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

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