Gefitinib-Induced Cutaneous Toxicities in Brown Norway Rats Are Associated with Macrophage Infiltration
Liangqin Wan1,2, Yalei Wang1, Yibo Tang1
1Beijing University of Chinese Medicine, Beijing, 100029, China.
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.
Insights
Gefitinib treatment causes skin rash and hair loss in rats. This study establishes a new animal model to investigate the mechanisms of skin toxicity from epidermal growth factor receptor (EGFR) inhibitors.
Area of Science:
- Pharmacology
- Dermatology
- Oncology
Background:
- Skin toxicity is a common side effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like gefitinib, used for non-small cell lung cancer (NSCLC).
- A validated animal model for studying EGFR-TKI-induced skin toxicity is currently lacking.
Purpose of the Study:
- To establish and characterize a novel rat model for gefitinib-induced skin toxicity.
- To investigate the pathological mechanisms underlying gefitinib-induced cutaneous adverse effects.
Main Methods:
- Brown Norway (BN) rats were administered varying doses of gefitinib (2.5, 5.0, or 10 mg/100 g/day) for 4 weeks.
- Phenotypic analysis included observation of rash, itching, and hair loss, alongside pathological skin examination.
- Immunohistochemistry, flow cytometry, and blood cell analysis were performed to assess inflammatory markers and cellular infiltration.
Main Results:
- Gefitinib administration resulted in dose-dependent weight loss, rash, itching, and hair loss.
- Pathological findings included epidermal thickening, decreased skin moisture, and keratinocyte apoptosis.
- Increased macrophage infiltration in the skin was observed, correlating with cutaneous toxicity.
- Gefitinib-induced toxicity was linked to elevated levels of inflammatory cytokines TREM-1, CINC-2, and CINC-3.
Conclusions:
- A Brown Norway rat model effectively replicates gefitinib-induced skin toxicity, characterized by epidermal changes and inflammation.
- Macrophage infiltration and specific inflammatory cytokines (TREM-1, CINC-2, CINC-3) play a significant role in the pathogenesis of gefitinib-induced cutaneous adverse events.
- This model provides a valuable tool for further research into the mechanisms and potential treatments for EGFR-TKI-related skin toxicities.
