Takashi Higuchi1,2,3, Norihiko Sugisawa1,2, Jun Yamamoto1,2, Hiromichi Oshiro1,2, Qinghong Han1, Norio Yamamoto3, Katsuhiro Hayashi3, Hiroaki Kimura3, Shinji Miwa3, Kentaro Igarashi3, Yuying Tan1, Shreya Kuchipudi4, Michael Bouvet2, Shree Ram Singh5, Hiroyuki Tsuchiya6, Robert M Hoffman7,8. 1. AntiCancer, Inc, 7917 Ostrow Street, San Diego, CA, 92111, USA. 2. Department of Surgery, University of California, San Diego, CA, USA. 3. Department of Orthopedic Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan. 4. Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA. 5. Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA. singhshr@mail.nih.gov. 6. Department of Orthopedic Surgery, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8641, Japan. tsuchi@med.kanazawa-u.ac.jp. 7. AntiCancer, Inc, 7917 Ostrow Street, San Diego, CA, 92111, USA. all@anticancer.com. 8. Department of Surgery, University of California, San Diego, CA, USA. all@anticancer.com.
Abstract
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.
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.