Clinical phase I-II and pharmacokinetic study of high-dose thymidine given by continuous intravenous infusion

Abstract

High-dose thymidine (dThd) was given to 12 patients with advanced hematological and solid tumors. The dose schedule used was 75 g/sq m/day, given i.v. continuously for 5 days or more. Myelosuppression, especially leukopenia, was the dose-limiting toxicity. Nonhematological toxicities affected the gastrointestinal tract (nausea, vomiting, anorexia, diarrhea, and indigestion) and the central nervous system (somnolence, headache, visual illusions, and memory impairment). Patients who had received cumulative doses of dThd developed alopecia. Thymine crystals were noted in the urine after refrigeration. Tumor regression (less than partial remission) occurred in one patient with melanoma. Three of four patients with acute leukemia had a fall in peripheral white blood cell counts and blasts but no marrow improvement. Four patients with adenocarcinoma (three colon, one unknown primary) had stable disease. Pharmacokinetic studies revealed that, at a dThd dose of 75 g/sq m/day, millimolar concentrations of dThd and thymine can be achieved in the plasma. The half-life of dThd was approximately 100 min. One-third of the plasma concentrations was measurable in the cerebrospinal fluid. dThd was mainly excreted by the kidneys.