Systems-based modelling of retinoid - drug interactions

基于系统的类维生素A-药物相互作用建模

• 批准号: 6761405
• 负责人: KEVIN C LEWIS
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6761405
• 关键词: adrenal glands; breast neoplasms; drug /agent; fenretinide; human tissue; mathematical model; model design /development; neoplasm /cancer pharmacology; nutrient drug interaction; nutrition aspect of cancer; nutrition related tag; pharmacokinetics; prostate; retina; retinoids; tissue /cell culture; vitamin metabolism

Interactions among native and synthetic retinoids, other nutrients, and certain hormones and chemopreventive and/or chemotherapeutic agents remain to be delineated. The relationship between these interactions and various carcinogenic processes are even less well characterized. After years of intensive study, the use of retinoids as chemopreventive and/or chemotherapeutic agents has yielded some encouraging results, but overall, results have been mixed. Nevertheless, the critical role of retinoids in normal cellular growth and differentiation processes requires that we better understand basic aspects of retinoid function and interactions independent of any potential chemopreventive and/or chemotherapeutic properties that might be found to be associated with these compounds. Moreover, the potential clinical usefulness of retinoids as chemopreventive and/or chemotherapeutic agents, which arguably has been limited in the past by a lack of understanding of basic aspects of the metabolism and related dynamics of these compounds, is unlikely to be fully realized until a number of basic areas of research in this area are clarified. To accomplish this, we have designed and are conducting a number of complementary in vivo and in vitro studies to examine the mechanisms involved in retinoid-nutrient-drug interactions and their role in cancer. Based on the results of our in vivo studies, we have developed physiologically-based, mathematical/compartmental models to describe the metabolism of retinoids and various retinoid interactions in a number of tissues. For example, our previous work has indicated that the synthetic retinoid 4-HPR interferes with normal uptake and/or metabolism of native retinoids in the eyes, prostate and adrenal gland, as well as a number of other tissues examined. Our findings in the eyes have provided a mechanistic explanation for the visual disturbances often observed in human trials using 4-HPR and moreover, they highlight the practical and clinical applicability of our overall approach. In contrast, administration of all-trans retinoic acid, another retinoid used as a chemopreventive and/or chemotherapeutic agent, was not associated with similar types of perturbations in retinoid kinetics, supporting the notion of retinoid and tissue specific effects associated with administration different types of retinoids. To test the hypotheses derived from our in vivo models and to study in greater detail the mechanisms involved in the alterations of native retinoid dynamics that we observed, we have screened and subsequently modified a number of in vitro systems to mimic physiological responses we have observed in vivo. Thus far, we have carried out studies in a novel tissue culture system for human retinal pigment epithelium as well as in normal and transformed human prostate and mammary cell lines. One focus of the latter work is to characterize perturbations of the normal dynamics of native retinoid following administration of certain retinoid or retinoid:drug combinations, and to relate these changes in dynamics to retinoid related events at the cellular and molecular level. The latter would include alterations in certain enzymatic activities as well as expression of certain retinoid-binding proteins, nuclear retinoid receptors, and transcription factors. Other studies, planned or in progress, will include in vivo turnover studies in normal female animals similar to those we have conducted with males, as well as related studies using mammary tumor models.

天然和合成类视黄醇、其他营养素以及某些激素和化学预防剂和/或化疗剂之间的相互作用仍有待描述。这些相互作用与各种致癌过程之间的关系甚至还不清楚。经过多年的深入研究，使用类维生素A作为化学预防和/或化疗剂已经取得了一些令人鼓舞的结果，但总体而言，结果好坏参半。然而，类视黄醇在正常细胞生长和分化过程中的关键作用要求我们更好地了解类视黄醇功能和相互作用的基本方面，独立于可能被发现与这些化合物相关的任何潜在的化学预防和/或化疗特性。此外，类视黄醇作为化学预防剂和/或化疗剂的潜在临床用途在过去可能因缺乏对这些化合物的代谢和相关动力学的基本方面的了解而受到限制，在该领域的许多基础研究领域得到澄清之前，不可能完全实现。为了实现这一目标，我们设计并正在进行许多补充的体内和体外研究，以检查类维生素A-营养素-药物相互作用的机制及其在癌症中的作用。根据我们的体内研究结果，我们开发了基于生理学的数学/区室模型来描述类维生素A的代谢以及许多组织中的各种类维生素A相互作用。例如，我们之前的工作表明，合成类视黄醇 4-HPR 会干扰眼睛、前列腺和肾上腺以及许多其他检查组织中天然类视黄醇的正常摄取和/或代谢。我们在眼睛中的发现为使用 4-HPR 的人体试验中经常观察到的视觉障碍提供了机械解释，此外，它们强调了我们整体方法的实际和临床适用性。相比之下，全反式视黄酸（另一种用作化学预防和/或化疗剂的类视黄酸）的施用与类视黄醇动力学中类似类型的扰动无关，这支持了与施用不同类型的类视黄醇相关的类视黄醇和组织特异性效应的概念。为了测试源自我们的体内模型的假设并更详细地研究我们观察到的天然类视黄醇动力学改变所涉及的机制，我们筛选并随后修改了许多体外系统以模拟我们在体内观察到的生理反应。到目前为止，我们已经在人类视网膜色素上皮以及正常和转化的人类前列腺和乳腺细胞系的新型组织培养系统中进行了研究。后一项工作的一个重点是表征在施用某些类维生素A或类维生素A：药物组合后天然类维生素A正常动力学的扰动，并将这些动力学变化与细胞和分子水平上的类维生素A相关事件联系起来。后者包括某些酶活性的改变以及某些类维生素A结合蛋白、核类维生素A受体和转录因子的表达的改变。其他计划或正在进行的研究将包括在正常雌性动物中进行的体内周转研究，类似于我们对雄性动物进行的研究，以及使用乳腺肿瘤模型的相关研究。