THE ANALYTICAL CHEMISTRY OF NEW ANTICANCER DRUGS

本项目的目标是开发和应用分析软件 方法：(1)建立新的抗肿瘤药物的结构和纯度 试剂及其代谢物，(2)测定物理和化学 抗癌新药的性质，(3)检测药物及其应用 生物样品中的代谢物在体内外的阐明 药理及体内药代动力学测定，以及(4)研究 潜在有用的合成转化的反应机理。 质谱仪、气相色谱和高效液体 层析，无论是单独的还是组合的，强调分析 接近了。目前的研究(生物化学、临床药理学、 方法增强和毒理学)集中在环戊烯 胞嘧啶，一种正在进行I期临床的碳环核苷 作为一种抗肿瘤药物进行试验。新陈代谢、分布和 这种药物在人体内的药代动力学已被测定 静脉推注和持续输液。一个敏感的、多维的 高效液相色谱分析已经发展到 测量细胞内活性代谢物环戊烯的水平 胞嘧啶三磷酸。该代谢物在患者体内的浓度 外周血单核细胞表现出广泛的变异和有限的 与母体药物的剂量或血药浓度相关。 生化研究进一步定义了内源性和外源性 环戊烯基胞嘧啶细胞毒性的生物调节剂。电浆 假尿苷也被认为是一种潜在的肿瘤生物标志物。 在上述第一阶段重复治疗周期后的负担 病人群体。

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.