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: J Galivan, M S Rhee, T B Johnson, T C Chou, M G Nair, M Bunni, D Priest
• Journal: Advances in enzyme regulation (Adv Enzyme Regul) Vol. 28 Pg. 13-21 ( 1989) ISSN: 0065-2571 [Print] England
• PMID: 2624172 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Folic Acid Antagonists
• Hypoxanthines
• Quinazolines
• Tetrahydrofolates
• Hypoxanthine
• lometrexol
• CB 3717
• Folic Acid
• Thymidine

Topics

• Animals
• Cell Line
• Cell Survival (drug effects)
• Folic Acid (analogs & derivatives, pharmacology)
• Folic Acid Antagonists (pharmacology)
• Hypoxanthine
• Hypoxanthines (pharmacology)
• Liver Neoplasms, Experimental
• Quinazolines (pharmacology)
• Rats
• Tetrahydrofolates (pharmacology)
• Thymidine (pharmacology)
• Tumor Cells, Cultured (cytology, drug effects, metabolism)