The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan

被引:65
|
作者
Sanchez, Eric [1 ]
Li, Mingjie [1 ]
Steinberg, Jeffrey A. [1 ]
Wang, Cathy [1 ]
Shen, Jing [1 ]
Bonavida, Benjamin [2 ]
Li, Zhi-Wei [1 ]
Chen, Haiming [1 ]
Berenson, James R. [1 ]
机构
[1] Inst Myeloma & Bone Canc Res, W Hollywood, CA 90069 USA
[2] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA USA
关键词
bortezomib; CEP-18770; melphalan; multiple myeloma; proteasome inhibitor; REFRACTORY MULTIPLE-MYELOMA; NF-KAPPA-B; THERAPEUTIC IMPLICATIONS; CHEMOTHERAPEUTIC-AGENTS; COMBINATION THERAPY; ANTITUMOR-ACTIVITY; DRUG-RESISTANCE; CELLS; PS-341; SENSITIVITY;
D O I
10.1111/j.1365-2141.2009.08008.x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The anti-multiple myeloma (MM) efficacy of bortezomib has led to the development of other proteasome inhibitors (PI), including CEP-18770 which has shown anti-MM effects in preclinical studies. However, the efficacy of orally (PO) or intravenously (IV) administered CEP-18770 in multiple MM models and in combination with conventional anti-MM therapies has not been evaluated. Herein, we show that CEP-18770 combined with melphalan or bortezomib induces synergistic inhibition of MM cell viability in vitro. In MM xenograft models, the addition of CEP-18770 IV to melphalan completely prevented the growth of both melphalan-sensitive and melphalan-resistant tumours. The combination of CEP-18770 IV and bortezomib induced complete regression of bortezomib-sensitive tumours and markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone. Single agent CEP-18770 PO also showed marked anti-MM effects in these xenograft models. These studies provide strong preclinical rationale for further development of this novel PI in the treatment of MM as a monotherapy as well as combined with either melphalan or bortezomib.
引用
收藏
页码:569 / 581
页数:13
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