Natural Inhibitors of Carcinogenesis

化学预防是一种治疗方法，其中通过口服能够抑制致癌过程的无毒剂来预防或延迟人类癌症。作为战胜癌症的国家努力的一个组成部分，这种方法的优点是显而易见的。多种潜在的癌症化学预防剂 已知，其中大部分是在经验基础上发现的。在三个独立机构的合作下，我们组建了一个多学科团队，专注于发现和表征天然产物或天然产物衍生物的新癌症化学预防剂。正如大量先例所证明的那样，大自然提供了广泛的化学多样性。与过去一样，我们将继续使用陆生植物材料（可食用） 并且不可食用），但是我们还将集中于从在癌症化学预防领域中尚未充分探索的新来源获得先导化合物，即，深海沉积物衍生微生物。一些独特的成分，用于治疗人类疾病，不能预期除了天然产物药物发现的实验过程。从充分表征的植物材料或深海微生物开始，制备提取物，并在一组体外生物测定中评价其活性，以指示抑制致癌作用的主要阶段。这些测定法已明确设计用于此目的，和一些方法，如脉冲超滤利用LC/MS，是非常原始的。活性物质在生理复杂性更高的二次测定系统中进行评价，经二次测定判定具有活性的物质进行生物测定指导的分级。活性成分是由物理和化学性质在结构上定义的， 光谱方法，或通过X射线晶体学。然后在更广泛的生物测定系统中对这些先导物进行评价，并将其视为开发的候选物。作为该计划项目的一部分，开发涉及化学合成或大规模分离，详细的机理研究，建立结构-活性关系，铅优化，使用最先进的结构生物学方法定义与靶分子的分子相互作用，以及在短期或长期研究中确定癌症化学预防潜力 用实验室动物进行。全程提供生物统计和分析（LC/MS/MS）支持。因此，该计划项目的范围需要促进新的癌症化学预防剂从领域或海洋的水平，到结构和机械定义的化学实体的水平。这些工作需要在两个核心部分和一个外部咨询委员会的协助下，协调四个独立项目的努力。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RAPID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，我们预计未来的进展将有增无减。

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.