Systems-based modelling of retinoid - drug interactions.

天然和人工合成的维甲酸、其他营养素和某些激素以及化学预防和/或化疗药物之间的相互作用仍有待描述。这些相互作用和各种致癌过程之间的关系甚至还没有得到很好的描述。经过多年的深入研究，维甲酸作为化学预防和/或化疗药物的使用已经取得了一些令人鼓舞的结果，但总体来说，结果喜忧参半。然而，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维甲酸功能的基本方面和相互作用，而不是与这些化合物可能被发现的任何潜在的化学预防和/或化疗特性有关。此外，维甲酸作为化学预防和/或化疗药物的潜在临床用途，在过去由于缺乏对这些化合物代谢和相关动力学的基本方面的了解而受到限制，在这一领域的一些基本研究领域得到澄清之前，不太可能完全实现。为了实现这一目标，我们已经设计并正在进行一些补充的体内和体外研究，以检查涉及维甲酸-营养-药物相互作用的机制及其在癌症中的作用。基于我们在体内的研究结果，我们开发了基于生理的、数学的/隔室模型来描述维甲酸的代谢和在许多组织中的各种维甲酸相互作用。例如，我们以前的工作表明，合成的维甲酸4-HPR干扰了眼睛、前列腺和肾上腺以及其他一些组织对天然维甲酸的正常摄取和/或代谢。我们在眼睛中的发现为在使用4-HPR的人体试验中经常观察到的视觉障碍提供了一个机械解释，而且，它们突出了我们整体方法的实用和临床适用性。相比之下，全反式维甲酸，另一种用作化学预防和/或化疗药物的维甲酸，与维甲酸动力学中类似类型的扰动无关，支持了维甲酸和组织特异性效应与给予不同类型的维甲酸相关的概念。为了测试我们体内模型得出的假说，并更详细地研究我们观察到的天然视黄醇动力学变化所涉及的机制，我们筛选并随后修改了一些体外系统，以模拟我们在体内观察到的生理反应。到目前为止，我们已经开展了一种新的人视网膜色素上皮组织培养系统的研究，以及在正常和转化的人前列腺和乳腺细胞系中的研究。后一项工作的一个重点是描述在给予某些维甲酸或维甲酸药物组合后，天然维甲酸正常动力学的扰动，并在细胞和分子水平上将这些动力学变化与维甲酸相关事件联系起来。后者包括某些酶活性的改变以及某些维甲酸结合蛋白、核维甲酸受体和转录因子的表达。其他已计划或正在进行的研究将包括与我们对雄性动物进行的类似的正常雌性动物体内周转研究，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.