Enhanced tumor regression and tissue repair when zoledronic acid is combined with ifosfamide in rat osteosarcoma.
The efficacy of zoledronic acid (ZOL), with or without the anticancer drug ifosfamide (IFO), was tested on primary bone tumor growth using a rat-transplantable model of osteosarcoma. The effects on bone remodeling and tumor growth were analyzed by radiography, micro-computed tomography (micro-CT), and histological staining. The in vitro effects of ZOL were studied by proliferation, apoptosis, and cell cycle analyses on the osteosarcoma cells OSRGA compared to rat primary osteoblasts. Treatment with ZOL was effective in preventing the formation of osteolytic lesions that developed in bone sites and in reducing the local tumor growth, as compared to the untreated rats. The combination of ZOL and IFO was more effective than each agent alone in preventing tumor recurrence, improving tissue repair, and increasing bone formation as revealed by the analysis of trabecular architecture. In vitro studies demonstrated that ZOL was more potent against the OSRGA cell line than osteoblasts (with a half-maximal inhibitory effect on proliferation seen at 0.2 and 20 microM, respectively), the ZOL-induced inhibition of OSRGA proliferation being due to cell cycle arrest in S-phase. No effect on OSRGA apoptosis could be observed in vitro, as assessed by Hoechst staining and caspase-1 and -3 activation. In situ cell death was determined by TUNEL staining on tumor tissue sections. No significant difference in TUNEL-positive cells could be observed between ZOL-treated and -untreated rats. This is the first report of the anti-bone resorption and antitumoral activities of zoledronic acid in a rat model of osteosarcoma, and its beneficial association with an antitumoral chemotherapeutic drug in preventing tumor recurrence.
Heymann
D
D
Université EA 3822; INSERM ERI 7, Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Faculté de Médecine, 1 rue Gaston Veil, 44035 Nantes cedex 1, France.
Ory
B
B
Blanchard
F
F
Heymann
M-F
MF
Coipeau
P
P
Charrier
C
C
Couillaud
S
S
Thiery
J P
JP
Gouin
F
F
Redini
F
F
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016723:Bone Remodeling / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage; D005355:Fibrosis; D007069:Ifosfamide / Q000008:administration & dosage; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D009336:Necrosis; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase / Q000187:drug effects; D015996:Survival Rate; D013977:Tibia / Q000000981:diagnostic imaging / Q000473:pathology; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D020169:Caspases; D007069:Ifosfamide