EFFECT OF METHOTREXATE AND 1-BETA-D-ARABINOFURANOSYLCYTOSINE ON POOLS OF DEOXYRIBONUCLEOSIDE TRIPHOSPHATES IN L1210-ASCITES-CELLS

  • 1 January 1981
    • journal article
    • research article
    • Vol. 41  (2) , 505-510
Abstract
Pools of deoxyribonucleoside triphosphates in [mouse leukemia] L1210 cells were assayed for drug-induced changes that might indicate the metabolic basis for retention of 1-.beta.-D-arabinofuranosylcytosine triphosphate by these cells after treatment with methotrexate (MTX) and 1-.beta.-D-arabinofuranosylcytosine (ara-C). Within 20 min after treatment with MTX, the pool of deoxy(d) TTP had decreased by about 50% and during the next 8 h decreased slowly to 30% of its initial level. When MTX-induced decreases in the cellular contents of dCTP, dATP and dGTP were normalized to percentages of the initial levels, they coincided with the 2nd slower phase of decrease in dTTP. Levels of both dTTP and dCTP remained constant in cells from mice treated with 0.9% NaCl solution; levels of dATP and dGTP decreased. MTX caused a significantly more rapid decrease in the level of dATP than did 0.9% NaCl solution but not in the level of dGTP. Over 9 h, after injection of ara-C, levels of dTTP and dCTP doubled; levels of dATP and dGTP remained unchanged. When ara-C and MTX were administered together, levels of dTTP, dATP and dGTP did not change significantly; the increase in dCTP was only 25% of the increase after treatment with ara-C alone. The most striking change in deoxyribonucleoside triphosphate pools after combined administration of MTX and ara-C was an increase in dCTP concentration that reached about 1/4 the concentration achieved with ara-C alone. MTX, by attenuating the ara-C-induced increase in dCTP, probably caused a change in the allosteric regulation of deoxycytidine kinase or deoxycytidylate deaminase (or both), thereby potentiating the activity of ara-C.

This publication has 1 reference indexed in Scilit: