MOAB:DNR CONJUGATES FOR THERAPY OF DRUG RESISTANT LEUKEM

我们的目的是使用蒽环类药物与抗肿瘤单克隆抗体偶联， 克服对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-抗体偶联物的作用 将在一个最近开发的 早幼粒细胞白血病细胞系对阿霉素耐药100倍， 倍于柔红霉素（HL-60/AR）。 不同的共价连接的缀合物 分子量、疏水性、降解性和对不同的 将研究抗原决定簇的药代动力学， 抵抗细胞的毒性。 这些细胞的细胞内分布 化合物将使用一种新的技术，数字化视频， 增强荧光显微镜，可以定量的变化， 真实的实时活细胞内特定点的药物浓度。 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， 和高尔基体。 这些细胞内药物积累的研究， 分布和体外细胞毒性将扩展到胚细胞， 从临床记录的患者中获得自我更新的克隆原细胞 耐药急性非淋巴细胞白血病，并有望打开 新的治疗方式。

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.