Growth inhibition of chronic myelogenous leukemia cells by ODN-1, an aptameric inhibitor of p210bcr-abl tyrosine kinase activity.
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.
Schwartz
G N
GN
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Liu
Y Q
YQ
Tisdale
J
J
Walshe
K
K
Fowler
D
D
Gress
R
R
Bergan
R C
RC
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
D004791:Enzyme Inhibitors; D009838:Oligodeoxyribonucleotides; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl