Manning H Charles, Merchant Nipun B, Foutch A Coe, Virostko John M, Wyatt Shelby K, Shah Chirayu, McKinley Eliot T, Xie Jingping, Mutic Nathan J, Washington M Kay, LaFleur Bonnie, Tantawy Mohammed Noor, Peterson Todd E, Ansari M Sib, Baldwin Ronald M, Rothenberg Mace L, Bornhop Darryl J, Gore John C, Coffey Robert J
Vanderbilt Institute of Imaging Science, Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
Clin Cancer Res. 2008 Nov 15;14(22):7413-22. doi: 10.1158/1078-0432.CCR-08-0239.
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.
评估非侵入性分子成像方法作为西妥昔单抗对无胸腺裸鼠体内生长的人结肠癌细胞系异种移植瘤治疗效果的相关生物标志物。在治疗和未治疗的荷瘤组中，评估分子成像与免疫组织化学分析之间的相关性，以量化表皮生长因子（EGF）结合、细胞凋亡和增殖情况。
合成了靶向表皮生长因子受体（EGFR）表达（NIR800 - EGF）和细胞凋亡（NIR700 - 膜联蛋白V）的光学成像探针，并在体外和体内进行评估。通过3'-[18F]氟-3'-脱氧胸苷（[18F]FLT）正电子发射断层扫描评估增殖情况。通过在西妥昔单抗敏感（DiFi）和不敏感（HCT - 116）的人结肠癌细胞系异种移植瘤中同时成像NIR800 - EGF、NIR700 - 膜联蛋白V和[18F]FLT，来评估西妥昔单抗对EGFR信号传导的抑制作用。在体内成像后，通过测量肿瘤大小以及对总EGFR和磷酸化EGFR、半胱天冬酶-3和Ki-67进行免疫组织化学分析，对成像结果进行验证。
肿瘤中NIR800 - EGF的积聚反映了相对EGFR表达以及西妥昔单抗对EGFR的占有率。通过半胱天冬酶-3的免疫组织化学染色评估，NIR700 - 膜联蛋白V的积聚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免疫组织化学分析，未观察到治疗组和未治疗组动物之间肿瘤增殖有显著差异。
分子成像可以准确评估人结肠癌细胞异种移植瘤中的EGF结合、增殖和细胞凋亡情况。这些成像方法可能对临床前研究中EGFR抑制的生物学效应进行连续、非侵入性监测有用。预计这些检测方法可适用于临床应用。
