ANALYSIS OF RETINOID MEDIATED ANTI-CANCER ACTIVITIES

大量研究表明，高维生素A饮食 类胡萝卜素对多种癌症有保护作用。其中一个 最引人注目的结果是去年由Hong和他的同事报告的 显示合成的维甲酸异维A酸(13-顺式维甲酸) 作为辅助治疗，大剂量使用可显著降低 鳞状细胞癌患者二次原发肿瘤的发生 头颈部的癌症。这些第二种原发肿瘤是 以下患者治疗失败和死亡的主要原因 成功地治疗了他们早期的原发肿瘤。这个 维甲酸防癌作用机制的研究进展 (合成维生素A衍生物)仍然知之甚少。一个 通过对维甲酸的鉴定，提供了势能模型 作为类固醇/甲状腺激素受体成员的受体(RAR) 超级大家庭。这些是配体激活的增强子蛋白，它们相互作用 与同源DNA序列结合，从而调节转录 相邻的发起人。我们实验室最近的一项令人兴奋的发现 揭示了RARs和细胞Jun/Fos之间的一种新机制 癌基因产物通过直接蛋白质/蛋白质相互拮抗 互动。因此，RAR在维甲酸的存在下可以直接 干扰信号转导途径，被许多生长所使用 因子以及病毒和细胞癌基因。我们在这里建议分析一下 这一新的作用机制和维甲酸类化合物的表征 抗癌基因活性和受体特异性。这种维甲酸是 可能有最小的副作用，副作用是主要的 目前使用的维甲酸有问题。RAR蛋白结构域的相互作用 C-jun/c-Fos癌蛋白的体外检测 诱变系统、瞬时转染法和凝胶滞留。 编码与RAR和c-jun相互作用的蛋白质的cDNA将是 选择和分析，使用最近描述的方法，采用 生物素化蛋白作为探针。这项研究的结果将 导致对核的分子机制的理解 受体可以干扰癌基因的活性，使设计成为可能 作为治疗药物的副作用减少的有效的新型维甲酸 对抗癌症。

A large number of studies have indicated that a diet high in vitamin A and carotenoids is protective against a variety of cancers. One of the most striking results was reported last year by Hong and co-workers who showed that the synthetic retinoid isotretinoin (13-cis retinoic acid) administered in a high dose as adjuvant therapy, reduces significantly the occurrence of second primary tumors in patients with squamous cell carcinomas of the head and neck. These second primary tumors are the major reason for treatment failure and death in patients which have undergone successful therapy of their early staged primary tumors. The mechanism underlying the cancer preventive effects of retinoids (synthetic vitamin A derivatives) is still poorly understood. A potential model was provided by the identification of retinoic acid receptors (RAR) as members of the steroid/thyroid hormone receptor superfamily. These are ligand-activated enhancer proteins which interact with cognate DNA sequences and thereby modulate transcription from adjacent promoters. A recent exciting finding in our laboratory has revealed a novel mechanism in which RARs and the cellular Jun/Fos oncogene products antagonize each other by direct protein/protein interaction. Thus, RAR in the presence of retinoids can directly interfere with the signal transduction pathway, used by many growth factors and viral and cellular oncogenes. We propose here an analysis of this new mechanism and the characterization of retinoids with optimal anti-oncogene activity and receptor specificity. Such retinoids are likely to have minimal side effects, side effects being the major problem with presently use retinoids. RAR protein domains interacting with the c-Jun/c-Fos oncoproteins will be determined using in vitro mutagenesis systems, transient transfection assays and gel retardation. CDNAS, encoding proteins that interact with RAR and c-Jun will be selected and analyzed, using a recently described approach employing biotinilated proteins as probes. The results from this research will lead to the understanding of the molecular mechanism by which nuclear receptors can interfere with oncogene activities and enable the design of potent novel retinoids with reduced side effects as therapeutics against cancers.