Abstract
We investigated whether antisense oligodeoxynucleotides complementary to bcr/abl mRNA or protein kinase antagonists display antitumor activity on Ph1-positive leukemia cell lines. bcr/abl antisense oligomers showed inhibitory effects on the in vitro growth of Ph1-positive leukemia cell lines in liquid culture, and further displayed an inhibitory effect on transformed murine hematopoietic cells using transfection with a retroviral vector expressing P210bcr/abl oncoprotein. However, in vitro treatment with a bcr/abl antisense oligomer did not completely abolish the expression of bcr/abl mRNA and did not display the desired "killing effect" on Ph1-positive leukemia cells. On the other hand, investigation of the effect on Ph1-positive leukemia cells by various types of protein kinase antagonists revealed that herbimycin A, a protein tyrosine kinase antagonist, displays preferential and remarkable suppression of the growth of Ph1-positive leukemia cells and P210bcr/abl associated transformed cells by virtue of suppressing bcr/abl protein tyrosine kinase activity. These results may provide important future insights in developing a new category of antitumor therapy by targeting oncogene products.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibiotics, Antineoplastic / pharmacology
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Antibiotics, Antineoplastic / therapeutic use*
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Base Sequence
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Benzoquinones
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Cell Division / drug effects
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DNA, Antisense / therapeutic use*
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Dose-Response Relationship, Drug
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Fusion Proteins, bcr-abl / antagonists & inhibitors*
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Fusion Proteins, bcr-abl / genetics
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Humans
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Lactams, Macrocyclic
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
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Molecular Sequence Data
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Neoplasm Proteins / antagonists & inhibitors*
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Philadelphia Chromosome
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Polymerase Chain Reaction
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Quinones / pharmacology
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Quinones / therapeutic use*
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RNA-Directed DNA Polymerase
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Rifabutin / analogs & derivatives
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Tumor Cells, Cultured / drug effects
Substances
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Antibiotics, Antineoplastic
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Benzoquinones
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DNA, Antisense
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Lactams, Macrocyclic
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Neoplasm Proteins
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Quinones
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Rifabutin
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herbimycin
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Protein-Tyrosine Kinases
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Fusion Proteins, bcr-abl
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RNA-Directed DNA Polymerase