Abstract
The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological interaction with gut microbiota. As a result, up to 40–100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation).
Highlights
Chemotherapy is in general associated with extensive anti-tumor effects, and serious adverse effects and long-term safety issues for both cancer patients and healthcare providers (Sougiannis et al, 2021)
Intestinal Mucositis: Pathophysiology and Treatment dosed with chemotherapeutics, depending drug and dosing regimen (Sonis et al, 2015; Villa and Sonis, 2015)
An inability to resist damage and/or rapidly repair and restore the epithelial barrier function after chemotherapy is detrimental to the cancer patient, as it can result in various pathologies, including inflammation, ulceration, pain, nausea, diarrhea, sepsis, and multiple organ dysfunction and failure (Keefe et al, 2004)
Summary
Chemotherapy is in general associated with extensive anti-tumor effects, and serious adverse effects and long-term safety issues for both cancer patients and healthcare providers (Sougiannis et al, 2021). One of the more common off-target toxicities is chemotherapeutics-induced intestinal mucositis (CIM), which is a complex gastrointestinal (GI) complication. The GI tract is vulnerable to antineoplastic drugs that inhibit cell growth and/or cell division, as the intestinal epithelial cells (IEC) proliferate rapidly and have a complex immunological interaction with the gut microbiota. Antineoplastic drugs such as 5-fluorouracil, methotrexate, irinotecan, and doxorubicin target the vulnerable GI tissue by interrupting DNA synthesis, leading to apoptosis. An inability to resist damage and/or rapidly repair and restore the epithelial barrier function after chemotherapy is detrimental to the cancer patient, as it can result in various pathologies, including inflammation, ulceration, pain, nausea, diarrhea, sepsis, and multiple organ dysfunction and failure (Keefe et al, 2004). In addition to reducing the quality-of-life of these patients, CIM often leads to dose-reduction and subsequent decrease of anticancer effect, sometimes even resulting in death
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