Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer.
Molecular imaging of therapeutic response to epidermal growth factor receptor blockade in colorectal cancer.
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DOI：
10.1158/1078-0432.ccr-08-0239
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发表时间：
2008-11-15
期刊：
影响因子：
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通讯作者：
Coffey RJ
中科院分区：
文献类型：
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作者：
Manning HC;Merchant NB;Foutch AC;Virostko JM;Wyatt SK;Shah C;McKinley ET;Xie J;Mutic NJ;Washington MK;LaFleur B;Tantawy MN;Peterson TE;Ansari MS;Baldwin RM;Rothenberg ML;Bornhop DJ;Gore JC;Coffey RJ
评价非侵入性分子影像学方法作为西妥昔单抗在裸鼠体内生长的人结直肠癌细胞系异种移植物中疗效的相关生物标志物。分子成像和免疫组化分析之间的相关性，以量化表皮生长因子（EGF）的结合，细胞凋亡和增殖进行了评估，在治疗和未治疗的肿瘤承载队列。合成了靶向EGF受体（EGFR）表达（NIR 800-EGF）和凋亡（NIR 700-Annexin V）的光学成像探针，并在体外和体内进行了评价。通过3′-[18 F]氟-3 ′-脱氧胸苷（[18 F] FLT）正电子发射断层扫描评估增殖。通过在西妥昔单抗敏感（DiFi）和不敏感（HCT-116）人结直肠癌细胞系异种移植物中同时成像NIR 800-EGF、NIR 700-膜联蛋白V和[18 F] FLT，评估西妥昔单抗对EGFR信号传导的抑制作用。通过测量肿瘤大小和免疫组化分析总EGFR和磷酸化EGFR、caspase-3和Ki-67，在体内成像后立即验证成像结果。肿瘤中的NIR 800-EGF蓄积反映了西妥昔单抗的相对EGFR表达和EGFR占有率。通过caspase-3免疫组织化学染色评估，NIR 700-Annexin V蓄积与西妥昔单抗诱导的细胞凋亡相关。通过[18F] FLT正电子发射断层扫描或Ki-67免疫组织化学，在给药和未给药动物之间未观察到肿瘤增殖的显著差异。分子影像学可以准确评估EGF结合，增殖和细胞凋亡在人结直肠癌异种移植。这些成像方法可能被证明是有用的串行，非侵入性监测EGFR抑制的生物学效应在临床前研究。预期这些测定可适用于临床使用。
To evaluate noninvasive molecular imaging methods as correlative biomarkers of therapeutic efficacy of cetuximab in human colorectal cancer cell line xenografts grown in athymic nude mice. The correlation between molecular imaging and immunohistochemical analysis to quantify epidermal growth factor (EGF) binding, apoptosis, and proliferation was evaluated in treated and untreated tumor-bearing cohorts. Optical imaging probes targeting EGF receptor (EGFR) expression (NIR800-EGF) and apoptosis (NIR700-Annexin V) were synthesized and evaluated in vitro and in vivo. Proliferation was assessed by 3′-[18F]fluoro-3′-deoxythymidine ([18F] FLT) positron emission tomography. Assessment of inhibition of EGFR signaling by cetuximab was accomplished by concomitant imaging of NIR800-EGF, NIR700-Annexin V, and [18F] FLT in cetuximab-sensitive (DiFi) and insensitive (HCT-116) human colorectal cancer cell line xenografts. Imaging results were validated by measurement of tumor size and immunohistochemical analysis of total and phosphorylated EGFR, caspase-3, and Ki-67 immediately following in vivo imaging. NIR800-EGF accumulation in tumors reflected relative EGFR expression and EGFR occupancy by cetuximab. NIR700-Annexin V accumulation correlated with cetuximab-induced apoptosis as assessed by immunohistochemical staining of caspase-3. No significant difference in tumor proliferation was noted between treated and untreated animals by [18F] FLT positron emission tomography or Ki-67 immunohistochemistry. Molecular imaging can accurately assess EGF binding, proliferation, and apoptosis in human colorectal cancer xenografts. These imaging approaches may prove useful for serial, noninvasive monitoring of the biological effects of EGFR inhibition in preclinical studies. It is anticipated that these assays can be adapted for clinical use.