Targeting of HER2 antigen for the treatment of disseminated peritoneal disease
Targeting of HER2 antigen for the treatment of disseminated peritoneal disease
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DOI：
10.1158/1078-0432.ccr-04-1226
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发表时间：
2004-12-01
影响因子：
11.5
通讯作者：
Brechbiel, MW
中科院分区：
文献类型：
--
作者：
Milenic, DE;Garmestani, K;Brechbiel, MW
本文报告的研究证明了以赫赛汀为靶向载体的α粒子靶向放射治疗腹膜疾病的疗效。使用CHX-A-DTPA接头，用铟-111和铋-213高效放射性标记赫赛汀，而不影响免疫反应性。一项初步放射免疫治疗研究，治疗携带5天LS-174 T（i. p.）异种移植物，一种低但均匀表达HER 2的人结肠癌，用单剂量Bi-213-CHX-A ″-赫赛汀，证明令人失望。这定义了肿瘤负荷/大小对肿瘤对使用α-辐射的放射免疫疗法的反应的影响。随后在小鼠中进行了更成功的实验，肿瘤负荷较低（3天）。观察到了特定的剂量反应（P = 0.009），尽管未确定最大耐受剂量，但基于动物体重的变化，选择500至750 μ Ci的剂量作为未来实验的操作剂量。500和750 μ Ci的模拟治疗小鼠的中位生存期分别从20.5天增加到43和59天。还在人胰腺癌腹膜疾病的第二种动物模型（Shaw）中评价了Bi-213-CHX-A”-赫赛汀的治疗效果。本研究的结果不像前一种模型那样引人注目，需要更高的剂量才能增加小鼠的存活率（P = 0.001）。
The studies reported herein demonstrate the efficacy of alpha-particle-targeted radiation therapy of peritoneal disease with Herceptin as the targeting vehicle. Using the CHX-A-DTPA linker, Herceptin was radiolabeled with indium-111 and bismuth-213 with high efficiency without compromising immunoreactivity. A pilot radioimmunotherapy study treating mice bearing 5-day LS-174T (i.p.) xenografts, a low but uniform HER2 expressing, human colon carcinoma, with a single dose of Bi-213-CHX-A"-Herceptin, proved disappointing. This defined the effect of tumor burden/size on tumor response to radioimmunotherapy with alpha-radiation. A more successful experiment with a lower tumor burden (3 days) in mice followed. A specific dose-response (P = 0.009) was observed, and although a maximum-tolerated dose was not determined, a dose of 500 to 750 muCi was selected as the operating dose for future experiments based on changes in animal weight. Median survival was increased from 20.5 days for the mock-treated mice to 43 and 59 days with 500 and 750 muCi, respectively. The therapeutic effectiveness of Bi-213-CHX-A"-Herceptin was also evaluated in a second animal model for peritoneal disease with a human pancreatic carcinoma (Shaw). The results of this study were not as dramatic as with the former model, and higher doses were required to obtain an increase in survival of the mice (P = 0.001).