Tumor Cells, Cultured; Uridine