THE ANALYTICAL CHEMISTRY OF NEW ANTICANCER DRUGS

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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, 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 (HPLC) is the primary analytical approach. Cyclopentenyl cytosine (CPE-C), a carbocyclic nucleoside whose Phase I clinical trial was suspended because of severe and unpredictable hypotension, continues under collaborative study. CPE-C infusion studies in dogs with hemodynamic and pharmacologic monitoring have produced some similarities to patient orthostatic hypotensive episodes, and the biochemical and pharmacological basis of this is being investigated. The use of CPE-C for in situ delivery to brain tumors also remains under consideration, since CPE-C exerts a pronounced antiproliferative effect against human glioblastoma in vitro that is mediated by the 5'-triphosphate metabolite CPE-CTP. A rapid method has been developed for the partial purification of human deoxycytidylate deaminase, a potential target for anticancer agents, from MOLT-4 lymphoblasts. This enzyme has been used to identify several novel deoxypyrmidine monophosphate analogues as potent competitive inhibitors with inhibition constants in the nanomolar range. An evaluation of methods and appropiate parameters for the rapid determination of hydrophobicity indices (log P, log k') has compared computer-assisted calculation with liquid-liquid partitioning and reverse-phase HPLC. All methods provide a good, but less than perfect, correlation. Reverse-phase HPLC on a polymer-based column provides the best alternative to direct determination of log P for cytosine and adenine nucleosides of low lipophilicity with potential antitumor activity.