Melphalan flufenamide inhibits osteoclastogenesis by suppressing proliferation of monocytes

Bone Reports

Thomas Lind¹  Annica J. Rasmusson²  Rolf Larsson²  Claes Andersson²  Ana Slipicevic²  Mårten Fryknäs²  Håkan Melhus²  Joachim Gullbo³  Fredrik Lehmann³  Konstantin Byrgazov³ 

[1] Correspondence to: K. Byrgazov, Department of Research, Oncopeptides, SE-111 37 Stockholm, Sweden.;Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden;Oncopeptides AB, Stockholm, Sweden;

关键词: Osteoclastogenesis;    Bone resorption;    Melflufen;    Melphalan;   

DOI  :  

来源: DOAJ

【 摘 要 】

Myeloma bone disease is a major complication in multiple myeloma affecting quality of life and survival. It is characterized by increased activity of osteoclasts, bone resorbing cells. Myeloma microenvironment promotes excessive osteoclastogenesis, a process of production of osteoclasts from their precursors, monocytes. The effects of two anti-myeloma drugs, melphalan flufenamide (melflufen) and melphalan, on the activity and proliferation of osteoclasts and their progenitors, monocytes, were assessed in this study. In line with previous research, differentiation of monocytes was associated with increased expression of genes encoding DNA damage repair proteins. Hence monocytes were more sensitive to DNA damage-causing alkylating agents than their differentiated progeny, osteoclasts. In addition, differentiated progeny of monocytes showed increased gene expression of immune checkpoint ligands which may potentially create an immunosuppressive microenvironment. Melflufen was ten-fold more active than melphalan in inhibiting proliferation of osteoclast progenitors. Furthermore, melflufen was also superior to melphalan in inhibition of osteoclastogenesis and bone resorption. These results demonstrate that melflufen may exert beneficial effects in patients with multiple myeloma such as reducing bone resorption and immunosuppressive milieu by inhibiting osteoclastogenesis.

【 授权许可】

Unknown