Interleukin-1 receptor antagonist attenuates cyclophosphamide-induced mucositis in a murine model.
OBJECTIVE
Cyclophosphamide is a cytotoxic chemotherapy drug that causes severe damages to hematopoietic and gastrointestinal systems. The aim of this study is to evaluate the protective effects of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on chemotherapy-induced mucositis (CIM) in a murine model of cyclophosphamide chemotherapy.


METHODS
In single chemotherapy models, equal numbers of gender-matched Balb/c mice were administered intraperitoneal injections of rhIL-1Ra at a dose of 1 mg/kg/day or vehicle for 5 continuous days, followed by single intraperitoneal injection of cyclophosphamide at doses of 100, 300, 400 or 550 mg/kg. In multiple cycles of chemotherapy models, mice were administered rhIL-1Ra or vehicle for 5 days, followed by cyclophosphamide injection at a dose of 300 mg/kg. The course has been repeated for 2 or 3 times with a 1-month break in between. In continuous chemotherapy models, mice were administered rhIL-1Ra or vehicle for 5 days, followed by cyclophosphamide injections at doses of 150 or 200 mg/kg/day for 3 days. Body weight and diarrhea were observed in each model. Intestinal morphology was observed in mice received 300 or 400 mg/kg cyclophosphamide chemotherapy.


RESULTS
CIM was induced by cyclophosphamide in a dose-dependent manner. RhIL-1Ra attenuated CIM with reduced body weight loss, diarrhea, intestinal injuries and mortality after CY chemotherapy.


CONCLUSIONS
The pretreatment with rhIL-1Ra effectively protected murine gastrointestinal system from clinically relevant cyclophosphamide regimens. The identification of these protective effects of rhIL-1Ra highlights clinical values of this protein for the prevention of CIM.
Xiang
Di
D
Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, 200240 Shanghai, China.
Guo
Yiping
Y
Zhang
Jing
J
Gao
Jin
J
Lu
Huili
H
Zhu
Shunying
S
Wu
Mingyuan
M
Yu
Yan
Y
Han
Wei
W
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D001835:Body Weight / Q000187:drug effects; D003520:Cyclophosphamide / Q000009:adverse effects*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D052016:Mucositis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D010446:Peptide Fragments / Q000627:therapeutic use*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000627:therapeutic use*
D018906:Antineoplastic Agents, Alkylating; D010446:Peptide Fragments; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D003520:Cyclophosphamide