Discovery of targeting peptides for selective therapy of medullary thyroid carcinoma
Discovery of targeting peptides for selective therapy of medullary thyroid carcinoma
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DOI：
10.1002/jgm.648
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Pützer, BM
中科院分区：
文献类型：
--
作者：
Böckmann, M;Drosten, M;Pützer, BM
背景腺病毒可有效感染广泛的靶细胞，从而阻止选择性基因转移。此外，包括原发性肿瘤在内的几种细胞类型和组织对腺病毒感染是难治的，主要是因为柯萨奇-腺病毒受体（CAR）的低表达水平。因此，识别癌症选择性配体，产生基因转移到肿瘤细胞，通过最大限度地减少正常细胞的转导是成功的癌症therapy.Methods的关键问题，我们初步分析了腺病毒受体在人甲状腺髓样癌（MTC细胞）的表达。MTC细胞特异性肽分离通过生物淘选噬菌体展示肽库对培养的癌细胞和肿瘤在体内，并进一步characterized.Results我们发现在CAR和α v-整合素蛋白水平之间的显着差异MTC衍生的TT细胞在体外和建立异种移植肿瘤小鼠，表明缺乏α v-整合素表达的肿瘤生长。通过进行三轮减法来鉴定MTC特异性候选物。当与野生型M13噬菌体或其他人细胞系和体内肿瘤组织相比时，所选的噬菌体显示出高达22倍的TT细胞结合效率。在特异性肽的存在下，最佳结合噬菌体归巢到TT细胞被清楚地阻断，而未观察到与非特异性肽的噬菌体竞争。最佳结合肽介导噬菌体的有效内化。重要的是，特异性结合和内化也介导的腺病毒context.Conclusions内的识别肽，我们的研究结果表明，所确定的配体应该是合适的，以提高选择性的腺病毒基因转移到甲状腺髓样肿瘤在体内。版权所有（C）2004约翰威利父子有限公司。
Background Adenovirus efficiently infects a broad range of target cells, thereby preventing selective gene transfer. Moreover, several cell types and tissues including primary tumors are refractory to adenoviral infection, mainly because of low expression levels of coxsackie-adenovirus receptor (CAR). Thus, identification of cancer-selective ligands which yield gene transfer to neoplastic cells by minimizing transduction of normal cells is a key issue for successful cancer therapy.Methods We initially analyzed adenoviral receptor expression in human medullary thyroid carcinoma (MTC cells. MTC cell-specific peptides were isolated by biopanning a phage display peptide library on cultured cancer cells and on tumors in vivo and further characterized.Results We found significant differences in CAR and alphav-integrin protein levels between MTC-derived TT cells in vitro and established xenograft tumors in mice, indicating a lack of av-integrin expression on growing tumors. MTC-specific candidates were identified by performing three rounds of subtraction. Selected phages showed up to 22-fold higher binding efficiency for TT cells when compared with wild-type M13 phage or other human cell lines and tumor tissue in vivo. Homing to TT cells of the best binding phage was clearly blocked in the presence of specific peptide, whereas no phage competition was observed with an unspecific peptide. The best binding peptide mediated efficient internalization of the phage. importantly, specific binding and internalization was also mediated by the identified peptide within the adenoviral context.Conclusions Our results indicate that the identified ligand should be suitable to improve selectivity of adenoviral gene transfer to medullary thyroid tumors in vivo. Copyright (C) 2004 John Wiley Sons, Ltd.