BCR/ABL oncoprotein-targeted antitumor activity of antisense oligodeoxynucleotides complementary to bcr/abl mRNA and herbimycin A, an antagonist of protein tyrosine kinase: inhibitory effects on in vitro growth of Ph1-positive leukemia cells and BCR/ABL oncoprotein-associated transformed cells

Leuk Lymphoma. 1993 Jul;10(4-5):307-16. doi: 10.3109/10428199309148553.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Antibiotics, Antineoplastic / therapeutic use*
  • Base Sequence
  • Benzoquinones
  • Cell Division / drug effects
  • DNA, Antisense / therapeutic use*
  • Dose-Response Relationship, Drug
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Lactams, Macrocyclic
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Molecular Sequence Data
  • Neoplasm Proteins / antagonists & inhibitors*
  • Philadelphia Chromosome
  • Polymerase Chain Reaction
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / enzymology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Quinones / pharmacology
  • Quinones / therapeutic use*
  • RNA-Directed DNA Polymerase
  • Rifabutin / analogs & derivatives
  • Tumor Cells, Cultured / drug effects

Substances

  • Antibiotics, Antineoplastic
  • Benzoquinones
  • DNA, Antisense
  • Lactams, Macrocyclic
  • Neoplasm Proteins
  • Quinones
  • Rifabutin
  • herbimycin
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl
  • RNA-Directed DNA Polymerase