Effect of a combined exposure to cytosine arabinoside, bryostatin 1, and recombinant granulocyte-macrophage colony-stimulating factor on the clonogenic growth in vitro of normal and leukemic human hematopoietic progenitor cells.
We have examined the effect of a combined 24 h exposure to cytosine arabinoside (ara-C) and the protein kinase C activator bryostatin 1, either alone or in conjunction with recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), on the clonogenic growth of 14 primary samples from acute myelogenous leukemia (AML) patients, as well as normal human committed and early hematopoietic progenitors. Incubation of blasts with 1 microM ara-C and 12.5 nM bryostatin 1(+/- 1.25 ng/ml rGM-CSF) resulted in a heterogeneous pattern of inhibitory effects toward primary leukemic colonies, ranging from 32-98%, and subadditive to synergistic drug interactions. However, exposure of blasts to ara-C and bryostatin 1, either with or without rGM-CSF, eliminated leukemic cell self-renewal in 80-93% of samples, and very substantially reduced growth in the remainder. Exposure of normal human bone marrow mononuclear cells to identical concentrations of ara-C and byostatin 1 permitted the survival of 23% of committed myeloid progenitors (granulocyte-macrophage colony-forming units), and greater than 50% when rGM-CSF was included. Finally, exposure of bone marrow populations highly enriched for progenitor cells (CD34+, DR-, CD71-) to ara-C and bryostatin 1 +/- rGM-CSF for 24 h led to minimal reductions (e.g. 10-15%) in the survival of early hematopoietic progenitors (high proliferative potential colony-forming cells). Together, these findings indicate that combined exposure in vitro to ara-C and bryostatin 1, both with and without rGM-CSF, effectively inhibits the growth of leukemic cells with self-renewal capacity, while sparing a significant fraction of normal committed and primitive hematopoietic progenitors.
Grant
S
S
Division of Hematology/Oncology, Medical College of Virginia, Richmond 23298.
Traylor
R
R
Bhalla
K
K
McCrady
C
C
Pettit
G R
GR
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D054713:Bryostatins; D002999:Clone Cells / Q000187:drug effects; D004347:Drug Interactions; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000473:pathology* / Q000628:therapy; D018942:Macrolides; D008875:Middle Aged; D011994:Recombinant Proteins / Q000494:pharmacology; D014740:Vidarabine / Q000008:administration & dosage / Q000494:pharmacology*
D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D011994:Recombinant Proteins; C046785:bryostatin 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D014740:Vidarabine