Effect of Herbimycin A, an Antagonist of Tyrosine Kinase, on bcrlabl Oncoprotein-Associated Cell Proliferations: Abrogative Effect on the Transformation of Murine Hematopoietic Cells by Transfection of a Retroviral Vector Expressing Oncoprotein P210bcf1ab' and Preferential Inhibition on Phl-Positive Leukemia Cell Growth

Herbimycin A, a benzoquinoid ansamycin antibiotic, was demonstrated t o decrease intracellular phosphorylation by protein tyrosine kinase (PTK). In Philadelphia chromosome (Phl)-positive leukemias such as chronic myelogenous leukemia (CML) and Phl-positive acute lymphoblastic leukemia (ALL), both of which express bcr-ab1 fused gene products (P2106cr-a*/ or P1906cr-ab/ protein kinase) with augumented tyrosine kinase activities, herbimycin A markedly inhibited the in vitro growth of the Phl-positive ALL cells and the leukemic cells derived from CML blast crisis. However, the same dose of herbimycin A did not inhibit in vitro growth of a broad spectrum of Phl-negative human leukemia cells, and several other protein kinase antagonists also displayed no preferential inhibition. Furthermore, we demonstrated that herbimycin A has an antagonizing effect on the growth of transformed cells by a transfection of retroviral amphotrophic vector expressing P2106crla*/ into a murine interleukin (IL)-3-