2005 Fiscal Year Final Research Report Summary
Basic research for clinical application of a novel FLT3 inhibitor and development of a model mouse for the evaluation of anti-leukemia cell effect.
| Project/Area Number |
16590932
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Nagoya University |
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Principal Investigator |
KIYOI Hitoshi Nagoya Univ., University Hospital, Assistant Professor, 医学部附属病院, 講師 (90314004)
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| Project Period (FY) |
2004 – 2005
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| Keywords | FLT3 / Leukemia / Molecular target therapy / Tyrosinekinase / Inhibitor |
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| Research Abstract |
We have developed a novel FLT3 kinase inhibitor by using a high-throughput screening. This inhibitor shows the selective growth inhibition against human leukemia cell-lines harboring FLT3 gene mutations, and of which IC_<50> is around 10 nM. The purpose of this study is confirming the proof of principle (POP) of this inhibitor for applying clinical use.
1. We first established the mutant FLT3-associated leukemia mouse model by inoculating mutant FLT3-expressing 32D cells into syngeneic C3H mice. These mice developed leukemia within a week after the inoculation of mutant FLT3-expressing 32D cells, then died within 2 weeks. However, when these mice were treated with the novel inhibitor for 2weeks from the 10th day after the inoculation, all mice revealed the cure from leukemia, confirming the POP of this inhibitor.
2. We next compared the effects on leukemia regression and normal haematopoiesis between the novel inhibitor and Ara-C. The administration of Ara-C could not only inhibit the leukemia cell growth but also induced severe BM suppression, while the novel inhibitor achieved leukemia cell regression without BM suppression.
3. These results indicated that the novel FLT3 inhibitor could bring the cure to the leukemia mice, while the appropriate surrogate marker, which can predict the effectiveness of the inhibitor in clinical use, is required. Since STAT5 is constitutively activated in the mutant FLT3-expressing cells, phospho-STAT5 is thought to be a candidate of the surrogate marker. We have developed a monoclonal antibody against phospho-STAT5, which can be used both in the western blotting and flow cytometry. By using this antibody, we demonstrated that the reduction level of phospho-STAT5 status, which was quantitated by FCM analysis, is associated with the growth inhibition of leukemia cells.
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