In conventional doses and schedules ara-C will result in complete remission in approximately 25% of previously untreated patients with acute non-lymphocytic leukemia. Despite continued therapy, however, these remissions are relatively brief and there are virtually no long-term survivors. Thus, 75% of the patients at presentation have """"""""natural"""""""" resistance to the drug and ultimately the remaining 25% of the patients will develop acquired drug resistance. We have shown the clinical utility of high dose ara-C (3000 mg/M2) (HiDAC) in overcoming resistance in patients will ANLL refractory to conventional doses (100 mg/M2). In adition, we have shown that sequential A'ase will potentiate ara-C in murine leukemia and the results of our pilot clinical trial are suggestive that the same occurs in patients. The proposed clinical trial will interrelate the pharmacokinetics of HiDAC and the effects of these high extracellular concentrations on the clonogenic fraction and the known biochemical determinants of ara-C action in human leukemia cells. The data related to the specific activity of dCyd kinase, pool size of ara-CTP, cellular retention of ara-CTP, and the incorporation of ara-CTP into DNA will be normalized to the proportion of cells in S phase as determined by 3HdThd suicide index and labelling index. This may clarify the disputed relationship of these observations to drug-induced cytotoxicity. The effect of the seuqntial use of A'ase on the ara-C """"""""determinants"""""""" will be studied in an attempt to understand the mechanism of the drug-drug interaction which leads to enhanced cytotoxicity. Thus, the overall aim is to conduct a clinical trial in conjunction with a study of the known biochemical pharmacological determinants of ara-C action in bone marrow leukemic blasts as they affect and are influenced by the sequential use of high dose ara-C (HiDAC) and asparaginase (A'ase) and to utilize these laboratory observations (a) as predictors of response inpatients with acute leukemia and, (b) for the further refinement of the therapeutic protocol by appropriate alterations in the doses and schedule of ara-C and A'ase and (c) to provide a biochemical pharmacologic rationale for the subsequent inclusion of other drugs into the protocol. A repeat of the entire panel of studies at the time of relapse will help to elucidate the mechanism of acquired resistance to ara-C and perhaps suggest means for circumventing this.
