Department of Gastroenterology, Gifu University School of Medicine, Gifu, Japan.
Hepatol Res. 2007 Sep;37 Suppl 2:S299-302. doi: 10.1111/j.1872-034X.2007.00201.x.
The strategy to prevent liver carcinogenesis consists of: (i) antiviral modalities such as vaccination, lamivudin, and interferon; (ii) anti-inflammatory modality; and (iii) chemoprevention using such compounds as retinoid analog and vitamin K. Cancer chemoprevention is defined as an approach where natural or synthetic chemical compound works to arrest or reverse premalignant cells by using physiological pathways. As a consequence, such a clone of premalignant cells is eradicated (clonal deletion) by differentiation induction or apoptosis, and thus the process toward the development of clinically detectable cancer is disrupted. A particularly effective candidate target of chemoprevention in liver diseases is an advanced stage of chronic hepatitis, that is supposed to contain transformed hepatocyte clone(s); that is, primary prevention from liver cirrhosis and prevention of recurrent and second primary hepatocellular carcinoma following the treatment of the initial cancer. Retinoid is a collective term of vitamin A analog that binds to nuclear retinoid receptors;retinoic acid receptors (RAR) and retinoid X receptors (RXR). After ligand coupling, these receptors form homo- or heterodimers, bind to the response element (RARE or RXRE) upstream of the target gene, and regulate the gene expression as a transcriptional factor. Biological phenotypes of such transcriptional regulation by retinoid include cellular differentiation, tissue morphogenesis, and programmed cell death (apoptosis). Due to these functions, retinoid analogs are clinically tried to prevent/treat carcinoma in a wide variety of organs including head and neck cancer, uterine cervical cancer, certain leukemia and liver cancer. In this article, clinical trials of retinoid analog to inhibit second primary hepatoma, supposed molecular mechanism of the action of the compound, and aberrant metabolism of RXR and its role in liver carcinogenesis are briefly reviewed.
（i）抗病毒方式，如疫苗接种、拉米夫定和干扰素；（ii）抗炎方式；和（iii）使用维甲酸类似物和维生素 K 等化合物进行化学预防。癌症化学预防被定义为一种方法，其中天然或合成化学化合物通过生理途径作用于阻止或逆转癌前细胞。因此，通过诱导分化或凋亡，消灭了癌前细胞的克隆（克隆删除），从而破坏了向临床可检测癌症发展的过程。肝脏疾病化学预防的一个特别有效的候选目标是慢性肝炎的晚期，该期应包含转化的肝细胞克隆；也就是说，原发性预防肝硬化和预防初始癌症治疗后复发性和第二原发性肝细胞癌。类视黄醇是与核视黄醇受体结合的维生素 A 类似物的统称；视黄酸受体（RAR）和视黄醇 X 受体（RXR）。配体偶联后，这些受体形成同源或异源二聚体，与靶基因上游的反应元件（RARE 或 RXRE）结合，并作为转录因子调节基因表达。类视黄醇通过这种转录调控产生的生物学表型包括细胞分化、组织形态发生和程序性细胞死亡（凋亡）。由于这些功能，类视黄醇类似物在包括头颈部癌症、子宫颈癌、某些白血病和肝癌在内的多种器官中被尝试用于预防/治疗癌症。本文简要回顾了类视黄醇类似物抑制第二原发性肝癌的临床试验、该化合物作用的分子机制以及 RXR 的异常代谢及其在肝癌发生中的作用。
