The cytotoxicity and microdosimetry of astatine-211-labeled chimeric monoclonal antibodies in human glioma and melanoma cells in vitro
The cytotoxicity and microdosimetry of astatine-211-labeled chimeric monoclonal antibodies in human glioma and melanoma cells in vitro
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DOI：
10.2307/3579925
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发表时间：
1998-02-01
影响因子：
3.4
通讯作者：
Zalutsky, MR
中科院分区：
文献类型：
--
作者：
Larsen, RH;Akabani, G;Zalutsky, MR
由于对这些潜在的治疗药物的临床评估已经开始，α粒子放射治疗化合物的细胞毒性越来越引起人们的关注。At-211是一种半衰期为7.2小时的放射性核素，发射5.87 MeV和7.45 MeV a粒子。在本工作中，我们研究了AT-211标记的嵌合单抗对D-247 MG人脑胶质瘤细胞和SK-Mel-28人黑色素瘤细胞的体外细胞毒作用。所研究的单抗为81C6，与细胞外基质抗原Tenascin反应，ME1-14，针对细胞膜抗原蛋白多糖软骨素硫酸盐，以及非特异性对照单抗TPS3.2。在L-h暴露于AT-211标记的单抗后，细胞摄取作为活性浓度的函数而增加。活性保留率也被测量，以计算与细胞和培养基相关联的累积活性。克隆形成的存活率作为活动浓度的函数在所有病例中都是线性的，没有发现肩部。根据测量的晶胞几何形状、累积活度和粒子的蒙特卡罗输运进行微剂量分析。当活性浓度为18kBq/ml，孵育1h时，特异性单抗与微集落结合的活性是非特异性单抗的2~5倍。计算结果表明，D-247 MG细胞在0.24-0.28Gy时存活分数为0.37，SK-Mel-28细胞在0.27-0.29Gy时存活分数为0.27-0.29Gy.D-247 MG细胞的微剂量学敏感性明显低于SK-Mel-28细胞(0.08比0.15)。对于这两种细胞系，要将存活率降低到0.37，平均只需1-2次阿尔法粒子撞击细胞核即可。(C)1998年，由辐射研究学会提供。
The cytotoxicity of alpha-particle-emitting endoradiotherapeutic compounds is of increasing interest because clinical evaluation of these potential therapeutic agents is commencing. Astatine-211 is a radionuclide with a 7.2-h half-life that emits 5.87 and 7.45 MeV a particles. In the present work, we have investigated the in vitro cytotoxicity of At-211-labeled chimeric monoclonal antibodies (mAbs) in monolayers of D-247 MG human glioma cells and SK-MEL-28 human melanoma cells. The mAbs studied were 81C6, reactive with the extracellular matrix antigen tenascin, Me1-14, directed against the cell membrane antigen proteoglycan chondroitin sulfate, and a nonspecific control mAb, TPS3.2. Cell uptake increased as a function of activity concentration after a l-h exposure to the At-211-labeled mAbs. The retention of activity was also measured to calculate cumulative activity associated with the cells and the medium. The clonogenic survival as a function of activity concentration was linear in all cases with no detectable shoulder. Microdosimetric analyses were performed based on measured cell geometry, cumulative activity and Monte Carlo transport of a particles. Using 18 kBq/ml activity concentration and 1 h of incubation, a two to five times higher activity bound to the microcolonies was found for the specific mAbs compared to the nonspecific mAb. These calculations indicated that a survival fraction of 0.37 was achieved with 0.24-0.28 Gy for D-247 MG cells and 0.27-0.29 Gy for SK-MEL-28 cells. The microdosimetric cell sensitivity, to, for D-247 MG cells was significantly lower than for SK-MEL-28 cells (0.08 compared to 0.15 Gy). For both cell lines, reduction in survival to 0.37 required an average of only 1-2 alpha-particle hits to the cell nucleus. (C) 1998 by Radiation Research Society.