THE ANALYTICAL CHEMISTRY OF NEW ANTICANCER DRUGS

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The goal of this project is the development and application of analytical methods to: (1) establish the structure and purity of new antitumor agents and their metabolites, (2) determine physical and chemical properties of new anticancer drugs, (3) measure drugs and their metabolites in biological samples to elucidate in vitro and in vivo pharmacology and to determine in vivo pharmacokinetics, and (4) study reaction mechanisms of potentially useful synthetic transformations. Mass spectrometry, gas chromatography and high-performance liquid chromatography, either alone or in combination, are emphasized analytical approaches. Current studies (biochemistry, clinical pharmacology, methods enhancement and toxicology) are focussed on cyclopentenyl cytosine, a carbocyclic nucleoside which is undergoing Phase I clinical trial as an antitumor agent. The metabolism, distribution and pharmacokinetics of this drug have been determined in humans after both iv bolus dosing and continuous infusion. A sensitive, multidimensional high-performance liquid chromatography assay has been developed to measure intracellular levels of the active metabolite, cyclopentenyl cytosine triphosphate. Concentrations of this metabolite in patient peripheral blood mononuclear cells show wide variation and limited correlation with either dose or plasma levels of parent drug. Biochemical studies have further defined endogenous and exogenous biomodulators of the cytotoxicity of cyclopentenyl cytosine. Plasma pseudouridine has also been measured as a potential biomarker of tumor burden following repeated cycles of treatment in the above Phase I patient population.