Reference - Detail
|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.|
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.
|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|
|Human and Animal Cells||32D(RCB1145)|