Chen O. Antitumor effect of recombinant arginase and use it to develop new methods of leukemia treatment

The thesis is devoted to the development of new metabolic combinational therapу of leukemia based on the administration of the drug recombinant arginase (rhARG), low doses of canavanine or exogenous NO donor and to study comparative responses of normal and tumor cells to combined effect of these drugs in vitro and in vivo. It was shown that rhARG induced apoptosis more selectively and effectively in leukemic cells as compared to normal PBL. We also found that exogenous NO donor, sodium nitroprusside, at physiologically compatible dose, did not counteract but augmented rhARG-mediated pro-apoptotic effect of arginine depletion in leukemic cells but not in resting lymphocytes and low doses of sodium nitroprusside can be recommended as a compensatory agent under arginine limitation in vivo. It was found that the natural plant arginine analogue - canavanine - inhibits gene expression of arginine anabolic enzymes in leukemia cells and selectively enhances the cytotoxic effect of rhARG on these cells. Administration of canavanine alone or in combination with pegylated arginase did not evoke any apparent toxic effects in experimental animals.