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目的评价无创性、临床可转化的MR成像生物标记物对侵袭性、MYCN高表达的神经母细胞瘤的Th-MYCN转基因小鼠模型的治疗反应。材料与方法所有试验均遵循当地伦理审查小组和英国内政部动物科学程序法案(1986年版),以及英国国家癌症研究中心的抗肿瘤动物试验福利指导原则。对Th-MYCN模型的腹部肿瘤行多参数MR成像。使用T2加权成像、对T1和T2自然弛豫时间定量测量、R2*的弛豫速率和动态对比增强MR成像等参数对肿瘤经过环磷酰胺(25mg/kg),血管分裂药ZD6126(200mg/kg)或抗血管生成剂西地尼布(6mg/kg,每日)治疗后的变化进行监测。任何显著性改变的测量参数、治疗组与对照组治疗前后发生巨大变化的,分别使用Student双尾配对或非配对t检验对数据进行检验,显著性水平为5%。结果使用环磷酰胺和西地尼布后48h可使肿瘤体积分别减小54%和20%(与治疗前相比,均为P<0.005;与对照组比较,均为P<0.005)。使用ZD6126治疗后24h内肿瘤的平均体积减小了45%(与治疗前相比,P<0.005;与对照组比较,P<0.005)。环磷酰胺、西地尼布及ZD6126的抗肿瘤作用均与肿瘤T1值的下降具有相关性(与治疗前相比,均为P<0.005;与对照组比较,均为P<0.005),初始T1值在治疗后发生的变化与肿瘤体积的变化具有相关性(r=0.56;P<0.005)。肿瘤对西地尼布的反应与MR成像对比增强所导出的体积转换常数(P=0.07;与对照组比较,P<0.05)和增强分数(P<0.05;与对照组比较,P<0.01)的下降具有相关性,与R2*值的升高具有相关性(P<0.005;与对照组比较,P<0.05)。结论 T1弛豫时间可以作为检测Th-MYCN型肿瘤小鼠治疗后反应的一种稳定的、无创性成像的生物标记物。Th-MYCN型肿瘤小鼠是儿童高发病率神经母细胞瘤的模型。T1的测量可以方便地在临床MR系统中应用,可应用于小儿神经母细胞瘤新的靶向治疗的临床观察中。
Objective To evaluate the therapeutic response of noninvasive, clinically-transformable MR imaging biomarkers to the invasive, MYCN-overexpressed Th-MYCN transgenic mouse model of neuroblastoma. Materials and Methods All tests followed the guidelines of the Local Ethics Review Team and the UK Department of Interior Animal Science Procedures Act of 1986 (1986 edition), as well as the National Cancer Research Center’s anti-tumor animal testing benefits guidelines. Multi-parametric MR imaging of abdominal tumors in the Th-MYCN model. T2-weighted imaging was used to measure the natural relaxation time of T1 and T2, the R2 * relaxation rate and the dynamic contrast-enhanced MR imaging for the tumor via cyclophosphamide (25mg / kg), VZZ6126 (200mg / kg ) Or anti-angiogenic agent sildenbucl (6 mg / kg, daily) after treatment. Any significant change in the measured parameters, treatment group and control group before and after treatment changed dramatically, respectively, using Student two-tailed paired or unpaired t-test data were tested, the significance level was 5%. Results Tumor volume was reduced by 54% and 20%, respectively, 48 h after cyclophosphamide and cediranib (P <0.005 vs pretreatment, P <0.005, respectively). The average volume of tumors was reduced by 45% within 24 h after treatment with ZD6126 (P <0.005 vs. pretreatment; P <0.005 vs. control). The anti-tumor effect of cyclophosphamide, cediranib and ZD6126 was correlated with the decrease of tumor T1 value (all P <0.005 compared with that before treatment; P <0.005 compared with the control group) Changes in T1 values after treatment were correlated with changes in tumor volume (r = 0.56; P <0.005). The volume conversion constants (P = 0.07; P <0.05 compared with control group) and enhancement fraction (P <0.05) of tumor response to cediranib and MR imaging enhanced compared with control group (P <0.01) (P <0.005; compared with the control group, P <0.05). Conclusion T1 relaxation time can be used as a stable, noninvasive imaging biomarker for detecting post-treatment response in Th-MYCN tumor-bearing mice. Th-MYCN tumor mice are a model of high-incidence neuroblastoma in children. The measurement of T1 can be easily applied in clinical MR system and can be applied in the clinical observation of new targeted therapy of pediatric neuroblastoma.