Despite surgical intervention and the use of combination chemotherapy, 35-40 percent of osteosarcoma patients still die of metastatic disease. The major goal of this research is to design a better approach for the therapy of metastasis of this disease. This application plans to test the concept that the appropriate combination of chemotherapy with biologic therapy designed to activate tumoricidal properties of macrophages will produce superior therapeutic results. The macrophage activator, liposomal muramyl tripeptide- phosphatidylethanolamine (L-MTP-PE) has significant antitumor activity, when administered after surgery and cisplatin (cDDP) therapy, against micrometastatic canine osteosarcoma. However, when L-MTP-PE and cDDP are given concurrently, the antitumor effect of L-MTP-PE is negated. When L- MTP-PE is given combined with doxorubicin, canine monocyte and pulmonary alveolar macrophage (PAM) cytotoxicity against osteosarcoma cells is enhanced. In dogs with osteosarcoma, the effect of L-MTP-PE combined with doxorubicin following amputation and cDDP chemotherapy will be evaluated in a randomized double-blind trial. Dogs will be monitored for development of pulmonary metastasis, and if detected will again receive L-MTP-PE or placebo, followed by thoracotomy to remove metastatic nodules to assess for evidence of antitumor activity. Liposomes will be continued after thoracotomy. In dogs with microscopic metastatic disease, to test for development of tumor-specific immunity, the applicant will perform delayed cutaneous hypersensitivity (DCH) testing using autologous tumor cells following treatment. The following comparisons will be made between treatment groups: response (metastasis-free and overall survival, incidence and distribution of metastases); PAM cytotoxicity and DCH reactivity, and; in dogs with macroscopic pulmonary metastatic disease, histologic and immunohistochemical characteristics of surgically removed pulmonary tumor nodules and surrounding matrix, and PAM cytotoxicity before and after L-MTP-PE or placebo.
| MacEwen, E Gregory; Pastor, Josep; Kutzke, Jonathan et al. (2004) IGF-1 receptor contributes to the malignant phenotype in human and canine osteosarcoma. J Cell Biochem 92:77-91 |
| MacEwen, E Gregory; Kutzke, Jon; Carew, Jennifer et al. (2003) c-Met tyrosine kinase receptor expression and function in human and canine osteosarcoma cells. Clin Exp Metastasis 20:421-30 |
