THE ANALYTICAL CHEMISTRY OF NEW ANTICANCER DRUGS

新抗癌药物的分析化学

• 批准号: 3774543
• 负责人: J A KELLEY
• 金额: --
• 依托单位: DIVISION OF CANCER TREATMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3774543
• 关键词: analytical chemistry; analytical method; antineoplastics; biomarker; chemical structure function; cyclopentane; cytosine analog; cytosine nucleotides; drug metabolism; drug screening /evaluation; gas chromatography; high performance liquid chromatography; human subject; human tissue; immunomodulators; mass spectrometry; method development; neoplasm /cancer pharmacology; nucleoside analog; pharmacokinetics; uridine

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.

该项目的目的是开发和应用分析 方法：（1）建立新抗肿瘤的结构和纯度 特工及其代谢物，（2）确定物理和化学 新抗癌药物的特性，（3）测量药物及其药物 生物样品中的代谢产物，以阐明体外和体内 药理学并确定体内药代动力学，（4）研究 潜在有用的合成转化的反应机制。 质谱，气相色谱和高性能液体 单独或组合色谱法被强调分析 方法。 当前研究（生物化学，临床药理学， 方法增强和毒理学）专注于环戊烯基 胞嘧啶，一种正在进行I期临床的碳环核苷 作为抗肿瘤剂的试验。 新陈代谢，分布和 两者都在人类中确定了这种药物的药代动力学 静脉注射剂量和连续输注。 敏感的多维 高性能液相色谱测定已开发为 测量活性代谢物环戊烯基的细胞内水平 三磷酸胞嘧啶。 该代谢物在患者中的浓度 外周血单核细胞显示较大变化，有限 与父母药物的剂量或血浆水平相关。 生化研究进一步定义了内源性和外源性 环戊烯基胞嘧啶的细胞毒性的生物调节剂。 等离子体 伪氨酸也已被测量为肿瘤的潜在生物标志物 在上述I阶段重复治疗周期之后的负担 患者人数。