EFFECTS OF HERBIMYCIN-A AND ITS DERIVATIVES ON GROWTH AND DIFFERENTIATION OF PH(1)-POSITIVE ACUTE LYMPHOID LEUKEMIA-CELL LINES

The molecular basis of the Philadelphia chromosome (Ph1) is a structur ally altered c-abl (bcr/;abl) gene which encodes an abnormally large p rotein with protein tyrosine kinase activity. Herbimycin A, an inhibit or of tyrosine kinase, preferentially inhibited the growth of Ph1-posi tive acute lymphoid leukemia (ALL) cell lines, as well as Ph1-positive chronic myeloid leukemia (CML) cell lines. Although noncytotoxic conc entrations of herbimycin A induced erythroid differentiation of two CM L-derived cell lines, K562 and KU812, in a previous study, the differe ntiation-inducing effect of herbimycin A on Ph1-positive ALL cell line s was less strong. Herbimycin A enhanced some differentiation-associat ed properties of one Ph1-positive ALL cell line, L2, but the effect of herbimycin A on the other Ph1-positive ALL cell lines was cytotoxic r ather than cytostatic (differentiation-inducing). Several derivatives of herbimycin A were synthesized and their effects on the cell prolife ration of Ph1-positive CML and ALL cell lines were examined. The sensi tivities of the Ph1-positive cell lines to herbimycin A derivatives we re different from the data on the rat kidney cell line infected with R ous sarcoma virus (v-src) derived from a previous study, suggesting bc r/abl kinase may differ in sensitivity from other tyrosine kinases. Mo reover, the sensitivities of the ALL cell lines were not the same as t hose of the CML cell lines. These results suggest that a specific inhi bitor of bcr/abl kinase could be an effective antileukemic agent again st Ph1-positive CML or ALL.