IN-VIVO ANTITUMOR-ACTIVITY OF HERBIMYCIN-A, A TYROSINE KINASE INHIBITOR, TARGETED AGAINST BCR ABL ONCOPROTEIN IN MICE BEARING BCR/ABL-TRANSFECTED CELLS/

Herbimycin A, a benzoquinoid ansamycin antibiotic, has been shown to r everse the oncogenic phenotype of p60(v-src) transformed cells because of the inhibition of src protein tyrosine kinase. We previously demon strated that herbimycin A displayed antitumor activity on the in vitro growth of Philadelphia chromosome-positive leukemia cells and BCR/ABL -transfected murine hematopoietic FDC-P2 cells through the inhibition of BCR/ABL protein tyrosine kinase. in this study, the transformed FDC -P2 cells were demonstrated to be tumorigenic in syngeneic DBA/2 mice. The intraperitoneal (i.p.) injection of the transformed tumor cells i nto DBA/2 mice induced infiltrations of abdominal organs, and then all of the mice died within time periods proportional to the cell numbers of inoculation. In mice that received an i.p. inoculation with greate r than 1 x 10(5) cells, in vivo administration of herbimycin A by i.p. injection inhibited tumor formation and significantly prolonged survi val time, and further, in mice inoculated with 1 x 10(4) cells, herbim ycin A completely suppressed the in vivo growth of transformant FDC-P2 cells and brought about a complete remission. The present study revea led the in vivo efficacy of herbimycin A in mice bearing BCR/ABL-trans fected cells.