背景:新生血管生成是肝细胞癌(HCC)的关键发病机制之一。血管紧张素转换酶抑制剂(ACE-Is)和血管紧张素受体阻滞剂(ARB)对肾素-血管紧张素系统(RAS)的调节似乎是肝癌的一种可能的辅助治疗方法。由于这些药物的抗血管生成和抗纤维化活性。
目的:阐明ARB和ACE-Is在HCC中的作用。
方法:我们使用访问最多的在线数据库(PubMed,科克伦图书馆,Scopus和WebofScience),输入查询术语\"血管紧张素转换酶抑制剂\"或\"ACE抑制剂\"或\"ACE-I\"和\"肝癌*\"或\"肝细胞癌;此外\"血管紧张素II1型受体阻滞剂\"或\"ARBs\"和\"肝癌\"或\"肝细胞癌\"。合格标准是:(1)前瞻性或回顾性临床研究;(2)流行病学研究;(3)体内或体外进行的实验研究。摘要,会议文件,和评论被排除在先验之外。我们的文献检索仅限于用英语发表的文章,在同行评审的期刊上。
结果:选择了31项研究。三项干预研究表明,ACE-Is仅在与维生素K或支链氨基酸联合使用时对HCC复发有明显的保护作用。总体生存率没有显著提高。在六项回顾性观察研究中,主要集中在总体生存率上,只有一个在ACE-Is组中表现出延长的生存期,而同时评估肿瘤复发的两项结果相互矛盾.所有实验研究均显示RAS抑制剂对肝癌发生的有益作用。大量的实验研究,在动物和细胞培养上进行,证明了ACE-Is和ARBs的抗血管生成和抗纤维化作用,由于抑制了一些细胞因子,如血管内皮生长因子,缺氧诱导因子-1a,转化生长因子-β和肿瘤坏死因子α。在接受此类药物后,在发展较少的HCC和肿瘤前病变的啮齿动物中证明了这些机制的全部或部分。
结论:在人类中,RAS抑制剂-单独或组合-显着抑制累积HCC复发,在不延长患者生存期的情况下,但是这些研究固有的一些局限性促使进一步的研究。
BACKGROUND: Neoangiogenesis is one of the key pathogenetic mechanisms in hepatocellular carcinoma (HCC). Modulation of the renin-angiotensin system (RAS) by angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) seems to be a possible adjuvant therapy for HCC, due to the anti-angiogenic and anti-fibrogenic activity of these drugs.
OBJECTIVE: To elucidate the role of ARBs and ACE-Is in HCC.
METHODS: We performed an electronic search of the literature using the most accessed online databases (PubMed, Cochrane library, Scopus and Web of Science), entering the query terms \"angiotensin-converting enzyme inhibitors\" OR \"ACE inhibitors\" OR \"ACE-I\" AND \"
hepatocarcinoma*\" OR \"hepatocellular carcinoma; moreover \"angiotensin II type 1 receptor blockers\" OR \"ARBs\" AND \"
hepatocarcinoma*\" OR \"hepatocellular carcinoma\". Eligibility criteria were: (1) prospective or retrospective clinical studies; (2) epidemiological studies; and (3) experimental studies conducted in vivo or in vitro. Abstracts, conference papers, and reviews were excluded a priori. We limited our literature search to articles published in English, in peer-reviewed journals.
RESULTS: Thirty-one studies were selected. Three interventional studies showed that ACE-Is had a significant protective effect on HCC recurrence only when used in combination with vitamin K or branched chain aminoacids, without a significant increase in overall survival. Of six retrospective observational studies, mainly focused on overall survival, only one demonstrated a prolonged survival in the ACE-Is group, whereas the two that also evaluated tumor recurrence showed conflicting results. All experimental studies displayed beneficial effects of RAS inhibitors on hepatocarcinogenesis. Numerous experimental studies, conducted either on animals and cell cultures, demonstrated the anti-angiogenetic and antifibrotic effect of ACE-Is and ARBs, thanks to the suppression of some cytokines such as vascular endothelial growth factor, hypoxia-inducible factor-1a, transforming growth factor-beta and tumor necrosis factor alpha. All or parts of these mechanisms were demonstrated in rodents developing fewer HCC and preneoplastic lesions after receiving such drugs.
CONCLUSIONS: In humans, RAS inhibitors - alone or in combination - significantly suppressed the cumulative HCC recurrence, without prolonging patient survival, but some limitations intrinsic to these studies prompt further investigations.