title: Kinetic rationale for cytokine-induced recruitment of myeloblastic leukemia followed by cycle-specific chemotherapy in vitro.
abstract: In patients with acute myeloblastic leukemia incomplete response to induction chemotherapy and short disease-free survival may be related to cell kinetic quiescence of leukemic cells. In this in vitro study, we tested the hypothesis that treatment with cytokines and subsequent chemotherapy (ARA-C, daunorubicin) can increase proliferation and enhance leukemic cell kill. We evaluated the effects of recombinant human interleukin-3 (rh-IL-3), granulocyte-macrophage colony stimulating factor (rhGM-CSF) and granulocyte colony stimulating factor (rhG-CSF) alone and in combination on AML (N = 11) and blastic phase CML (N = 3) samples. Cellular DNA and RNA, incorporation of bromodeoxyuridine (BrdU), cell growth fraction, cell viability, and differentiation markers were evaluated in vitro. A decrease of the quiescent cell population (p = 0.003) and an increase in S-phase cells (p = 0.001) was observed in 8/11 AML samples treated with cytokine combinations. Pronounced heterogeneity or proliferative response was seen between individual cases and different cytokines, but in the majority of the samples IL-3 was most effective. Significantly increased Ki67 expression (p = 0.009) and BrdU incorporation (p = 0.01) were also found after exposure to cytokines indicating an increase in growth fraction. DNA synthesis time was unaffected. Eight samples of AML were treated for 24 hr with ara-C following 2 days of in vitro cytokine incubation. Evaluation of leukemic cell kill showed increased cytotoxicity in three of those five samples which had significant depletions of G0 cells and increases in S-phase. None of the leukemic samples without recruitment from G0 had an increase in ARA-C cytotoxicity. This study provides detailed cell kinetic analysis of cytokine effects on AML blasts and provides a rationale for a novel approach to the treatment of AML.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
authors.forename: A
authors.initials: A
authors.lastname: Tafuri
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; D003561:Cytarabine