Zoledronic acid inhibits primary bone tumor growth in Ewing sarcoma.
BACKGROUND
Zoledronic acid has been shown to be effective in the treatment of osteoporosis, hypercalcemia, and metastatic bone tumors. The efficacy of zoledronic acid on primary bone tumors has not been investigated.


METHODS
A primary bone tumor mouse model was established. Intratibia injection of TC71 cells resulted in an osteolytic bone tumor. Four days after injection the mice were treated with zoledronic acid alone, paclitaxel alone, or zoledronic acid plus paclitaxel. Control mice were treated with phosphate-buffered saline. Bone tumor growth was assessed using a Faxitron Specimen Radiography System. The gene expression was detected by reverse-transcription polymerase chain reaction (RT-PCR), ELISA, and immunohistochemistry. Osteoclast formation was determined by tartrate-resistant acid phosphatase (TRAP) staining.


RESULTS
Zoledronic acid induced apoptosis in TC71 human Ewing sarcoma cells and inhibited cell proliferation. Five weeks after injection, 89% of mice in the control group developed osteolytic bone tumors. Paclitaxel had little effect on bone tumor growth, with 78% of mice developing tumors. By contrast, 44% of mice treated with zoledronic acid developed bone tumors. The most effective treatment was zoledronic acid plus paclitaxel. Tumor incidence in the combination therapy group was only 22%. Osteoclasts were quantified using TRAP staining. There was a decrease in TRAP-positive osteoclasts in tumor tissues from zoledronic acid-treated animals compared to control animals. RT-PCR, immunohistochemistry, and ELISA assay demonstrated that zoledronic acid up-regulated osteoprotegerin expression.


CONCLUSIONS
These results suggest that zoledronic acid induces apoptosis and inhibits primary bone tumor growth in Ewing sarcoma through a mechanism involving the up-regulation of osteoprotegerin. Zoledronic acid may provide a novel therapeutic approach for the treatment of patients with Ewing sarcoma.
Zhou
Zhichao
Z
Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Guan
Hui
H
Duan
Xiaoping
X
Kleinerman
Eugenie S
ES
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053244:Osteoprotegerin; D017239:Paclitaxel / Q000627:therapeutic use; D011859:Radiography; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D000077211:Zoledronic Acid
D000972:Antineoplastic Agents, Phytogenic; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006023:Glycoproteins; D007093:Imidazoles; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D000077211:Zoledronic Acid; D017239:Paclitaxel