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Research Papers:

Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model

Kentaro Igarashi, Kei Kawaguchi, Shukuan Li, Qinghong Han, Yuying Tan, Emily Gainor, Tasuku Kiyuna, Kentaro Miyake, Masuyo Miyake, Takashi Higuchi, Hiromichi Oshiro, Arun S. Singh, Mark A. Eckardt, Scott D. Nelson, Tara A. Russell, Sarah M. Dry, Yunfeng Li, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Hiroyuki Tsuchiya, Fritz C. Eilber and Robert M. Hoffman _

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Oncotarget. 2018; 9:19263-19272. https://doi.org/10.18632/oncotarget.24996

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Abstract

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

Correspondence to:

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

ABSTRACT

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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