RADIOIMMUNOTHERAPY OF ATHYMIC MICE BEARING HUMAN-COLON CARCINOMAS WITH MONOCLONAL-ANTIBODY B72.3 - HISTOLOGICAL AND AUTORADIOGRAPHIC STUDY OF EFFECTS ON TUMORS AND NORMAL ORGANS
RADIOIMMUNOTHERAPY OF ATHYMIC MICE BEARING HUMAN-COLON CARCINOMAS WITH MONOCLONAL-ANTIBODY B72.3 - HISTOLOGICAL AND AUTORADIOGRAPHIC STUDY OF EFFECTS ON TUMORS AND NORMAL ORGANS
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DOI：
10.1016/0277-5379(87)90259-8
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发表时间：
1987-06-01
期刊：
影响因子：
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通讯作者：
COLCHER, D
中科院分区：
文献类型：
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作者：
ESTEBAN, JM;SCHLOM, J;COLCHER, D
单克隆抗体（MAb）B72.3已成功地连接到几种放射性核素形成稳定的复合物，并在体外和体内分析，而没有显着损失的免疫反应性。先前的研究已经证明放射性碘标记的B72.3可以选择性地结合在无胸腺小鼠中生长的人结直肠癌。最近在转移性结直肠癌患者的临床试验中也获得了同样的成功定位。高度的选择性结合的单克隆抗体hs导致我们调查其作为放射免疫剂的潜力。给携带人结肠癌异种移植物的无胸腺小鼠注射300或500 μ Ci的131 I-B72.3 IgG，以评价放射性标记的MAb对肿瘤生长的作用以及对重要器官的潜在毒副作用。在用131 I-B72.3 IgG处理的小鼠中，与注射PBS的对照小鼠或接受未标记的B72. 3 IgG的对照小鼠相比，观察到对人结肠癌异种移植物生长的显著抑制。在接种放射性标记的MAb后17天，来自这些对照小鼠的肿瘤比来自处理小鼠的肿瘤重2.7至3.7倍。放射自显影研究表明，在MAb给药后11天，放射性在整个肿瘤块中呈不均匀分布。随着时间的推移，肿瘤周边的放射性显著低于主要由非活性组织组成的中间区域;这些结果表明，具有较高有丝分裂率的更具生物活性的周边肿瘤区域可能部分逃脱了单次给药的辐射效应。当循环中放射性标记的单克隆抗体水平降低时，肿瘤细胞可能继续分裂。在用高剂量方案（500 μ Ci）注射的小鼠中毒性很明显，证实骨髓发育不全，证明10只动物中有2只是致命的。较低剂量（300 μ Ci）导致骨髓抑制约10%。50%的细胞，这被证明是非致命的。治疗组小鼠的肿瘤显示出由致死剂量的131 I-B72.3引起的广泛坏死，该剂量的131 I-B72.3不可逆地损伤了细胞。还发现辐射诱导的细胞终末分化，表现为治疗动物中有丝分裂计数急剧减少（0-2 vs.对照肿瘤中每10个高倍视野中观察到12-14个）。
Monoclonal antibody (MAb) B72.3 has been linked successfully to several radionuclides forming stable complexes and analyzed in vitro and in vivo without significant loss of its immunoreactivity. Previous studies have demonstrated that radioiodinated B72.3 can selectively bind to human colorectal carcinomas grown in athymic mice. The same successful localization has been obtained more recently in clinical trials in patients with metastatic colorectal carcinomas. The high degree of selective binding of the MAb hs led us to investigate its potential as a radioimmunotherapeutic agent. Athymic mice bearing human colon carcinoma xenografts were injected with either 300 or 500 .mu.Ci of 131I-B72.3 IgG to assess the effect of the radiolabeled MAb on the tumor growth as well as potential toxic side effects in vital organs. In mice treated with the 131I-B72.3 IgG, a marked inhibition of the growth of the human colon carcinoma xenografts was noticed in comparison with control mice injected with PBS or control mice that received unlabeled B72.3 IgG. The tumors from these control mice weighted 2.7 to 3.7 times more than the tumors from the treated mice at 17 days post-inoculation of the radiolabeled MAb. Autoradiographic studies demonstrated a heterogeneous distribution of radioactivity throughout the tumor mass at 11 days post-administration of MAb. With time, the periphery of the tumor contained significantly less radioactivity than the medial areas composed of predominantly non-viable tissue; these findings suggest that the more biologically active peripheral tumor zones, with higher mitotic rates, could have partially escaped the radiation effect of the single dose administered. The tumor cells could have continued dividing when the levels of circulating radiolabeled monoclonal antibody had decreased. Toxicity was readily evident in the mice injected with the high-dose regimen (500 .mu.Ci), with confirmed bone marrow aplasia that proved lethal for 2 of 10 animals. The lower dose (300 .mu.Ci) resulted in a bone marrow suppression of approx. 50% of the cells, which proved to be non-lethal. The tumors in the treated mice showed extensive necrosis caused by the lethal dose of 131I-B72.3 that irreversibly damaged the cells. Radiation-induced terminal differentiation of cells was also found as manifested by the drastically decreased mitotic count (0-2 vs. 12-14 per 10 high power fields seen in control tumors) in treated animals.