In vivo treatment of mutant FLT3-transformed murine leukemia with a tyrosine kinase inhibitor.

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.

• Authors: M Zhao, H Kiyoi, Y Yamamoto, M Ito, M Towatari, S Omura, T Kitamura, R Ueda, H Saito, T Naoe
• Journal: Leukemia (Leukemia) Vol. 14 Issue 3 Pg. 374-8 (Mar 2000) ISSN: 0887-6924 [Print] England
• PMID: 10720129 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzoquinones
• Enzyme Inhibitors
• Hydroquinones
• Interleukin-3
• Lactams, Macrocyclic
• Neoplasm Proteins
• Phthalimides
• Proto-Oncogene Proteins
• Quinones
• Tyrphostins
• tyrphostin A9
• Rifabutin
• herbimycin
• Genistein
• FLT3 protein, human
• Flt3 protein, mouse
• Protein-Tyrosine Kinases
• Receptor Protein-Tyrosine Kinases
• fms-Like Tyrosine Kinase 3
• erbstatin
• 4,5-dianilinophthalimide

Topics

• 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, genetics, physiology)
• Quinones (therapeutic use)
• Receptor Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, physiology)
• Rifabutin (analogs & derivatives)
• Signal Transduction (drug effects)
• Transfection
• Tyrphostins (therapeutic use)
• fms-Like Tyrosine Kinase 3