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Blood, 15 January 2006, Vol. 107, No. 2, pp. 655-660. Prepublished online as a Blood First Edition Paper on July 26, 2005; DOI 10.1182/blood-2005-01-0293. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-01-0293v1 107/2/655    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Menu, E. Articles by Vanderkerken, K. Search for Related Content PubMed PubMed Citation Articles by Menu, E. Articles by Vanderkerken, K. Related Collections Hemostasis, Thrombosis, and Vascular Biology Neoplasia Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Inhibiting the IGF-1 receptor tyrosine kinase with the cyclolignan PPP: an in vitro and in vivo study in the 5T33MM mouse model Eline Menu, Helena Jernberg-Wiklund, Thomas Stromberg, Hendrik De Raeve, Leonard Girnita, Olle Larsson, Magnus Axelson, Kewal Asosingh, Kenneth Nilsson, Ben Van Camp, and Karin Vanderkerken From the Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium; Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; Department of Pathology, University of Antwerp, Antwerp, Belgium; Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden; and Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden. Insulin-like growth factor 1 (IGF-1) plays a pleiotropic role in multiple myeloma (MM), that is, in survival, proliferation, chemotaxis, and angiogenesis. Strategies targeting the IGF-1 receptor (IGF-1R) may therefore be important to develop efficient anti-MM agents. In this work we investigated the effect of an IGF-1R tyrosine kinase (IGF-1RTK) inhibitor (picropodophyllin or PPP) in the 5T33MM mouse model. In vitro data showed that PPP reduced IGF-1R autophosphorylation and downstream ERK activation, leading to inhibition of IGF-1–stimulated proliferation and vascular endothelial growth factor (VEGF) secretion of MM cells. In an in vivo study, PPP reduced the bone marrow tumor burden and serum paraprotein in 5T33MM mice by 77% and 90%, respectively, compared to vehicle-treated animals. Angiogenesis was assessed by quantifying the microvessel density on CD31-stained paraffin sections and this was reduced by 60% in the PPP-treated group. In a separate survival experiment, Kaplan-Meier analysis demonstrated a significant increase in survival in PPP-treated 5T33MM animals compared to the vehicle controls (28 versus 18 days). These data suggest that the IGF-1RTK inhibitor PPP possesses a marked antitumor activity and strongly points to the possibility of using IGF-1R inhibitors in the treatment of MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Shi, R. Lai, Q. Lin, A. S. Iqbal, L. C. Young, L. W. Kwak, R. J. Ford, and H. M. Amin IGF-IR tyrosine kinase interacts with NPM-ALK oncogene to induce survival of T-cell ALK+ anaplastic large-cell lymphoma cells Blood, July 9, 2009; 114(2): 360 - 370. [Abstract] [Full Text] [PDF] M. Q. Lacy, M. Alsina, R. Fonseca, M. L. Paccagnella, C. L. Melvin, D. Yin, A. Sharma, M. Enriquez Sarano, M. Pollak, S. Jagannath, et al. Phase I, Pharmacokinetic and Pharmacodynamic Study of the Anti-Insulinlike Growth Factor Type 1 Receptor Monoclonal Antibody CP-751,871 in Patients With Multiple Myeloma J. Clin. Oncol., July 1, 2008; 26(19): 3196 - 3203. [Abstract] [Full Text] [PDF] M. A. Economou, S. Andersson, D. Vasilcanu, C. All-Ericsson, E. Menu, A. Girnita, L. Girnita, M. Axelson, S. Seregard, and O. Larsson Oral Picropodophyllin (PPP) Is Well Tolerated In Vivo and Inhibits IGF-1R Expression and Growth of Uveal Melanoma Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2337 - 2342. [Abstract] [Full Text] [PDF] M. A. Economou, J. Wu, D. Vasilcanu, L. Rosengren, C. All-Ericsson, I. van der Ploeg, E. Menu, L. Girnita, M. Axelson, O. Larsson, et al. Inhibition of VEGF Secretion and Experimental Choroidal Neovascularization by Picropodophyllin (PPP), an Inhibitor of the Insulin-like Growth Factor-1 Receptor Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2620 - 2626. [Abstract] [Full Text] [PDF] R. Vasilcanu, D. Vasilcanu, B. Sehat, S. Yin, A. Girnita, M. Axelson, and L. Girnita Insulin-Like Growth Factor Type-I Receptor-Dependent Phosphorylation of Extracellular Signal-Regulated Kinase 1/2 but not Akt (Protein Kinase B) Can Be Induced by Picropodophyllin Mol. Pharmacol., March 1, 2008; 73(3): 930 - 939. [Abstract] [Full Text] [PDF] K. Vanderkerken, S. Medicherla, L. Coulton, H. De Raeve, A. Willems, M. Lawson, B. Van Camp, A. A. Protter, L. S. Higgins, E. Menu, et al. Inhibition of p38{alpha} Mitogen-Activated Protein Kinase Prevents the Development of Osteolytic Bone Disease, Reduces Tumor Burden, and Increases Survival in Murine Models of Multiple Myeloma Cancer Res., May 15, 2007; 67(10): 4572 - 4577. [Abstract] [Full Text] [PDF] O. Larsson and M. Axelson Cyclolignans as Inhibitors of the Insulin-like Growth Factor-I Receptor Cancer Res., March 15, 2007; 67(6): 2899 - 2899. [Full Text] [PDF] M. C. Manara, L. Landuzzi, P. Nanni, G. Nicoletti, D. Zambelli, P. L. Lollini, C. 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Girnita The Insulin-Like Growth Factor-I Receptor Inhibitor Picropodophyllin Causes Tumor Regression and Attenuates Mechanisms Involved in Invasion of Uveal Melanoma Cells Clin. Cancer Res., February 15, 2006; 12(4): 1383 - 1391. [Abstract] [Full Text] [PDF] T. Stromberg, S. Ekman, L. Girnita, L. Y. Dimberg, O. Larsson, M. Axelson, J. Lennartsson, U. Hellman, K. Carlson, A. Osterborg, et al. IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells Blood, January 15, 2006; 107(2): 669 - 678. [Abstract] [Full Text] [PDF]

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