Chen F M, Taylor C R, Epstein A L
Department of Pathology, University of Southern California School of Medicine, Los Angeles 90033.
Cancer Res. 1989 Aug 15;49(16):4578-85.
In contrast to normal tissues, many malignant tumors contain a high proportion of dead and dying cells. The loss of membrane integrity that accompanies cellular degeneration permits macromolecules, including antibodies, to freely enter the cell cytoplasm. Based upon these observations, it was hypothesized that monoclonal antibodies to intracellular antigens, which are integral structural components and are retained by degenerating cells, may be used to target a wide range of human malignancies. Previous studies by our laboratory utilizing these principles have demonstrated the feasibility of imaging four different histological types of human cancer in a nude mouse model, using monoclonal antibodies directed against insoluble intranuclear antigens. The present study describes the application of this approach, designated tumor necrosis treatment, for the radioimmunotherapy of transplantable ME-180 human cervical carcinomas in the nude mouse. Groups of tumor-bearing nude mice received three weekly treatments of 150 or 300 microCi of 131I-labeled experimental (TNT-1) or control (Lym-1) monoclonal antibodies. Detailed biodistribution data, dosimetric evaluations, and therapeutic results are presented to demonstrate the effective and preferential targeting of 131I-labeled TNT-1 monoclonal antibody within the tumor. In the experimental groups, the dose delivered to the tumor was sufficient to induce clinical regressions in 88% of treated animals, without evidence of toxicity to normal tissues. Complete regressions were obtained in 25% of the mice treated with high dose TNT-1. Microscopic examination of the implantation sites of these mice demonstrated the presence of acute radiation damage and residual keratin-positive tumor cells showing marked evidence of degeneration. Dosimetric data obtained over the 3-week treatment period showed that, unlike control treated mice, which received approximately 500 cGy each week, the experimental animals received increasing doses of radiolabeled antibody with each treatment (averages for weeks 1, 2, and 3: 1066, 2046, and 2476 cGy, respectively). In accordance with these data, enhanced imaging and therapeutic responses were observed with each therapeutic dose in the TNT-1-treated groups, compared with controls. These results indicate that TNT-1 therapy produces an ever expanding population of TNT-1-positive targets in the tumor as a result of the centrifugal killing of adjacent viable tumor cells. To help illustrate these results, a four-compartment model of the dose distribution kinetics of TNT-1 is presented for discussion with respect to the possible application of this method for the imaging and treatment of cancer in
与正常组织相比，许多恶性肿瘤含有高比例的死亡和濒死细胞。细胞变性伴随的膜完整性丧失使包括抗体在内的大分子能够自由进入细胞质。基于这些观察结果，有人提出，针对细胞内抗原（这些抗原是不可或缺的结构成分且被变性细胞保留）的单克隆抗体可用于靶向多种人类恶性肿瘤。我们实验室先前利用这些原理进行的研究已证明，在裸鼠模型中使用针对不溶性核内抗原的单克隆抗体对四种不同组织学类型的人类癌症进行成像的可行性。本研究描述了这种被称为肿瘤坏死治疗的方法在裸鼠中对可移植的ME - 180人宫颈癌进行放射免疫治疗的应用。荷瘤裸鼠组每周接受三次治疗，每次注射150或300微居里的131I标记的实验性（TNT - 1）或对照性（Lym - 1）单克隆抗体。给出了详细的生物分布数据、剂量学评估和治疗结果，以证明131I标记的TNT - 1单克隆抗体在肿瘤内的有效且优先靶向作用。在实验组中，给予肿瘤的剂量足以使88%接受治疗的动物出现临床缓解，且无对正常组织产生毒性的迹象。高剂量TNT - 1治疗的小鼠中有25%实现了完全缓解。对这些小鼠植入部位的显微镜检查显示存在急性辐射损伤以及残留的角蛋白阳性肿瘤细胞，这些细胞呈现出明显的变性迹象。在为期3周的治疗期间获得的剂量学数据表明，与每周接受约500 cGy照射的对照治疗小鼠不同，实验动物每次治疗接受的放射性标记抗体剂量都在增加（第1、2和3周的平均值分别为1066、2046和2476 cGy）。根据这些数据，与对照组相比，TNT - 1治疗组中每次治疗剂量都观察到成像和治疗反应增强。这些结果表明，由于对相邻存活肿瘤细胞的离心性杀伤，TNT - 1治疗在肿瘤中产生了不断扩大的TNT - 1阳性靶点群体。为了帮助说明这些结果，给出了TNT - 1剂量分布动力学的四室模型，以供讨论该方法在癌症成像和治疗中的可能应用
