title: Exogenous IL-1Ra attenuates intestinal mucositis induced by oxaliplatin and 5-fluorouracil through suppression of p53-dependent apoptosis.
abstract: Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect of many chemoagents, resulting in weight loss, diarrhea, and even death. The current treatments for CIM are palliative and have limited benefit. Interleukin-1 receptor antagonist is a natural antagonist of interleukin-1. Our previous studies showed the protective effect of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on the intestine in mice after 5-fluorouracil chemotherapy. In this study, we further evaluated rhIL-1Ra in the treatment of CIM induced by different chemoagents and their combination. Normal as well as tumor-bearing mice were administered oxaliplatin (L-OHP), 5-fluorouracil, or their combination to induce intestinal mucositis and mortality. rhIL-1Ra administered after the chemotherapy, but not after the onset of diarrhea, significantly improved mouse survival, attenuated body weight loss, and reduced the incidence, severity, and duration of diarrhea. Histological examination showed that rhIL-1Ra-treated mice had a relatively intact mucosa structure, more proliferating crypt cells, and higher acid mucin content than the vehicle-treated mice. rhIL-1Ra suppressed crypt apoptosis by reducing the levels of proapoptotic proteins in wild-type, but not in IL-1RI or p53 mice. In addition, rhIL-1Ra was as effective as octreotide acetate in the treatment of chemotherapy-induced diarrhea, but with the advantage of reducing the epithelial apoptosis, the major cause of CIM. Importantly, the tumor sensitivity to chemotherapy was not affected by rhIL-1Ra. Thus, our data strongly suggest that rhIL-1Ra may be useful for the treatment of intestinal mucositis and improving the quality of life for cancer patients on chemotherapy.
authors.affiliation: aLaboratory of Regeneromics, School of Pharmacy bShanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Gao
authors.forename: Lan
authors.initials: L
authors.lastname: Qian
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.forename: Shunying
authors.initials: S
authors.lastname: Zhu
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Guan
authors.forename: Hao
authors.initials: H
authors.lastname: Ye
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Han
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy; D005472:Fluorouracil / Q000008:administration & dosage; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D052016:Mucositis / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D015282:Octreotide / Q000627:therapeutic use; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011994:Recombinant Proteins / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D053590:Interleukin 1 Receptor Antagonist Protein; D009944:Organoplatinum Compounds; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D000077150:Oxaliplatin; D015282:Octreotide; D005472:Fluorouracil