Gefitinib-Induced Cutaneous Toxicities in Brown Norway Rats Are Associated with Macrophage Infiltration
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ORIGINAL ARTICLE
Gefitinib-Induced Cutaneous Toxicities in Brown Norway Rats Are Associated with Macrophage Infiltration Liangqin Wan,1,2 Yalei Wang,1 Yibo Tang,1 Yan Tan,1 Fang He,1 Yali Zhang,1 Ke Yang,1 Ziwei Chen,1 Chenchen Song,1 Ruoxi Gu,1 Ce Zhang,1 Xu Wang,1 Peng Wei,1 Tonghua Liu,1 Miao Jiang,1,3 and Qian Hua 1,3
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.
Abstract—
KEY WORDS: gefitinib; macrophages; cutaneous toxicities; Brown Norway rats.
INTRODUCTION
Liangqin Wan, Yalei Wang and Yibo Tang contributed equally to this work. 1
Beijing University of Chinese Medicine, Beijing, 100029, China Beijing Gulou Hospital of Traditional Chinese Medicine, Beijing, 100000, China 3 To whom correspondence should be addressed at Beijing University of Chinese Medicine, Beijing, 100029, China. E-mails: [email protected]; [email protected] 2
Gefitinib (Iressa, ZD1839) has been approved for use as a first-line drug for the treatment of non-small cell lung cancer (NSCLC). Skin toxicity is the most common adverse effect associated with this treatment. In controlled clinical trials, 60% of patients treated with gefitinib developed skin rashes, and approximately 32% of these symptoms were severe or life-threatening [1, 2], resulting in the discontinuation of treatment in the majority of the patients
0360-3997/20/0000-0001/0 # 2020 Springer Science+Business Media, LLC, part of Springer Nature
Wan, Wang, Tang, Tan, He, Zhang, Yang, Chen, Song, Gu, Zhang, Wang, Wei, Liu, Jiang, and Hua [1]. In other clinical trials, epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI)–induced hepatotoxicity occurred in approximately 15% of lung adenocarcinoma patients treated with gefitinib [3]. EGFR- tyrosine kinase inhibitors (EGFR-TKIs) are thought to affect basal keratino
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