Pyrazole: preclinical reassessment

Pyrazole (NSC-45410) is a low molecular weight, heterocyclic compound which has been considered for reevaluation in the clinic as a potential cytotoxic agent (Fig. 1). Discovered in 1893, pyrazole is best known as an inhibitor of liver alcohol dehydrogenase (ki = 0.2 uM), and as a result, has been used extensively in studies of alcohol metabolism. In 1960, pyrazole was identified as being active in preclinical antitumor models, which led to preliminary clinical testing. The early Phase I studies were not followed by disease specific Phase II trials, and the clinical activity of the drug has never been evaluated. This omission was noted by the National Cancer Institute's Project for the Review of Old Drugs (PROD), at which time it was also noted that pyrazole is selectively toxic to thyroid tissue in an animal model. Hence, interest in pyrazole was revived for two reasons: (a) failure to screen it for clinical activity in the 1960's, and (b) current interest in discovering drugs with selective toxicity to specific tissues for evaluation of their activity in malignancies arising in the target tissue. In this review, we summarize the evidence which has accumulated concerning pyrazole's potential role as an anticancer agent.