Development of hepatic impairment aggravates chemotherapy-induced peripheral neuropathy following oxaliplatin treatment: Evidence from clinical and preclinical studies

Journal of Pharmacological Sciences

Fumiko Sekiguchi¹  Shigekatsu Hatanaka²  Rika Nishimura²  Maho Tsubota²  Atsufumi Kawabata²  Risa Domoto²  Dengli Wang²  Masanori Fujitani³  Yuichi Koizumi³  Tomoyoshi Miyamoto³  Riki Kamaguchi³  Misato Matsuno³  Masahiro Nishibori³ 

[1] Department of Pharmacy, Seichokai Fuchu Hospital, Izumi, Japan;Pathophysiology, Faculty of Pharmacy, Kindai University, Higashi-Osaka, Japan;;Laboratory of Pharmacology &

关键词: Chemotherapy-induced peripheral neuropathy (CIPN);    Oxaliplatin;    Hepatic injury;    High mobility group box 1 (HMGB1);    Thrombomodulin alfa;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 CCl4 or 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. CCl4 released 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.

【 授权许可】

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