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Targeting the IGF-1R using picropodophyllin in the therapeutical 5T2MM mouse model of multiple myeloma: beneficial effects on tumor growth, angiogenesis, bone disease and survival
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
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2007 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 121, no 8, 1857-1861 p.Article in journal (Refereed) Published
Abstract [en]

During the last decade, a central role for insulin-like growth factor 1 (IGF-1) in the pathophysiology of multiple myeloma (MM) has been well established. IGF-I provided by the tumor-microenvironment interaction may directly and indirectly facilitate the migration, survival and expansion of the MM cells in the bone marrow (BM). The inhibition of the IGF-1R-mediated signaling pathway has recently been suggested to be a possible new therapeutic principle in MM. Using the mouse 5T2MM model, we now demonstrate that targeting the IGF-1R using picropodophyllin (PPP) in a therapeutical setting not only has strong antitumor activity on the established MM tumor but also influences the BM microenvironment by inhibiting angiogenesis and bone disease, having a profound effect on the survival of the mice. At therapeutically achievable concentrations of PPP, the average survival was 180 days for the PPP-treated mice as compared to 100 days for vehicle-treated mice. PPP used as single drug treatment in the 5T2MM model resulted in a decrease of tumor burden by 65% while the paraprotein concentrations were reduced by 75%. This decrease was associated with a significant inhibition of tumor-associated angiogenesis and osteolysis. The present studies on the biological effects of PPP in the 5T2MM model constitute an important experimental platform for future therapeutic implementation.

Place, publisher, year, edition, pages
2007. Vol. 121, no 8, 1857-1861 p.
Keyword [en]
Angiogenesis Inhibitors/*pharmacology, Animals, Antineoplastic Agents/*pharmacology, Bone Neoplasms/*prevention & control, Disease Models; Animal, Kaplan-Meiers Estimate, Mice, Multiple Myeloma/blood supply/*drug therapy/pathology, Neovascularization; Pathologic/*prevention & control, Podophyllotoxin/*analogs & derivatives/pharmacology, Receptor; IGF Type 1/*drug effects
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-16091DOI: 10.1002/ijc.22845ISI: 000249508200029PubMedID: 17546599OAI: oai:DiVA.org:uu-16091DiVA: diva2:43862
Available from: 2008-05-21 Created: 2008-05-21 Last updated: 2011-01-22Bibliographically approved

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Jernberg-Wiklund, HelenaNilsson, Kenneth
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