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.
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Publications
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Clinical Studies
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