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 reverse the oncogenic phenotype of p60v-src transformed cells because of the inhibition of src protein tyrosine kinase. We previously demonstrated 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 into 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 greater than 1 x 10(5) cells, in vivo administration of herbimycin A by i.p. injection inhibited tumor formation and significantly prolonged survival time, and further, in mice inoculated with 1 x 10(4) cells, herbimycin A completely suppressed the in vivo growth of transformant FDC-P2 cells and brought about a complete remission. The present study revealed the in vivo efficacy of herbimycin A in mice bearing BCR/ABL-transfected cells.
Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
M
M
Okabe
Y
Y
Uehara
T
T
Noshima
T
T
Itaya
Y
Y
Kunieda
M
M
Kurosawa
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D016227:Benzoquinones; D015153:Blotting, Western; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D047029:Lactams, Macrocyclic; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology / Q000627:therapeutic use*; D017828:Rifabutin / Q000031:analogs & derivatives; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl