Gene-targeted specific inhibition of chronic myeloid leukemia cell growth by BCR-ABL antisense oligodeoxynucleotides.
Philadelphia-chromosome positive chronic myeloid leukemia cells in chronic phase (CML-CP) or blast crisis (CML-BC) and normal bone marrow cells (NBMC) were incubated in vitro with antisense oligonucleotide specific against the BCR/ABL breakpoint junction to examine the possibility of selective inhibition of leukemia growth. Growth capability was determined in vitro by colony assay in semisolid medium in the presence of interleukin 3 (IL-3) and granulocyte-macrophage colony stimulating factor (GM-CSF). The 18-mer antisense directed against the specific BCR/ABL mRNA breakpoint region diminished the colony formation by CML-CP and CML-BC cells, but not by NBMC. Scrambled oligomer did not affect significantly the growth of leukemic and normal cells. If CML-BC cells were mixed with NMBC and incubated with specific BCR/ABL antisense oligomer, leukemic colonies were selectively inhibited, as was shown by reverse, transcriptase-polymerase chain reaction (RT-PCR) performed to detect BCR/ABL mRNA in single colonies. These results confirm the possibility of selective inhibition of leukemia cells by antisense treatment.
Skórski
T
T
Jefferson Cancer Institute, Thomas Jefferson University, Philadelphia.
Szczylik
C
C
Malaguarnera
L
L
Calabretta
B
B
D001483:Base Sequence; D001752:Blast Crisis / Q000473:pathology; D001853:Bone Marrow / Q000737:chemistry / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology*; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D016313:Genes, abl / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D015466:Leukemia, Myeloid, Chronic-Phase / Q000235:genetics / Q000473:pathology*; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000473:pathology
D007377:Interleukin-3; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016044:Fusion Proteins, bcr-abl