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首页> 外文期刊>Cancer prevention research. >Testing Novel Pyrimidinyl Rexinoids: A New Paradigm for Evaluating Rexinoids for Cancer Prevention
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Testing Novel Pyrimidinyl Rexinoids: A New Paradigm for Evaluating Rexinoids for Cancer Prevention

机译：测试新型嘧啶基戒指：一种新的范例，用于评估癌症预防的戒指

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Rexinoids, selective ligands for retinoid X receptors (RXR), have shown promise in preventing many types of cancer. However, the limited efficacy and undesirable lipidemic side-effects of the only clinically approved rexinoid, bexarotene, drive the search for new and better rexinoids. Here we report the evaluation of novel pyrimidinyl (Py) analogues of two known chemopreventive rexinoids, bexarotene (Bex) and LG100268 (LG268) in a new paradigm. We show that these novel derivatives were more effective agents than bexarotene for preventing lung carcinogenesis induced by a carcinogen. In addition, these new analogues have an improved safety profile. PyBex caused less elevation of plasma triglyceride levels than bexarotene, while PyLG268 reduced plasma cholesterol levels and hepatomegaly compared with LG100268. Notably, this new paradigm mechanistically emphasizes the immunomodulatory and anti-inflammatory activities of rexinoids. We reveal new immunomodulatory actions of the above rexinoids, especially their ability to diminish the percentage of macrophages and myeloid-derived suppressor cells in the lung and to redirect activation of M2 macrophages. The rexinoids also potently inhibit critical inflammatory mediators including IL6, IL1 beta, CCL9, and nitric oxide synthase (iNOS) induced by lipopolysaccharide. Moreover, in vitro iNOS and SREBP (sterol regulatory element-binding protein) induction assays correlate with in vivo efficacy and toxicity, respectively. Our results not only report novel pyrimidine derivatives of existing rexinoids, but also describe a series of biological screening assays that will guide the synthesis of additional rexinoids. Further progress in rexinoid synthesis, potency, and safety should eventually lead to a clinically acceptable and useful new drug for patients with cancer.
机译：Rexinoids，用于类视黄醇X受体（RXR）的选择性配体，在预防许多类型的癌症方面表现出承诺。然而，唯一的临床批准的戒指，苯甲肾上腺素效果有限，不希望的脂肪激活副作用，驱动搜索新的和更好的戒指。在这里，我们在新的范例中报告了两种已知的化学预防性戒指，苯甲苯（BEX）和LG100268（LG268）的新型嘧啶基（PY）类似物的评价。我们表明这些新的衍生物比异甲烯更有效，用于预防致癌致癌致癌致癌作用。此外，这些新的类似物具有改进的安全性。 Pybex导致血浆甘油三酯水平的升高而不是面甲苯二甲酸，而PylG268与LG100268相比减少了血浆胆固醇水平和肝肿大。值得注意的是，这种新的范式机械地强调了戒指的免疫调节和抗炎活性。我们揭示了上述戒指的新免疫调节作用，尤其是它们在肺中减少巨噬细胞和骨髓源性抑制细胞的百分比并重定向M2巨噬细胞的激活能力。戒指还易于抑制脂多糖诱导的IL6，IL1β，CCL9和一氧化氮合酶（InOS）的临界炎症介质。此外，体外Inos和Srebp（甾醇调节元件结合蛋白）诱导测定分别与体内疗效和毒性相关。我们的结果不仅报告了现有戒指的新型嘧啶衍生物，而且描述了一系列生物筛查测定，这将引导额外的戒毒品的合成。戒毒合成，效力和安全性的进一步进展最终应导致癌症患者的临床可接受和有用的新药。

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