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

Abstract

We investigated whether antisense oligodeoxynucleotides complementary to bcr/abl mRNA or protein kinase antagonists display antitumor activity on Ph -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 p210^bcr/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 P210^bcr/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.

Key Words:

• bcr/abl gene
• Ph¹-positive leukemia
• antisense oligomer
• herbimycin A
• protein tyrosine kinase