Systems-based modelling of retinoid - drug interactions.

天然和合成类维生素a、其他营养物质、某些激素和化学预防和/或化学治疗剂之间的相互作用仍有待研究。这些相互作用与各种致癌过程之间的关系就更不清楚了。经过多年的深入研究，类维生素a作为化学预防和/或化疗药物的使用已经产生了一些令人鼓舞的结果，但总体而言，结果好坏参半。然而，类维甲酸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维甲酸功能和相互作用的基本方面，而不依赖于可能发现与这些化合物相关的任何潜在的化学预防和/或化学治疗特性。此外，类维生素a作为化学预防和/或化学治疗药物的潜在临床用途，在过去由于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，不太可能完全实现，直到该领域的一些基本研究领域得到澄清。为了实现这一目标，我们设计并正在进行一系列补充性的体内和体外研究，以检查类维甲酸-营养-药物相互作用的机制及其在癌症中的作用。基于我们体内研究的结果，我们开发了基于生理的数学/室模型来描述类维甲酸的代谢和各种类维甲酸在许多组织中的相互作用。例如，我们之前的研究表明，合成类维甲酸4-HPR会干扰眼睛、前列腺和肾上腺以及其他一些组织对天然类维甲酸的正常摄取和/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制解释，而且，它们突出了我们整体方法的实用性和临床适用性。相反，全反式维甲酸（另一种用作化学预防和/或化学治疗剂的类维甲酸）的施用与类维甲酸动力学中类似类型的扰动无关，支持了类维甲酸和组织特异性效应与施用不同类型的类维甲酸相关的概念。为了验证从体内模型中得出的假设，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，我们已经在一种新的人类视网膜色素上皮组织培养系统以及正常和转化的人类前列腺和乳腺细胞系中进行了研究。后一项工作的一个重点是描述在给予某些类维甲酸或类维甲酸药物组合后天然类维甲酸正常动力学的扰动，并将这些动力学变化与细胞和分子水平上的类维甲酸相关事件联系起来。后者将包括某些酶活性的改变，以及某些类视黄酮结合蛋白、核类视黄酮受体和转录因子的表达。其他计划或正在进行的研究将包括在正常雌性动物身上进行的体内周转研究，类似于我们在雄性动物身上进行的研究，以及使用乳腺肿瘤模型进行的相关研究。

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.