Prevention of postoperative progression of pulmonary metastases in osteosarcoma by antiangiogenic therapy using endostatin.
BACKGROUND
We have previously offered data suggesting a positive linkage of postoperative up-regulation of systemic angiogenic activity and postoperative progression of pulmonary metastasis in osteosarcoma. The finding that the significant down-regulation of endostatin was critical in angiogenic elevation after primary tumor removal suggests that endostatin is a candidate for antiangiogenic therapy for osteosarcoma.


METHODS
In the current study, we evaluated the effect of antiangiogenic therapy using endostatin on postoperative progression of pulmonary metastasis from osteosarcoma. Mouse osteosarcoma cell line LM 8 cells were inoculated in subcutaneous layer of nude mice. Two weeks after tumor inoculation, the primary tumor was removed surgically, and antiangiogenic therapy using adenovirus encoding endostatin expression vector (Ad5CMV-mEnd) was performed. Two weeks after the antiangiogenic treatment, pulmonary metastasis was evaluated by counting the number of metastatic nodules. The evaluation of systemic angiogenic activity was performed using Matrigel plug assay.


RESULTS
Two weeks after the viral injection, mice were sacrificed, and the macroscopic pulmonary metastases were counted. Notably, the number of pulmonary metastases was smaller in the mice injected with Ad5CMV-mEnd than in controls, accompanied by significant suppression of systemic angiogenic activity. In addition, the sizes of the pulmonary metastases of the mice injected with Ad5CMV-mEnd were smaller than in the control group.


CONCLUSIONS
Our results indicate that antiangiogenic therapy using endostatin has the potential to prevent postoperative progression of pulmonary metastasis from osteosarcoma. Although this therapeutic strategy cannot provide a cure for osteosarcoma, it should enable osteosarcoma patients to coexist with dormant pulmonary metastasis and lead to improvement of their prognosis.
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
Mitsunori
M
Kaya
Takuro
T
Wada
Satoshi
S
Nagoya
Toshihiko
T
Yamashita
D020533:Angiogenesis Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D001859:Bone Neoplasms / Q000097:blood / Q000473:pathology / Q000601:surgery*; D045744:Cell Line, Tumor; D018450:Disease Progression; D043169:Endostatins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000097:blood / Q000473:pathology / Q000601:surgery*; D009389:Neovascularization, Pathologic / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D011184:Postoperative Period
D020533:Angiogenesis Inhibitors; D043169:Endostatins