The effects of combined antifolates on inhibition of growth of murine leukemia cells cultured in vitro.
The synergistic effect of trimetrexate (TMTX) and sulphonamide derivatives of quinazoline on the cultured 5178Y murine leukemia cells was examined. On exposure to the slightly inhibitory concentrations of TMTX (0.1 nM) in combination with 2-desamino-2-methyl-10-propargyl-5,8-dideaza-pteroyl-sulphoglyc ine (DMPDDSF) (0.02 microM) a synergistic inhibitory effect of the antifolates on cell growth was observed. These two drugs in the same combination caused also synergistic inhibition of de novo synthesis of thymidylate in intact cells as measured by tritium release from [5-(3)H]deoxyuridylate. This was accompanied by a marked reduction in intracellular concentration of 5,10-methylenetetrahydro-pteroyl-polyglutamate (5,10CH2H4PteGlu(n)) (0.2 microM) and dihydropteroyl-polyglutamate (0.12 microM). In these conditions de novo biosynthesis of purine was decreased by 50%. These observations show that growth inhibition by combined antifolates is mediated by intracellular depletion of the substrate of thymidylate synthase -- 5,10CH2H4PteGlu(n). The results obtained strongly suggest that under certain conditions inhibition of thymidylate synthesis by DMPDDSF is intensified by prior application of TMTX -- an inhibitor of dihydrofolate reductase.
Balińska
M
M
M. Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw. mlb@nencki.gov.pl
Szablewska
I
I
Janiszewska
D
D
Bartuzi
K
K
Pawełczak
K
K
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / 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; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000096:biosynthesis; D016597:Trimetrexate / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
C111037:2-desamino-2-methyl,-10-propargyl-5,8-dideaza-pteroylsulpho-glycine; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011624:Pteroylpolyglutamic Acids; C024897:dihydropteroylpolyglutamate; D013938:Thymidine Monophosphate; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase; D016597:Trimetrexate