Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor

被引:75
作者
Bonfil, RD
Sabbota, A
Nabha, S
Bernardo, MM
Dong, Z
Meng, H
Yamamoto, H
Chinni, SR
Lim, IT
Chang, M
Filetti, LC
Mobashery, S
Cher, ML
Fridman, R
机构
[1] Wayne State Univ, Sch Med, Dept Urol, Detroit, MI 48201 USA
[2] Barbara Ann Karmanos Canc Inst, Detroit, MI USA
[3] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA
[4] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
[5] Univ Notre Dame, Walther Canc Res Ctr, Notre Dame, IN 46556 USA
关键词
matrix metalloproteinases; endothelium; NIMP-2; MMP-9; gelatinase inhibitor;
D O I
10.1002/ijc.21645
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Metastasis to the bone is a major clinical complication in patients with prostate cancer (PC). However, therapeutic options for treatment of PC bone metastasis are limited. Gelatinases are members of the matrix metalloproteinase (MMP) family and have been shown to play a key role in PC metastasis. Herein, we investigated the effect of SB-3CT, a covalent mechanism-based MMP inhibitor with high selectivity for gelatinases, in an experimental model of PC bone metastases. Intraperitoneal (i.p.) treatment with SB-3CT (50 mg/kg) inhibited intraosseous growth of human PC3 cells within the marrow of human fetal femur fragments previously implanted in SCID mice, as demonstrated by histomorphometry and Ki-67 immunohistochemistry. The anti-osteolytic effect of SB-3CT was confirmed by radiographic images. Treatment with SB-3CT also reduced intratumoral vascular density and bone degradation in the PC3 bone tumors. A direct inhibition of bone marrow endothelial cell invasion and tubule formation in Matrigel by SB-3CT in vitro was also demonstrated. The use of the highly selective gelatinase inhibitors holds the promise of effective intervention of metastases of PC to the bone. (c) 2005 Wiley-Liss, Inc.
引用
收藏
页码:2721 / 2726
页数:6
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