The enhancement of the activity of 10-propargyl-5,8-dideazafolate and 5,10-dideazatetrahydrofolate by inhibitors of dihydrofolate reductase.
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).
Galivan
J
J
Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-0509.
Rhee
M S
MS
Johnson
T B
TB
Chou
T C
TC
Nair
M G
MG
Bunni
M
M
Priest
D
D
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
D005493:Folic Acid Antagonists; D007042:Hypoxanthines; D011799:Quinazolines; D013763:Tetrahydrofolates; D019271:Hypoxanthine; C045894:lometrexol; C031662:CB 3717; D005492:Folic Acid; D013936:Thymidine