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《中华肺部疾病杂志》[ISSN:1006-6977/CN:61-1281/TN]

卷:

期数:

2020年06期

页码:

781-784

栏目:

药物与临床

出版日期:

2020-12-20

文章信息/Info

Title:

Association between CYP2D6 gene polymorphism and liver injury, rash, and diarrhea after targeted therapy inpatients with non-small cell lung cancer

作者:

卢 喜¹; 俞婷婷²; 韩志刚²

830011 乌鲁木齐,新疆医科大学附属肿瘤医院胸腹放疗科¹、肺内一科²

Author(s):

Lu Xi¹;  Yu Tingting²;  Han Zhigang².

Department of Chest and Abdomen Radiotherapy¹, Department of Pulmonary Inpatients², Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi 830011, China

关键词:

非小细胞肺癌;  EGFR-TKI;  CYP2D6×; 10;  CYP2D6×; 5;  药物性肝损伤

Keywords:

Non-small cell lung cancer;  EGFR-TKI;  CYP2D6×; 10;  CYP2D6×; 5;  Drug-induced liver injury

分类号:

-

DOI:

10.3877/cma.j.issn.1674-6902.2020.06.014

摘要:

目的 比较非小细胞肺癌(non-small cell lung cancer, NSCLC)患者CYP2D6×10与CYP2D6×5基因多态性的差异与经靶向治疗(吉非替尼、厄洛替尼、克唑替尼)后出现肝损伤,皮疹,腹泻不良反应的相关性,探索靶向药物治疗常见不良反应与CYP2D6基因多态性的关联。方法 选择新疆医科大学附属肿瘤医院2016年1月至2019年12月经靶向治疗(吉非替尼、厄洛替尼、克唑替尼)的NSCLC患者,采用限制性片段长度多态性聚合酶链反应(polymerase chain reaction-restriction fragment length polymorphism, PCR-RFLP)检测患者CYP2D6×10与CYP2D6×5基因型分布及等位基因频率。比较基因型分布差异和等位基因差异在出现肝损伤、腹泻、皮疹组与无患者组的差异。结果 CYP2D6×10 基因多态性及等位基因频率在发生肝损害组与无肝损害组差异有统计学意义(P<0.05),皮疹组和腹泻组均与CYP2D6×10 基因多态性及等位基因频率差异无相关性。腹泻有关的唯一相关因素是否有化疗史(P=0.002),皮疹相关的因素是分期P=0.000。结论 NSCLC靶向治疗药物性肝损伤的预测方面CYP2D6基因多态性可能是其中有效的指标之一,可指导NSCLC患者临床用药。

Abstract:

Objective To compare the differences between CYP2D6×10 and CYP2D6×5 gene polymorphisms in patients with non-small cell lung cancer(NSCLC)and the correlation between liver injury, skin rash and diarrhea adverse reactions after targeted therapy(geffitinib, erlotinib and crizotinib), and to explore the correlation between common adverse reactions after targeted drug therapy and CYP2D6 gene polymorphism. Methods NSCLC patients treated with targeted therapy(gifitinib, Erlotinib, crezoltini)from January 2016 to December 2019 were selected from the Affiliated Tumor Hospital of Xinjiang Medical University. The polymorphism of CYP2D6×10 and CYP2D6×5 genotypes and allelic frequencies were detected by using the restricted segment length polymorphism polymerase Chain reaction-restriction fragment Length polymorphism(PCR-RFLP). Genotype distribution differences and allelic differences in patients with liver injury, diarrhea, and rash were compared with those without. Results There were statistically significant differences in CYP2D6×10 gene polymorphism and allele frequency between the groups with and without liver damage(P<0.05), and there was no correlation between CYP2D6×10 gene polymorphism and allele frequency difference between the skin rash group and the diarrhea group. The only factor associated with diarrhea was a history of chemotherapy(P=0.002), and the factor associated with rash was staging(P=0.000). Conclusion CYP2D6 gene polymorphism may be one of the effective indicators for the prediction of drug-induced liver injury in TARGETED NSCLC therapy, which can guide the clinical medication of NSCLC patients.

参考文献/References:

1 钱桂生. 肺癌不同病理类型发病率的变化情况及其原因[J/CD]. 中华肺部疾病杂志(电子版), 2011, 4(1): 1-5.
2 张瑞婕, 戢福云, 钱桂生, 等. 接触蛋白-1在原发性肺鳞状细胞癌组织中的表达及临床意义[J/CD]. 中华肺部疾病杂志(电子版), 2020, 13(2): 139-143.
3 Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015[J]. CA cancer J Clin, 2016, 66(2): 115-132.
4 Ghafoor Q, Baijal S, Taniere P, et al. Epidermal Growth factor receptor (EGFR)kinase Inhibitors and non-small cell Lung Cancer(NSCLL)-Advances in Molecular Diagnostic Techniques to Facilitate Targeted Therapy[J]. Pathol Oncol Res, 2018, 24(4): 723-731.
5 Chen Z, Fillmore CM, Hammerman PS, et al. Non-small-cell lung cancers: a heterogeneous set of diseases[J]. Nat Rev Cancer, 2014, 14(8): 535-546.
6 Shen T, Liu Y, Shang J, et al. Incidence and Etiology of Drug-Induced Liver Injury in Mainland China[J]. Gastroenterology, 2019, 156(8): 2230-2241.e2211.
7 European Association for the Study of the Liver. Electronic address eee, Clinical Practice Guideline Panel C, Panel m, et al. EASL Clinical Practice Guidelines: Drug-induced liver injury[J]. J Hepatol, 2019, 70(6): 1222-1261.
8 Zienolddiny S, Campa D, Lind H, et al. A comprehensive analysis of phase I and phase Ⅱ metabolism gene polymorphisms and risk of non-small cell lung cancer insmokers[J]. Carcinogenesis, 2008, 29(6): 1164-1169.
9 范亚莉, 李娜苗, 张莹莹, 等. 埃克替尼与厄洛替尼治疗晚期非小细胞肺癌疗效与安全性的Meta分析[J]. 现代肿瘤医学, 2019, 27(10): 1736-1740.
10 王慧琳, 韩 红, 朱慧瑛. 晚期非小细胞肺癌分子靶向药物治疗的不良反应及护理[J]. 护士进修杂志, 2017, 32(8): 744-746.
11 丁传彪. 埃克替尼在晚期非小细胞肺癌靶向治疗中的疗效观察[J]. 中国生化药物杂志, 2017, 37(11): 111-112,114.
12 田方圆, 吴 斌, 占 美, 等. 克唑替尼治疗非小细胞肺癌有效性和安全性的系统评价[J]. 华西医学, 2017, 32(7): 28-34.
13 张 磊, 王 京. 小分子蛋白酪氨酸激酶抑制剂的研究进展[J]. 化学试剂, 2014, 36: 901-912.
14 陈雪琴, 杨邵瑜, 马胜林. 肺癌靶向药物肝脏毒性作用研究进展[J]. 中国肺癌杂志, 2014, 9: 685-688.
15 Gu A, Shi C, Xiong L, et al. Efficacy and safety evaluation of icotinib in patients with advanced non-small-cell lung cancer[J]. Chin JCancer Res, 2013, 25(1): 90-94.
16 Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy(LUXLung1): a phase 2b/3 randomised trial[J]. Lancet Oncol, 2012, 13(5): 528-538.
17 Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations(LUXLungLUXLung: a phase 2 trial[J]. Lancet Oncol, 2012, 13(5): 539-548.
18 Sequist LV, Yang JC, Yamamoto N, et al. Symptom control and quality of life in LUX-Lung 3: A Phase Ⅲ study of afatinib or cisplatin plus pemetrexed in patient swith metastatic lung adenocarcinoma with EGFR mutations[J]. Clin Oncol, 2013, 31(27): 3327-3334.
19 Katakami N, Atagi S, Goto K, et al. LUX-Lung 4: a phase Ⅱ trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both[J]. Clin Oncol, 2013, 31(27): 3335-3341.
20 陶 虹, 郭丽丽, 唐俊舫, 等. 阿法替尼一线治疗5例晚期肺腺癌患者的不良反应分析及相关文献回顾[J]. 中国肺癌杂志, 2014, 17(4): 342-346.
21 马 丽, 张树才. ALK阳性非小细胞肺癌靶向治疗研究进展[J]. 中国肺癌杂志, 2014, 17: 850-854.
22 Tornio A, Backman JT. Cytochrome P450 in pharmacogenetics:an update[J]. Adv Pharmacol, 2018, 83: 3-32.
23 谢 倩, 单 莉, 俞婷婷. EGFR-TKI肝脏毒性与CYP2D6基因多态性的相关性研究[J]. 心理医生, 2019, 25(6): 126-128.
24 Haslemo T, Eliasson E, Jukic MM, et al. Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6-Metabolized Drugs and Hemodynamic Responses Among Older Patients CYP2D6×41 versus CYP2D6×9 or CYP2D6×10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients[J]. Br J Clin Pharmacol, 2019, 85: 194-201.
25 Gu A, Shi C, Xiong L, et al. Efficacy and safety evaluation of icotinib in patients with advanced non-small-cell lung cancer[J]. Chin JCancer Res, 2013, 25(1): 90-94.
26 Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy(LUXLung1): a phase 2b/3 randomised trial[J]. Lancet Oncol, 2012, 13(5): 528-538.
27 Chen Y, Zhou D, Tang W, et al. Physiologically Based Pharmacokinetic Modeling to Evaluate the Systemic Exposure of Gefitinib in CYP2D6 Ultrarapid Metabolizers and Extensive Metabolizers[J]. J Clin Pharmacol, 2018, 58(4): 485-493.
28 Fang P, Zheng X, He J, et al. Functional characterization of wild-type and 24 CYP2D6 allelic variants on gefitinib metabolism in vitro[J]. Drug Des Devel Ther, 2017, 21(11): 1283-1290.
29 Kobayashi H, Sato K, Niioka T, et al. Effects of polymorphisms in CYP2D6 and ABC transporters and side effects induced by gefitinib on the pharmacokinetics of the gefitinib metabolite,O-desmethyl gefitinib[J]. Med Oncol, 2016, 33(6): 57-66.
30 Semba Y, Akiyoshi T, Hibino H, et al. Profile of the inhibitory effects of gefitinib on CYP2D6 variants in vitro[J]. Int J Clin Pharmacol Ther, 2020, 58(10): 539-542.
31 Yang JC, Shih JY, Su WC, et al. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations(LUXLungLUXLung:a phase 2 trial[J]. Lancet Oncol, 2012,13(5): 539-548.
32 Kunimasa K, Yoshioka H, Iwasaku M, et al. Successful treatment of non-small cell lung cancer with gefitinib after severeerlotinib-related hepatotoxicity[J]. Intern Med, 2012, 51(4): 431-434.

备注/Memo

备注/Memo:

基金项目: 新疆维吾尔自治区自然科学基金面上项目(2017D01C381)
通信作者: 韩志刚, Email: 16428614@qq.com

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更新日期/Last Update: 2020-12-20