Mechanism of synergistic cell killing when methotrexate precedes cytosine arabinoside: study of L1210 and human leukemic cells.
Synergistic killing of L1210 cells occurs when methotrexate (MTX) is administered just before 1-beta-D-arabinofuranosylcytosine (Ara-C). This pehnomenon is dependent upon both the dose and time of exposure to MTX. Such increased killing of cells can be explained by the enhanced intracellular accumulation of Ara-C in cells exposed to MTX. This enhancement of Ara-C entry into cells was only observed when the dose of MTX was high enough (1, 10, and 100 muM) to result in free intracellular nondihydrofolate reductase-bound MTX. At the highest doses of MTX (10 and 100 muM) Ara-C triphosphate was increased eightfold and deoxycytidine triphosphate was decreased by 50%. Therefore, the maximum synergistic cell kill when MTX precedes Ara-C may be the consequence of greater inhibition of DNA polymerase by th;e increased Ara-C triphosphate in the presence of the decreasing natural substrate of this enzyme, deoxycytidine triphosphate. Enhanced Ara-C accumulation after administration of MTX was also observed in human acute myelogenous leukemia cells.
D000818:Animals; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D003561:Cytarabine / Q000008:administration & dosage* / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage*; D051379:Mice
D003854:Deoxyribonucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D008727:Methotrexate