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Zoledronic acid suppresses lung metastases and prolongs overall survival of osteosarcoma-bearing mice
Version of Record online: 3 NOV 2005
Copyright © 2005 American Cancer Society
Volume 104, Issue 11, pages 2522–2529, 1 December 2005
How to Cite
Ory, B., Heymann, M.-F., Kamijo, A., Gouin, F., Heymann, D. and Redini, F. (2005), Zoledronic acid suppresses lung metastases and prolongs overall survival of osteosarcoma-bearing mice. Cancer, 104: 2522–2529. doi: 10.1002/cncr.21530
- Issue online: 18 NOV 2005
- Version of Record online: 3 NOV 2005
- Manuscript Revised: 11 AUG 2005
- Manuscript Accepted: 11 AUG 2005
- Manuscript Received: 14 JAN 2005
- Ministere de la Recherche. Grant Number: ACI TS/0220044
- Comite des Pays de Loire de la Ligue Contre le Cancer
- zoledronic acid;
- lung metastases;
Although there is no doubt that bisphosphonates (BPs), specific inhibitors of osteoclasts, are beneficial for the treatment of bone metastases, their effects on visceral metastases are unclear. The effect of zoledronic acid (ZOL) was examined in vivo on lung metastasis progression and animal survival, and in vitro on the cellular mechanisms involved.
An animal model of lung metastasis was developed in C3H/He mice inoculated intravenously with a spontaneous murine osteosarcoma POS-1 cell line. Lung metastasis was determined at the time of autopsy. ZOL was assessed in vitro on POS-1 cell proliferation, cell cycle progression, and caspase-1 and -3 activities.
The overall survival in five independent experiments (two series treated with ZOL 0.1 mg/kg twice a week, and three series with 0.1 mg/kg five times a week) showed a significant increase of the actuarial survival: 0.422 ± 0.07 in ZOL-treated animals versus 0.167 ± 0.07 in controls (P = 0.036). Lung metastases were absent in all ZOL-treated mice that survived more than 21 days postinjection as revealed by macroscopic and histologic analysis. In vitro, a 48-hour incubation with 10 μM ZOL inhibited POS-1 cell line proliferation associated with cell cycle arrest in S-phase. In addition, ZOL induced a weak increase of caspase-3 activity, but not caspase-1.
We demonstrate that ZOL exerts a direct antitumor effect on POS-1 cells in vitro, significantly diminishes osteosarcoma-induced lung metastasis in vivo, thereby prolonging survival of POS-1-inoculated animals. Cancer 2005. © 2005 American Cancer Society.