Colorectal cancer chemoprevention with phytochemical combinations

描述(申请人提供)：结直肠癌(CRC)在全球范围内高度流行，死亡率很高。目前正在临床试验中探索活性膳食化学物质作为癌症预防补充剂的可能性。我们的长期目标是澄清 代谢对前景看好的植物化学物质的药代动力学和相关临床疗效的影响。重要的是，虽然植物化学物质的组合越来越显示出比单一药物更有效，但这种协同作用背后的机制尚不清楚。具体地说，到目前为止，还没有关于饮食植物化学组合如何调节葡萄糖醛酸化酶--即尿苷二磷葡萄糖醛酸基转移酶(哺乳动物UGT；人UGT，小鼠UGT)--的研究。这一建议是基于这样一个假设，即植物化学组合协同诱导哺乳动物UGT。因此，植物化学组合可能比单一制剂更有效地灭活致癌物。为此，提出了两个具体目标：1)评价植物化学物质单独和联合诱导UGT。基于单个抗增殖IC50的植物化学组合反式白藜芦醇+姜黄素和反式白藜芦醇+白杨素的比率将 单独与每种植物化学物质进行测试和比较。人UGT的诱导将在转化的人肠道Caco-2细胞中进行评估，而小鼠UGTS将在小鼠肠上皮正常和癌前(YAMC和IMCE)细胞以及小鼠肝脏ImHep细胞中进行评估。在上述A部分中产生最显著结果的组合将在正常的C57BL小鼠模型中进行活体测试。2)评价UGT诱导作为植物化学预防的一种机制。植物化学联合诱导UGT的协同作用是否是增强化学预防的机制将在小鼠身上进行评估。目标1预测疗效最高的组合将在葡聚糖硫酸钠+2-amino-1-methyl-6-phenylimidazo[4，5-b]pyridine(DSS/PhIP)结肠腺癌小鼠模型中进行测试，并将测量异常隐窝病灶(ACF)、肿瘤大小/频率和UGT诱导。化学预防效果将与已知的结直肠癌预防药物塞来昔布进行比较。来自拟议AIMS的数据将构成未来研究的基础，以评估受植物化学物质调节的额外代谢酶和转运体。

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.