Chemoprevention of colon cancer via neonatal imprinting

通过新生儿印记化学预防结肠癌

• 批准号: 7321591
• 负责人: Aramandla Ramesh
• 金额: $ 7.33万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-20 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321591
• 关键词: Adult; Affect; American; Animals; Aromatic Polycyclic Hydrocarbons; Attenuated; Benzo(a)pyrene; Bioavailable; Breast; CYP1A1 gene; Cancer Etiology; Characteristics; Chemical Agents; Chemicals; Chemoprevention; Chemopreventive Agent; Chronic; Colon; Colon Carcinoma; Colon, Rectum; Colonic Neoplasms; Colorectal; Colorectal Cancer; Cytochrome P450; DNA; DNA Adduction; DNA Adducts; DNA Modification Process; Data; Development; Diet; Dose; End Point; Environment; Environmental Exposure; Enzymes; Epoxide hydrolase; Esophagus; Etiology; Exposure to; Family; Fibrinogen; Food; Fruit; Genus Cola; Glutathione S-Transferase; Goals; Histologic; Human; Intervention; Kinetics; Life; Life Style; Location; Longevity; Lung; Malignant Neoplasms; Measures; Mediating; Metabolic Biotransformation; Metabolic Pathway; Mus; Neonatal; Neoplasm Metastasis; Numbers; Nutritional; Organ; Phytochemical; Pilot Projects; Plants; Plasma; Preventive; Principal Investigator; Process; Quality of life; Range; Rattus; Resveratrol; Risk; Role; Severities; Staging; Stomach; Surveys; Testing; Time; Tissues; Toxic Environmental Substances; Toxic effect; Transgenic Mice; Translating; Treatment Cost; adduct; adenoma; base; benzo(a)pyrene-DNA adduct; cancer therapy; carcinogenesis; chemical group; chemotherapeutic agent; colon carcinogenesis; cyclooxygenase 2; day; dihydrodiol dehydrogenases; environmental chemical; human study; imprint; improved; indexing; insight; male; men; neonatal exposure; novel; prenatal; prevent; prophylactic; size; trans-1,2-dihydrobenzene-1,2-diol dehydrogenase

DESCRIPTION (provided by applicant): Benzo(a)pyrene (BaP) is an ubiquitous environmental toxicant that belongs to the polycyclic aromatic hydrocarbon (PAH) family of compounds and causes toxicity and cancer to a variety of organs. Our preliminary studies have demonstrated that neonatal administration of rats with resveratrol (RVT) reduces BaP induction of the cytochrome P450 (CYP) family of enzymes in adult rats subsequent to exposure to BaP, with a concomitant reduction in the formation and distribution of reactive metabolites in plasma and target tissues. Our proposed studies will test the hypothesis that RVT modulates BaP-induced colon carcinogenesis through cytochrome P450 (CYP) mediated metabolic pathways. A related hypothesis that will be tested in our studies is that the bioavailable dose of BaP that contributes to toxicity/cancer during a lifespan can be altered by "imprinting" with RVT treatment during the neonatal period, and that such an action, if ultimately translated into human studies, could have a significant effect on the quality and perhaps even the extent of life, in general, and in reducing the onset of colorectal cancer, in particular. More than 90 million Americans - 58 % of whom are men -- have or are at risk of developing cancer of colon and rectum, and the treatment costs are estimated to be $8.4 billion annually in the U.S. Since it is estimated that diet contributes to 80% of the known colorectal cancer cases, and because of PAH's ubiquity in foods and in environment due to industrial emissions, it is not unreasonable to attribute environmental exposure serving as one of the factors in initiating or accelerating colorectal cancer cases. We will test our hypotheses in adult male transgenic mice with the following specific aims: 1. Investigate the chemopreventive effect of neonatal resveratrol on BaP-DNA adduct formation, persistence and BaP-induced adenomas in colon and rectum of adult ApcMin mice; and 2. Determine whether neonatal exposure to resveratrol alters the expression and activities of BaP biotransformation enzymes and metabolite profile in adult ApcMin mice. This pilot project will provide important new information regarding the contribution of phytochemicals such as RVT towards delaying or preventing the development of colorectal carcinogenesis. Also, the data obtained will be useful for assessment and/or synthesis of other naturally occurring plant-based chemicals that could be tested in the early life as a means of preventing the development of cancer in adult life, thus improving the quality of life.

描述（由申请人提供）： 苯并（a）pyrene（BAP）是一种普遍存在的环境毒物，属于多环芳烃烃（PAH）化合物的家族，并引起对各种器官的毒性和癌症。我们的初步研究表明，用白藜芦醇（RVT）对大鼠进行新生儿给药，从而减少了成年大鼠的细胞色素P450（CYP）酶家族的BAP诱导，后来暴露于BAP的成年大鼠中，并降低了bap的bap，并降低了在浆中和目标组织中的一致性减少和分布的质量分类和质量分类。我们提出的研究将检验以下假设，即RVT通过细胞色素P450（CYP）介导的代谢途径调节BAP诱导的结肠癌发生。在我们的研究中将检验的一个相关假设是，可以通过在新生儿期间对RVT治疗进行“烙印”来改变有助于毒性/癌症的生物利用剂量，如果最终将其转化为人类研究，则可以将这种行动带入人类的质量和可能的范围，甚至可能对癌症进行癌症的范围，并在癌症的范围内产生重大影响，并在癌症的范围内进行癌症，并在癌症中进行癌症，并在癌症中添加了癌症。超过9000万美国人（其中58％是男性）有或有患结肠和直肠癌癌的风险，据估计，在美国，每年估计每年84亿美元，因为估计饮食会导致已知的结直肠癌病例中的80％，并且由于PAH在环境中造成了不合理的因素，因此在环境中造成了不合适的因素，因此可以造成不合适的环境。引发或加速结直肠癌病例。我们将在成年男性转基因小鼠中测试我们的假设：1。研究新生儿白藜芦醇对成年apcmin小鼠的结肠和直肠的BAP-DNA加合物形成，持久性和BAP诱导的腺瘤的化学预防作用；和2。确定新生儿暴露于白藜芦醇是否会改变成年APCMIN小鼠中BAP生物转化酶和代谢物的表达和活性。该试点项目将提供有关植物化学物质（例如RVT）对延迟或防止结直肠癌发生的贡献的重要新信息。同样，获得的数据将有助于评估和/或合成其他天然植物性化学物质，这些化学物质可以在早期生命中进行测试，以防止成人生活中癌症的发展，从而改善生活质量。