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

Abstract

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.

• Authors: Tomoyoshi Miyamoto, Risa Domoto, Fumiko Sekiguchi, Riki Kamaguchi, Rika Nishimura, Misato Matsuno, Maho Tsubota, Masanori Fujitani, Shigekatsu Hatanaka, Yuichi Koizumi, Dengli Wang, Masahiro Nishibori, Atsufumi Kawabata
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 148 Issue 3 Pg. 315-325 (Mar 2022) ISSN: 1347-8648 [Electronic] Japan
• PMID: 35177211 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Chemical References

• Antineoplastic Agents
• HMGB1 Protein
• HMGB1 protein, mouse
• Oxaliplatin

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents (adverse effects)
• Cells, Cultured
• Chemical and Drug Induced Liver Injury (etiology)
• Disease Progression
• Female
• HMGB1 Protein (metabolism)
• Humans
• Male
• Mice, Inbred Strains
• Middle Aged
• Oxaliplatin (adverse effects)
• Peripheral Nervous System Diseases (chemically induced, genetics)
• Retrospective Studies
• Severity of Illness Index
• Mice