The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York 12208, USA.
J Clin Endocrinol Metab. 2010 Apr;95(4):1972-80. doi: 10.1210/jc.2009-1926. Epub 2010 Feb 4.
Tetraiodothyroacetic acid (tetrac) blocks angiogenic and tumor cell proliferation actions of thyroid hormone initiated at the cell surface hormone receptor on integrin alphavbeta3. Tetrac also inhibits angiogenesis initiated by vascular endothelial growth factor and basic fibroblast growth factor.
We tested antiangiogenic and antiproliferative efficacy of tetrac and tetrac nanoparticles (tetrac NP) against human medullary thyroid carcinoma (h-MTC) implants in the chick chorioallantoic membrane (CAM) and h-MTC xenografts in the nude mouse.
h-MTC cells were implanted in the CAM model (n = 8 per group); effects of tetrac and tetrac NP at 1 microg/CAM were determined on tumor angiogenesis and tumor growth after 8 d. h-MTC cells were also implanted sc in nude mice (n = 6 animals per group), and actions on established tumor growth of unmodified tetrac and tetrac NP ip were determined.
In the CAM, tetrac and tetrac NP inhibited tumor growth and tumor-associated angiogenesis. In the nude mouse xenograft model, established 450-500 mm(3) h-MTC tumors were reduced in size over 21 d by both tetrac formulations to less than the initial cell mass (100 mm(3)). Tumor tissue hemoglobin content of xenografts decreased by 66% over the course of administration of each drug. RNA microarray and quantitative real-time PCR of tumor cell mRNAs revealed that both tetrac formulations significantly induced antiangiogenic thrombospondin 1 and apoptosis activator gene expression.
Acting via a cell surface receptor, tetrac and tetrac NP inhibit growth of h-MTC cells and associated angiogenesis in CAM and mouse xenograft models.
四碘甲状腺原氨酸乙酸盐（tetrac）可阻断甲状腺激素在整合素 alphavbeta3 细胞表面激素受体处引发的血管生成和肿瘤细胞增殖作用。tetrac 还可抑制血管内皮生长因子和碱性成纤维细胞生长因子引发的血管生成。
我们检测了 tetrac 和 tetrac 纳米颗粒（tetrac NP）对鸡胚绒毛尿囊膜（CAM）中人类甲状腺髓样癌（h-MTC）植入物以及裸鼠中 h-MTC 异种移植物的抗血管生成和抗增殖作用。
将 h-MTC 细胞植入 CAM 模型中（每组 8 只）；8 天后，测定 1 μg/CAM 下 tetrac 和 tetrac NP 对肿瘤血管生成和肿瘤生长的影响。还将 h-MTC 细胞皮下植入裸鼠（每组 6 只动物），测定未修饰的 tetrac 和 tetrac NP 腹腔注射对已建立的肿瘤生长的作用。
在 CAM 中，tetrac 和 tetrac NP 抑制了肿瘤生长和肿瘤相关的血管生成。在裸鼠异种移植模型中，450-500mm3 的 h-MTC 肿瘤在 21 天内被两种 tetrac 制剂缩小到小于初始细胞团（100mm3）。肿瘤组织血红蛋白含量在两种药物给药过程中降低了 66%。肿瘤细胞 mRNA 的 RNA 微阵列和定量实时 PCR 显示，两种 tetrac 制剂均显著诱导了抗血管生成的血小板反应蛋白 1 和凋亡激活基因的表达。
tetrac 和 tetrac NP 通过细胞表面受体发挥作用，可抑制 CAM 和小鼠异种移植模型中 h-MTC 细胞的生长及其相关血管生成。
