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 greater than 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.