Natural Inhibitors of Carcinogenesis

致癌的天然抑制剂

• 批准号: 7364176
• 负责人: John M. Pezzuto
• 金额: $ 130.34万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-09-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364176
• 关键词: Natural; Inhibitors; Carcinogenesis

Chemoprevention is a therapeutic method wherein human cancer is prevented or delayed through oral consumption of nontoxic agents capable of inhibiting the process of carcinogenesis. As an integral component of the national effort to defeat cancer, the merit of this approach is intuitively obvious. A variety of potential cancer chemopreventive agents are known, most of which were discovered on an empirical basis. With the cooperation of three separate institutions, we have assembled a multidisciplinary team focused on the discovery and characterization of new cancer chemopreventive agents that are natural products or natural product derivatives. As established by ample precedent, nature provides broad chemical diversity. As in the past, we will continue to work with terrestrial plant materials (edible and nonedible), but we will also concentrate on obtaining lead compounds from a novel source that has not been adequately explored in the area of cancer chemoprevention, i.e., deep ocean sediment-derived microorganisms. Some unique constituents, useful for the treatment of human ailments, cannot be anticipated aside from the experimental process of natural product drug discovery. Starting with well-characterized plant materials or deep sea microorganisms, extracts are prepared and evaluated for activity in a panel of in vitro bioassays indicative of inhibiting major stages of carcinogenesis. These assays have been explicitly designed for this purpose, and some of the methodology, such as pulsed-ultrafiltration utilizing LC/MS, is highly original. Active materials are evaluated in secondary assay systems of greater physiologic complexity, and those judged to be active with a secondary discriminator are subjected to bioassay-guided fractionation. Active principles are structurally-defined by physical and spectroscopic methods, or by X-ray crystallography. The leads are then evaluated in a broader array of bioassay systems, and considered as candidates for development. As part of this program project, development involves chemical synthesis or large-scale isolation, detailed mechanistic studies, establishment of structure-activity relationships, lead optimization, definition of molecular interactions with target molecules using state-of-the-art methods of structural biology, and determination of cancer chemopreventive potential in short- or long-term studies conducted with laboratory animals. Biostatistical and analytical (LC/MS/MS) support is provided throughout. The scope of the program project thereby entails promoting new cancer chemopreventive agents from the level of the field or sea, to the level of structurally- and mechanistically-defined chemical entities of proven therapeutic efficacy. These undertakings require the coordinated effort of four separate projects that are assisted by two core components, and an External Advisory Board. To facilitate utilization of the newly discovered agents for the prevention of human cancers, which is the long-term objective of this program project, partnerships will be fostered with the NCI (e.g, through the RAPID program) or the private sector. All elements of the program project have proven effective, and we anticipate unabated progress in the future.

化学预防是一种治疗方法，通过口服能够抑制癌变过程的无毒药物来预防或推迟人类癌症的发生。作为国家抗击癌症努力的一个组成部分，这种方法的优点直观地说是显而易见的。多种潜在的癌症化学预防药物 是已知的，其中大部分是在经验的基础上发现的。在三个不同机构的合作下，我们组建了一个多学科团队，专注于发现和表征新的癌症化学预防药物，这些药物是天然产品或天然产品衍生品。正如大量的先例所确立的那样，大自然提供了广泛的化学多样性。像过去一样，我们将继续使用陆地植物材料(可食用 但我们也将专注于从一种在癌症化学预防领域尚未得到充分探索的新来源，即深海沉积物衍生微生物中获得铅化合物。除了天然产物药物发现的实验过程外，一些对治疗人类疾病有用的独特成分是无法预料的。从具有良好特性的植物材料或深海微生物开始，制备提取物，并在一组表明抑制癌症发生的主要阶段的体外生物测试中评估其活性。这些分析都是专门为此目的而设计的，其中一些方法，如利用LC/MS的脉冲超滤，具有很高的原创性。活性物质在生理复杂性更高的二级检测系统中进行评估，而那些用二级鉴别器判断为活性的材料则接受生物测定指导的分级。主动原则在结构上由物理和 光谱分析方法，或X射线结晶学。然后，在更广泛的生物检测系统中对这些线索进行评估，并将其视为开发的候选对象。作为该计划项目的一部分，开发包括化学合成或大规模分离、详细的机理研究、结构-活性关系的建立、先导优化、使用最先进的结构生物学方法确定与目标分子的分子相互作用，以及在短期或长期研究中确定癌症的化学预防潜力。 用实验动物进行实验。生物统计和分析(LC/MS/MS)支持贯穿始终。因此，该计划项目的范围需要将新的癌症化学预防药物从现场或SEA的水平推广到结构和机械定义的具有已证实治疗效果的化学实体的水平。这些工作需要四个独立项目的协调努力，这四个项目得到两个核心组成部分和一个外部咨询委员会的协助。为了促进利用新发现的药物预防人类癌症，这是该计划项目的长期目标，将与NCI(例如，通过快速计划)或私营部门建立伙伴关系。该计划项目的所有要素都已被证明是有效的，我们预计未来将取得有增无减的进展。