Modulation of 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity in L1210 cells by fluoropyrimidine pretreatment.
The effect of pretreatment with the fluoropyrimidines 5-fluorouracil (FUra), 5-fluorouridine (FUrd), 5-fluoro-2'-deoxyuridine (FdUrd), and 5'-deoxy-5-fluorouridine (5'-dFUrd) on the intracellular metabolism and in vitro cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C) was explored in L1210 cells. A 4-hr exposure to 100 microM FUra, FUrd, or FdUrd produced greater than 3-fold increments in the intracellular accumulation of [3H]deoxycytidine, and 2-fold increments in the intracellular accumulation of [3H]ara-C were produced over a 1-hr exposure. Intracellular 1-beta-D-arabinofuranosylcytosine 5'-triphosphate levels in cells exposed to these 3 agents were also increased over 2-fold. L1210 cells exposed sequentially to 1 microM FUra, FUrd, or FdUrd followed by 5 microM ara-C for 1 hr resulted in synergistic cell killing measured by soft-agar cloning. Although intracellular 2'-deoxycytidine 5'-triphosphate levels were reduced in cells treated for 4 hr with FUra and FUrd, this was not associated directly with the maximum accumulation of ara-C. FdUrd treatment was as effective as FUra and FUrd at enhancing ara-C accumulation and 1-beta-D-arabinofuranosylcytosine 5'-triphosphate formation and producing synergistic cytotoxicity; however, the 2'-deoxycytidine 5'-triphosphate pools were minimally affected. 5'-Deoxy-5-fluorouridine did not increase intracellular ara-C accumulation, reduce intracellular 2'-deoxycytidine 5'-triphosphate levels, or enhance ara-C cytotoxicity. This sequential drug interaction is similar to that which we have observed when methotrexate precedes ara-C and provides a rational basis from which further in vivo studies can be designed.
D000818:Animals; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002999:Clone Cells; D003561:Cytarabine / Q000378:metabolism* / Q000494:pharmacology; D003854:Deoxyribonucleotides / Q000378:metabolism; D003857:Deoxyuridine / Q000378:metabolism; D004347:Drug Interactions; D005467:Floxuridine / Q000494:pharmacology*; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D007939:Leukemia L1210; D051379:Mice; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology
D003854:Deoxyribonucleotides; D005467:Floxuridine; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D005468:Fluorodeoxyuridylate; C001943:5-fluorouridine; D005472:Fluorouracil; C025034:doxifluridine; D003857:Deoxyuridine; D014529:Uridine