Development of hepatic impairment aggravates chemotherapy-induced peripheral neuropathy following oxaliplatin treatment: Evidence from clinical and preclinical studies
Development of hepatic impairment aggravates chemotherapy-induced peripheral neuropathy following oxaliplatin treatment: Evidence from clinical and preclinical studies
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奥沙利铂治疗后肝损伤的发生会加重化疗引起的周围神经病变：来自临床和临床前研究的证据
DOI：
10.1016/j.jphs.2022.01.006
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发表时间：
2022
影响因子：
3.5
通讯作者：
Kawabata Atsufumi
中科院分区：
文献类型：
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作者：
Miyamoto Tomoyoshi;Domoto Risa;Sekiguchi Fumiko;Kamaguchi Riki;Nishimura Rika;Matsuno Misato;Tsubota Maho;Fujitani Masanori;Hatanaka Shigekatsu;Koizumi Yuichi;Wang Dengli;Nishibori Masahiro;Kawabata Atsufumi
奥沙利铂经常引起周围神经病变，这是一种剂量限制性不良反应，在极少数情况下会导致肝窦阻塞综合征。因此，我们进行了一项回顾性队列研究，以探讨奥沙利铂诱导的周围神经病变（OIPN）与肝损伤之间的关系，然后进行基础研究来分析其潜在机制。对接受奥沙利铂治疗的癌症患者的病历分析表明，奥沙利铂治疗期间肝损伤的实验室检查参数，包括 AST、ALT 和 APRI（AST 与血小板比值指数）适度升高，与 OIPN 的严重程度（1-4 级）呈正相关，并与后期 OIPN 等级≥2 级的幸存者发生率相关。在小鼠中，CCl4 或乙醇诱导的肝损伤会加速小鼠的 OIPN，这种效应是通过能够促进其凝血酶依赖性降解的中和抗体或血栓调节蛋白 α 使已知参与 OIPN 的高迁移率族蛋白 1 (HMGB1) 失活来阻止的。奥沙利铂还加重小鼠的肝损伤。 CCl4从培养的肝实质细胞中释放HMGB1，奥沙利铂在临床可达到的浓度下从肝实质和非实质细胞中释放HMGB1。我们的临床和临床前数据表明，奥沙利铂治疗期间出现的轻度肝功能损害与后来 OIPN 的恶化有关。
Oxaliplatin often induces peripheral neuropathy, a dose-limiting adverse reaction, and in rare cases leads to sinusoidal obstruction syndrome. We thus conducted a retrospective cohort study to examine the relationship between oxaliplatin-induced peripheral neuropathy (OIPN) and hepatic impairment, and then perform a fundamental study to analyze the underlying mechanisms. Analysis of medical records in cancer patients treated with oxaliplatin indicated that laboratory test parameters of hepatic impairment including AST, ALT and APRI (AST to platelet ratio index) moderately increased during oxaliplatin treatment, which was positively correlated with the severity of OIPN (grades 1–4), and associated with later incidence of survivors with OIPN grades ≥2. In mice, hepatic injury induced by CCl4or ethanol accelerated OIPN in mice, an effect prevented by inactivation of high mobility group box 1 (HMGB1), known to participate in OIPN, by the neutralizing antibody or thrombomodulin alfa capable of promoting its thrombin-dependent degradation. Oxaliplatin also aggravated the hepatic injury in mice. CCl4released HMGB1 from cultured hepatic parenchymal cells, and oxaliplatin at clinically achievable concentrations released HMGB1 from hepatic parenchymal and non-parenchymal cells. Our clinical and preclinical data suggest that the development of mild hepatic impairment during oxaliplatin treatment is associated with later aggravation of OIPN.