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Recent Patents on Anti-Cancer Drug Discovery

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ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

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Research Article

Adverse Effects of Gefitinib on Skin and Colon in a Lung Cancer Mouse Model

Author(s): Yalei Wang, Shuo Cheng, Huawei Zhang, Yali Zhang, Chengcheng Ding, Tiantian Peng, Weihang Chen, Ke Yang, Jiani Zhang, Yan Tan, Xu Wang, Zhaoheng Liu, Peng Wei, Miao Jiang* and Qian Hua*

Volume 19, Issue 3, 2024

Published on: 21 August, 2023

Page: [308 - 315] Pages: 8

DOI: 10.2174/1574892818666230727143750

Price: $65

Abstract

Background: Gefitinib, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI), frequently causes side effects when used to treat non-small cell lung cancer.

Objective: The purpose of this experiment was to investigate the side effect of gefitinib on the skin and colon of mice.

Methods: Male Balb/c nu-nu nude mice aged 4-5 weeks were used as xenograft tumor models, and gefitinib at 150 mg/kg and 225 mg/kg was started at 9 days after the xenograft tumor grew out. The mice's weights and tumor volumes were tracked concurrently, and the mouse skin adverse reactions and diarrhea were observed during the treatment. The animal tissues were subjected to biochemical and pathological evaluations after 14 days.

Results: Gefitinib effectively decreased the size and weight of transplanted tumors in nude mice, while also lowering body weight and raising indexes of the liver and spleen. Gefitinib could cause skin adverse reactions and diarrhea in mice. Further pathological investigation revealed tight junction- related markers in the mice's skin and colon to be reduced and macrophages and neutrophils to be increased after gefitinib treatment.

Conclusion: The findings imply that gefitinib has negative effects on the skin and colon. Gefitinib- induced skin and colon adverse reactions in mice have been successfully modeled in this study.

« Previous Next »
[1]
Maity S, Pai KSR, Nayak Y. Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance. Pharmacol Rep 2020; 72(4): 799-813.
[http://dx.doi.org/10.1007/s43440-020-00131-0] [PMID: 32666476]
[2]
Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol 2018; 12(1): 3-20.
[http://dx.doi.org/10.1002/1878-0261.12155] [PMID: 29124875]
[3]
Da Cunha Santos G, Shepherd F A, Tsao M S. EGFR mutations and lung cancer. Annu Rev Pathol 2011; 6: 49-69.
[http://dx.doi.org/10.1146/annurev-pathol-011110-130206]
[4]
Singh M, Jadhav HR. Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors. Drug Discov Today 2018; 23(3): 745-53.
[http://dx.doi.org/10.1016/j.drudis.2017.10.004] [PMID: 29031620]
[5]
Nan X, Xie C, Yu X, Liu J. EGFR TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Oncotarget 2017; 8(43): 75712-26.
[http://dx.doi.org/10.18632/oncotarget.20095] [PMID: 29088904]
[6]
He J, Huang Z, Han L, Gong Y, Xie C. Mechanisms and management of 3rd-generation EGFR-TKI resistance in advanced non-small cell lung cancer (Review). Int J Oncol 2021; 59(5): 90.
[http://dx.doi.org/10.3892/ijo.2021.5270] [PMID: 34558640]
[7]
Wu J, Lin Z. Non-small cell lung cancer targeted therapy: Drugs and mechanisms of drug resistance. Int J Mol Sci 2022; 23(23): 15056.
[http://dx.doi.org/10.3390/ijms232315056] [PMID: 36499382]
[8]
Diana P, Pecoraro C, Carbone D, Cascioferro SM, Parrino B. Multi or single-kinase inhibitors to counteract drug resistance in cancer: What is new? Curr Med Chem 2023; 30(7): 776-82.
[http://dx.doi.org/10.2174/0929867329666220729152741] [PMID: 35909291]
[9]
Ding PN, Lord SJ, Gebski V, et al. Risk of treatment-related toxicities from EGFR tyrosine kinase inhibitors: A meta-analysis of clinical trials of gefitinib, erlotinib, and afatinib in advanced EGFR -mutated non-small cell lung cancer. J Thorac Oncol 2017; 12(4): 633-43.
[http://dx.doi.org/10.1016/j.jtho.2016.11.2236] [PMID: 28007626]
[10]
Lacouture ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 2006; 6(10): 803-12.
[http://dx.doi.org/10.1038/nrc1970] [PMID: 16990857]
[11]
Hofheinz RD, Deplanque G, Komatsu Y, et al. Recommendations for the prophylactic management of skin reactions induced by epidermal growth factor receptor inhibitors in patients with solid tumors. Oncologist 2016; 21(12): 1483-91.
[http://dx.doi.org/10.1634/theoncologist.2016-0051] [PMID: 27449521]
[12]
Tao G, Chityala PK. Epidermal growth factor receptor inhibitor-induced diarrhea: Clinical incidence, toxicological mechanism, and management. Toxicol Res 2021; 10(3): 476-86.
[http://dx.doi.org/10.1093/toxres/tfab026] [PMID: 34141161]
[13]
Lichtenberger BM, Gerber PA, Holcmann M, et al. Epidermal EGFR controls cutaneous host defense and prevents inflammation. Sci Transl Med 2013; 5(199): 199ra111.
[http://dx.doi.org/10.1126/scitranslmed.3005886] [PMID: 23966300]
[14]
Lee E J, Whang J H, Jeon N K, et al. The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses proliferation and invasion of human oral squamous carcinoma cells via p53 independent and MMP, uPAR dependent mechanism. Ann N Y Acad Sci 2007; 1095(113): 28.
[http://dx.doi.org/10.1196/annals.1397.015]
[15]
Zhang Y, Wang Y, Chen Z, et al. Comparison of gefitinib-induced skin adverse reactions (SAR) in C57BL/6 and FVB/N mice. Toxicol Res 2021; 10(2): 334-44.
[http://dx.doi.org/10.1093/toxres/tfab008] [PMID: 33884183]
[16]
Wan L, Wang Y, Tang Y, et al. Gefitinib-induced cutaneous toxicities in brown norway rats are associated with macrophage infiltration. Inflammation 2020; 43(6): 2137-46.
[http://dx.doi.org/10.1007/s10753-020-01281-2] [PMID: 33025329]
[17]
Pastore S, Mascia F, Mariani V, Girolomoni G. The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol 2008; 128(6): 1365-74.
[http://dx.doi.org/10.1038/sj.jid.5701184] [PMID: 18049451]
[18]
Wang Y, Zhang Y, Ding C, et al. Exploration of the potential mechanism of Qi Yin San Liang San decoction in the treatment of EGFRI-related adverse skin reactions using network pharmacology and in vitro experiments. Front Oncol 2022; 12: 790713.
[http://dx.doi.org/10.3389/fonc.2022.790713]
[19]
Secombe KR, Coller JK, Gibson RJ, Wardill HR, Bowen JM. The bidirectional interaction of the gut microbiome and the innate immune system: Implications for chemotherapy‐induced gastrointestinal toxicity. Int J Cancer 2019; 144(10): 2365-76.
[http://dx.doi.org/10.1002/ijc.31836] [PMID: 30155890]
[20]
Secombe K R, Van Sebille Y Z A, Mayo B J, et al. Diarrhea induced by small molecule tyrosine kinase inhibitors compared with chemotherapy: Potential role of the microbiome. Integr Cancer Ther 2020; 19: 1534735420928493.
[http://dx.doi.org/10.1177/1534735420928493]
[21]
Fluhr JW, Feingold KR, Elias PM. Transepidermal water loss reflects permeability barrier status: Validation in human and rodent in vivo and ex vivo models. Exp Dermatol 2006; 15(7): 483-92.
[http://dx.doi.org/10.1111/j.1600-0625.2006.00437.x] [PMID: 16761956]
[22]
Imhof RE, De Jesus MEP, Xiao P, Ciortea LI, Berg EP. Closed-chamber transepidermal water loss measurement: Microclimate, calibration and performance. Int J Cosmet Sci 2009; 31(2): 97-118.
[http://dx.doi.org/10.1111/j.1468-2494.2008.00476.x] [PMID: 19175433]
[23]
Günzel D, Yu ASL. Claudins and the modulation of tight junction permeability. Physiol Rev 2013; 93(2): 525-69.
[http://dx.doi.org/10.1152/physrev.00019.2012] [PMID: 23589827]
[24]
Shi K, Qu L, Lin X, et al. Deep-fried atractylodis rhizoma protects against spleen deficiency-induced diarrhea through regulating intestinal inflammatory response and gut microbiota. Int J Mol Sci 2019; 21(1): 124.
[http://dx.doi.org/10.3390/ijms21010124] [PMID: 31878055]
[25]
Murillas R, Larcher F, Conti CJ, Santos M, Ullrich A, Jorcano JL. Expression of a dominant negative mutant of epidermal growth factor receptor in the epidermis of transgenic mice elicits striking alterations in hair follicle development and skin structure. EMBO J 1995; 14(21): 5216-23.
[http://dx.doi.org/10.1002/j.1460-2075.1995.tb00206.x] [PMID: 7489711]
[26]
Negretti NM, Ye Y, Malavasi LM, et al. A porcine ligated loop model reveals new insight into the host immune response against Campylobacter jejuni. Gut Microbes 2020; 12(1): 1814121.
[http://dx.doi.org/10.1080/19490976.2020.1814121] [PMID: 32887530]
[27]
Kim M, Chung KS, Hwang SJ, et al. Protective effect of Cicer arietinum L. (Chickpea) ethanol extract in the dextran sulfate sodium-induced mouse model of ulcerative colitis. Nutrients 2020; 12(2): 456.
[http://dx.doi.org/10.3390/nu12020456] [PMID: 32059355]

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