RETINOID MEDIATED ANTICANCER ACTIVITIES

大量研究表明，富含维生素A的饮食 而类胡萝卜素可以预防多种癌症。之一 最引人注目的结果是去年洪和同事报告的， 显示合成的维甲酸异维甲酸（13-顺式维甲酸） 作为辅助治疗以高剂量施用， 鳞状细胞癌患者第二原发肿瘤发生率 头部和颈部的癌症。这些第二原发性肿瘤是 治疗失败和患者死亡的主要原因 成功治疗了早期原发性肿瘤。的 维甲酸预防癌症的机制 （合成维生素A衍生物）仍然知之甚少。一 通过对维甲酸的鉴定，为进一步研究维甲酸的生物学活性提供了一种可能的模型 作为类固醇/甲状腺激素受体成员的RAR受体 超家族这些是配体激活的增强子蛋白， 与同源DNA序列，从而调节转录， 相邻的启动子。我们实验室最近有一项令人兴奋的发现， 揭示了一种新的机制，其中RAR和细胞Jun/Fos 癌基因产物通过直接蛋白质/蛋白质相互拮抗 互动因此，在类维生素A存在下的RAR可以直接 干扰信号转导途径，用于许多生长 因子和病毒及细胞癌基因。我们在这里提出一个分析， 这种新的机制和最佳的维甲酸的表征 抗癌基因活性和受体特异性。这类维甲酸是 可能有最小的副作用，副作用是主要的 目前使用维甲酸的问题。RAR蛋白结构域相互作用 c-Jun/c-Fos癌蛋白将使用体外 诱变系统、瞬时转染测定和凝胶阻滞。 CDNAS，编码与RAR和c-Jun相互作用的蛋白质， 选择和分析，使用最近描述的方法， 生物素化蛋白质作为探针。这项研究的结果将 从而了解核反应的分子机制， 受体可以干扰癌基因的活动， 副作用减少的有效新型类维生素A作为治疗剂 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.