BCR ABL ONCOPROTEIN-TARGETED ANTITUMOR-ACTIVITY OF ANTISENSE OLIGODEOXYNUCLEOTIDES COMPLEMENTARY TO BCR ABL MESSENGER-RNA AND HERBIMYCIN-A,AN ANTAGONIST OF PROTEIN-TYROSINE KINASE - INHIBITORY EFFECTS ON IN-VITRO GROWTH OF PH(1)-POSITIVE LEUKEMIA-CELLS AND BCR ABL ONCOPROTEIN-ASSOCIATED TRANSFORMED-CELLS

We investigated whether antisense oligodeoxynucleotides complementary to bcr/abl mRNA or protein kinase antagonists display antitumor activi ty on Ph1-positive leukemia cell lines. bcr/abl antisense oligomers sh owed inhibitory effects on the in vitro growth of Ph1-positive leukemi a cell lines in liquid culture, and further displayed an inhibitory ef fect on transformed murine hematopoietic cells using transfection with a retroviral vector expressing P210bcr/abl oncoprotein. However, in v itro treatment with a bcr/abl antisense oligomer did not completely ab olish the expression of bcr/abl mRNA and did not display the desired ' 'killing effect'' on Ph1-positive leukemia cells. On the other hand, i nvestigation of the effect on Ph1-positive leukemia cells by various t ypes of protein kinase antagonists revealed that herbimycin A, a prote in tyrosine kinase antagonist, displays preferential and remarkable su ppression 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 targetin g oncogene products.