Colorectal cancer chemoprevention with phytochemical combinations

利用植物化学组合进行结直肠癌化学预防

• 批准号: 8436171
• 负责人: Swati Nagar
• 金额: $ 7.19万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436171
• 关键词: 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]pyridine; Aberrant crypt foci; Adopted; Base Ratios; Biological Assay; Caco-2 Cells; Carcinogens; Cells; Chemicals; Chemoprevention; Chemopreventive Agent; Clinical Trials; Colon; Colon Adenocarcinoma; Colorectal Cancer; Curcumin; Data; Detection; Diet; Dietary Phytochemical; Drug Kinetics; Drug Metabolic Detoxication; Enzymes; Epithelial; Evaluation; Exhibits; Food; Frequencies; Future; Goals; Hepatic; Human; In Vitro; Inbred C57BL Mice; Individual; Intestines; Investigation; Left; Liver; Malignant Neoplasms; Measures; Metabolism; Methods; Mus; Phytochemical; Preventive; Research; Reverse Transcriptase Polymerase Chain Reaction; Small Intestines; Sodium Dextran Sulfate; Study models; Testing; Time; Tissues; Treatment Protocols; UGT1A1 gene; Uridine; Validation; Western Blotting; Work; base; burden of illness; cancer chemoprevention; celecoxib; chrysin; clinical efficacy; colorectal cancer prevention; design; drug testing; enzyme activity; in vivo; metabolic abnormality assessment; mortality; mouse model; novel; prevent; trans-resveratrol; tumor

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is highly prevalent worldwide and exhibits high mortality. Active dietary chemicals are currently being explored as complementary cancer preventive agents in clinical trials. Our long-term goal is to elucidate the impact of metabolism on the pharmacokinetics and associated clinical efficacy of promising phytochemicals. Importantly, while combinations of phytochemicals are increasingly shown to be more efficacious than single agents alone, mechanisms underlying this synergy are not understood. Specifically, there is no research to date on how dietary phytochemical combinations modulate glucuronidating enzymes - i.e. uridine diphosphoglucuronosyltransferases (mammalian UGT; human UGT, mouse ugt). This proposal is based on the hypothesis that phytochemical combinations synergistically induce mammalian UGTs. Phytochemical combinations might thus more effectively inactivate carcinogens than single agents. Toward this, two specific aims are proposed: 1) Evaluate UGT induction by phytochemicals alone and in combination. Phytochemical combinations trans-resveratrol + curcumin and trans-resveratrol + chrysin in ratios based on individual antiproliferative IC50s will be tested and compared against each phytochemical alone. Induction of human UGTs will be evaluated in transformed human intestinal Caco-2 cells, while mouse ugts will be evaluated in mouse intestine epithelial normal and preneoplastic (YAMC and IMCE) cells, as well as mouse hepatic ImHep cells. Combinations that yield most significant results in part A above will be tested in vivo in a normal C57BL mouse model. 2) Evaluate UGT induction as a mechanism for chemoprevention by phytochemical combinations. Whether synergistic UGT induction by phytochemical combinations is a mechanism for enhanced chemoprevention will be evaluated in mice. Combinations with the highest predicted efficacy from Aim 1 will be tested in a dextran sulfate sodium + 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (DSS/PhIP) colon adenocarcinoma mouse model, and aberrant crypt foci (ACF), tumor size/frequency, and ugt induction will be measured. Chemopreventive efficacy will be compared against that of Celecoxib, a known CRC preventive agent. Data from the proposed aims will form the basis of future studies to evaluate additional metabolizing enzymes and transporters that are modulated by phytochemicals.

描述（由申请人提供）：结直肠癌（CRC）在全世界范围内非常流行，并且死亡率很高。 目前正在临床试验中探索活性膳食化学品作为补充癌症预防剂。 我们的长期目标是阐明 代谢对有前途的植物化学物质的药代动力学和相关临床功效的影响。 重要的是，虽然越来越多的证据表明植物化学物质的组合比单独使用单一药物更有效，但这种协同作用的机制尚不清楚。 具体而言，迄今为止还没有关于膳食植物化学组合如何调节葡萄糖醛酸化酶（即尿苷二磷酸葡萄糖醛酸基转移酶（哺乳动物 UGT；人类 UGT、小鼠 UGT））的研究。 该提议基于植物化学组合协同诱导哺乳动物 UGT 的假设。 因此，植物化学组合可能比单一药物更有效地灭活致癌物质。 为此，提出了两个具体目标：1）评估单独和组合植物化学物质对 UGT 的诱导作用。 根据个体抗增殖 IC50 的比例，反式白藜芦醇 + 姜黄素和反式白藜芦醇 + 白杨素的植物化学组合将 单独对每种植物化学物质进行测试和比较。 人类 UGT 的诱导将在转化的人肠道 Caco-2 细胞中进行评估，而小鼠 ugt 的诱导将在小鼠肠上皮正常细胞和肿瘤前期（YAMC 和 IMCE）细胞以及小鼠肝 ImHep 细胞中进行评估。 上述 A 部分中产生最显着结果的组合将在正常 C57BL 小鼠模型中进行体内测试。 2) 评估 UGT 诱导作为植物化学组合化学预防的机制。 将在小鼠中评估植物化学组合协同 UGT 诱导是否是增强化学预防的机制。 将在葡聚糖硫酸钠 + 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶 (DSS/PhIP) 结肠腺癌小鼠模型中测试目标 1 中预测功效最高的组合，并测量异常隐窝病灶 (ACF)、肿瘤大小/频率和 ugt 诱导。 化学预防功效将与塞来昔布（一种已知的结直肠癌预防药物）的效果进行比较。 拟议目标的数据将构成未来研究的基础，以评估由植物化学物质调节的其他代谢酶和转运蛋白。