Molecular targeting of carbonic anhydrase IX in mice with hypoxic HT29 colorectal tumor xenografts.
Molecular targeting of carbonic anhydrase IX in mice with hypoxic HT29 colorectal tumor xenografts.
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DOI：
10.1371/journal.pone.0010857
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发表时间：
2010-05-27
期刊：
影响因子：
3.7
通讯作者：
Smith-Jones PM
中科院分区：
文献类型：
--
作者：
Carlin S;Khan N;Ku T;Longo VA;Larson SM;Smith-Jones PM
碳酸酐酶IX（CAIX）是一种跨膜蛋白，参与肿瘤酸碱平衡的酶调节。CAIX已显示在许多缺氧肿瘤类型中升高。本研究的目的是确定cG 250的完整片段和IgG片段在缺氧肿瘤模型中体内靶向CAIX的效率。用111 In-DO 3A-cG 250、111 In-DO 3A-F（ab '）2-cG 250和111 In-DO 3A-Fab-cG 250进行常规生物分布研究。用肿瘤缺氧、血液灌注和内源性CAIX表达的标志物进行肿瘤的另外的离体分析。将所有四个数据集进行数字关联，以确定用于确定HT 29结肠癌异种移植物中缺氧的最佳试剂。HT 29人结肠直肠肿瘤异种移植物在血液灌注差的缺氧区域中显示出强的CAIX表达。在7天的研究期间，完整的IgG在这些缺氧区域的周边具有初始的高局灶性摄取，并渗透到CAIX表达最高的区域。较低分子量的抗体片段具有进入高CAIX表达区域的更快摄取，但在最佳成像时间具有低得多的绝对摄取。对于使用基于cG 250抗体的试剂的缺氧诱导的CAIX的临床检测，在注射后7天用完整IgG成像将允许CAIX的最灵敏和准确的检测。
Carbonic anhydrase IX (CAIX) is a membrane spanning protein involved in the enzymatic regulation of tumor acid-base balance. CAIX has been shown to be elevated in a number of hypoxic tumor types. The purpose of this study was to determine the efficiency of intact and IgG fragments of cG250 to target CAIX in vivo in a hypoxic tumor model. Conventional biodistribution studies were performed with 111In-DO3A-cG250, 111In-DO3A-F(ab')2-cG250 and 111In-DO3A-Fab-cG250. Additional ex vivo analysis of the tumor was performed with markers for tumor hypoxia, blood perfusion and endogenous CAIX expression. All four data sets were digitally correlated to determine the optimal agent for determining hypoxia in a HT29 colon cancer xenograft. The HT29 human colorectal tumor xenografts show strong CAIX expression in hypoxic areas of poor blood perfusion. The intact IgG had an initial high focal uptake at the periphery of these hypoxic regions and penetration into the areas of highest CAIX expression over the 7-day study period. The lower molecular weight antibody fragments had a faster uptake into areas of high CAIX expression, but had a much lower absolute uptake at the optimal imaging times. For the clinical detection of hypoxia induced CAIX using cG250 antibody based agents, imaging with the intact IgG at 7 days post injection would allow for the most sensitive and accurate detection of CAIX.
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