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Clinical and Pharmacological Studies with 5-Hydroxy-2-formylpyridine Thiosemicarbazone¹

Department of Medicine and Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510 [R. C. D., B. R. T., K. C. A., J. R. B., A. C. S., W. A. C.]; Microbiological Associates, Inc., Bethesda, Maryland 20014, [R. T.]; and National Cancer Institute, NIH, Bethesda, Maryland 20014 [J. A. R. M.]

5-Hydroxy-2-formylpyridine thiosemicarbazone (5-HP) is the first of a relatively new class of antineoplastic agents, the -(N)-heterocyclic carboxaldehyde thiosemicarbazones, to be studied in man. This study characterizes the toxicity and pharmacological disposition of the drug in 13 patients. Plasma levels of 5-HP decayed in biphasic mode with an initial half-life of 2.5 to 10.5 min. Of the administered dose, 47 to 75% was excreted within 24 hr, and the major metabolites (50 to 74% or urinary radioactivity) were glucuronide conjugates. A characteristically dark green urine resulted from the excretion of significant amounts of iron (2 to 11 mg/24 hr) in chelate form with 5-HP. The incorporation of thymidine-³H into DNA was inhibited in isolated normal and leukemic leukocyte suspensions after exposure in vitro and in vivo to 5-HP. Transient decreases in blast counts were observed in three of five patients with acute leukemia, although no remissions were obtained. No antitumor effects were noted in eight patients with solid tumors. Administration of larger doses of drug was limited by gastrointestinal toxicity. Mild myelosuppressant effects and hemolysis were noted in five patients treated with 5-day courses of drug. While toxicity appears to limit the usefulness of this compound as an antineoplastic agent, antileukemic activity was shown, and studies of other members of this class of agents are warranted.

¹ Supported in part by Grants CA 5138, CA 08341, and CA 02817 and Contract PH 43-68-1283 from the USPHS, as well as by Grants T-355 and ET-14F from the American Cancer Society.

² To whom correspondence should be addressed, at the Yale University School of Medicine, 333 Cedar Street, New Haven, Conn. 06510.

Received 1/ 3/72. Accepted 3/24/72.

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