Oral recombinant methioninase combined with oxaliplatinum and 5-fluorouracil regressed a colon cancer growing on the peritoneal surface in a patient-derived orthotopic xenograft mouse model
Introduction
The elevated methionine (MET) requirement of cancer cells is referred to as MET dependence (Hoffman, 1984, 2015a, 2017; Stern and Hoffman, 1984; Wang et al., 2019). The elevated MET use in cancer is called the "Hoffman effect" analogous to the Warburg effect of excess glucose consumption by cancers. Comparison of radioactive MET- and glucose- PET (positron-emission tomography) imaging has shown a stronger signal with MET suggesting that the Hoffman effect is more pronounced than the Warburg effect (Hoffman, 2015a, 2017; Xu et al., 2017).
MET restriction by recombinant methioninase (rMETase) can inhibit the growth of cancer cells in vitro and in vivo (Hoffman, 2015a, 2017). rMETase has been used as a treatment strategy for various types of cancer (Hoffman, 2015a; Kreis and Hession, 1973; Tan et al., 2010; Xin et al., 2013, 2018; Yano et al., 2014, 2016).
Previous studies have shown that intra-peritoneal recombinant methioninase injection (ip-rMETase) was effective against patient-derived orthotopic xenograft (PDOX) mouse models of recalcitrant cancer (Kawaguchi et al., 2017a,2018a,c; Igarashi et al., 2018a,b]. Recently, we reported that oral recombinant methioninase (o-rMETase) was significantly more effective than intraperitoneal injection rMETase (ip-rMETase) indicating the potential widespread use of rMETase for cancer treatment (Higuchi et al., 2018; Higuchi et al., 2019; Kawaguchi et al., 2018a; Kawaguchi et al., 2017b; Kawaguchi et al., 2018d; Oshiro et al., 2019; Park et al., 2019a).
Orthotopic implantation of intact tumor tissue in appropriate mouse models can result in metastasis resembling the clinical pattern, unlike subcutaneous transplantation. Our laboratory has used surgical orthotopic implantation (SOI) to establish PDOX nude-mouse models from patient tumor specimens (Fu and Hoffman, 1993; Hiroshima et al., 2014; Hiroshima et al., 2015; Hoffman, 2015b; Igarashi et al., 2018a,2018b,c; Kawaguchi et al., 2017a,2017b; Kawaguchi et al., 2018c,d,e; Kawaguchi et al., 2016; Kiyuna et al., 2016; Metildi et al., 2014; Murakami et al., 2016; Wang et al., 1992; Yamamoto et al., 2016). The PDOX orthotopic models are much more patient-like than the ectopic subcutaneous models (Hoffman, 2015b). However, in orthotopic models, it is difficult to visualize tumor growth. To address this problem of imaging such orthotopic tumor grafts, we have recently developed the technology to introduce fluorescent protein-expressing stroma into tumors by passaging tumor grafts through transgenic nude mice expressing fluorescent protein (Suetsugu et al., 2012).
The present report demonstrates the efficacy of o-rMETase using a PDOX model of colon cancer growing on the peritoneal surface in nude mouse, with brightly labeled red fluorescent protein (RFP)-expressing stroma for imaging.
Section snippets
Mice
Athymic nu/nu nude mice and transgenic RFP expressing athymic nu/nu mice (four to 6 weeks) were obtained from AntiCancer Inc. (San Diego, CA). All surgical procedures and imaging were performed in accordance with an AntiCancer Institutional Animal Care and Use Committee (IACUC)-protocol specifically approved for this study, and in accordance with the principles and procedures outlined in the National Institutes of Health Guide for the Care and Use of Animals under Assurance Number A3873-1.
Non-invasive red fluorescence imaging of colon cancer growing on the peritoneal surface of the PDOX model
Orthotopically-implanted tumors grew in the peritoneum of non-transgenic nude mice. These tumors had sufficient red fluorescent stroma from previous growth in RFP nude mice to permit non-invasive imaging through the abdominal wall (Fig. 1A-D). Confocal laser microscopy showed persistence of the RFP-expressing stroma in frozen sections (Fig. 2A, B).
Tumor histology
Histologically, the untreated control tumor mainly comprised viable carcinoma cells. (Fig. 2C) In contrast, tumor treated with the combination of
Discussion
Recently, a paper appeared with the title “The new anticancer era: tumor metabolism targeting” (Borriello and Della Ragione, 2017). However, this “new anticancer era” started in 1959 with the observation of Sugimura et al. that depriving animals of MET arrested tumor growth (Sugimura et al., 1959). The Warburg effect refers to the significantly increased uptaked glucose by cancer cells. In addition to calorie restriction, specific amino acid restriction has been studied in the past to treat
Declaration of Competing Interest
JHP, HO, KM, TH, SNY, ZZ, NS, JY and RMH are or were unsalaried associates of AntiCancer Inc. QH, MZ and YT are employee of AntiCancer Inc. AntiCancer Inc. uses PDOX models for contract research. The Authors declare that there are no potential conflicts of interest.
Acknowledgements
This paper is dedicated to the memory of A.R. Moossa, Sun Lee, MD, Professor Li Jiaxi and Masaki Kitajima, MD.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
References (47)
Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis. A review and synthesis
Biochim. Biophys. Acta
(1984)- et al.
Combination therapy of tumor-targeting Salmonella typhimurium A1-R and oral recombinant methioninase regresses a BRAF-V600E-negative melanoma
Biochem. Biophys. Res. Commun.
(2018) - et al.
Oral recombinant methioninase (o-rMETase) is superior to injectable rMETase and overcomes acquired gemcitabine resistance in pancreatic cancer
Cancer Lett.
(2018) - et al.
Fluorescence-guided surgery of prostate cancer bone metastasis
J. Surg. Res.
(2014) - et al.
Gemcitabine combined with docetaxel precisely regressed a recurrent leiomyosarcoma peritoneal metastasis in a patient-derived orthotopic xenograft (PDOX) model
Biochem. Biophys. Res. Commun.
(2019) - et al.
Low methionine ingestion by rats extends life span
J Nutr
(1993) - et al.
Quantitative nutritional studies with water-soluble, chemically defined diets. VIII. The forced feeding of diets each lacking in one essential amino acid
Arch. Biochem. Biophys.
(1959) - et al.
Nutritional control of aging
Exp. Gerontol.
(2003) - et al.
The new anticancer era: tumor metabolism targeting
Cell Cycle
(2017) - et al.
Human ovarian carcinoma metastatic models constructed in nude mice by orthotopic transplantation of histologically-intact patient specimens
Anticancer Res.
(1993)
Oral Recombinant Methioninase Combined with Caffeine and Doxorubicin Induced Regression of a Doxorubicin-resistant Synovial Sarcoma in a PDOX Mouse Model
Anticancer Res.
Oral Recombinant Methioninase, Combined With Oral Caffeine and Injected Cisplatinum, Overcome Cisplatinum-Resistance and Regresses Patient-derived Orthotopic Xenograft Model of Osteosarcoma
Anticancer Res.
Metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model is inhibited by neoadjuvant chemotherapy in combination with fluorescence-guided surgery with an anti-CA 19-9-conjugated fluorophore
PLoS One
Tumor-Targeting Salmonella typhimurium A1-R Arrests a Chemo-Resistant Patient Soft-Tissue Sarcoma in Nude Mice
PLoS One
Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey
Expert Opin. Biol. Ther.
Patient-derived orthotopic xenografts: better mimic of metastasis than subcutaneous xenografts
Nat. Rev. Cancer
The wayward methyl group and the cascade to cancer
Cell Cycle
Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: decoy, trap and kill chemotherapy moves toward the clinic
Cell Cycle
Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase
J. Cell Biochem.
Vemurafenib-resistant BRAF-V600E-mutated melanoma is regressed by MEK-targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model
Oncotarget
Combination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma in a patient-derived orthotopic xenograft (PDOX) mouse model
Oncotarget
Tumor-Targeting Salmonella typhimurium A1-R Sensitizes Melanoma With a BRAF-V600E Mutation to Vemurafenib in a Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model
J. Cell Biochem.
Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for chronic clinical cancer therapy and prevention
Cell Cycle
Cited by (20)
Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer
2023, Biochemical and Biophysical Research CommunicationsCitation Excerpt :It has been shown to reduce blood methionine levels for up to 6 h after oral administration, making it more realistic than intraperitoneal administration [23]. o-rMETase has also shown efficacy in mouse models of various cancers and has shown synergy in combination with chemotherapy including gemcitabine, 5-FU, etc. [25,26,34,40,41]. We have already started to use rMETase in clinical practice: rMETase was administered every two weeks in combination with the combination of 5-fluorouracil/leucovorin, irinotecan, and oxaliplatinum for Stage IV advanced pancreatic cancer and in combination with a low methionine diet [42].
Combination of oral recombinant methioninase and decitabine arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma patient-derived orthotopic xenograft mouse model
2020, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Recombinant methioninase (rMETase), a Pseudomonas putida enzyme cloned in Escherichia coli, targets MET-addicted cancer cells by severely depleting MET [15,16]. We have reported the efficacy of oral administrations of rMETase (o-rMETase) on various chemo-resistant cancers grown in patient derived orthotopic xenograft (PDOX) models [17–20]. Decitabine (5-Aza-2′-deoxycytidine, DAC), a deoxy-derivative of azacitidine, is an epigenetic drug that binds irreversibly to DNA methyltransferase and causes DNA hypomethylation when incorporated into newly synthesized DNA [21].
Artificial Diets with Altered Levels of Sulfur Amino Acids Induce Anticancer Activity in Mice with Metastatic Colon Cancer, Ovarian Cancer and Renal Cell Carcinoma
2023, International Journal of Molecular Sciences