Ginger for Chemoprevention of Colorectal Cancer

描述(申请人提供)：结直肠癌(CRC)是美国癌症死亡的第二大原因。据估计，2004年将出现146,940例新病例，导致56,730例死亡。目标是采用筛查方法检测结直肠癌的早期发展，并被认为可以将结直肠癌死亡率降低33%。尽管有这些数字，但筛查的广泛使用仍然很差。因此，指出了预防腺瘤性息肉及其发展为结直肠癌的筛查替代方法。 生姜已经在动物和人体模型中进行了化学预防潜力的研究，显示出作为预防结直肠癌的药物的前景。目前，生姜的化学预防作用机制尚不清楚，但被认为是通过抑制花生四烯酸途径和其他控制细胞增殖的机制来实现的。然而，生姜的生物利用度以及给药生姜影响炎症生物标志物的最佳剂量和时间尚未得到检验。此外，由于生姜独特的香气，需要检查是否足够致盲。因此，建议使用标准化的(5%{6}-姜酚)生姜产品进行一系列研究，以探索以下问题：(1)IA期研究，以评估生姜的单剂量药代动力学、急性毒性和最大耐受量(MTD)；(2)研究有效地使研究参与者对生姜香气致盲的方法；(3)IB期研究，以确定多剂量的药代动力学、慢性毒性和生姜对直肠粘膜PGE2的影响；以及(4)一项IIA期随机、双盲、安慰剂对照临床试验，以评估生姜对息肉或结直肠癌高危人群结肠粘膜和腺瘤中PGE2和COX2水平的影响。 这笔赠款还建议培训一名基本技能方面的初级研究人员，使其成为癌症化学预防植物学领域的独立研究人员。这项研究计划旨在培养以下方面的能力：(1)了解化学预防的基本原理和化学保护剂的开发；(2)测量生物体液中的植物代谢物；(3)进行生物检测以检测结肠粘膜组织中的炎性生物标志物；(4)设计化学预防领域的临床前和临床试验；以及(5)在结肠镜检查中发现息肉和结直肠癌。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States. An estimated 146,940 new cases of CRC will develop in 2004, resulting in 56,730 deaths. Screening methods that detect the early development of CRC, and are thought to reduce CRC mortality by as much as 33 percent, are the goal. Despite these figures, wide spread use of screening remains poor. Consequently, alternative methods to screening that prevent the development of adenomatous polyps and their development to CRC is indicated. Ginger, which has been studied in animal and human models for its chemopreventive potential, shows promise as an agent for preventing CRC. Currently, ginger's chemopreventive mechanisms of action are unknown but are thought to be via inhibition of arachidonate pathways and other mechanisms of cellular proliferative control. However, the bioavailability of ginger as well as the optimal dose and schedule for administering ginger to effect biomarkers of inflammation has not been examined. Also, due to ginger's unique aroma, adequate blinding needs to be examined. Hence, a series of studies using a standardized (5% {6 }-gingerols) ginger product are proposed to explore these questions: (1) a Phase IA study to evaluate the single-dose pharmacokinetics, acute toxicity, and maximum tolerated dose (MTD) of ginger; (2) a study to examine the methods for effectively blinding study participants to ginger's aroma; (3) a Phase IB study to determine the multi-dose pharmacokinetics, chronic toxicity, and effect of ginger on rectal mucosa PGE2; and (4) a Phase IIA randomized, double-blinded, placebo-controlled, clinical trial, to assess the effect of ginger on PGE2 and COX2 levels in colonic mucosa and adenomas in individuals at high risk for developing polyps or CRC. This grant also proposes to train a junior researcher in the essential skills to become an independent investigator in the area of botanicals for cancer chemoprevention. This program of study is designed to develop competencies in: (1) understanding the underlying principles of chemoprevention and the development of chemopreventitive agents; (2) measuring plant metabolites in biological fluids; (3) conducting bioassays to detect inflammatory biomarkers in colonic mucosal tissue; (4) designing pre-clinical and clinical trials in the area of chemoprevention; and (5) identifying polyps and colorectal cancer when seen during colonoscopies.