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Inhibition of DNA Synthesis in Normal and Malignant Human Cells by Triazinate (Baker's Antifol) and Methotrexate¹

Departments of Medicine [R. T. S., W. L. S., J. R. B.] and Pharmacology [R. T. S., A. R. C., J. R. B.], Yale University School of Medicine, New Haven, Connecticut 06510

Triazinate (TZT), a triazine folate antagonist, is a potent inhibitor of dihydrofolate reductase from mammalian cells. Because antitumor activity of triazinate in experimental tumors correlated closely with the in vitro inhibition of DNA synthesis in tumor cells derived from these tumors, we studied cells from patients with leukemia, solid tumor effusions, and cells from normal marrow to determine their in vitro sensitivity to TZT. DNA synthesis in cells from patients with acute leukemia was less sensitive to TZT than it was to methotrexate (MTX) at 2 x 10^-6 M concentration of the inhibitor, whereas the sensitivity was similar at 10^-5 M. This could be accounted for by the known greater sensitivity of dihydrofolate reductase to MTX than to TZT, and the observation that, whereas intracellular drug levels were similar at low (2 x 10^-6 M) extracellular concentrations of TZT or MTX, at the higher (10^-5 M) extracellular drug concentration intracellular TZT was >3 times intracellular MTX. In vitro inhibition of DNA synthesis in cells obtained after patients were treated with TZT was correlated with drug serum concentration and with leukemia cell kill.

The sensitivity of cells from solid tumor effusions to TZT was similar to the sensitivity to MTX. Since patients can tolerate doses of TZT five times higher than MTX with less toxicity, there may be advantage to the clinical use of TZT in some tumor cell types.

¹ Supported by USPHS Contract NO 1 CM 33711 from Division of Cancer Treatment, National Cancer Institute, NIH, and USPHS Grants CA 08010 and CA 08341.

² To whom requests for reprints should be addressed, at Medical College of Ohio, P. O. Box 6190, Toledo, Ohio 43614.

³ American Cancer Society Research Professor.

Received 4/16/76. Accepted 6/18/76.