Synergistic effect of 5-fluorodeoxyuridine and quinazoline antifolates on murine leukemia self-cultured in vitro.
The effect of thymidylate synthase inhibitors, fluorodeoxyuridine (FdUrd) and its two sulphonamide derivatives was examined in the culture of murine leukemia cells -- 5178Y (parental subline) and its fluorodeoxyuridine resistant subline 5178Y/F. A synergistic effect of the antimetabolites on cell survival was observed on exposure of the culture of either line to a slightly inhibitory concentration of FdUrd (1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphogluta mate or 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphoglyci ne. This effect was accompanied by a marked reduction, in both cell lines of intracellular concentration of 5,10-methylenetetrahydro-pteroyl-polyglutamate, although its concentration in the resistant subline was 3 times as high as in the parental line. The inhibitory effect of combined drugs on the cellular pool of folates in 5178Y line depended also on the sequence of drug addition, whereas in the FdUrd resistant line this sequence was without any effect. The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by antifolates is intensified by a prior use of FdUrd.
Balińska
M
M
M. Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw.
Szablewska
I
I
Janiszewska
D
D
Brzezińska
A
A
Pawełczak
K
K
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004351:Drug Resistance; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005467:Floxuridine / Q000008:administration & dosage*; D005492:Folic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005493:Folic Acid Antagonists / Q000008:administration & dosage*; D007940:Leukemia L5178 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010453:Peptide Synthases / Q000378:metabolism; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D011623:gamma-Glutamyl Hydrolase / Q000378:metabolism
C111037:2-desamino-2-methyl,-10-propargyl-5,8-dideaza-pteroylsulpho-glycine; C111036:2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroylsulphoglutamine; D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011624:Pteroylpolyglutamic Acids; C024897:dihydropteroylpolyglutamate; D005467:Floxuridine; D005492:Folic Acid; D013940:Thymidylate Synthase; D011623:gamma-Glutamyl Hydrolase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase