Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States.
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States.
Adv Cancer Res. 2022;155:131-166. doi: 10.1016/bs.acr.2022.02.007. Epub 2022 Mar 21.
Chemotherapy-induced gastrointestinal dysfunction is a common occurrence associated with many different classes of chemotherapeutic agents. Gastrointestinal toxicity includes mucositis, diarrhea, and constipation, and can often be a dose-limiting complication, induce cessation of treatment and could be life threatening. The gastrointestinal epithelium is rich in rapidly dividing cells and hence is a prime target for chemotherapeutic drugs. The incidence of gastrointestinal toxicity, including diarrhea and mucositis, is extremely high for a wide array of chemotherapeutic and radiation regimens. In fact, 60%-100% of patients on high-dose chemotherapy suffer from gastrointestinal side effects. Unfortunately, treatment options are limited, and therapy is often restricted to palliative care. Therefore, there is a great unmet therapeutic need for preventing and treating chemotherapy-induced gastrointestinal toxicities in the clinic. In this review, we discuss our current understanding of the mechanisms underlying chemotherapy-induced diarrhea and mucositis, and emerging mechanisms involving the enteric nervous system, smooth muscle cells and enteric immune cells. Recent evidence has also implicated gut dysbiosis in the pathogenesis of not only chemotherapy-induced mucositis and diarrhea, but also chemotherapy-induced peripheral neuropathy. Oxidative stress induced by chemotherapeutic agents results in post-translational modification of ion channels altering neuronal excitability. Thus, investigating how chemotherapy-induced changes in the gut- microbiome axis may lead to gut-related toxicities will be critical in the discovery of new drug targets for mitigating adverse gastrointestinal effects associated with chemotherapy treatment.
化疗引起的胃肠道功能障碍是一种常见的现象，与许多不同类别的化疗药物有关。胃肠道毒性包括黏膜炎、腹泻和便秘，而且往往是剂量限制的并发症，可导致治疗停止，甚至可能危及生命。胃肠道上皮富含快速分裂的细胞，因此是化疗药物的主要靶点。包括腹泻和黏膜炎在内的胃肠道毒性的发生率对于广泛的化疗和放疗方案都非常高。事实上，60%-100%的接受高剂量化疗的患者都有胃肠道副作用。不幸的是，治疗选择有限，治疗往往限于姑息治疗。因此，临床上迫切需要预防和治疗化疗引起的胃肠道毒性。在这篇综述中，我们讨论了我们目前对化疗引起的腹泻和黏膜炎的机制的理解，以及涉及肠神经系统、平滑肌细胞和肠免疫细胞的新兴机制。最近的证据还表明，肠道微生物失调不仅与化疗引起的黏膜炎和腹泻有关，而且与化疗引起的周围神经病变有关。化疗药物引起的氧化应激导致离子通道的翻译后修饰，改变神经元的兴奋性。因此，研究化疗引起的肠道微生物群轴变化如何可能导致与肠道相关的毒性，对于发现减轻与化疗治疗相关的不良胃肠道影响的新药物靶点将是至关重要的。
