Journal Article

Oral-recombinant Methioninase Converts an Osteosarcoma from Methotrexate-resistant to -sensitive in a Patient-derived Orthotopic-xenograft (PDOX) Mouse Model

Jun, Yamamoto, Michael, Bouvet, Noriyuki, Masaki, Kotaro, Nishida, Yutaro, Kubota, Yasunori, Tome, Kazuyuki, Hamada, Robert M, Hoffman, Yusuke, Aoki, Qinghong, Han

2022

Overview

Osteosarcoma is the most common bone sarcoma. Although surgery and chemotherapy are initially effective, the 5-year survival is approximately 60% to 80%, and has not improved over three decades. We have previously shown that methionine restriction (MR) induced by oral recombinant methioninase (o-rMETase), is effective against osteosarcoma in patient-derived orthotopic xenograft (PDOX) nude-mouse models. In the present report, the efficacy of the combination of oral o-rMETase and methotrexate (MTX) was examined in an osteosarcoma PDOX mouse model. An osteosarcoma-PDOX model was previously established by implanting tumor fragments into the proximal tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups: control; o-rMETase alone; MTX alone; combination of o-rMETase and MTX. The mice were sacrificed after 4 weeks of treatment. The combination of o-rMETase and MTX showed significantly higher efficacy compared to the control group (p=0.04). The combination also showed significantly higher efficacy compared to MTX alone (p=0.04). No significant efficacy of o-rMETase alone or MTX alone compared to control was shown (p=0.21, 1.00, respectively). Only the combination of o-rMETase and MTX reduced the cancer-cell density in the osteosarcoma tumor. rMETase converted an osteosarcoma PDOX from MTX-resistant to MTX-sensitive and thereby shows future clinical potential.

• Publisher: Anticancer Research USA Inc,International Institute of Anticancer Research
• Subject: Administration, Oral / Animal models / Animals / Antimetabolites, Antineoplastic / Antimetabolites, Antineoplastic - therapeutic use / Antineoplastic Combined Chemotherapy Protocols / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Bone cancer / Bone Neoplasms / Bone Neoplasms - drug therapy / Bone Neoplasms - pathology / Bone surgery / Bone tumors / Cancer therapies / Carbon-Sulfur Lyases / Carbon-Sulfur Lyases - therapeutic use / Cell cycle / Cell density / Chemotherapy / Dihydrofolate reductase / Disease Models, Animal / Drug Resistance, Neoplasm / Drug Resistance, Neoplasm - drug effects / Effectiveness / Humans / Medical prognosis / Medical research / Methionine / Methotrexate / Methotrexate - therapeutic use / Mice / Mice, Nude / Osteosarcoma / Osteosarcoma - drug therapy / Osteosarcoma - pathology / Patients / Salmonella / Sarcoma / Tibia / Treatment Outcome / Tumor Burden / Tumor Burden - drug effects / Tumors / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation