Zoledronic acid suppresses lung metastases and prolongs overall survival of osteosarcoma-bearing mice.
BACKGROUND
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.


METHODS
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.


RESULTS
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 microM 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.


CONCLUSIONS
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.
Ory
Benjamin
B
Universite de Nantes EA 3822; INSERM ERI 7, Physiopathologie de la Resorption Osseuse et Therapie des Tumeurs Osseuses Primitives, Faculte de Medecine, Nantes, France.
Heymann
Marie-Françoise
MF
Kamijo
Akira
A
Gouin
François
F
Heymann
Dominique
D
Redini
Françoise
F
D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004164:Diphosphonates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000401:mortality / Q000556:secondary*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid