The enhancement of the activity of 10-propargyl-5,8-dideazafolate and 5,10-dideazatetrahydrofolate by inhibitors of dihydrofolate reductase

Adv Enzyme Regul. 1989;28:13-21. doi: 10.1016/0065-2571(89)90060-5.

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).

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Substances

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