Based on the hypothesis of increased sensitivity of residual tumor to cycle-active drug during the growth-perturbed state following initial cytoreductive therapy, we have designed studies which have met with clinical success. To explore this hypothesis and refine our therapies, we will identify interdependent cell growth and pharmacological parameters which may together predict for clinical responsiveness in patients with acute myelogenous leukemia who receive treatment with a timed sequence of cell cycle-dependent cytarabine (ara-C). By examining the residual homogeneous clonogenic cell uncovered in vivo by initial drug therapy and in vitro after growth stimulation, we have a unique opportunity to determine growth-altered ara-C pharmacology in this non-steady state. To define and apply criteria that can be used clinically to discriminate ara-C sensitive and ara-C resistant populations of leukemic cells, we will measure in vitro and in vivo the effect of drug-primed cell growth on net intracellular ara-C activation and distribution, drug delivery, and clinical response to timed sequential therapy with ara-C. These cytokinetic and biochemical parameters obtained longitudinally at initial diagnosis, during remission induction with timed sequential therapy, and at leukemia relapse will be examined to determine if changing patterns of induced cell growth and ara-C metabolism in these cells will over time correlate with achievement and duration of unmaintained complete remission.
The aim i s to use those defined clinical-laboratory correlates of response to designate proper intensive therapies in remission or at relapse.
| Karp, J E; Burke, P J; Donehower, R C (1990) Effects of rhGM-CSF on intracellular ara-C pharmacology in vitro in acute myelocytic leukemia: comparability with drug-induced humoral stimulatory activity. Leukemia 4:553-6 |
| Karp, J E; Donehower, R C; Enterline, J P et al. (1989) In vivo cell growth and pharmacologic determinants of clinical response in acute myelogenous leukemia. Blood 73:24-30 |
| Geller, R B; Burke, P J; Karp, J E et al. (1989) A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74:1499-506 |
| Karp, J E; Donehower, R C; Dole, G B et al. (1987) Correlation of drug-perturbed marrow cell growth kinetics and intracellular 1-B-D-arabinofuranosylcytosine metabolism with clinical response in adult acute myelogenous leukemia. Blood 69:1134-40 |
| Karp, J E; Donehower, R C; Burke, P J (1987) An in vitro model to predict clinical response in adult acute myelogenous leukemia. Semin Oncol 14:172-81 |
