title: The enhancement of the activity of 10-propargyl-5,8-dideazafolate and 5,10-dideazatetrahydrofolate by inhibitors of dihydrofolate reductase.
abstract: Treatment of H35 hepatoma cells with the lipid soluble dihydrofolate reductase inhibitors metoprine and trimetrexate cause a nearly 10-fold increase in the toxicity of the antipyrimidine folate analogue PDDF and the antipurine folate analogue DDATHF. Evaluation of these interactions by the combination index developed by Chou (17-20) yields results conforming to synergistic interactions. The capacity of PDDF to inhibit thymidylate synthase in intact cells as measured by tritium release from [5-3H]deoxyuridine was increased by approximately the same amount by preincubation with the dihydrofolate reductase inhibitors. The primary effect of the reductase inhibitors in causing greater activity may be a reduction in cellular folates which can cause 5,10-CH2H4PteGlun to decrease and cellular PDDF (polyglutamates) to increase. These conditions would favor inhibition of thymidylate synthase by PDDF by promoting formation of the stable, inhibited PDDF (polyglutamates)-thymidylate synthase-dUMP complex (12).
authors.affiliation: Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-0509.
authors.forename: J
authors.initials: J
authors.lastname: Galivan
authors.forename: M S
authors.initials: MS
authors.lastname: Rhee
authors.forename: T B
authors.initials: TB
authors.lastname: Johnson
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: M G
authors.initials: MG
authors.lastname: Nair
authors.forename: M
authors.initials: M
authors.lastname: Bunni
authors.forename: D
authors.initials: D
authors.lastname: Priest
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D019271:Hypoxanthine; D007042:Hypoxanthines / Q000494:pharmacology; D008114:Liver Neoplasms, Experimental; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D013763:Tetrahydrofolates / Q000494:pharmacology*; D013936:Thymidine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
chemical_list: D005493:Folic Acid Antagonists; D007042:Hypoxanthines; D011799:Quinazolines; D013763:Tetrahydrofolates; D019271:Hypoxanthine; C045894:lometrexol; C031662:CB 3717; D005492:Folic Acid; D013936:Thymidine