MOAB:DNR CONJUGATES FOR THERAPY OF DRUG RESISTANT LEUKEM

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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.