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Research Articles: Therapeutics, Targets, and Development

Zoledronic acid inhibits osteosarcoma growth in an orthotopic model

¹ Departments of Orthopaedics and Surgery, University of Melbourne, St. Vincent's Hospital Melbourne, and ² Bone and Soft Tissue Sarcoma Service, Peter MacCallum Cancer Centre, Melbourne, Australia

Requests for reprints: Crispin R. Dass, Department of Orthopaedics, St. Vincent's Hospital Melbourne, P.O. Box 2900, Fitzroy 3065, Melbourne, Australia. Phone: 61-3-9288-3954; Fax: 61-3-9416-3610. E-mail: crispin.dass{at}svhm.org.au

Abstract

Zoledronic acid (ZOL) has been shown to reduce osteolysis in bone metastasis. Its efficacy in osteosarcoma has not been convincingly proved in a clinically relevant model for the disease. In vitro, ZOL decreased osteosarcoma cell proliferation, mainly due to an increase in apoptosis in a dose-dependent fashion. There was a decrease in cell migration at 10 µmol/L concentrations, but invasion was inhibited at a much lower dose of 0.1 µmol/L. Reverse transcription-PCR showed that ZOL overall caused an increased expression of osteocalcin and decreased expression of alkaline phosphatase, osteopontin, osteonectin, and vascular endothelial growth factor, with no change in expression of osteoprotegerin. ZOL administration s.c. twice weekly at 0.12 mg/kg to SaOS-2 tumor–bearing mice resulted in primary tumor growth inhibition, reduction in lung metastases, and dramatic decrease in osteolysis. Furthermore, in the ZOL cohort, there was a clear reduction in the number of osteoclasts in bone exposed to tumor and a lower tumor vessel density. These data point to the adjuvant potential of ZOL in the management of osteosarcoma not only for its antiosteolytic properties but also for its ability to directly halt tumor cell growth and metastasis via its effects on viability, invasion, differentiation, and angiogenesis. [Mol Cancer Ther 2007;6(12):3263–70]

Grant support: The Australian Orthopaedics Association, the Victorian Orthopaedics Research Trust, and the Cancer Council Victoria.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

³ P.S. Mackie and P.F.M. Choong, unpublished data.

Received 8/ 9/07; revised 10/ 8/07; accepted 10/15/07.