Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model
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Kentaro Igarashi1,2,3, Kei Kawaguchi1,2, Shukuan Li1, Qinghong Han1, Yuying Tan1, Emily Gainor1, Tasuku Kiyuna1,2, Kentaro Miyake1,2, Masuyo Miyake1,2, Takashi Higuchi1,2, Hiromichi Oshiro1,2, Arun S. Singh4, Mark A. Eckardt5, Scott D. Nelson6, Tara A. Russell7, Sarah M. Dry6, Yunfeng Li6, Norio Yamamoto3, Katsuhiro Hayashi3, Hiroaki Kimura3, Shinji Miwa3, Hiroyuki Tsuchiya3, Fritz C. Eilber7 and Robert M. Hoffman1,2
1AntiCancer, Inc., San Diego, California, USA
2Department of Surgery, University of California, San Diego, California, USA
3Department of Orthopaedic Surgery, Kanazawa University, Kanazawa, Japan
4Division of Hematology-Oncology, University of California, Los Angeles, CA, USA
5Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA
6Department of Pathology, University of California, Los Angeles, CA, USA
7Division of Surgical Oncology, University of California, Los Angeles, CA, USA
Robert M. Hoffman, email: [email protected]
Fritz C. Eilber, email: [email protected]
Hiroyuki Tsuchiya, email: [email protected]
Keywords: synovial sarcoma; patient-derived orthotopic xenograft; PDOX; recombinant methioninase; doxorubicin
Received: February 22, 2018 Accepted: March 15, 2018 Published: April 10, 2018
Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks; G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48; rMETase: p < 0.005; DOX combined with rMETase < 0.0001). DOX combined with rMETase was significantly more effective than both DOX alone (p < 0.001) and rMETase alone (p < 0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r-METase can overcome DOX-resistance in this recalcitrant disease.
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