Conjugation of anticancer drugs

抗癌药物的结合

• 批准号: 7661917
• 负责人: Swati Nagar
• 金额: $ 7.5万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661917
• 关键词: AlamarBlue; Antibodies; Antineoplastic Agents; Beta-glucuronidase; Binding; Biological Assay; Biological Availability; Breast Cancer Cell; Caco-2 Cells; Cell Death; Cell Line; Cell Proliferation; Cells; Chemicals; Chemopreventive Agent; Collaborations; Colon; Colorectal Cancer; Complex; Data; Developed Countries; Developing Countries; Development; Dietary Polyphenol; Disease; Drug Interactions; Early Diagnosis; Enzyme Kinetics; Enzymes; Estradiol; Estrogens; Evaluation; Exhibits; Future; Glucuronidase Inhibitor; Glucuronides; Glucuronosyltransferase; Goals; HCT116 Cells; HT29 Cells; Hepatic; Hepatocyte; High Pressure Liquid Chromatography; Human; Incubated; Inorganic Sulfates; Intestines; Isoenzymes; Kinetics; Knowledge; Light; Liver; Malignant Neoplasms; Measures; Mediating; Metabolism; Minor; Modeling; Oral; Parents; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Play; Production; Property; Prostaglandin-Endoperoxide Synthase; Proteins; Rattus; Regulation; Reporting; Research; Resveratrol; Rodent Model; Role; Science; Screening procedure; Steryl-sulfatase; Testing; Thapsigargin; Therapeutic Effect; Treatment Efficacy; UGT1A1 gene; Universities; Unspecified or Sulfate Ion Sulfates; Uridine; Western Blotting; Xenobiotics; base; colon cancer cell line; colorectal cancer prevention; compliance behavior; dietary antioxidant; drug development; enzyme activity; enzyme substrate; fetal; human tissue; inhibitor/antagonist; mortality; polyphenol; protein expression; research study; sulfation; sulfotransferase; trans-resveratrol; treatment duration; tumor

DESCRIPTION (provided by applicant): Colorectal cancer is a preventable yet highly prevalent disease worldwide. Poor patient compliance with screening procedures increases the mortality due to colorectal cancer. There is an urgent need for chemopreventive measures for this tumor type. One of the most promising chemopreventives in recent years is the dietary polyphenol resveratrol (RSV). While RSV has shown effective anticancer properties in cellular and rodent models, one limit to its development as a drug is its extremely high metabolism and resultant low oral bioavailability. There is ample evidence for therapeutic efficacy of RSV despite its high metabolism. The pharmacologic effects of RSV metabolites have never been elucidated. The overall goal of this proposal is to characterize the pharmacology of the major conjugated metabolites of RSV, and to delineate the effect of RSV on conjugating enzyme expression and activity. This research will advance our knowledge of a potential new chemopreventive drug, RSV, its pharmacology, and its potential for drug-drug interactions. We hypothesize that RSV conjugation plays an important role in its therapeutic effects via either inactivation or production of active metabolites. RSV is additionally hypothesized to alter its own conjugation by inhibition or induction of xenobiotic conjugating enzymes. Two specific aims are proposed: 1) Determine the pharmacologic activity of RSV conjugates, and 2) Characterize the effect of RSV on human uridine glucuronosyltransferase (UGT) and sulfotransferase (SULT) induction / inhibition. We will synthesize the major metabolites of RSV and test their role in cell proliferation with colon cancer cell lines (FHC controls, Caco-2, HT-29, and HCT-116) as our model. We will additionally evaluate changes in UGT / SULT protein expression and enzyme activity in human hepatocytes as well as colon cells upon treatment with RSV or its metabolites. Protein expression will be quantitated with western blot analysis, while enzyme activity will be characterized with specific substrates toward each isozyme. Taken together, these experiments will provide the first evaluation of the pharmacology of RSV metabolites, and the effect of RSV in regulation of enzymes responsible for its metabolism.

描述（由申请人提供）： 结直肠癌是一种可预防但在全世界范围内高度流行的疾病。患者对筛查程序的依从性差会增加结直肠癌的死亡率。迫切需要针对这种肿瘤类型采取化学预防措施。近年来最有前途的化学预防剂之一是膳食多酚白藜芦醇（RSV）。虽然 RSV 在细胞和啮齿动物模型中显示出有效的抗癌特性，但其作为药物开发的一个限制是其极高的代谢率和由此导致的低口服生物利用度。尽管 RSV 的代谢率很高，但仍有充足的证据表明它具有治疗功效。 RSV 代谢物的药理作用尚未阐明。该提案的总体目标是表征 RSV 主要缀合代谢物的药理学，并描述 RSV 对缀合酶表达和活性的影响。这项研究将增进我们对潜在的新型化学预防药物 RSV、其药理学及其药物相互作用潜力的了解。我们假设 RSV 结合通过灭活或产生活性代谢物在其治疗效果中发挥重要作用。另外还假设 RSV 通过抑制或诱导异生素结合酶来改变其自身的结合。提出了两个具体目标：1) 确定 RSV 缀合物的药理活性，2) 表征 RSV 对人尿苷葡萄糖醛酸基转移酶 (UGT) 和磺基转移酶 (SULT) 诱导/抑制的影响。我们将合成 RSV 的主要代谢物，并以结肠癌细胞系（FHC 对照、Caco-2、HT-29 和 HCT-116）为模型，测试它们在细胞增殖中的作用。我们还将评估用 RSV 或其代谢物治疗后人肝细胞和结肠细胞中 UGT / SULT 蛋白表达和酶活性的变化。蛋白质表达将通过蛋白质印迹分析进行定量，而酶活性将通过针对每种同工酶的特定底物进行表征。总而言之，这些实验将首次评估 RSV 代谢物的药理学，以及 RSV 在调节负责其代谢的酶方面的作用。