The goal of this project is the development and application of bioanalytical methods to: (1) establish the structure and purity of new antitumor agents and their metabolites, (2) determine physical, chemical and biochemical properties of new anticancer drugs and (3) measure drugs and their metabolites, and potential biomodulators and biomarkers in biological samples to elucidate in vitro and in vivo pharmacology and to determine in vivo pharmacokinetics. High-performance liquid chromatography is the primary analytical approach. Current studies (biochemistry, preclinical pharmacology, and toxicology) focus cyclopentenyl cytosine (CPE-C), a carbocyclic nucleoside whose Phase I clinical trial has been suspended because of severe and unpredictable hypotension. CPE-C infusion studies in dogs with hemodynamic and pharmacologic monitoring have produced some similarities to patient hypotensive episodes, where the canine response to cardiovascular stress has been progressively diminished. This effect continues under investigation. A tetrahydropyridoindole of novel structure has been identified as a dihydroorotate dehydrogenase inhibitor of equal or greater potency than brequinar, the most potent inhibitor of this enzyme of pyrimidine biosynthesis currently known.
