In:
Blood, American Society of Hematology, Vol. 107, No. 5 ( 2006-03-01), p. 2079-2089
Abstract:
In multiple myeloma (MM), both vascular endothelial (VEGF) and basic fibroblast growth factor (bFGF) promote tumor growth and survival. We have used the novel indolinone BIBF 1000 to study effects of simultaneous inhibition of VEGF, FGF and transforming growth factor-β on MM cells and their interactions with bone marrow stroma cells (BMSCs). Both, in the absence and presence of myeloma-stroma cell contacts, BIBF 1000 abrogated BMSC-derived secretion of interleukin-6 (IL-6). In addition, BIBF 1000 directly induced apoptosis in t(4;14)–positive cell lines as well as in CD138+ marrow cells from patients with t(4;14) myeloma. To a similar extent, BIBF 1000 induced apoptosis in MM.1S and MM.1R cells carrying the translocation t(14;16). In case of MM.1S and other dexamethasone-sensitive t(14;16) cell lines, BIBF 1000 and dexamethasone had additive proapoptotic effects. Induction of apoptosis by BIBF 1000 was associated with inhibition of the mitogen-activated protein kinases (MAPK) pathway in t(4;14) and inhibition of the phosphatidyl-inositol-3 kinase/AKT pathway in t(14;16) cells. Apoptotic effects did not occur in t(4;14)–or t(14;16)–positive MM cells carrying n- or k-Ras mutations. The data provide the rationale for clinical evaluation of this class of targeted kinase inhibitors in MM with focus on defined cytogenetic subgroups.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2004-11-4250
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2006
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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