Clinical toxicity associated with tiazofurin

Jean L. Grem, Larry Rubinstein, Susan A. King, Bruce D. Cheson, Michael J. Hawkins, Dale D. Shoemaker

Research output: Contribution to journalArticle

15 Scopus citations


Tiazofurin, an investigational antimetabolite, is undergoing clinical evaluation in leukemia. We analyzed the data base of 198 patients entered in Phase I trials to characterize the incidence and severity of toxicities associated with tiazofurin according to dose and schedule. Severe myelosuppression occurred infrequently, and was not dose-dependent. A five day bolus schedule had a higher incidence of severe or life-threatening neutropenia than other schedules. Tiazofurin produced lymphopenia which was not dose-dependent in the range of 23-36% decrease from baseline, and the effect on lymphocyte count was generally greater than the decline in neutrophil count. Non-hematologic toxicity of a moderate or worse severity (≥ grade 2) included nausea and vomiting (18% of all courses), serum transaminase elevations (SGOT, 16%; SGPT, 9%), rash (9%), stomatitis (3%), conjunctivitis (3%), headache (10%), other signs of central nervous system toxicity (8%), and cardiac toxicity, primarily pleuropericarditis (4%). Dose-related cutaneous toxicity, headache, and nausea and vomiting were evident in the five day bolus schedule, and myalgia was more frequently reported at higher doses on the single dose schedule. The five day continuous infusion (CI) schedule had a higher incidence of neurotoxicity, cardiac toxicity, SGPT elevations and ocular toxicity than the daily for five days bolus schedule, but none of these differences attained statistical significance. Although the peak plasma concentrations of tiazofurin achieved with the five day bolus schedule were 3-fold higher than the steady-state plasma levels seen with an equal dose given by CI, the area under the concentration-time curve (AUC) was approximately 1.6-fold higher with CI. These observations suggest that both high peak plasma concentrations (above 400 uM) and prolonged exposure to plasma levels exceeding 50 uM may result in a higher incidence of serious non-hematologic toxicity.

Original languageEnglish (US)
Pages (from-to)227-238
Number of pages12
JournalInvestigational New Drugs
Issue number2
StatePublished - May 1990


  • IMP dehydrogenase
  • phase I trials
  • tiazofurin

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Fingerprint Dive into the research topics of 'Clinical toxicity associated with tiazofurin'. Together they form a unique fingerprint.

  • Cite this

    Grem, J. L., Rubinstein, L., King, S. A., Cheson, B. D., Hawkins, M. J., & Shoemaker, D. D. (1990). Clinical toxicity associated with tiazofurin. Investigational New Drugs, 8(2), 227-238.