摘要
目的：在结肠癌裸鼠皮下移植瘤模型中，探讨磁共振动态增强扫描（DCE-MRI）联合多梯度敏感因子b值的扩散加权成像（DWI）技术无创性评价肿瘤血管生成以及抗肿瘤血管药物治疗后反映肿瘤血管关闭情况的应用价值，并探讨DCE-MRI及DWI技术评估抗肿瘤药物早期疗效的作用。方法：10只结肠癌裸鼠皮下移植瘤模型连续四天进行DCE-MRI、多b值的DWI扫描及常规MRI检查，动态观察以下参数的变化：信号最大上升斜率（MSI）、血浆容积分数（Vp）、血管外细胞外容积分数（Ve）、微血管转运常数（K~(trans)）、反流速率常数（K_(ep)）及各类表观扩散系数值（ADC_(3b)、ADC_(10b)、ADC_(low)、ADC_(high)、ADC_(perf)），分别于第三天及第四天MRI扫描结束后各处死5只载瘤裸鼠行病理免疫组化方法测定移植瘤的微血管密度（Microvessel density，MVD）计数、血管内皮生长因子（Vascular endothelial growth factor，VEGF）表达和增殖细胞核抗原（Proliferating cell nuclear antigen，PCNA）检测，分析MRI各参数与病理免疫组化结果的相关性。随后，50只结肠癌裸鼠皮下移植瘤随机分为三组（对照组10只、抗肿瘤血管药物治疗组20只、抗肿瘤细胞毒性药物治疗组20只），分别在治疗前、治疗后1h、24h、48h行DCE-MRI及多b值的DWI检查，动态观察上述各参数值的变化，并于治疗后24h及治疗后48h MRI检查结束后，每组分别随机处死一半载瘤裸鼠行病理免疫组化染色，MRI各参数与病理免疫组化结果进行相关性分析。结果：在无任何药物干预情况下，随着观察时间的延长，K~(trans)、K_(ep)、MSI及ADC_(perf)值逐渐增加，ADC_(3b)及ADC_(10b)值逐渐减低（P＜0.05）。K~(trans)与K_(ep)、MSI、ADC_(perf)四个参数之间相互均存在正相关性；而K~(trans)、K_(ep)分别与ADC_(3b)及ADC_(10b)值之间具有负相关性。ADC_(perf)值分别与MVD计数、VEGF计分具有较好的正相关性；ADC_(10b)与MVD计数、VEGF计分及PCNA计分呈显著的负相关性。K~(trans)、MSI分别与MVD计数、VEGF计分及PCNA计分均具有很好的正相关性；K_(ep)与MVD计数及VEGF计分之间存在线性相关。在抗肿瘤血管药物及抗肿瘤细胞毒性药物的干预下，三组间各ADC值及K~(trans)、Vp、K_(ep)、MSI均存在统计学差异。两组药物治疗后1h，各参数均明显下降；治疗后24h，抗肿瘤血管药物组中ADC_(low)、ADC_(perf)值及DCE-MRI各参数持续下降，到治疗后48h轻度恢复；而抗肿瘤细胞毒性药物组中各参数值在治疗后24h开始轻度恢复。在药物干预的情况，ADC_(3b)、ADC_(10b)与免疫组化结果呈负相关，ADC_(perf)、K~(trans)、K_(ep)、MSI与免疫组化结果呈正相关。Ve、Vp值与免疫组化染色之间无相关性。因子分析法分析后将K~(trans)、Vp、K_(ep)、MSI、ADC_(perf)、ADC_(low)值归为肿瘤微循环灌注因子，ADC_(3b)、ADC_(10b)、ADC_(high)值归为细胞代谢因子，Ve为综合因子。结论：DCE-MRI及多b值的DWI技术获得的定量及半定量参数可以作为影像生物标记物无创性的评价肿瘤血管生长状态及评估抗肿瘤血管药物治疗后肿瘤血管的关闭情况。K~(trans)、K_(ep)、MSI、ADC_(perf)、ADC_(low)值主要用于评价肿瘤微循环灌注情况，而ADC_(3b)、ADC_(10b)、ADC_(high)值主要反映肿瘤细胞密度及组织水肿情况，Vp及Ve值的价值尚未肯定。两种技术的联合应用可以从肿瘤微循环灌注及细胞代谢方面全面的反映药物治疗后的早期变化，有利于药物早期疗效的评价，有望成为抗肿瘤血管药物研发过程中药物临床四期试验评估药物疗效的主要观察终点之一，促进药物的研发和临床应用。
Objective: To discuss dynamic contrast-enhanced (DCE-MRI) combined withdiffusion-weighted MR imaging (DWI) for noninvasive evaluation of tumor angiogenesisand tumor vessel closure after anti-angiogenesis drugs treatment, and to exploreDCE-MRI and DWI assessment value of early effect of anticancer treatment. Methods:DCE-MRI, DWI scans and conventional MRI were performed for four consecutive daysin10subcutaneous colon cancer xenograft model. The following parameters weredynamic observation, including maximum slope of increase (MSI), microvascularpermeability transfer constant (K~(trans)), volume fraction of the plasma space (Vp),extravascular extracellular volume fraction (Ve), microvascular permeability refluxconstant (K_(ep)) and various types of apparent diffusion coefficient (ADC_(3b), ADC_(10b),ADC_(low), ADC_(high), ADC_(perf)).Immunohistochemical examination were observed at third andfourth days, including microvessel density (MVD), vascular endothelial growth factor(VEGF) and proliferating cell nuclear antigen (PCNA). Correlation analysis wasperformed between MRI parameters and immunohistochemistry. Subsequently,50subcutaneous colon cancer xenograft model were randomly divided into three groups (10in the control group,20in the anti-angiogenesis drug treatment group,20in the anti-tumorcytotoxic drug treatment group). DWI and DCE-MRI were acquired at baseline,1h,24hand48h post-treatment. The MRI imaging biomarkers were quantified and correlatedwith immunohistochemical examination in24h and48h post-treatment. Results: In theabsence of any drug intervention case, tumor K~(trans), K_(ep), MSI and ADC_(perf)graduallyincreased, ADC_(3b)and ADC_(10b)gradually reduce With the extension of the observation time.There was positively correlation between K~(trans)and K_(ep), MSI, ADC_(perf). However, therewas respectively negative correlation between K~(trans), K_(ep)and ADC_(3b), ADC_(10b). ADC_(perf)were positively correlated well with the MVD and VEGF. ADC_(10b)were negatively correlated significantly with MVD, VEGF and PCNA. There are positive correlationbetween K~(trans), MSI and MVD, VEGF and PCNA. There are linear correlation betweenK_(ep)and MVD and VEGF. Under the drug intervention, the value of ADCs and K~(trans), Vp,K_(ep), MSI were significant difference between the three groups. Two drug groups1h aftertreatment, all parameters decreased significantly;24h after treatment, ADC_(low), ADC_(perf)and parameters from DCE-MRI continued to decline in the anti-angiogenesis drug group,however, various parameters mild recovery in the anti-tumor cytotoxic drugs group.ADC_(3b), ADC_(10b)and immunohistochemistry were negatively correlated. ADC_(perf), K~(trans), K_(ep),MSI and immunohistochemistry were positively correlated. No correlation between Ve,Vp and immunohistochemistry. Analysis of the factor analysis, K~(trans), Vp, K_(ep), MSI,ADC_(perf)and ADC_(low)classified as tumor microcirculation factor, ADC_(3b), ADC_(10b)andADC_(high)normalized for cell metabolism factor, and Ve is integrated factor. Conclusion:Obtaining MRI quantitative and semi-quantitative parameters from DCE-MRI and DWIused as imaging biomarkers can be noninvasive evaluation of tumor angiogenesis andassessment of tumor vascular closure after anti-angiogenesis drugs treatment. K~(trans), K_(ep),MSI, ADC_(perf)and ADC_(low)are mainly used for the evaluation of tumor microcirculation,ADC_(3b), ADC_(10b)and ADC_(high)value mainly reflects the density of tumor cells and tissueedema, and the application value of the Vp and Ve have not confirmed. Combination ofthe two technologies make the more comprehensively reflect the early changes after drugtherapy from tumor microcirculation and cell metabolism, and conducive to the evaluationof the early effects of the drugs. MRI is expected to become one of the main endpoint ofthe evaluation of drug efficacy in the development process of tumor vascular medicine,and to facilitate drug development and clinical application.
引文
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