An in vitro model to predict clinical response in adult acute myelogenous leukemia.
The relationship between in vitro leukemic cell growth kinetics, intracellular biochemical pharmacology of 1-beta-D-arabinofuranosylcytosine (ara-C), and clinical response to ara-C-containing timed sequential therapy was examined in leukemic marrow populations from 62 adults with acute myelogenous leukemia (AML). Leukemic blasts from 45 previously untreated and 17 relapse patients were obtained before therapy, and cultured in autologous pretreatment serum (APS) and in serum containing drug-induced humoral stimulatory activity (HSA). While all cell populations cultured in HSA demonstrated increased proliferation, only growth-stimulated cohorts from those patients achieving complete remission with ara-C-based therapy demonstrated enhanced intracellular drug activation and active drug retention relative to cells maintained in APS, whereas cells from nonresponsive patients demonstrated no such HSA-induced increases in intracellular ara-C metabolism. In this in vitro model system, sensitive AML populations behave similarly to normal hematopoietic cohorts, with direct linkage of HSA-perturbed growth and net pharmacologic parameters, while refractory cohorts evince uncoupling of these determinants in the growth-stimulated state. This model identifies behavior patterns that may discriminate clinical sensitivity from clinical resistance and may serve to predict clinical outcome to timed sequential therapy with ara-C.
Karp
J E
JE
Donehower
R C
RC
Burke
P J
PJ
D000328:Adult; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001769:Blood; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D003561:Cytarabine / Q000008:administration & dosage* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D003470:Culture Media; D004273:DNA, Neoplasm; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate