Purpose: Cancers are methionine (MET) and methylation addicted, causing them to be highly sensitive to MET restriction. The present study determined the efficacy of restricting MET with oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, azacitidine (AZA) on a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. Methods: The osteosarcoma PDOX models were randomized into five treatment groups of six mice: control; doxorubicin (DOX) alone; AZA alone; o-rMETase alone; o-rMETase-AZA combination. Tumor size and body weight were measured during the 14 days of treatment. Results: We found that tumor growth was arrested only by the o-rMETase–AZA combination treatment, as tumors with this treatment exhibited tumor necrosis with degenerative change. Conclusion: This study suggests that o-rMETase-AZA combination has clinical potential for patients with chemoresistant osteosarcoma.
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