Inhibition of catabolism of radiolabeled antibodies by tumor cells using lysosomotropic amines and carboxylic ionophores.
Inhibition of catabolism of radiolabeled antibodies by tumor cells using lysosomotropic amines and carboxylic ionophores.
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发表时间：
1990-02
期刊：
影响因子：
11.2
通讯作者：
O. Press;K. DeSantes;S. K. Anderson;F. Geissler
中科院分区：
文献类型：
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作者：
O. Press;K. DeSantes;S. K. Anderson;F. Geissler
研究了在存在和不存在已知影响内化配体细胞内代谢的多种药物的情况下，恶性T淋巴细胞和B淋巴细胞降解放射性碘单克隆抗体（MoAb）的速率。针对 CD2、CD3、CD5 和抗 mu 表面抗原的 125I-MoAb 经历快速内吞作用，随后迅速降解，并在 24 小时内以游离的三氯乙酸可溶性 125I 形式释放大于或等于初始结合放射性的 50%。溶酶体胺类（氯喹、氯化铵、金刚烷胺）、羧基离子载体（莫能菌素、尼日利亚菌素）、钙通道阻滞剂（维拉帕米）、硫脲类药物（丙硫氧嘧啶）、溶酶体酶抑制剂（亮肽素）和秋水仙碱均可抑制放射性碘化单克隆抗体的代谢，并增强肿瘤细胞对 125I-单克隆抗体的保留。最有效的药物（例如莫能菌素、尼日利亚菌素）可将游离 125I 的释放减少 90% 以上，并在 24 小时内将放射性保留率提高 300% 以上。免疫过氧化物酶电子显微镜实验和破碎细胞细胞器的 Percoll 梯度分离实验表明，高浓度的莫能菌素 (10-20 µM) 延迟了 125I-MoAb 向溶酶体的转移，但其他机制（例如 pH 中和）在较低浓度 (1-3 µM) 下也起作用。这些药物的临床施用可以增强肿瘤细胞对放射免疫缀合物的保留，从而改善放射免疫闪烁显像和放射免疫治疗。
The rates of degradation of radioiodinated monoclonal antibodies (MoAbs) by malignant T- and B-lymphoid cells were studied in the presence and absence of a variety of pharmacological agents known to affect the intracellular metabolism of internalized ligands. 125I-MoAbs directed against the CD2, CD3, CD5, and anti-mu surface antigens underwent rapid endocytosis, followed by prompt degradation with release of greater than or equal to 50% of the initially bound radioactivity as free, trichloroacetic acid-soluble 125I within 24 h. Lysosomotropic amines (chloroquine, ammonium chloride, amantadine), carboxylic ionophores (monensin, nigericin), calcium channel blockers (verapamil), thionamides (propylthiouracil), lysosomal enzyme inhibitors (leupeptin), and colchicine all inhibited metabolism of radioiodinated MoAbs and enhanced retention of 125I-MoAbs by tumor cells. The most effective agents (e.g., monensin, nigericin) diminished the release of free 125I by greater than 90% and enhanced retention of radioactivity by greater than 300% at 24 h. Experiments with immunoperoxidase electron microscopy and Percoll gradient fractionation of organelles from disrupted cells suggested that high concentrations of monensin (10-20 microM) delayed transfer of 125I-MoAbs to lysosomes, but other mechanisms (e.g., pH neutralization) were operative at lower concentrations (1-3 microM). Clinical administration of these agents may enhance retention of radioimmunoconjugates by tumor cells, resulting in improved radioimmunoscintigraphy and radioimmunotherapy.