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Interleukin-1 receptor antagonist attenuates cyclophosphamide-induced mucositis in a murine model

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Abstract

Purpose

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.

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Abbreviations

rhIL-1Ra:

Recombinant human inteuleukin-1 receptor antagonist

CY:

Cyclophosphamide

CIM:

Chemotherapy-induced mucositis

CID:

Chemotherapy-induced diarrhea

BW:

Body weight

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Acknowledgments

This work is supported by China Ministry of Science and Technology (grant “863” 2007AA02Z149; “New drug initiative” 2009ZX09103-743), National Natural Science Foundation of China (grant 30801419), and Science and Technology Commission of Shanghai Municipality (grant 075407071; 09540700600).

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Authors and Affiliations

  1. Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, 200240, Shanghai, China

    Di Xiang, Yiping Guo, Jing Zhang, Jin Gao, Huili Lu, Mingyuan Wu & Wei Han

  2. Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, 200240, Shanghai, China

    Shunying Zhu & Yan Yu

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  1. Di Xiang
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Correspondence to Yan Yu or Wei Han.

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Xiang, D., Guo, Y., Zhang, J. et al. Interleukin-1 receptor antagonist attenuates cyclophosphamide-induced mucositis in a murine model. Cancer Chemother Pharmacol 67, 1445–1453 (2011). https://doi.org/10.1007/s00280-010-1439-1

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