THE TYROSINE KINASE INHIBITOR CGP57148B SELECTIVELY INHIBITS THE GROWTH OF BCR-ABL-POSITIVE CELLS

The Philadelphia chromosome found in virtually all cases of chronic my eloid leukemia (CML) and in about one third of the cases of adult acut e lymphoblastic leukemia is formed by a reciprocal translocation betwe en chromosomes 9 and 22 that results in the fusion of BCR and ABL gene tic sequences. This BCR-ABL hybrid gene codes for a fusion protein wit h deregulated tyrosine kinase activity that can apparently cause malig nant transformation. CGP57148B, a 2-phenylaminopyrimidine derivative, has been shown to selectively inhibit the tyrosine kinase of ABL and B CR-ABL. We report here that this compound selectively suppresses the g rowth of colony-forming unit-granulocyte/macrophage (CFU-GM) and burst -forming unit-erythroid derived from CML over a P-logarithmic dose ran ge with a maximal differential effect at 1.0 mu mol/L. However, almost all CML colonies that grow in the presence of 1.0 mu mol/L CGP57148B are BCR-ABL-positive, which may reflect the fact that residual normal clonogenic myeloid precursors are infrequent in most patients with CML . We also studied the effects of CGP57148B on hematopoietic cell lines . Proliferation was suppressed in most of the BCR-ABL-positive lines; all five BCR-ABL-negative lines were unaffected, We conclude that this new agent may have significant therapeutic applications. (C) 1997 by The American Society of Hematology.