TREATMENT OF PHILADELPHIA-CHROMOSOME-POSITIVE HUMAN LEUKEMIA IN SCID MOUSE MODEL WITH HERBIMYCIN-A, BCR-ABL TYROSINE KINASE-ACTIVITY INHIBITOR

The molecular basis of the Philadelphia chromosome (Ph(1)) is a structurally altered c-abl (bcr-abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin A, which effectively reduced intracellular phosphorylation by bcr-abl tyrosine kinase, preferentially inhibited the growth of Ph(1)-positive leukemia cell lines. Injection of Ph(1)-positive and -negative leukemia cell lines into mice with severe combined immunodeficiency (SCID) resulted in the death of all mice due to leukemia, although the severity of illness varied according to the cell lines used. Administration of herbimycin A significantly enhanced the survival of mice inoculated with the Ph(1)-positive leukemia cell lines tested but barely affected the survival of mice inoculated with the Ph(1)-negative leukemia cell lines tested. These results suggest that herbimycin A and related compounds may be useful for the treatment of Ph(1)-positive leukemia. The disease that developed using the Ph(1)-positive leukemia cell line NALM-20 resembled human Ph(1)-positive acute lymphoid leukemia. There was an inverse relationship between the survival time of mice and the number of cells inoculated. The SCID mouse-NALM-20 human leukemia chimera would be a good experimental model for screening tyrosine kinase inhibitors as therapeutic agents against Ph(1)-positive leukemia. (C) 1995 Wiley-Liss, Inc.