Enhanced production of intracellular ara-CTP after sequential use of methotrexate and 1-beta-D-arabinofuranosylcytosine.
Synergistic antiproliferative effect has been proven in vitro when mouse leukemic cells were sequentially treated with MTX and ara-C. The mechanism of this combination effect not well elucidated but the intracellular uptake of ara-C was higher when cells were pre-exposed to MTX. In this experiment, the intracellular ara-CTP was measured by HPLC after MTX and ara-C were sequentially administered to BDF1 mice bearing L1210 leukemic cell, either being sensitive or resistant to MTX. When MTX at the dose of 12 mg/kg was preceded 6 h and 3 h to ara-C at the dose of 25 mg/kg, the intracellular levels of ara-CTP were found to be significantly higher as compared with those of ara-C alone as control group. At 1 h after ara-C, ara-CTP was measured about 165 and 130% of the control levels, respectively, and at 12 h, ara-CTP was over 4 times higher of control level with group of mice to which MTX was preceded 6 h prior to MTX. On the contrary, the enhancement of ara-CTP production was definitely diminished with MTX-resistant cells in the same administrative model. From our present experiment, the time sequential modulation of intracellular ara-CTP production by MTX was reconfirmed in vivo, and this modulation might depend upon the sensitivity of MTX of leukemic cells.
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001085:Arabinofuranosylcytosine Triphosphate / Q000096:biosynthesis*; D001088:Arabinonucleotides / Q000096:biosynthesis*; D003561:Cytarabine / Q000008:administration & dosage*; D003845:Deoxycytosine Nucleotides / Q000032:analysis; D004334:Drug Administration Schedule; D007939:Leukemia L1210 / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D051379:Mice; D008815:Mice, Inbred Strains
D001088:Arabinonucleotides; D003845:Deoxycytosine Nucleotides; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; C024107:2'-deoxycytidine 5'-triphosphate; D008727:Methotrexate