Selective cytotoxicity of drug-monoclonal antibody conjugates against murine bladder tumor cells.
Selective cytotoxicity of drug-monoclonal antibody conjugates against murine bladder tumor cells.
复制标题
药物-单克隆抗体缀合物对小鼠膀胱肿瘤细胞的选择性细胞毒性。
DOI：
10.1248/cpb.35.1128
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发表时间：
1987
影响因子：
1.7
通讯作者：
T. Niijima
中科院分区：
文献类型：
--
作者：
S. Iwasa;E. Konishi;K. Kondo;T. Suzuki;H. Akaza;T. Niijima
将丝裂霉素C(MMC)和甲氨蝶呤(MTX)等抗肿瘤药物与抗小鼠膀胱癌MBT-2细胞株的单抗偶联，以提高其药物活性。丝裂霉素C通过高碘酸氧化葡聚糖和二硫代吡啶化血清白蛋白两种载体与抗体偶联，甲氨蝶呤直接或通过二硫代吡啶化血清白蛋白或多聚L赖氨酸通过酰胺键与抗体偶联。测定了它们对MBT-2膀胱肿瘤细胞、MCA克隆15胚胎细胞和P388白血病细胞的生长抑制作用。细胞毒性试验表明，药物-抗体免疫结合物对抗体反应性MBT-2细胞的细胞毒作用是非免疫性药物结合物的10~100倍，对抗体非反应性细胞的细胞毒作用与非免疫结合物相似。对未结合抗体的竞争性抑制也证实了这种选择性细胞毒性，表现出对抗体与靶细胞表面抗原结合的依赖性。通过评估免疫结合物体外治疗MBT-2细胞后对肿瘤生长的抑制，进一步评估了靶向效应。接受免疫结合物处理的细胞的小鼠有一半在接种后40d以上存活，而接受未结合药物、单独抗体或非免疫结合物处理的细胞的7只小鼠中，没有一只在接种后40d存活。
Antitumor agents including mitomycin C (MMC) and methotrexate (MTX) were coupled to monoclonal antibodies against murine bladder tumor cell line MBT-2 for the purpose of enhancing their drug activity. MMC was conjugated with antibody through two carriers, periodate-oxidized dextran and dithiopyridylated serum albumin, and MTX was conjugated with antibody either directly or through dithiopyridylated serum albumin or poly-L-lysine via an amide bond. These conjugates were assayed for growth inhibitory effect on MBT-2 bladder tumor cells, MCA clone 15 embryo cells and P388 leukemic cells. The cytotoxicity tests demonstrated that drug-antibody immune conjugates were 10 to 100 times more cytotoxic against antibody-reactive MBT-2 cells than nonimmune drug conjugates and showed a similar level of cytotoxicity against antibody-nonreactive cells to that of the nonimmune conjugates. This selective cytotoxicity was also confirmed by competitive inhibition of unconjugated antibody, showing a dependency on antibody binding to the target cell surface antigens. The targeting effect was further assessed by evaluating the suppression of tumor growth subsequent to in vitro treatment of MBT-2 cells with immune conjugates. Half of the mice receiving cells treated with immune conjugates survived more than 40 d after inoculation, while none or one of 7 mice receiving cells treated with unconjugated drug, antibody alone or nonimmune conjugates survived at 40 d after inoculation.