title: Growth inhibition of chronic myelogenous leukemia cells by ODN-1, an aptameric inhibitor of p210bcr-abl tyrosine kinase activity.
abstract: p210bcr-abl-Related tyrosine kinase activity has been shown to cause chronic myelogenous leukemia (CML), a disease of bone marrow stem cells. Having previously demonstrated that the aptameric oligonucleotide, ODN-1, could inhibit p210bcr-abl kinase activity, the current study sought to determine if ODN-1 could selectively inhibit the growth of CML cells relative to that of normal bone marrow. ODN-1, when introduced by electroporation into peripheral blood mononuclear cells (PBMC) from patients with CML, decreased the number of committed progenitors (CML CFU-GM) by an average of 67%+/-19% (mean+/-SEM, range 28-98%). Treatment of CML PBMC with ODN-1 was also shown to decrease the number of more primitive cobblestone area-forming cells (CAFC) by 35%-87%. In contrast, there was little suppressive effect by the combination of electroporation and ODN-1 on either CFU-GM or CAFC numbers from normal donor bone marrow. These studies suggest that inhibition of p210bcr-abl protein-tyrosine kinase (PTK) activity by ODN-1 is associated with some degree of selective growth inhibition of p210bcr-abl-transformed cells. p210bcr-abl kinase inhibitory agents may be useful for the ex vivo purging of bone marrow or peripheral blood progenitor/stem cells in the setting of autologous transplantation for CML.
authors.affiliation: Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Schwartz
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Tisdale
authors.forename: K
authors.initials: K
authors.lastname: Walshe
authors.forename: D
authors.initials: D
authors.lastname: Fowler
authors.forename: R
authors.initials: R
authors.lastname: Gress
authors.forename: R C
authors.initials: RC
authors.lastname: Bergan
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D009838:Oligodeoxyribonucleotides; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl