Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model

Background/Aim: obesity is a world-wide recalcitrant problem leading to many diseases. Dietary methionine restriction (MR) has been shown to prevent obesity, but it is an onerous regimen. The present study aimed to determine the effects of oral recombinant methionase (o-rMETase), on preventing obesity in mice on a high-fat diet. Materials and Methods: Male C57BL/6J mice in the control group were fed a control diet (CD) (+6.5% fat) for 25 days, and others were fed a high-fat (HF) diet (+34.3% fat) for 25 days. Then, the mice were divided into three dietary groups: 1) HF + phosphate buffered saline (PBS) group; 2) HF + o-rMETase group; and 3) untreated non-HF group. Results: The mice on the CD increased in body weight by 14% during experimental period of 25 days; in contrast the mice in the HF+PBS group increased by 33%; however, the mice on the HF+o-rMETase group increased only by 14% (p=0.02,. Conclusion: The HF+ o-rMETase group had the same weight increase as untreated mice on a normal fat diet, demonstrating the potential for o-rMETase to eliminate the need for dieting to maintain normal body weight. 489

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“…Methionine calculation. Methionine was determined with an HPLC procedure described previously (28,29).…”

Section: Methodsmentioning

confidence: 99%

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

Tashiro

Han

Tan

et al. 2020

In Vivo

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“…We also showed that recombinant methioninase (rMETase) suppressed ES PDOX growth by lowering the blood methionine (MET) and the intra-tumor MET level [24]. However, neither treatment regressed the ES PDOX.…”

Section: Introductionmentioning

confidence: 99%

Combining Tumor-Selective Bacterial Therapy with <b><i>Salmonella typhimurium</i></b> A1-R and Cancer Metabolism Targeting with Oral Recombinant Methioninase Regressed an Ewing’s Sarcoma in a Patient-Derived Orthotopic Xenograft Model

Miyake

Kiyuna

et al. 2018

Chemotherapy

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Background: Ewing’s sarcoma (ES) is a recalcitrant disease in need of transformative therapeutics. Objectives: The aim of this study was to investigate the efficacy of tumor-selective Salmonella typhimurium A1-R combined with tumor metabolism targeting with oral administration of recombinant methioninase (o-rMETase), on an ES patient-derived orthotopic xenograft (PDOX) model. Methods: The ES PDOX models were previously established in the right chest wall. The ES PDOX models were randomized into 5 groups when the tumor volume reached 80 mm³: G1: untreated control; G2: doxorubicin; G3: S. typhimurium A1-R; G4: o-rMETase; G5: S. typhimurium A1-R combined with o-rMETase. All mice were sacrificed on day 15. Body weight and tumor volume were assessed twice a week. Results: S. typhimurium A1-R and o-rMETase respectively suppressed tumor growth as monotherapies (p = 0.050 and p = 0.032). S. typhimurium A1-R combined with o-rMETase regressed tumor growth significantly compared to untreated group on day 15 (p < 0.032). S. typhimurium A1-R combined with o-rMETase group was significantly more effective than S. typhimurium A1-R or o-rMETase monotherapy (p = 0.032, p = 0.032). Conclusions: The present results suggest that the combination of S. typhimurium A1-R and o-rMETase has promise to be a transformative therapy for ES.

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“…Recently, PDOX models of sarcoma (47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64), cervical cancer (65-67) as well as melanoma (68)(69)(70)(71)(72)(73)(74) have also been developed.…”

Section: Patient-derived Orthotopic Xenograft (Pdox) Mouse Models Of mentioning

confidence: 99%

Visualizing the Tumor Microenvironment by Color-coded Imaging in Orthotopic Mouse Models of Cancer

Suetsugu

Shimizu

Saji

et al. 2018

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Abstract. The tumor microenvironment (TME) contains stromal cells in a complex interaction with cancer cells. This relationship has become better understood with the use of fluorescent proteins for in vivo imaging cancer-cell or stromal-cell targeting by potential therapeutics can be visualized. Color-coded imaging enabled the visualization of apparent fusion of cancer and stromal cells. Color-coded imaging is a powerful tool visualizing the interaction of cancer and stromal cells during cancer progression and treatment.In vivo imaging with fluorescent proteins was pioneered by our laboratories and has been particularly useful for studying tumor growth, invasion, cancer-cell trafficking, metastasis, angiogenesis, and other aspects of tumor progression (1-5). Multicolored proteins have allowed the color-coding of cancer cells growing in vivo such as between highly-and poorly-metastatic cells, cancer stem and non-stem cells, and gene transfer between cancer cells (3, 4,(6)(7)(8)(9)(10)(11)(12)(13).The present review focuses on color-coded imaging of cancer and stromal cells in the tumor microenvironment (TME).Transgenic nude mice expressing fluorescent proteins for colorcode imaging of the TME. The green fluorescent protein (GFP)-expressing athymic nude mouse was obtained by crossing nontransgenic nude mice with the transgenic C57/B6 GFP mouse in which the β-actin promoter drives GFP. In the adult GFP nude mice, most organs brightly expressed GFP, including the heart, lungs, spleen, pancreas, esophagus, stomach, duodenum, and the entire digestive system from the tongue to the anus; the male and female reproductive systems; brain and spinal cord; and the circulatory system, including the heart and major arteries and veins. The bared skeleton also highly expressed GFP (14).

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Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model

Cited by 73 publications

References 49 publications

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

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

Combining Tumor-Selective Bacterial Therapy with <b><i>Salmonella typhimurium</i></b> A1-R and Cancer Metabolism Targeting with Oral Recombinant Methioninase Regressed an Ewing’s Sarcoma in a Patient-Derived Orthotopic Xenograft Model

Visualizing the Tumor Microenvironment by Color-coded Imaging in Orthotopic Mouse Models of Cancer

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