COX-2 expression in chondrosarcoma: A role for celecoxib treatment?

Schrage, Y.M.; Machado, I.; Meijer, D.; Briaire-de Bruijn, I.; van den Akker, B.E.; Taminiau, A.H.M.; Kalinski, T.; Llombart-Bosch, A.; Bovée, J.V.M.G.

doi:10.1016/j.ejca.2009.11.002

« Previous Next »European Journal of Cancer
Volume 46, Issue 3 , Pages 616-624, February 2010

COX-2 expression in chondrosarcoma: A role for celecoxib treatment?

Y.M. Schrage
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
I. Machado
- Department of Pathology, University of Valencia, Valencia, Spain
D. Meijer
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
I. Briaire-de Bruijn
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
B.E. van den Akker
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
A.H.M. Taminiau
- Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands
T. Kalinski
- Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany
A. Llombart-Bosch
- Department of Pathology, University of Valencia, Valencia, Spain
J.V.M.G. Bovée
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
- Corresponding author: Address: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Tel.: +31 715266617; fax: +31 715266952.

Received 4 September 2009; accepted 10 November 2009. published online 10 December 2009.

Abstract

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 E₂ (PGE₂) ELISA) and cell viability were measured. The (prophylactic) effect of celecoxib on chondrosarcoma growth in vivo was studied for 8weeks 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 6weeks 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.

Keywords: Bone tumours, Chondrosarcoma, COX-2 inhibition, Therapy, Xenograft