MOAB-DNR CONJUGATES FOR THERAPY--DRUG RESISTANT LEUKEMIA

我们的目标是使用抗肿瘤单抗偶联的蒽环类药物 克服阿霉素或柔红霉素耐药性的抗体 急性非淋巴细胞白血病。药物-抗体偶联的作用 将在一名新近开发的特性化人类身上进行测试 对阿霉素耐药100倍和50倍的早幼粒白血病细胞株 折叠成柔红霉素(HL-60/AR)。不同结构的共价键合共轭化合物 不同聚合物的分子量、疏水性、降解性和亲和力 将研究抗原决定簇的药代动力学和 对耐药细胞的毒性。这些物质在细胞内的分布 化合物将使用一种新技术--数字化视频进行可视化 增强荧光显微镜，可以量化变化 活细胞内特定时间点的药物浓度实时监测。 这些变化将与细胞毒性相关，并与对 各种细胞器，包括细胞膜、线粒体、细胞核、 和高尔基仪器。这些关于细胞内药物积累的研究， 分布和体外细胞毒性将扩展到原始细胞和 临床确诊的慢性粒细胞白血病患者克隆细胞的自我更新 耐药的急性非淋巴细胞白血病，有望打开 通往新的治疗方式的道路。

Our objective is to use anthracyclines conjugated to antitumor monoclonal antibodies to overcome drug resistance to doxorubicin or daunorubicin in acute nonlymphocytic leukemia. The effects of drug-antibody conjugated will be tested on a recently developed and characterized human promyelocytic leukemia cell line resistant 100 fold to doxorubicin and 50 fold to daunorubicin (HL-60/AR). Covalently-linked conjugates of different molecular weights, hydrophobicity, degradability and affinity for different antigenic determinants will be studied for their pharmacokinetics and toxicity in resistant cells. The intracellular distribution of these compounds will be visualized using a new technique, digitized video intensification fluorescence microscopy which can quantitate changes in drug concentration at specific points within viable cells in real time. These changes will be correlated with cytotoxicity, and with effects on various cell organelles, including cell membranes, mitochondria, nucleus, and the Golgi apparatus. These studies of intracellular drug accumulation, distribution and in vitro cytotoxicity will be extended to blast cells and to self renewing clonogenic cells from patients with clinically documented drug resistance acute nonlymphocytic leukemia, and will hopefully open the way to new treatment modalities.