EFFECT OF COMBINED INHIBITORS OF THYMIDYLATE SYNTHASE-5-FLUORODEOXYURIDINE AND QUINAZOLINE ANTIFOLATES ON MURINE LEUKEMIA-CELLS CULTURED IN-VITRO

The synergistic effect of two different inhibitors of thymidylate synt hase - FdUrd and sulphonamide derivatives on murine leukemia cells - 5 178Y (parental subline) and 5178Y/F (its fluorodeoxyuridine resistant subline) in culture was examined. Upon the exposure of cultures from b oth lines to a slightly inhibitory concentration of FdUrd (1nM) in com bination with yl-10-propargyl-5,8-dideaza-pteroylsulphoglutamine or -g lycine a synergistic effect of antimetabolites on cell growth was obse rved This was accompanied by a marked reduction in intracellular conce ntration in both cell lines of 5,10CH(2)H(4)PteGlu; the intracellular concentration of 5,10CH(2)H(4)PteGlu(n) in the resistant subline was 3 times higher than in parental line. The inhibitory effect of combined drugs on the cellular pool of 5178Y of the two antimetabolites also d epends on the sequence of their addition; however in the FdUrd resista nt cell-line the dependence on the sequence of the addition was not ob served. The results obtained strongly suggest that under certain condi tions inhibition of thymidylate synthesis by antifolates is intensifie d by proprior use of FdUrd.