Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Eur J Cancer. 2010 Feb;46(3):616-24. doi: 10.1016/j.ejca.2009.11.002. Epub 2009 Dec 11.
Chondrosarcomas are resistant to conventional chemo- and radiotherapy. A subset of chondrosarcomas arises secondarily in the benign tumour syndromes enchondromatosis (EC) and multiple osteochondromas (MO), and prevention of tumour development would greatly improve prognosis. We therefore investigated the effect of selective COX-2 inhibition on chondrosarcoma growth. COX-2 expression was studied in central- and peripheral cartilaginous tumours. The effect of COX-2 inhibition was assessed in four high-grade chondrosarcoma cell lines using celecoxib and NS-398 treatment. COX-2 activity (prostaglandin E(2) (PGE(2)) ELISA) and cell viability were measured. The (prophylactic) effect of celecoxib on chondrosarcoma growth in vivo was studied for 8 weeks using a xenograft model of cell line CH2879 in immunoincompetent nude mice. High COX-2 protein expression was mainly found in solitary peripheral chondrosarcoma and in enchondromatosis-related central chondrosarcoma, which was confirmed by qPCR. After 72h of celecoxib treatment, a significant decrease in cell viability was observed in three chondrosarcoma cell lines. In vivo, celecoxib initially slowed tumour growth in chondrosarcoma xenografts; however, after prolonged treatment relapsed tumour growth was observed. Tumour volume was negatively associated with celecoxib serum levels, and seemed smaller in the high-dose prophylactic treatment group. We confirmed the expression of COX-2 in 65% of chondrosarcomas, and COX-2 inhibition by celecoxib diminished cell viability in vitro. The initial response and the decrease in tumour volume with increased celecoxib serum levels in vivo supported a role for celecoxib, although relapsed tumour growth after 6 weeks was worrisome. Also the role of high-dose prophylactic celecoxib in preventing the development of benign and malignant cartilage tumours in EC and MO patients deserves further investigation.
软骨肉瘤对常规化疗和放疗具有耐药性。软骨肉瘤的一个亚组继发于良性肿瘤综合征软骨发育不全（EC）和多发性软骨瘤（MO），预防肿瘤发展将极大地改善预后。因此，我们研究了选择性 COX-2 抑制对软骨肉瘤生长的影响。研究了中央和周围软骨肿瘤中的 COX-2 表达。使用塞来昔布和 NS-398 治疗四种高级别软骨肉瘤细胞系，评估 COX-2 抑制的效果。通过 COX-2 活性（前列腺素 E（2）（PGE（2））ELISA）和细胞活力进行测量。使用免疫缺陷裸鼠的 CH2879 细胞系异种移植模型研究了塞来昔布对软骨肉瘤生长的（预防）作用，为期 8 周。高 COX-2 蛋白表达主要见于孤立性外周软骨肉瘤和与软骨发育不全相关的中央软骨肉瘤，这通过 qPCR 得到了证实。塞来昔布治疗 72 小时后，三种软骨肉瘤细胞系的细胞活力明显下降。在体内，塞来昔布最初减缓了软骨肉瘤异种移植瘤的生长；然而，经过长时间的治疗后，观察到肿瘤复发生长。肿瘤体积与塞来昔布血清水平呈负相关，并且在高剂量预防治疗组中似乎较小。我们证实了 COX-2 在 65%的软骨肉瘤中的表达，并且塞来昔布抑制 COX-2 降低了体外细胞活力。体内 COX-2 血清水平增加时的初始反应和肿瘤体积减少支持塞来昔布的作用，尽管 6 周后肿瘤复发生长令人担忧。在 EC 和 MO 患者中，高剂量预防性塞来昔布在预防良性和恶性软骨肿瘤发展中的作用也值得进一步研究。
