Oral-recombinant Methioninase Lowers the Effective Dose and Eliminates Toxicity of Cisplatinum for Primary Osteosarcoma of the Mammary Gland in a Patient-derived Orthotopic Xenograft Mouse Model

Abstract

Background/Aim: Primary osteosarcoma of the mammary gland is a very rare disease, accounting for under 1% of all mammary gland malignancies. There is no established first-line treatment, and prognosis is poor compared to conventional breast cancer. We previously demonstrated the efficacy of cisplatinum and eribulin in a patient-derived orthotopic xenograft (PDOX) mouse model of primary breast osteosarcoma. However, these drugs show significant clinical toxicity. All cancers are addicted to methionine (Hoffman effect). In the present study, we determined whether methionine restriction with oral recombinant methioninase (o-rMETase) would lower the effective dose of cisplatinum in a PDOX model of primary osteosarcoma of the mammary gland, thereby reducing its toxicity. Materials and Methods: Mouse PDOX models of primary osteosarcoma of the breast were randomized into the following groups: control; cisplatinum (weekly at 3 or 6 mg/kg); twice-daily o-rMETase; or o-rMETase combined with 3 mg/kg cisplatinum, with treatment for 2 weeks. Results: Cisplatinum at 6 mg/kg significantly inhibited breast osteosarcoma growth compared with the untreated control and mice treated with 3 mg/kg cisplatinum (p=0.01 and 0.009, respectively). There was no significant difference in tumor growth between mice treated with cisplatinum at 3 mg/kg and the control (p=0.16). Combination therapy with cisplatinum at 3 mg/kg and twice daily o-rMETase regressed the osteosarcoma of the mammary gland (p=0.009), similar to the inhibition by cisplatinum at 6 mg/kg alone. Cisplatinum at 6 mg/kg caused a significant loss of mouse body weight, compared to the control (p=0.02). There was no significant body-weight loss with the combination therapy of o-rMETase and cisplatinum at 3 mg/kg, compared to the untreated control. Conclusion: o-rMETase halved the effective dose of cisplatinum, thereby eliminating cisplatinum toxicity, demonstrating a future clinical strategy for therapy of osteosarcoma of the breast.

Recombinant Methioninase Lowers the Effective Dose of Regorafenib Against Colon-Cancer Cells: A Strategy for Widespread Clinical Use of a Toxic Drug

“…The results of the present study suggest that rMETase, when combined with regorafenib, can reduce the effective dose of regorafenib and thereby also reduce its toxicity. Previously, we showed in an orthotopic mouse model of osteosarcoma that combining rMETase with cisplatinum reduced its effective dose by 50% (18). A similar effect is predicted for the combination of regorafenib and rMETase in future in vivo experiments.…”

Synergy of Combining Methionine Restriction and Chemotherapy: The Disruptive Next Generation of Cancer Treatment

“…Hoshiya et al originally demonstrated the synergistic efficacy of cisplatinum and methionine restriction in vitro and on a xenograft mouse model utilizing the human breast cancer cell line MX-1 (34). In addition, cisplatinum combined with rMETase showed efficacy for colon cancer cell lines (Colo205, SW620, HCT15, and HT29) xenograft mouse models (35), and osteosarcoma PDOX and orthotopic xenograft mouse models (36)(37)(38), and a bladder-cancer orthotopic mouse model (39).…”

Precise and Facile Endotracheal Lung-tumor-implantation Mouse Model Visualized by GFP Expression

“…All mice were kept under standard conditions of 12 h light/dark cycles and were maintained and bred in a barrier facility with a high efficacy particulate air (HEPA)-filtered rack. An Institutional Animal Care and Use Committee (IACUC) protocol was approved, in accordance with the National Institutes of Health (NIH) Guide for the Care and Use of Animals, under Assurance Number A3873-1, as previously described in studies of mouse models of osteosarcoma (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32).…”