Titre du document / Document title

Targeting receptor kinases by a novel indolinone derivative in multiple myeloma : abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups

Auteur(s) / Author(s)

BISPING Guido ; KROPFF Martin ; WENNING Doris ; DREYER Britta ; BESSONOV Sergey ; HILBERG Frank ; ROTH Gerald J. ; MUNZERT Gerd ; STEFANIC Martin ; STELLJES Matthias ; SCHEFFOLD Christian ; MÜLLER-TIDOW Carsten ; LIEBISCH Peter ; LANG Nicola ; TCHINDA Jöelle ; SERVE Hubert L. ; MESTERS Rolf M. ; BERDEL Wolfgang E. ; KIENAST Joachim ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Medicine/Hematology and Oncology, University of Muenster, Muenster, ALLEMAGNE
⁽²⁾ Boehringer Ingelheim Austria GmbH, Vienna, AUTRICHE
⁽³⁾ Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riss, ALLEMAGNE
⁽⁴⁾ Department of Internal Medicine III, University Hospital Ulm, Ulm, ALLEMAGNE
⁽⁵⁾ University Hospital GroBhadern, Department of Medicine III, Ludwig-Maximilians-University, Munich, ALLEMAGNE
⁽⁶⁾ Institute of Human Genetics, University of Muenster, Muenster, ALLEMAGNE

Résumé / 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-p on MM cells and their interactions with bone marrow stroma cells (BMSCs). Both, in the absence and presence of myelomastroma 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.

Revue / Journal Title

Blood   ISSN 0006-4971 

Source / Source

2006, vol. 107, n^o5, pp. 2079-2089 [11 page(s) (article)] (54 ref.)

Langue / Language

Anglais

Editeur / Publisher

The Americain Society of Hematology, Washington, DC, ETATS-UNIS  (1946) (Revue)

Localisation / Location

INIST-CNRS, Cote INIST : 3178, 35400015341440.0450