THE ANALYTICAL CHEMISTRY OF NEW ANTICANCER DRUGS

本项目的目标是开发和应用分析 方法：（1）确定新抗肿瘤化合物的结构和纯度 制剂及其代谢产物，（2）确定物理和化学 抗癌新药的性质，（3）衡量药物及其 生物样品中的代谢物，以阐明体外和体内 药理学和确定体内药代动力学，和（4）研究 潜在有用的合成转化的反应机理。 质谱、气相色谱和高效液相色谱 色谱法，无论是单独或组合，强调分析 接近。 目前的研究（生物化学，临床药理学， 方法增强和毒理学）集中在环戊烯基 胞嘧啶，一种碳环核苷，正在进行I期临床试验， 作为抗肿瘤剂的试验。 代谢、分布和 该药物的药代动力学已经在人体中测定， 静脉推注给药和连续输注。 一个敏感的，多方面的 已经开发了高效液相色谱分析， 测量活性代谢物环戊烯基的细胞内水平 三磷酸胞嘧啶 患者体内该代谢物的浓度 外周血单个核细胞表现出广泛的变化和有限的 与母体药物剂量或血浆水平的相关性。 生物化学研究进一步界定了内源性和外源性 环戊烯基胞嘧啶的细胞毒性的生物调节剂。 血浆 假尿苷也被测量为肿瘤的潜在生物标志物 上述I期重复治疗周期后的负荷 患者人群。

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.