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

• 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.

Nyckelord

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

MEDICINE

MEDICIN

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