Oral recombinant methioninase (o-rMETase) is superior to injectable rMETase and overcomes acquired gemcitabine resistance in pancreatic cancer

Kawaguchi, Koji; Miyake, Kentaro; Han, Qinghong; Li, Shukuan; Tan, Yuying; Igarashi, Kentaro; Kiyuna, Tasuku; Miyake, Masuyo; Higuchi, Takashi; Oshiro, Hiromichi; Zhang, Zhiying; Razmjooei, Sahar; Wangsiricharoen, Sintawat; Bouvet, Michael; Singh, Shree Ram; Unno, Michiaki; Hoffman, Robert M.

doi:10.1016/j.canlet.2018.06.016

Cited by 57 publications

(54 citation statements)

References 82 publications

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“…Our laboratory has recently developed oral rMETase (o-rMETase) which has been shown to be highly effective in mouse models of cancer as injectable o-rMETase (20)(21)(22)(23)(24)(25)(26)(27). In the present report, we show that o-rMETase prevents obesity in mice on a high-fat diet, thereby opening a new paradigm for obesity prevention.…”

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confidence: 55%

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

Tashiro

Han

Tan

et al. 2020

In Vivo

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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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confidence: 55%

“…Our laboratory developed rMETase from Pseudomonas putida, cloned in Escherichia coli, as a very efficient means of MR (16). A big advance was our laboratory's development of o-rMETase which makes administration safe and easy without side-effects (20,(21)(22)(23)(24)(25)(26)(27).…”

Section: Discussionmentioning

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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“…The elevated use of MET in cancer appears to be due to aberrant transmethylation reactions [25]. Recently, we reported the efficacy of oral administration of rMETase on melanoma and pancreatic cancer PDOX model [26, 35]. …”

Section: Resultsmentioning

confidence: 99%

“…1a). These dosages were determined as previously described [10, 14, 26]. Tumor size and body weight were checked 2 times a week.…”

Section: Methodsmentioning

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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“…Athymic nu/nu nude mice (AntiCancer, Inc., San Diego, CA, USA), 4-6 weeks old, were used in this experiment. Animal housing and their diet were as previously described (10). Mice were observed on a daily basis and humanely sacrificed by CO 2 inhalation with humane-endpoint criteria described in previous publications (10,11).…”

Section: Methodsmentioning

confidence: 99%

Induction of Metastasis by Low-dose Gemcitabine in a Pancreatic Cancer Orthotopic Mouse Model: An Opposite Effect of Chemotherapy

Sugisawa¹,

Miyake²,

Higuchi³

et al. 2019

Anticancer Res

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Background/Aim: Gemcitabine is standard first-line treatment for patients with advanced pancreatic cancer, however the efficacy is limited. Although acquired drug resistance and side-effects are known to limit efficacy, opposite effects of a drug, which enhance the malignancy of treated cancer, have been observed but are not well understood. The aim of the present study was to determine whether gemcitabine has such opposite effects on the BxPC-3 human pancreatic cancer cell line expressing green fluorescent protein in an orthotopic mouse model. Materials and Methods: BxPC-3-GFP tumors grown subcutaneously in nude mice were harvested. Tumor fragments were orthotopically implanted in the tail of the pancreas of nude mice using the technique of surgical orthotopic implantation. The BxPC-3-GFP orthotopic models were divided randomly into three groups: Group 1: untreated control; Group 2: low-dose gemcitabine (weekly intraperitoneal injection at 25 mg/kg for 6 weeks); Group 3: high-dose gemcitabine (weekly intraperitoneal injection at 125 mg/kg for 6 weeks). Each group comprised eight mice. Tumor size, fluorescent area of metastases, and body weight were measured. Results: Low-and high-dose gemcitabine inhibited primary tumor growth in a dose-dependent manner, and to the greatest extent by high-dose gemcitabine compared to the untreated control (p=0.0134). In contrast, the extent of metastasis on the peritoneum was significantly increased by low-dose gemcitabine compared to the untreated control (p=0.0112). The extent of metastasis showed no significant difference between the untreated control and mice treated with high-dose gemcitabine. Body weight of the treated mice was not significantly different from that of the untreated mice. Conclusion: The use of very bright GFP expressing of BxPC-3 cells and the orthotopic model demonstrated an unexpected increase in metastasis by low-dose gemcitabine. Future experiments will investigate the mechanism of this phenomenon.Pancreatic cancer accounts for approximately 3% of all cancer in the United States and about 7% of all cancer deaths (1). The 5-year survival rate of patients diagnosed with pancreatic cancer is still only 9%, despite improvements in the past decade. Gemcitabine has been standard first-line treatment for patients with advanced pancreatic cancer since 1997 (2). Although many clinical trials tested new chemotherapy drugs combined with gemcitabine for pancreatic cancer, only combination therapy with nab-paclitaxel has been shown to be superior to gemcitabine alone (3).The efficacy of chemotherapy against pancreatic cancer is limited in most cases due to drug resistance. Chemotherapy itself may induce some changes in the tumor microenvironment which can promote cancer cell proliferation and metastasis (4). We previously showed that the chemotherapeutic cyclophosphamide actually enhanced the malignancy of implanted 5339 This article is freely accessible online.

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Oral recombinant methioninase (o-rMETase) is superior to injectable rMETase and overcomes acquired gemcitabine resistance in pancreatic cancer

Cited by 57 publications

References 82 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

Induction of Metastasis by Low-dose Gemcitabine in a Pancreatic Cancer Orthotopic Mouse Model: An Opposite Effect of Chemotherapy

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