| Autor: |
Stover EH; Division of Hematology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA., Chen J, Lee BH, Cools J, McDowell E, Adelsperger J, Cullen D, Coburn A, Moore SA, Okabe R, Fabbro D, Manley PW, Griffin JD, Gilliland DG |
| Jazyk: |
angličtina |
| Zdroj: |
Blood [Blood] 2005 Nov 01; Vol. 106 (9), pp. 3206-13. Date of Electronic Publication: 2005 Jul 19. |
| DOI: |
10.1182/blood-2005-05-1932 |
| Abstrakt: |
AMN107 is a small molecule tyrosine kinase inhibitor developed, in the first instance, as a potent inhibitor of breakpoint cluster region-abelson (BCR-ABL). We tested its effectiveness against fusion tyrosine kinases TEL-platelet-derived growth factor receptorbeta (TEL-PDGFRbeta) and FIP1-like-1 (FIP1L1)-PDGFRalpha, which cause chronic myelomonocytic leukemia and hypereosinophilic syndrome, respectively. In vitro, AMN107 inhibited proliferation of Ba/F3 cells transformed by both TEL-PDGFRbeta and FIP1L1-PDGFRalpha with IC50 (inhibitory concentration 50%) values less than 25 nM and inhibited phosphorylation of the fusion kinases and their downstream signaling targets. The imatinib mesylate-resistant mutant TEL-PDGFRbeta T681I was sensitive to AMN107, whereas the analogous mutation in FIP1L1-PDGFRalpha, T674I, was resistant. In an in vivo bone marrow transplantation assay, AMN107 effectively treated myeloproliferative disease induced by TEL-PDGFRbeta and FIP1L1-PDGFRalpha, significantly increasing survival and disease latency and reducing disease severity as assessed by histopathology and flow cytometry. In summary, AMN107 can inhibit myeloid proliferation driven by TEL-PDGFRbeta and FIP1L1-PDGFRalpha and may be a useful drug for treatment of patients with myeloproliferative disease who harbor these kinase fusions. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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