SELECTIVE ERADICATION OF LEUKEMIC CELLS

The aim is to establish a rational basis for the use of the naturally-occurring nucleoside deoxycytidine as a potentially host-selective protective agent, and to implement phase I-II studies employing high-dose deoxycytidine in patients with refractory leukemia and solid tumors. These efforts are based on preclinical studies suggesting that supraphysiologic concentrations of deoxycytidine stimulate the growth of normal but not leukemic myeloid progenitor cells, and preferentially protect normal elements from the in vitro inhibitory effects of inhibitors of de novo pyrimidine biosynthesis (e.g., thymidine and 3-deazauridine) as well as cytosine arabinoside. Biochemical studies of high-dose deoxycytidine metabolism will be performed in human leukemic myeloblasts in order to determine whether the selective inability of deoxycytidine to protect these cells is related to impaired nucleotide formation (e.g., decreased deoxycytidine kinase activity) or augmented degradative processes (e.g., increased activity of cytidine deaminase, deoxycytidylate deaminase or 5'-nucleotidase). Soft agar cloning studies will be performed designed to compare the effects of deoxycytidine on pyrimidine antagonist-mediated growth inhibition in normal human (CFU-GM) and leukemic (L-CFU) myeloid progenitor cells. The objective will be to identify deoxycytidine and pyrimidine antagonist dose relationships and schedules exerting a selective cytotoxic effect toward leukemic cells while sparing their normal counterparts. In conjunction with these preclinical studies, a phase I study of high-dose deoxycytidine will be initiated with the aim of establishing the safety and feasibility of achieving high plasma deoxycytidine concentrations exhibiting a selective protective effect toward normal elements in in vitro studies. Shortly thereafter, a phase I study of continuously-administered cytocine arabinoside in conjunction with a fixed dose of deoxycytidine will be implemented, also with the aim of achieving plasma cytosine arabinoside and deoxycytidine concentrations exerting a selective cytotoxic effect toward leukemic cells in preclinical studies. A subsequent phase I study of thymidine and 3-deazauridine administered with high-dose deoxycytidine will also be designed. The ultimate aim of this proposal will be to make dose recommendations for phase II studies employing high-dose deoxycytidine in conjunction with pyrimidine antagonists in patients with refractory leukemia and solid tumors.