Differential selectivity of 5-fluorouracil and 5'-deoxy-5-fluorouridine in cultured human B lymphocytes and mouse L1210 leukemia.
The role of differential metabolic activation of a 5-fluorouracil (FU) prodrug, 5'-deoxy-5-fluorouridine (dFUR), in achieving selective cytotoxicity was investigated in cultured human (dFUR), in achieving selective cytotoxocity was investigated in cultured human B lymphocytes and murine leukemia L1210 cells. B cells were cross-sensitive to FU and dFUR. On the other hand, leukemia L1210 cells were sensitive to FU but resistant to dFUR. The difference in the biological activities of FU and dFUR in B and L1210 cells correlated with (a) the metabolism of dFUR to FU by intact B (60% conversion) and L1210 (no conversion) cells, and (b) the phosphorylase activity of B (660 nmoles converted in 2 hr per mg protein) and L1210 (undetectable) cells. The intracellular metabolism of FU and dFUR was studied using a reversed-phase ion-pair high pressure liquid chromatographic assay. FU and dFUR shared similar metabolic pathways in B cells; their anabolites included FU ribose and deoxyribose nucleosides and nucleotides. In L1210 cells, FU was anabolized to 5-fluorouridine triphosphate and 5-fluorodeoxyuridine monophosphate, whereas dFUR was present mainly as the unchanged drug. Further metabolism studies using dFUR with tritium label in either the FU moiety or the altered sugar moiety established that the metabolic pathway of dFUR to cytotoxic FU anabolites in the B cells was via phosphorolysis to FU. These data indicate that, on a cellular level, an FU prodrug such as dFUR, which is activated by cytosolic enzyme, has a different selectivity from that of FU, and that the basis of differential selectivity is the initial phosphorolysis to FU.
D000818:Animals; D000970:Antineoplastic Agents; D001202:Ascitic Fluid / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005260:Female; D005467:Floxuridine / Q000378:metabolism / Q000494:pharmacology*; D005472:Fluorouracil / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007939:Leukemia L1210 / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D014543:Uridine Phosphorylase / Q000378:metabolism
D000970:Antineoplastic Agents; D005467:Floxuridine; D004247:DNA; D014543:Uridine Phosphorylase; D005472:Fluorouracil; C025034:doxifluridine