Macklis R M, Kaplan W D, Ferrara J L, Atcher R W, Hines J J, Burakoff S J, Coleman C N
Department of Radiology, Dana Farber Cancer Institute, Boston, MA 02115.
Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1377-87. doi: 10.1016/0360-3016(89)90938-3.
Short-lived isotopes that emit alpha particles have a number of physical characteristics which make them attractive candidates for radioimmunotherapy. Among these characteristics are high linear energy transfer and correspondingly high cytotoxicity; particle range limited to several cell diameters from the parent atom; low potential for repair of alpha-induced DNA damage; and low dependence on dose rate and oxygen enhancement effects. This report reviews the synthesis, testing and use in animal models of an alpha particle emitting radioimmunoconjugate constructed via the noncovalent chelation of Bismuth-212 to a monoclonal IgM antibody specific for the murine T cells/neuroectodermal surface antigen, Thy 1.2. These 212Bi-anti-Thy 1.2 immunoconjugates are capable of extraordinary cytotoxicity in vitro, requiring approximately three 212Bi-labeled conjugates per target cell to suppress 3H-thymidine incorporation to background levels. The antigen specificity afforded by the monoclonal antibody contributes a factor of approximately 40 to the radiotoxicity of the immunoconjugate. Animals inoculated with a Thy 1.2+ malignant ascites were cured of their tumor in an antigen-specific fashion by intraperitoneal doses of approximately 200 microCi per mouse. Alpha particle emitting radioimmunoconjugates show great potential for regional and intracavitary molecular radiotherapy.
发射α粒子的短寿命同位素具有许多物理特性，使其成为放射免疫治疗的理想候选物。这些特性包括高线性能量传递以及相应的高细胞毒性；粒子射程限制在距母原子几个细胞直径的范围内；α诱导的DNA损伤修复潜力低；以及对剂量率和氧增强效应的低依赖性。本报告综述了通过将铋 - 212与针对鼠T细胞/神经外胚层表面抗原Thy 1.2的单克隆IgM抗体进行非共价螯合构建的发射α粒子的放射免疫缀合物在动物模型中的合成、测试和应用。这些212Bi - 抗Thy 1.2免疫缀合物在体外具有非凡的细胞毒性，每个靶细胞大约需要三个212Bi标记的缀合物才能将3H - 胸腺嘧啶核苷掺入抑制到背景水平。单克隆抗体提供的抗原特异性使免疫缀合物的放射毒性增加了约40倍。接种了Thy 1.2 +恶性腹水的动物通过每只小鼠腹腔注射约200微居里的剂量以抗原特异性方式治愈了肿瘤。发射α粒子的放射免疫缀合物在区域和腔内分子放疗方面显示出巨大潜力。
