Yoshiji Hitoshi, Noguchi Ryuichi, Namisaki Tadashi, Moriya Kei, Kitade Mitsuteru, Aihara Yosuke, Douhara Akitoshi, Kawaratani Hideto, Nishimura Norihisa, Fukui Hiroshi
Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan,
J Gastroenterol. 2014 Oct;49(10):1421-9. doi: 10.1007/s00535-013-0906-y. Epub 2013 Nov 7.
Given the well-documented adverse side effects of sorafenib, many sorafenib-treated patients may need the reduced initial dose of the compound, and an alternative sorafenib-based therapy, which exerts similar clinical benefit, is anticipated. An angiostatic therapy with sorafenib is considered one of the promising approaches for chemoprevention of hepatocellular carcinoma. The aim of the current study was to elucidate the combination effect of low dose of sorafenib and angiotensin-II receptor blocker (ARB) on hepatocarcinogenesis, especially in conjunction with angiogenesis.
The chemopreventive effect on the development of liver preneoplastic lesions, angiogenesis, and several indices was elucidated in rats. We also performed several sets of in vitro experiments to examine the mechanisms involved.
Using a non-diabetic rat model of steatohepatitis with choline deficient L-amino acid-defined diet, sorafenib demonstrated marked inhibition of preneoplastic lesions in a dose dependent manner. Combined treatment with ARB (losartan) at a clinically comparable dose and half dose of sorafenib resulted in the inhibitory effect equivalent to that of common dose of sorafenib along with suppression of hepatic neovascularization and potent angiogenic factor, vascular endothelial growth factor. Furthermore, similar combined inhibitory outcomes were observed in several sets of in vitro studies.
Since the combinatorial treatment using low doses of sorafenib and ARB could sufficiently induce inhibitory effect on the development of preneoplastic lesions at the magnitude similar to the conventional dose of sorafenib, this regimen may provide new strategy for patients intolerant of the usual dose of sorafenib in the future.
鉴于索拉非尼存在诸多已被充分记录的不良副作用，许多接受索拉非尼治疗的患者可能需要降低该化合物的初始剂量，因此人们期待一种能产生相似临床益处的基于索拉非尼的替代疗法。索拉非尼的血管生成抑制疗法被认为是肝细胞癌化学预防的有前景的方法之一。本研究的目的是阐明低剂量索拉非尼与血管紧张素 II 受体阻滞剂（ARB）联合对肝癌发生的影响，尤其是与血管生成相关的影响。
在大鼠中阐明了对肝脏癌前病变发展、血管生成及若干指标的化学预防作用。我们还进行了多组体外实验以研究其中涉及的机制。
在使用胆碱缺乏的 L - 氨基酸限定饮食的非糖尿病性脂肪性肝炎大鼠模型中，索拉非尼以剂量依赖性方式显著抑制癌前病变。临床可比剂量的 ARB（氯沙坦）与半剂量索拉非尼联合治疗产生的抑制效果等同于常规剂量索拉非尼，同时抑制了肝脏新生血管形成及强效血管生成因子血管内皮生长因子。此外，在多组体外研究中也观察到了类似的联合抑制结果。
由于低剂量索拉非尼与 ARB 的联合治疗能够充分诱导对癌前病变发展的抑制作用，其程度与索拉非尼常规剂量相似，该方案未来可能为不耐受常规剂量索拉非尼的患者提供新策略。
