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、3种计量药物及其代谢产物的性质 用于阐明体外和体内药理学， 以确定体内药代动力学，并研究4反应机制 潜在有用的合成转化。 质谱法，气体 色谱法和高效液相色谱法，单独 或结合起来，强调分析方法。 目前的研究 （生物化学，临床药理学和方法增强）是 重点是环戊烯基胞嘧啶，一种碳环核苷， 目前作为抗肿瘤药物正在进行I期临床试验。 的 该药物在人体内的代谢、分布和药代动力学 在静脉推注给药和连续输注后测定。 一 新的胞嘧啶特异性反应已被用于制备荧光 增加胞嘧啶的HPLC测量灵敏度的衍生物 核苷如环戊烯基胞嘧啶。 生物化学研究已经定义了内源性和外源性生物调节剂 这种药剂的细胞毒性。 血浆假尿苷 作为肿瘤负荷的生物标志物进行研究， 在I期患者人群中进行治疗。

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, and methods enhancement) are focused on cyclopentenyl cytosine, a carbocyclic nucleoside which is presently undergoing Phase I clinical trial as an antitumor agent. The metabolism, distribution and pharmacokinetics of this drug in humans have been determined after both iv bolus dosing and continuous infusion. A novel cytosine-specific reactions has been employed to make a fluorescent derivative to increase HPLC measurement sensitivity for cytosine nucleosides such as cyclopentenyl cytosine in biological fluids. Biochemical studies have defined endogenous and exogenous biomodulators of the cytotoxicity of this agent. Plasma pseudouridine is being investigated as a biomarker of tumor burden following repeated cycles of treatment in a Phase I patient population.