Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, TCAR, Riboxamide, NSC 286193) is a novel C-
nucleoside with antitumor activity against several murine
tumor models, including
Lewis lung carcinoma. The mechanism whereby this compound exerts its
antineoplastic effects is most likely related to a state of
guanine nucleotide depletion whereby the anabolite,
thiazole-4-carboxamide adenine dinucleotide, potently inhibits inosine-5'-monophosphate
dehydrogenase. This Phase I study was designed to determine the maximally tolerated dose of
Tiazofurin administered on a 5-day, every-28-day schedule.
Tiazofurin levels were measured using a high-pressure liquid chromatography assay, and pharmacokinetic studies were performed in patients treated at each dose level. Nineteen patients received a total of 24 courses of the
drug in doses ranging from 550 to 2200 mg/sq m. The dose-limiting toxicities were
pleuropericarditis and a general illness best described as a "viral-like" syndrome (manifested by severe malaise,
headaches, myalgias,
fever,
nausea,
vomiting, and
diarrhea). Other toxicity included myelosuppression,
hyperuricemia, elevated serum
creatine phosphokinase and
serum glutamic oxaloacetic transaminase,
conjunctivitis,
mucositis, and desquamation of the palms of the hands. Plasma clearance of
Tiazofurin followed a biexponential pattern with a harmonic mean terminal half-life of 7.6 h. The mean volume of distribution at steady state was 30 liters/sq m, and the mean plasma clearance was 3 liters/h/sq m. The total cumulative urinary excretion ranged from 15 to 49%. The maximally tolerated dose of
Tiazofurin on a 5-day schedule was 1650 mg/sq m. The recommended dose for Phase II evaluations is 1100 mg/sq m for 5 days. However, exploration of other schedules which might allow administration of more
Tiazofurin combined with biochemical studies including
thiazole-4-carboxamide adenine dinucleotide measurements would be desirable.