Twenty-four patients with advanced solid tumors and seven with acute leukemia were treated with a triazine folate antagonist, triazinate, to determine the toxicity spectrum, the maximum tolerated dose, and the pharmacological disposition of the drug. Negligible toxicity was seen with single doses of 20 to 225 mg/sq m given as a 0.5-hr infusion. Single doses of 300 to 600 mg/sq m infused over 0.5 to 3 hr caused moderate to severe central neurological impairment with light headedness, somnolence, visual disturbances, weakness, and in one patient, severe respiratory distress and cyanosis. Skin, mucous membrane, and bone marrow toxicity were mild to moderate with single doses. When triazinate was given by a multiple-dose schedule every 12 to 24 hr, there was no neurological toxicity, but mucositis, skin toxicity, and myelotoxicity were increased. Five patients developed an erythematous to desquamative rash at the site of previous or concurrent radiotherapy. Serum disappearance of triazinate was at least bionsiderable variation from patient to patient. Single i.v. doses of 300 mg/sq m resulted in serum levels of 10(-5) M or higher for 8 hr and, with repeated doses, this level could be maintained. Administration p.o. resulted in serum concentrations less than 10% of that achieved after i.v. administration. Cerebrospinal fluid concentrations were 2% or less of the serum levels in five or six patients, 1 to 4 hr after i.v. treatment. Urinary excretion varied from 12 to 71% (median, 43%) of the total dose injected during the first 24 hr. Measurable objective solid tumor responses were not seen in this Phase 1 study, although two patients had stabilization of previously advancing disease. Decreases in peripheral blasts occurred in both types of acute leukemia, but improvement in the bone marrow was not observed.