2006 Fiscal Year Final Research Report Summary
Holocular Targeted Therapy in hemabrogical neoplasm: Telomerase Inhibition
| Project/Area Number |
16590965
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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 | Tokyo Medical University |
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Principal Investigator |
TAUCHI Tetsuzo Tokyo Medical University, Medicine, Associate Professor, 医学部, 講師 (80281377)
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| Project Period (FY) |
2004 – 2006
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| Keywords | Telomerace / Apoptosis / Targeted Therapy |
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| Research Abstract |
Dasatinib is an ATP-competitive, multi-targeted SRC and ABL kinase inhibitor that can bind BCR-ABL in both the active and inactive conformations. In the view of the fact that the combination of imatinib and dasatinib shows the additive/synergistic growth inhibition on a wild type p210 BCR-ABL expressing cells, we reasoned that these ABL kinase inhibitors might induce the different molecular pathways. To address this question, we used DNA microarrays to identify genes whose transcription was altered by imatinib and dasatinib. K562 cells were cultured with imatinib or dasatinib for 16 hrs, and gene expression data were obtained from three independent microarray hybridizations. Almost all of the imatinib-and dasatinib-responsive genes appeared to be similarly increased or decreased in K562 cells ; however, small subsets of genes were identified as selectively altered expression by either imatinib or dasatinib. One of the distinct genes which are selectively modulated by dasatinib are CDK2
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and CDK8, which had a maximal reduction of <5-fold in microarray screen. To assess the functional importance of dasatinib regulated genes, we used RNA interference to determine whether reduction of CDK2 and CDK8 affected the growth inhibition. K562 cells and TF-1BCR-ABL cells pretreated with CDK2 or CDK8 siRNA showed additive growth inhibition with imatinib but not with dasatinib. These findings demonstrate that the additive/synergistic growth inhibition by imatinib and dasatinib may be mediated in part by CDK2 and CDK8. Despite promising results from clinical studies of ABL kinase inhibitors, a challenging problem that remains is T315I mutation against which neither nilotinib nor dasatinib showed significant activity. We observed a dose-dependent reduction in the level of BCR-ABL autophosphorylation in VE-465-treated cells. Exposure to the combination of VE-465 and imatinib exerted enhanced apoptotic effect in K562 cells. Combined treatment with VE-465 and imatinib caused more attenuation of the levels of phospho-AKT, and c-Myc in K562 cells. The vehicle-treated mice died of a condition resembling acute leukemia by 28 days, however, nearly all mice treated with VE-465 (75mg/kg b.i.d. ; ip for 14 days) survived for more than 56 days. Histopathologic analysis of vehicle-treated mice revealed infiltration of the spleen. In contrast, histopathologic analysis of organs from VE-465-treated mice demonstrated normal tissue architecture. Taken together, the present study shows that VE-465 exhibits a desirable therapeutic index that can reduce the in vivo growth of T315I mutant form and wild type of BCR-ABL-expressing cells in an efficacious manner. Less
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Research Products
(10 results)
