Effect of the protein kinase C activating agent bryostatin 1 on the clonogenic response of leukemic blast progenitors to recombinant granulocyte-macrophage colony-stimulating factor.
Bryostatin 1 is a macrocyclic lactone activator of protein kinase C which has displayed promising antileukemic potential in pre-clinical studies. We have assessed the effect of bryostatin 1 on the in vitro clonogenic response of leukemic myeloblasts obtained from 12 patients with acute non-lymphocytic leukemia to recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), and have compared these responses to those of normal human hematopoietic progenitors. Although leukemic blast progenitors responded in a heterogenous manner to bryostatin 1 as a single agent, co-administration of 12.5 or 100 nM bryostatin 1 in conjunction with 1.25 ng/ml rGM-CSF resulted in a significant reduction in colony formation (compared to rGM-CSF alone) in 8/12 specimens, and sub-additive stimulatory effects in all samples. In addition, the exposure of cells to 12.5 nM bryostatin 1, either alone or in conjunction with 1.25 ng/ml rGM-CSF, substantially reduced or eliminated leukemic cell self-renewal capacity in all samples assayed. In contrast to the effects observed in leukemic cells, exposure of adherent and T-cell depleted normal bone marrow mononuclear cells to equivalent concentrations of bryostatin 1 and rGM-CSF consistently produced supra-additive effects on the growth of normal committed myeloid progenitors (day 14 CFU-GM). When normal marrow cells were further enriched for progenitors (MY-10+), concentrations of bryostatin 1 that were unable to support growth when administered alone significantly potentiated the number of GM colonies formed in response to rGM-CSF. These studies suggest that bryostatin 1 may modulate the in vitro response of certain normal and leukemic progenitor cells to rGM-CSF, and that the nature of this response differs between the two cell types. They also indicate that bryostatin 1 may be particularly effective in limiting the self-renewal capacity of leukemic myeloblasts, an in vitro characteristic with potentially important in vivo significance.
Grant
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Division of Hematology/Oncology, Medical College of Virginia, Richmond 23298-0230.
Pettit
G R
GR
Howe
C
C
McCrady
C
C
D000941:Antigens / Q000276:immunology; D054713:Bryostatins; D002455:Cell Division / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004789:Enzyme Activation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D018942:Macrolides; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000941:Antigens; D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D011994:Recombinant Proteins; D015240:Phorbol 12,13-Dibutyrate; C046785:bryostatin 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011493:Protein Kinase C