Molecular Biological Approach towards Efficient Radioimmunotherapy

本研究的目的是从分子生物学的角度评价放射性标记的单克隆抗体处理的肿瘤细胞。研究了放射性标记抗体的剂量和分级的影响，得到以下结果.用~（131）I标记的抗CEA单克隆抗体孵育产生CEA的人胃癌细胞：（1）未观察到肿瘤细胞凋亡。(2)细胞毒性呈剂量依赖性，重复孵育的细胞毒性高于单次孵育.用~（131）I标记的单克隆抗体与小鼠白血病细胞共孵育：（1）肿瘤细胞出现凋亡。(2)在与I-131标记的无关抗体或I-131孵育的肿瘤细胞中观察到凋亡，表明凋亡对放射性标记的抗体没有特异性.用~（131）I标记的抗CEA单克隆抗体注射荷人胃癌裸鼠：（1）任何剂量的~（131）I标记抗体均未引起肿瘤细胞凋亡。(2)当小鼠瘤内注射I-131标记的抗体时，在异种移植物中观察到坏死。分级降低肿瘤对I-131的摄取.用~（131）I标记的抗体腹腔注射荷白血病细胞的荷瘤小鼠、裸鼠和SCID小鼠，结果发现：（1）所有小鼠的白血病细胞均出现凋亡。(2)低剂量的I-131-抗体仅在异种小鼠中观察到细胞凋亡。高剂量的I-131标记抗体可引起SCID小鼠的放射损伤，表明细胞凋亡是通过免疫原性途径发生的。(2)细胞凋亡是血液肿瘤放射免疫治疗中与宿主免疫原性相关的重要因素。

The aim of this study is to evaluate the tumor cells treated with radiolabeled monoclonal antibodies from the molecular biological point of view. The effects of dose of radiolabeled antibodies and fractionation were investigated to get the following results.1. Human gastric cancer cells producing CEA were incubated with I-131-labeled anti-CEA monoclonal antibody :(1) No apoptosis was observed in tumor cells.(2) Cytotoxicity was dose dependent, and repeated incubation caused higher toxicity than one incubations.2. Murine leukemia cells were incubated with I-131-labeled monoclonal antibody which was reactive with cell surface antigen :(1) Apoptosis was observed in tumor cells.(2) Apoptosis was observed in tumor cells which were incubated with I-131-labeled irrelevant antibody or I-131 ; indicating that apoptosis is not specific for radiolabeled antibodies.3. Athymic nude mice bearing human gastric cancer xenografts were injected with I-131-labeled anti-CEA monoclonal antibody :(1) No apoptosis was observed in tumor cells by any dose of I-131-labeled antibody.(2) Necrosis was observed in xenografts when mice were injected with I-131-labeled antibody intratumorally. Fractionation reduced the uptake of I-131 in the tumors.4. Hetero, athymic nude, or SCID mice bearing leukemia cells intraperitoneally were injected with I-131-labeled antibody :(1) Apoptosis was observed in leukemia cells in any mice.(2) Apoptosis was observed in only hetero mice by the low dose of I-131-antibody. High does of I-131-labeled antibody caused the radiation damage in SCID mice ; indicating that apoptosis occurred through the immunogenic pathways.5.The study suggested that :(1) Apoptosis would not be mainly involved in solid tumors by radioimmunotherapy.(2) Apoptosis is an important factors in hematological tumors in conjunction with the immunogenecity from the host when it is treated by radioimmunotherapy.