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: 8243209
• 负责人: Swati Nagar
• 金额: $ 7.65万
• 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 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243209
• 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. PUBLIC HEALTH RELEVANCE: This project focuses on prevention of colorectal cancer with promising dietary chemicals. The proposed studies will evaluate efficacy of dietary chemical combinations in increasing metabolism and therefore greater detoxification of cancer-causing agents. Preventing colorectal cancer with safe chemicals derived from foods is expected to significantly decrease the burden of this disease.

描述（申请人提供）：结直肠癌（CRC）在世界范围内非常普遍，具有高死亡率。目前正在临床试验中探索活性膳食化学物质作为补充癌症预防剂。我们的长期目标是阐明