This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Galivan, J. Articles by Kerwar, S. S. Search for Related Content PubMed PubMed Citation Articles by Galivan, J. Articles by Kerwar, S. S.

Antifolate Drug Interactions: Enhancement of Growth Inhibition Due to the Antipurine 5,10-Dideazatetrahydrofolic Acid by the Lipophilic Dihydrofolate Reductase Inhibitors Metoprine and Trimetrexate¹

Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany, New York 12201 [J. G., Z. N., M. R.]; and Connective Tissue and Arthritis Research Unit, Department of Inflammation and Immunology, Medical Research Division, American Cyanamid Company, Lederle Laboratories, Pearl River, New York 10965 [D. B., A. L. O., S. S. K.]

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 combination 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.

¹ This work was supported by NIH Grants CA25933 and CA46126 from the National Cancer Institute, USPHS/Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Wadsworth Center for Laboratories and Research, New York State Department of Health, Empire State Plaza, Albany, NY 12201.

Received 11/ 3/87. Revised 2/ 1/88. Accepted 2/ 8/88.