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

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.

MD-1 Deficiency Accelerates Myocardial Inflammation and Apoptosis in Doxorubicin-Induced Cardiotoxicity by Activating the TLR4/MAPKs/Nuclear Factor kappa B (NF-κB) Signaling Pathway

“…Doxorubicin (DOX) is an anthracycline antibiotic commonly used for the treatment of a broad scope of clinical cancers, including soft-tissue sarcomas, leukemias, and lymphomas [1,2]. Despite its effectiveness in the treatment of various cancers, its irreversible and dose-dependent inductions of life-threatening cardiotoxicity to the heart limits its clinical application and remains one of its most important problems [3].…”

Oral Recombinant Methioninase Prevents Obesity in Mice on a High-fat Diet

“…Dietary MR involves severe protein restriction and is unpalatable to most patients for cancer therapy. Enzymatic MR has also been described with methioninase (L-metionine α-deamino-γ-mercaptomethane lyase) (15)(16)(17)(18)(19). Our laboratory has developed recombinant methioninase (rMETase) with the Pseudomonas putida gene inserted in Escherichia coli and has targeted cancer in mouse models with high efficacy, especially in combination with chemotherapy (16)(17)(18)(19).…”

Efficacy of Recombinant Methioninase (rMETase) on Recalcitrant Cancer Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models: A Review

“…The effectiveness of the combination therapy of rMETase and chemotherapy was also shown in pancreatic cancer [50] and several types of sarcoma [52,53,54,55,56] in addition to BRAF-wild melanoma [48,49] (Table 1).…”