RRC ID 68497
Author Zhao M, Kiyoi H, Yamamoto Y, Ito M, Towatari M, Omura S, Kitamura T, Ueda R, Saito H, Naoe T.
Title In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor.
Journal Leukemia
Abstract Somatic mutation of the FLT3 gene, in which the juxtamembrane domain has an internal tandem duplication, is found in 20% of human acute myeloid leukemias and causes constitutive tyrosine phosphorylation of the products. In this study, we observed that the transfection of mutant FLT3 gene into an IL3-dependent murine cell line, 32D, abrogated the IL3-dependency. Subcutaneous injection of the transformed 32D cells caused leukemia in addition to subcutaneous tumors in C3H/HeJ mice. To develop a FLT3-targeted therapy, we examined tyrosine kinase inhibitors for in vitro growth suppression of the transformed 32D cells. A tyrosine kinase inhibitor, herbimycin A, remarkably inhibited the growth of the transformed 32D cells at 0.1 microM, at which concentration it was ineffective in parental 32D cells. Herbimycin A suppressed the constitutive tyrosine phosphorylation of the mutant FLT3 but not the phosphorylation of the ligand-stimulated wild-type FLT3. In mice transplanted with the transformed 32D cells, the administration of herbimycin A prolonged the latency of disease or completely prevented leukemia, depending on the number of cells inoculated and schedule of drug administration. These results suggest that mutant FLT3 is a promising target for tyrosine kinase inhibitors in the treatment of leukemia.
Volume 14(3)
Pages 374-8
Published 2000-3-1
DOI 10.1038/sj.leu.2401680
PMID 10720129
MeSH Animals Antineoplastic Agents / therapeutic use* Benzoquinones Cell Line, Transformed / transplantation Cell Transformation, Neoplastic / genetics* Drug Screening Assays, Antitumor Enzyme Inhibitors / therapeutic use* Female Genistein / therapeutic use Humans Hydroquinones / therapeutic use Interleukin-3 / pharmacology Lactams, Macrocyclic Leukemia, Experimental / drug therapy* Mice Mice, Inbred C3H Neoplasm Proteins / antagonists & inhibitors* Neoplasm Transplantation Phosphorylation / drug effects Phthalimides / therapeutic use Protein Processing, Post-Translational / drug effects Protein-Tyrosine Kinases / antagonists & inhibitors* Proto-Oncogene Proteins / antagonists & inhibitors Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / physiology* Quinones / therapeutic use Receptor Protein-Tyrosine Kinases / antagonists & inhibitors Receptor Protein-Tyrosine Kinases / genetics Receptor Protein-Tyrosine Kinases / physiology* Rifabutin / analogs & derivatives Signal Transduction / drug effects Transfection Tyrphostins / therapeutic use fms-Like Tyrosine Kinase 3
IF 8.665
Human and Animal Cells 32D(RCB1145)