Methotrexate-induced changes in the levels of 1-beta-D-arabinofuranosylcytosine triphosphate in L1210 cells.
Treatment with methotrexate (MTX) plus 1-beta-D-arabinofuranosylcytosine (ara-C) on Days 1, 4, and 7 after i.p. inoculation of L1210 ascites cells was more effective than treatment with one drug on Days 1, 4, and 7 followed by the second drug on Days 2, 5, and 8. Simultaneous treatment with both drugs was associated with a retention of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) but no increase in the activity of deoxycytidine kinase in L1210 cells, whereas pretreatment with MTX 24 hr before the administration of ara-C was associated with approximately 2-fold increases in the level of ara-CTP and of deoxycytidine kinase in L1210 cells. However, from 5 hr after treatment with ara-C, higher levels of ara-CTP were observed in L1210 cells treated simultaneously with both drugs than in cells from animals pretreated with MTX 24 hr before treatment with ara-C. The superiority of simultaneous treatment over sequential treatment and the synergism between MTX and ara-C, previously reported for this schedule of simultaneous treatment, are attributed in part to the MTX-induced retention of ara-CTP and the increased exposure of L1210 cells to ara-CTP that results from the slower clearance of ara-CTP.
D000818:Animals; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism*; D001086:Arabinofuranosyluracil / Q000097:blood; D001088:Arabinonucleotides / Q000378:metabolism*; D003561:Cytarabine / Q000008:administration & dosage* / Q000097:blood; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004359:Drug Therapy, Combination; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D013997:Time Factors
D001088:Arabinonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D001086:Arabinofuranosyluracil; D003842:Deoxycytidine Kinase; D008727:Methotrexate