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 synthase-FdUrd and sulphonamide derivatives on murine leukemia cells-5178Y (parental subline) and 5178Y/F (its fluorodeoxyuridine resistant subline) in culture was examined. Upon the exposure of cultures from both lines to a slightly inhibitory concentration of FdUrd (1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphogluta mine or -glycine a synergistic effect of antimetabolites on cell growth was observed. This was accompanied by a marked reduction in intracellular concentration in both cell lines of 5,10CH2H4PteGlu; the intracellular concentration of 5,10CH2H4PteGlu(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 depends on the sequence of their addition; however in the FdUrd resistant cell-line the dependence on the sequence of the addition was not observed. The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by antifolates is intensified by proprior use of FdUrd.
Balinska
M
M
M. Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
Szablewska
I
I
Janiszewska
D
D
Brzezinska
A
A
Pawelczak
K
K
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005467:Floxuridine / Q000493:pharmacokinetics / Q000633:toxicity*; D005492:Folic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics / Q000633:toxicity*; D007940:Leukemia L5178 / Q000473:pathology*; D008099:Liver / Q000201:enzymology; D008727:Methotrexate / Q000633:toxicity; D051379:Mice; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D016597:Trimetrexate / Q000633:toxicity; D014407:Tumor Cells, Cultured
C111036:2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphoglutamine; D005493:Folic Acid Antagonists; D005467:Floxuridine; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D016597:Trimetrexate; D008727:Methotrexate