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Gefitinib-Induced Cutaneous Toxicities in Brown Norway Rats Are Associated with Macrophage Infiltration

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Abstract

Gefitinib (Iressa), is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), used in the targeted treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC). Skin toxicity is the major adverse effect observed in patients treated with EGFR-targeted TKIs such as gefitinib and erlotinib. To date, a corresponding skin animal model has not been established to address the mechanisms of these effects. Therefore, we analyzed the skin rash phenotype and its pathological features in Brown Norway (BN) rats treated with gefitinib 2.5 mg, 5.0 mg, or 10 mg/100 g/day for 4 weeks. We found that treatment with gefitinib led to weight loss, rash, itching, and hair loss in a dose-dependent manner. We also investigated the skin pathology and found that the animal model showed thickening of the epidermis, loss of moisture, and apoptosis of keratinocytes. Immunohistochemistry, flow cytometry, and analysis of monocytes and leukocytes in the blood revealed increased macrophage infiltration was associated with the cutaneous toxicities induced by gefitinib in the BN rats. Finally, we found that gefitinib-induced cutaneous toxicity is significantly associated with three inflammatory cytokines known to be secreted by activated macrophages, TREM-1, CINC-2, and CINC-3.

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Funding

This work was supported by the Tibetan foundation projects (Project No. 2017XTCX012), National Natural Science Foundation projects (Project No. 81973667), New Teacher Initial Funding (Project No. 2018-JYBZZ-XJSJJ011), and National Center International Research (Project No. 2015B01022).

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Author notes

  1. Liangqin Wan, Yalei Wang and Yibo Tang contributed equally to this work.

Authors and Affiliations

  1. Beijing University of Chinese Medicine, Beijing, 100029, China

    Liangqin Wan, Yalei Wang, Yibo Tang, Yan Tan, Fang He, Yali Zhang, Ke Yang, Ziwei Chen, Chenchen Song, Ruoxi Gu, Ce Zhang, Xu Wang, Peng Wei, Tonghua Liu, Miao Jiang & Qian Hua

  2. Beijing Gulou Hospital of Traditional Chinese Medicine, Beijing, 100000, China

    Liangqin Wan

Authors
  1. Liangqin Wan
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  2. Yalei Wang
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  5. Fang He
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  14. Tonghua Liu
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  15. Miao Jiang
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Contributions

Liangqin Wan contributed to study design and initial manuscript and was responsible for the whole experiments. Yalei Wang, Fang He, Yali Zhang, Ke Yang, Ziwei Chen, Chenchen Song, Ruoxi Gu, and Ce Zhang contributed to data organization and analysis. All authors were partially carried out the experiment and analyzed the data. Yan Tan helped correct the manuscript. Yibo Tang, Miao Jiang, Xu Wang, Peng Wei, Yan Tan, and Qian Hua conceptualized and designed the study. Tonghua Liu revised the manuscript.

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Correspondence to Miao Jiang or Qian Hua.

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Wan, L., Wang, Y., Tang, Y. et al. Gefitinib-Induced Cutaneous Toxicities in Brown Norway Rats Are Associated with Macrophage Infiltration. Inflammation 43, 2137–2146 (2020). https://doi.org/10.1007/s10753-020-01281-2

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