Antifolate drug interactions

Enhancement of growth inhibition due to the antipurine 5,10-dideazatetrahydrofolic acid by the lipophilic dihydrofolate reductase inhibitors metoprine and trimetrexate

J. Galivan, Z. Nimec, M. Rhee, D. Boschelli, A. L. Oronsky, S. S. Kerwar

Research output: Contribution to journalArticle

Abstract

The presence of low concentrations of the lipophilic dihydrofolate reductase inhibitors metoprine or trimetrexate, which cause little inhibition in the growth of cultured hepatoma cells in combiantion with weakly inhibiting concentrations of 5,10-dideazatetrahydrofolate, exhibit greater activity than would be predicted by the activity of the individual components. Growth inhibition by this inhibitor of glycineaminoribonucleotide transferase alone or in the presence of the reductase inhibitors is prevented by hypoxanthine indicating that the combination of drugs is enhancing the activity of 5,10-dideazatetrahydrofolate against purine biosynthesis. H35 hepatoma cells resistant to methotrexate (100-fold) as a result of a transport defect are 40-fold resistant to 5,10-dideazatetrahydrofolate suggesting that this analogue enters hepatoma cells at least in part by the reduced folate coenzyme-methotrexate transport system. The transport-resistant cells are also susceptible to enhanced inhibition of cell growth by low levels of reductase inhibitors in combination with 5,10-dideazatetrahydrofolate. These results have a corollary in an earlier study showing that the same concentrations of metoprine and trimetrexate could enhance the growth inhibition and cytotoxicity of the folate-based inhibitor of thymidylate synthase, 10-propargyl-5,8-dideazafolic acid (Galivan et al., Cancer Res., 47:5256-5260), 1987). Combinations of 5,10-dideazatetrahydrofolic acid and 10-propargyl-5,8-dideazafolic acid are less growth inhibitory than that predicted by each of the folate analogues alone. It is possible that the effects of all these combinations are related to distortions in the folate pools caused by the folate analogues being used in combination. Two methods of analysis, one graphical and one mathematical, were used to analyze the drug interactions described in this presentation. The enhancement effect seen with the lipophilic dihydrofolate reductase inhibitors and 5,10-dideazatetrahydrofolate clearly represents a supraadditive or a synergistic drug interaction. In contrast the combination of the folate-based inhibitors of purine (5,10-dideazatetrahydrofolic acid) and thymidylate biosynthesis (N10-propargyl-5,8-dideazafolate) exhibit frank antagonism under certain conditions.

Original languageEnglish (US)
Pages (from-to)2421-2425
Number of pages5
JournalCancer Research
Volume48
Issue number9
StatePublished - 1988
Externally publishedYes

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Trimetrexate
Folic Acid Antagonists
Drug Interactions
Folic Acid
Growth
Hepatocellular Carcinoma
Methotrexate
Oxidoreductases
Thymidylate Synthase
Growth Inhibitors
Hypoxanthine
Coenzymes
Drug Combinations
Transferases
metoprine
lometrexol
Cultured Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Antifolate drug interactions : Enhancement of growth inhibition due to the antipurine 5,10-dideazatetrahydrofolic acid by the lipophilic dihydrofolate reductase inhibitors metoprine and trimetrexate. / Galivan, J.; Nimec, Z.; Rhee, M.; Boschelli, D.; Oronsky, A. L.; Kerwar, S. S.

In: Cancer Research, Vol. 48, No. 9, 1988, p. 2421-2425.

Research output: Contribution to journalArticle

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abstract = "The presence of low concentrations of the lipophilic dihydrofolate reductase inhibitors metoprine or trimetrexate, which cause little inhibition in the growth of cultured hepatoma cells in combiantion with weakly inhibiting concentrations of 5,10-dideazatetrahydrofolate, exhibit greater activity than would be predicted by the activity of the individual components. Growth inhibition by this inhibitor of glycineaminoribonucleotide transferase alone or in the presence of the reductase inhibitors is prevented by hypoxanthine indicating that the combination of drugs is enhancing the activity of 5,10-dideazatetrahydrofolate against purine biosynthesis. H35 hepatoma cells resistant to methotrexate (100-fold) as a result of a transport defect are 40-fold resistant to 5,10-dideazatetrahydrofolate suggesting that this analogue enters hepatoma cells at least in part by the reduced folate coenzyme-methotrexate transport system. The transport-resistant cells are also susceptible to enhanced inhibition of cell growth by low levels of reductase inhibitors in combination with 5,10-dideazatetrahydrofolate. These results have a corollary in an earlier study showing that the same concentrations of metoprine and trimetrexate could enhance the growth inhibition and cytotoxicity of the folate-based inhibitor of thymidylate synthase, 10-propargyl-5,8-dideazafolic acid (Galivan et al., Cancer Res., 47:5256-5260), 1987). Combinations of 5,10-dideazatetrahydrofolic acid and 10-propargyl-5,8-dideazafolic acid are less growth inhibitory than that predicted by each of the folate analogues alone. It is possible that the effects of all these combinations are related to distortions in the folate pools caused by the folate analogues being used in combination. Two methods of analysis, one graphical and one mathematical, were used to analyze the drug interactions described in this presentation. The enhancement effect seen with the lipophilic dihydrofolate reductase inhibitors and 5,10-dideazatetrahydrofolate clearly represents a supraadditive or a synergistic drug interaction. In contrast the combination of the folate-based inhibitors of purine (5,10-dideazatetrahydrofolic acid) and thymidylate biosynthesis (N10-propargyl-5,8-dideazafolate) exhibit frank antagonism under certain conditions.",
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