切换至 "中华医学电子期刊资源库"

中华肺部疾病杂志(电子版) ›› 2020, Vol. 13 ›› Issue (06) : 781 -784. doi: 10.3877/cma.j.issn.1674-6902.2020.06.014

药物与临床

"CYP2D6"基因多态性和NSCLC靶向治疗后肝损伤、皮疹及腹泻的相关性
卢喜1, 俞婷婷2, 韩志刚2,()   
  1. 1. 830011 乌鲁木齐,新疆医科大学附属肿瘤医院胸腹放疗科
    2. 830011 乌鲁木齐,新疆医科大学附属肿瘤医院肺内一科
  • 收稿日期:2020-09-13 出版日期:2020-12-25
  • 通信作者: 韩志刚
  • 基金资助:
    新疆维吾尔自治区自然科学基金面上项目(2017D01C381)

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

Xi Lu1, Tingting Yu2, Zhigang Han2,()   

  1. 1. Department of Chest and Abdomen Radiotherapy, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi 830011, China
    2. Department of Pulmonary Inpatients, Affiliated Tumor Hospital of Xinjiang Medical University, Urumqi 830011, China
  • Received:2020-09-13 Published:2020-12-25
  • Corresponding author: Zhigang Han
引用本文:

卢喜, 俞婷婷, 韩志刚. "CYP2D6"基因多态性和NSCLC靶向治疗后肝损伤、皮疹及腹泻的相关性[J]. 中华肺部疾病杂志(电子版), 2020, 13(06): 781-784.

Xi Lu, Tingting Yu, Zhigang Han. Association between CYP2D6 gene polymorphism and liver injury, rash, and diarrhea after targeted therapy inpatients with non-small cell lung cancer[J]. Chinese Journal of Lung Diseases(Electronic Edition), 2020, 13(06): 781-784.

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。

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.

表1 患者临床特征与不良反应相关性
表2 患者不良反应与基因频率及基因型相关性[n(%)]
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.
[1] 赵蒙蒙, 黄洁, 余荣环, 王葆青. 过表达小GTP酶Rab32抑制非小细胞肺癌细胞侵袭性生长[J]. 中华肺部疾病杂志(电子版), 2024, 17(04): 512-518.
[2] 张桂萍, 丘勇林, 湛绮婷, 孙乐栋. 晚期非小细胞肺癌血清Ape1/Ref-1对放射性肺损伤发生的预测意义[J]. 中华肺部疾病杂志(电子版), 2024, 17(04): 519-523.
[3] 韩晓宇, 李柯育, 赵志菲, 高建平. SNHG17过表达对非小细胞肺癌切除术预后的意义[J]. 中华肺部疾病杂志(电子版), 2024, 17(04): 543-547.
[4] 刘松, 张进召, 贾艳云. 帕博利珠单抗治疗晚期非小细胞肺癌反应降低与抗生素预处理的关系[J]. 中华肺部疾病杂志(电子版), 2024, 17(04): 553-557.
[5] 李多, 郝昭昭, 陈延伟, 南岩东. 血清PTX3表达与非小细胞肺癌骨转移的相关性分析[J]. 中华肺部疾病杂志(电子版), 2024, 17(04): 558-562.
[6] 陈旭, 牛凯, 孙建国. 放疗联合免疫治疗对驱动基因阴性NSCLC的困惑分析及应对策略[J]. 中华肺部疾病杂志(电子版), 2024, 17(03): 341-348.
[7] 杨静, 附舰, 康艳霞. 血浆ctDNA T790M突变和总代谢肿瘤体积对晚期EGFR突变NSCLC患者TKIs治疗及预后意义[J]. 中华肺部疾病杂志(电子版), 2024, 17(03): 379-384.
[8] 赵海燕, 靳海涛, 孔莺, 何瑞远. 血浆NGS-ctDNA对EGFR-TKIs治疗晚期NSCLC患者的预后意义[J]. 中华肺部疾病杂志(电子版), 2024, 17(03): 385-391.
[9] 白丽丽, 江榆, 黄亮亮, 白莹, 张敏. 作业疗法在非小细胞肺癌患者术后康复中应用分析[J]. 中华肺部疾病杂志(电子版), 2024, 17(03): 411-415.
[10] 李静静, 许金花, 吴国峰, 任亚俊, 张骞云. 伏美替尼一线治疗EGFR突变晚期NSCLC脑转移的临床分析[J]. 中华肺部疾病杂志(电子版), 2024, 17(03): 426-429.
[11] 尹炳驿, 张楚楚, 刘艺, 林洪生. 益气清金汤加味治疗晚期非小细胞肺癌的临床分析[J]. 中华肺部疾病杂志(电子版), 2024, 17(03): 462-465.
[12] 罗孝平, 封敏, 黄川, 唐茜, 蒋艳, 胡莉丽. 渐进式抗阻训练干预在非小细胞肺癌中的临床应用[J]. 中华肺部疾病杂志(电子版), 2024, 17(03): 472-474.
[13] 关计添, 尤克增, 耿义群, 孙树宜, 赖凌峰, 沈智威, 张晓磊, 周腾, 黄淮栋, 杨琳, 程焱, 吴烁华, 赵芝泓, 庄彩玉, 吴仁华. 质子磁共振波谱对急性肝损伤兔肝脏脂质与葡萄糖代谢评估价值的研究[J]. 中华诊断学电子杂志, 2024, 12(03): 160-165.
[14] 张迅夫, 马金山, 蒋云龙, 加纳提·托勒恒, 侯昌剑, 萨伍提·斯拉吉丁. GATA3在非小细胞肺癌组织中的表达及临床病理意义[J]. 中华胸部外科电子杂志, 2024, 11(03): 175-179.
[15] 李子健, 王锐, 钟云鹏, 张迪轩, 梁韵娟, 杨超, 何建行, 李树本. 自体肺移植术在胸部恶性肿瘤中的临床应用[J]. 中华胸部外科电子杂志, 2024, 11(03): 193-200.
阅读次数
全文


摘要