Bortezomib Alone or in Combination with the Histone Deacetylase Inhibitor JNJ-26481585: Effect on Myeloma Bone Disease in the 5T2MM Murine Model of Myeloma

被引:56
作者
Deleu, Sarah
Lemaire, Miguel
Arts, Janine [2 ]
Menu, Eline
Van Valckenborgh, Els
Broek, IsabeHe Vande
De Raeve, Hendrik
Coulton, Les [3 ]
Van Camp, Ben
Croucher, Peter [3 ]
Vanderkerken, Karin [1 ]
机构
[1] Vrije Univ Brussel, Myeloma Res Ctr Brussels, Dept Haematol & Immunol, UZ Brussel, B-1090 Brussels, Belgium
[2] Johnson & Johnson Pharmaceut R&D, Ortho Biotech Oncol Res & Dev, Beerse, Belgium
[3] Univ Sheffield, Sch Med, Sect Musculoskeletal Sci, Sheffield, S Yorkshire, England
关键词
MULTIPLE-MYELOMA; PROTEASOME INHIBITOR; IN-VIVO; CELLS; APOPTOSIS; INDUCTION; GROWTH;
D O I
10.1158/0008-5472.CAN-08-4472
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The proteasome inhibitor bortezomib (Velcade) is currently approved as second-line treatment of multiple myeloma (MM). MM-related bone disease is one of the most debilitating complications of MM. Besides supportive care with biphosphonates, which have proven efficacy in reducing and delaying skeletal-related events, there is no specific treatment of lytic bone lesions. The present study investigated the effect of bortezomib alone or in combination with a hydroxamate-based histone deacetylase inhibitor, JNJ-26481585 on tumor burden, and MM bone disease in the 5T2MM model. Injection of 5T2MM cells into C57Bl/KaLwRij mice resulted in MM bone disease, characterized by an increase in the percentage osteoclasts, a decrease in osteoblasts, trabecular bone volume, trabecular number, and the development of bone lesions. Treatment of 5T2MM-bearing mice with bortezomib significantly reduced tumor burden, angiogenesis, and MM bone disease. More importantly, the combination of bortezomib with JNJ-26481585 resulted in a more pronounced reduction of osteoclasts and increase of osteoblasts, trabecular bone volume, and trabecular number compared with bortezomib as single agent. These data suggest that bortezomib has bone remodeling properties that can be improved in combination with low dose JNJ-26481585. The study indicates that this combination therapy could be a useful strategy for the treatment of MM patients, especially in those patients with skeletal complications. [Cancer Res 2009;69(13):5307-11]
引用
收藏
页码:5307 / 5311
页数:5
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