药物相关分子靶标检测在儿童颅外恶性实体瘤38例个体化治疗中的应用
약물상관분자파표검측재인동로외악성실체류38례개체화치료중적응용
Primary identification of genomic markers of drug sensitivity for individualized therapy in 38 children with extracranial malignant solid tumors
  • 万方数据
    中华实用儿科临床杂志 중화실용인과림상잡지
    Journal of Applied Clinical Pediatrics
    2014年 14期 1107-1111 ,共5页

    蒋马伟%吴晔明%周仁华%张弛%吕凡%陆冬青%欧阳凤秀%李玉华%袁晓军

    장마위%오엽명%주인화%장이%려범%륙동청%구양봉수%리옥화%원효군

    儿童%颅外恶性实体瘤%药物相关分子靶标检测%个体化治疗 兒童%顱外噁性實體瘤%藥物相關分子靶標檢測%箇體化治療
    인동%로외악성실체류%약물상관분자파표검측%개체화치료
    Child%Extracranial malignant solid tumors%Genomic markers of drug sensitivity%Individualized therapy
    目的 探讨药物相关分子靶标检测在儿童颅外恶性实体瘤个体化治疗中的作用和意义.方法 将2011年4月至2013年4月期间于上海交通大学医学院附属新华医院治疗的38例难治性儿童颅外恶性实体瘤的手术标本及外周血,通过免疫组织化学、酶联免疫吸附试验、荧光原位杂交、聚合酶链式反应扩增和测序的方法检测肿瘤药物相关分子靶标.共检测15种化疗药物和2种靶向药物的基因表达或突变.结果 入组的38例标本中,35例为手术标本,其中3例为二次手术标本、3例为外周血标本送检肿瘤药物相关分子靶标.检测了肿瘤标本化疗药物分子靶点DNA拓扑异构酶ⅡA(TopoⅡA)34例、微管蛋白β3(Tubulinβ3) 32例、人切除修复交叉互补基因1(ERCC1) 28例、DNA拓扑异构酶Ⅰ(TOPO Ⅰ)28例、DNA修复蛋白O6-甲基鸟嘌呤-DNA-甲基转移酶(MGMT) 20例、胸苷酸合成酶(TS) 13例、核糖核苷酸还原酶M1 (RRM1)6例.68.75％对氟尿嘧啶及培美曲赛敏感,66.67％对吉西他滨敏感,56.25％对长春碱类敏感;而67.65％对蒽环类/依托泊苷敏感性低,64.29％对铂类药物、拓扑替康/伊立替康敏感性低,63.64％对替莫唑胺敏感性低.外周血标本化疗药物分子靶点33例CYP2C9*3、14例二氢叶酸还原酶(DHFR C829T)基因多态性PCR测序,结果显示100.00％和93.33％对环磷酰胺和甲氨蝶呤敏感;用外周血标本化疗药物分子靶点检测肿瘤化疗药物毒性反应情况,结果 显示100.00％环磷酰胺及甲氨蝶呤毒副反应弱,76.19％伊立替康/依托泊苷毒副反应弱;肿瘤标本靶向药物基因血管内皮生长因子受体-2 15例、表皮生长因子受体(EGFR)5例和外周血标本细胞间黏附分子-1检测10例,显示68.00％对贝伐珠单抗敏感,EGFR 5例都无扩增,对络氨酸激酶抑制剂无效.依据上述检测结果,对标准化疗方案疗效欠佳的患儿,及时调整治疗策略后,取得了初步效果.结论 本研究首次在儿童颅外恶性实体瘤的治疗中引入药物相关性分子靶标的检测,对于开展规范化治疗基础上的个体化治疗方案的选择及药物毒副作用的预测,提供了实验室依据.
    목적 탐토약물상관분자파표검측재인동로외악성실체류개체화치료중적작용화의의.방법 장2011년4월지2013년4월기간우상해교통대학의학원부속신화의원치료적38례난치성인동로외악성실체류적수술표본급외주혈,통과면역조직화학、매련면역흡부시험、형광원위잡교、취합매련식반응확증화측서적방법검측종류약물상관분자파표.공검측15충화료약물화2충파향약물적기인표체혹돌변.결과 입조적38례표본중,35례위수술표본,기중3례위이차수술표본、3례위외주혈표본송검종류약물상관분자파표.검측료종류표본화료약물분자파점DNA탁복이구매ⅡA(TopoⅡA)34례、미관단백β3(Tubulinβ3) 32례、인절제수복교차호보기인1(ERCC1) 28례、DNA탁복이구매Ⅰ(TOPO Ⅰ)28례、DNA수복단백O6-갑기조표령-DNA-갑기전이매(MGMT) 20례、흉감산합성매(TS) 13례、핵당핵감산환원매M1 (RRM1)6례.68.75％대불뇨밀정급배미곡새민감,66.67％대길서타빈민감,56.25％대장춘감류민감;이67.65％대은배류/의탁박감민감성저,64.29％대박류약물、탁복체강/이립체강민감성저,63.64％대체막서알민감성저.외주혈표본화료약물분자파점33례CYP2C9*3、14례이경협산환원매(DHFR C829T)기인다태성PCR측서,결과현시100.00％화93.33％대배린선알화갑안접령민감;용외주혈표본화료약물분자파점검측종류화료약물독성반응정황,결과 현시100.00％배린선알급갑안접령독부반응약,76.19％이립체강/의탁박감독부반응약;종류표본파향약물기인혈관내피생장인자수체-2 15례、표피생장인자수체(EGFR)5례화외주혈표본세포간점부분자-1검측10례,현시68.00％대패벌주단항민감,EGFR 5례도무확증,대락안산격매억제제무효.의거상술검측결과,대표준화료방안료효흠가적환인,급시조정치료책략후,취득료초보효과.결론 본연구수차재인동로외악성실체류적치료중인입약물상관성분자파표적검측,대우개전규범화치료기출상적개체화치료방안적선택급약물독부작용적예측,제공료실험실의거.
    Objective To identify the significance of genomic markers of drug sensitivity for individualized therapy in children with extracranial malignant solid tumors.Methods The surgical specimens and peripheral blood samples in 38 children with refractory extracranial malignant solid tumors were collected between Apri.2011 and Apri.2013.The genomic markers of anticancer drug sensitivity were examined,including gene expression or mutation of 15 chemotherapeutic agents and two targeted drugs by methods of immunohistochemical staining,enzyne linked immunosorbent assay,fluorescence in situ hybridization,polymerase chain reaction amplification and sequencing.Results Among all of 38 samples,35 were firstly surgical specimens and 3 secondary surgical specimens,and 3 of them were peripheral blood samples.The tumor tissue of the targets for chemotherapeutic agents such as topoisomerase Ⅱ A (TOPO Ⅱ A) in 34 cases,Tubulinβ3 in 32 cases,excision repair cross-complementing 1 (ERCC1) in 28 cases,topoisomerase Ⅰ (TOPO Ⅰ) in 28 cases,O6-methylguanine-DNA methyltransferase (MGMT) in 20 eases,thymidylate synthase (TS) in 13 cases and ribonucleotide reductase M 1 (RRM1)in 6 cases were examined.The 68.75％ samples were fluorouracil and pemetrexed sensitivity,66.67％ samples gemcitabine sensitivity,56.25％ samples vincristine(VCR) sensitivity;while 67.65％ had low sensitivity to anthracycline/etoposide,64.29％ had low sensitivity to platinum and topotecan/irinotecan;63.64％ had low sensitivity to temozolomide(TMZ).What's more,the peripheral blood of the targets for chemotherapeutic agents such as CYP2C9 * 3 genotypes in 33 cases and dihydrofolate reductase (DHFR C829T) genotypes in 14 cases were detected,and found that 100.00％ and 93.33％ of samples had cyclophosphamide and methotrexate sensitivity,respectively.Furthermore,peripheral blood was used to test the targets for chemotherapy toxicity and found that 100.00％ of cyclophosphamide and methotrexate toxicity were weak,76.19％ of irinotecan and etoposide toxicity was weak.Additionally,tumor tissues of the genomic markers for targeted drugs,such as vascular endothelial growth factor receptor-2 (VEGFR-2) in 15 cases,epidermal growth factor receptor (EGFR) in 5 cases and intercellular cell adhesion molecule-1 in 10 cases,were examined.Up to 68.00％ samples were detected sensitive to Bevacizumab.EGFR was not amplified in any case studied and Tyrosine kinase inhibitor response was invalid.On the basis of the above test results,therapeutic strategy for the patients who had unsatisfactory curative effect and then they achieved preliminary effect were promptly adjusted.Conclusions This study firstly examined the genomic markers of drug sensitivity in children with extracranial malignant solid tumors,which provide laboratory basis for individualized treatment selection and drug side effects prediction.
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