A novel therapeutic strategy for medullary thyroid cancer based on radioiodine therapy following tissue-specific sodium iodide symporter gene expression
A novel therapeutic strategy for medullary thyroid cancer based on radioiodine therapy following tissue-specific sodium iodide symporter gene expression
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DOI：
10.1210/jc.2004-2140
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发表时间：
2005-08-01
影响因子：
5.8
通讯作者：
Spitzweg, C
中科院分区：
文献类型：
--
作者：
Cengic, N;Baker, CH;Spitzweg, C
内容：与乳头状和滤泡状甲状腺癌相比，甲状腺髓样癌（MTC）由于其对放射性碘治疗的无反应性以及对化疗和放疗的有限反应性而仍然难以治疗。目的：为了研究一种替代治疗方法，我们在人钠碘同向转运体（hNIS）治疗后，使用降钙素启动子进行基因转移以将hNIS基因表达靶向MTC细胞（TT）。设计：用表达载体稳定转染TT细胞，其中hNIS cDNA与降钙素启动子偶联。功能hNIS表达证实碘积累试验，北方和Western印迹分析，免疫染色，并在体外克隆形成assay.Results：hNIS转染TT细胞表现出高氯酸盐敏感的碘摄取，积累125-I约12倍，在体外与有机化的4%积累的碘导致碘流出显着减少。通过使用单克隆hNIS特异性抗体的蛋白质印迹分析证实NIS蛋白表达，其显示分子量为80-90 kDa的主要条带。此外，hNIS转染的TT细胞的免疫染色显示hNIS特异性免疫反应性，这主要是膜相关的。在体外克隆形成试验中，84%的NIS转染的TT细胞被杀死暴露于131-I，而只有约0.6%的对照cells were killed.Conclusions：一个治疗效果的131-I已被证明在MTC细胞诱导后的组织特异性碘摄取活性的降钙素启动子定向hNIS的表达。本研究表明NIS作为治疗基因的潜力，允许在组织特异性NIS基因转移后进行MTC的放射性碘治疗。
Context: In contrast to papillary and follicular thyroid cancer, medullary thyroid cancer (MTC) remains difficult to treat due to its unresponsiveness to radioiodine therapy and its limited responsiveness to chemo- and radiotherapy.Objective: To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of MTC after human sodium iodide symporter (hNIS) gene transfer using the calcitonin promoter to target hNIS gene expression to MTC cells (TT).Design: TT cells were stably transfected with an expression vector, in which hNIS cDNA was coupled to the calcitonin promoter. Functional hNIS expression was confirmed by iodide accumulation assays, Northern and Western blot analysis, immunostaining, and in vitro clonogenic assay.Results: hNIS-transfected TT cells showed perchlorate-sensitive iodide uptake, accumulating 125-I about 12-fold in vitro with organification of 4% of accumulated iodide resulting in a significant decrease in iodide efflux. NIS protein expression was confirmed by Western blot analysis using a monoclonal hNIS-specific antibody, which revealed a major band of a molecular mass of 80-90 kDa. In addition, immunostaining of hNIS-transfected TT cells revealed hNIS-specific immunoreactivity, which was primarily membrane associated. In an in vitro clonogenic assay, 84% of NIS-transfected TT cells were killed by exposure to 131-I, whereas only about 0.6% of control cells were killed.Conclusions: A therapeutic effect of 131-I has been demonstrated in MTC cells after induction of tissue-specific iodide uptake activity by calcitonin promoter-directed hNIS expression. This study demonstrates the potential of NIS as a therapeutic gene, allowing radioiodine therapy of MTC after tissue-specific NIS gene transfer.