Abstract
According to American Society of Clinical Oncology, no agents are recommended for the prevention of chemotherapy-induced peripheral neuropathy (CIPN), and duloxetine is the only agent that has appropriate evidence to support its use for patients with established CIPN. We have shown that extracellular high mobility group box 1 (HMGB1), a nuclear protein, released from certain cells including macrophages (MMφ) participates in the pathogenesis of CIPN, and that CIPN is prevented by thrombomodulin (TM) alfa (TMα), an anti-DIC agent, capable of causing thrombin-dependent HMGB1 degradation. The anti-CIPN effect of TMα was also demonstrated in humans by a clinical study, and is being intensively investigated in a Japan-U.S. joint clinical trial. In our study, anticoagulants did not only reverse the anti-CIPN effect of TMα, but also aggravated CIPN in mice, possibly through inhibition of thrombin-dependent HMGB1 degradation by endothelial TM, the latter evidence ascertained in humans by our clinical study. Conversely, our clinical study in breast cancer patients treated with paclitaxel (PCT) identified postmenopausal patients as a high risk group for CIPN, and our basic study showed that ovariectomy aggravated CIPN in PCT-treated mice, an effect reversed by estrogen that inhibited PCT-induced HMGB1 release from MMφ. We thus recommend a preventive intervention using TMα for CIPN-prone groups like postmenopausal patients. Collectively, an integrated clinical and basic study is beneficial to investigate the pathogenesis and prevention strategy of CIPN.
