Research ArticleArticle
Open Access

Oral Installation of Recombinant Methioninase-producing Escherichia coli into the Microbiome Inhibits Colon-cancer Growth in a Syngeneic Mouse Model

YUTARO KUBOTA, QINGHONG HAN, KAZUYUKI HAMADA, YUSUKE AOKI, NORIYUKI MASAKI, KOYA OBARA, ANTON BARANOV, MICHAEL BOUVET, TAKUYA TSUNODA and ROBERT M. HOFFMAN
Cancer Genomics & Proteomics November 2022, 19 (6) 683-691; DOI: https://doi.org/10.21873/cgp.20351

Abstract

Background/Aim: All cancer types so far tested are methionine-addicted. Targeting the methionine addiction of cancer with recombinant methioninase (rMETase) has shown great progress in vitro, in mouse models, and in the clinic. However, administration of rMETase requires multiple doses per day. In the present study, we determined if rMETase-producing Escherichia coli JM109 (E. coli JM109-rMETase) might be an effective anticancer agent when installed into the microbiome. Materials and Methods: E. coli JM109-rMETase was administered to a syngeneic model of MC38 colon cancer growing subcutaneously in C57BL/6 mice. JM109-rMETase was administered orally by gavage to the mice twice per day. Tumor size was measured with calipers. Results: The administration of E. coli JM109-rMETase twice a day significantly inhibited MC38 colon-cancer growth. E. coli JM109-rMETase was found in the stool of treated mice, indicating it had entered the microbiome. Conclusion: The present study indicates the potential of microbiome-based treatment of cancer targeting methionine addiction.

Key Words:

Cancer cells are generally addicted to methionine (1-6) due to excess transmethylation reactions occurring in cancer cells (7-10). Therefore, cancer cells require a greater amount of methionine than normal cells. Cancer cells cannot survive under conditions of methionine restriction (1-10). This specific feature of methionine addiction is a fundamental and general hallmark of cancer and is termed the Hoffman effect (11). Under the condition of methionine restriction, cancer cells are arrested in the late S/G2 phase of the cell cycle (12-14).

Methionine restriction is effective against cancer in vitro and in vivo (1-10, 14-18). Methionine restriction of cancer cells sensitizes them to cytotoxic chemotherapy, possibly due to late S/G2 cell-cycle arrest (16, 19-22). Recently, Gao et al. confirmed our findings that methionine restriction enhanced chemotherapy efficacy, using colorectal cancer and soft-tissue sarcoma in patient-derived xenograft models. The report of Gao et al. also showed that methionine restriction disrupts the flux of one-carbon metabolism and affects vulnerabilities involving redox and nucleotide metabolism in the patient-derived xenograft model and human studies (23). Dietary methionine restriction combined with cytotoxic agents showed efficacy over the cytotoxic agent alone in clinical trials of melanoma, glioma, colorectal cancer, and gastric cancer (24-27).

All protein sources contain methionine, and it is difficult for patients with cancer to restrict methionine strictly by diet alone. For this reason, we have developed recombinant methioninase (rMETase), which breaks down methionine (17, 28, 29). rMETase is produced by fermentation of recombinant Escherichia coli transformed with the methioninase gene from Pseudomonas putida (P. putida) (28, 29). Recently, we have reported the efficacy of rMETase for multiple cancer types using the patient-derived orthotopic xenograft model (18, 30-39). rMETase was initially administered by intravenous or intraperitoneal injection. However, recently we showed that rMETase was highly effective when administered orally (40-54). However, oral administration of methioninase requires multiple doses each day. Therefore, in the present study, we investigated the efficacy of rMETase-producing E. coli JM109 (E. coli JM109-rMETase) when installed orally to the microbiome. We hypothesized that when E. coli JM109-rMETase is in the microbiome, rMETase can be delivered constantly to the intestine and inhibit tumor growth.

Materials and Methods

Culture of E. coli JM109-rMETase. E. coli JM109 was used as the host strain for the expression of rMETase. The rMETase gene from P. putida was cloned into E. coli JM109 using plasmid pATG3131, which also includes the tetracycline (TC) resistance gene (28, 29). The resulting E. coli JM109-rMETase was pre-cultured in 5 ml of Luria-Bertani (LB) liquid medium with TC (32 μg/ml) for 8 hours at 37°C. Preculture broth was transferred to a 400 ml culture medium with TC (32 μg/ml) and cultivated overnight. After culture, isopropyl-β-D-thiogalactopyranoside (IPTG) was added at a final concentration of 0.3 mM for 4 hours at 28°C to induce expression of rMETase. The optical density at 600 nM was used to determine the amount of live E. coli JM109-rMETase in the medium. After manually counting colonies, we determined that an O.D. 600 of 0.7 comprises approximately 1.0×109 colony-forming units (CFU)/ml of E. coli JM109-rMETase. E. coli JM109-rMETase was harvested and diluted with phosphate-buffered saline (PBS), and 20% glycerin was added for storage at −80°C until administration to mice.

E. coli JM109 competent cells were prepared the same as E. coli JM109-rMETase but without TC in the LB medium, and IPTG was not added to the culture.

E. coli JM109-rMETase tolerability study in C57BL/6 mice. Firstly, we conducted a preliminary study to evaluate the tolerability of the C57BL/6 mouse to E. coli JM109-rMETase. Three different doses of E. coli JM109-rMETase (106, 108 and 1010 CFU/100 μl) were prepared and fed by oral gavage to healthy C57BL/6 mice in the morning and evening, for 1 week, and the weight of each mouse was assessed.

rMETase activity assay. rMETase activity was determined from α-ketobutyrate produced from L-methionine, as previously reported (55). We examined the rMETase activity produced by different amounts E. coli JM109-rMETase. Assuming an intestinal environment, 20 mM deoxycholic acid was added to E. coli JM109-rMETase treated with IPTG, as described above, in order to release the rMETase from the bacteria (56). After the addition of 0.5 mM pyridoxal 5’-phosphate and 0.5 mg/ml dithiothreitol for 3 hours, rMETase activity was evaluated.

We examined rMETase activity in E. coli, cultured with IPTG, from mouse stool. We adjusted the bacterial density and sonicated the bacteria for 30 seconds after adding, pyridoxal 5’-phosphate and dithiothreitol and then evaluated rMTEase activity.

Animals and diets. C57BL/6 mice (AntiCancer Inc., San Diego, CA, USA) aged 4-6 weeks old were used in the present study. The mice were housed in a barrier facility with a HEPA-filtered rack under typical light/dark cycles of 12 hours. An autoclaved laboratory rodent diet was fed to mice from 9 a.m. to 5 p.m. during this study. Approval was received from the AntiCancer Institutional Animal Care and Use Committee’s ethical committee under National Institutes of Health Guide Assurance Number 3873-1. All experiments were performed in accordance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) 2.0 criteria (57).

Cell culture. The MC38 mouse colon cancer cell line (58) was cultured in high-glucose Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum and 100 IU/ml penicillin/streptomycin at 37°C in a humidified environment containing 5% carbon dioxide.

Establishment of subcutaneous tumors. Eighteen C57BL/6 male mice were injected subcutaneously with 106 MC38 cells in the right flank. One week after injection, subcutaneous tumors were established.

Treatment study design. Mice implanted with MC38 subcutaneously were randomized into three groups of six mice each: Group 1: Untreated control given 100 μl PBS orally twice daily (9 a.m. and 5 p.m.) for 14 days; Group 2: E. coli JM109 competent cells (1010/100 μl) orally by gavage twice daily (9 a.m. and 5 p.m.) for 14 days: Group 3: E. coli JM109-rMETase cells (1010/100 μl) orally by gavage twice daily (9 a.m. and 5 p.m.) for 14 days. TC (0.5 g/l) was added to the mouse’s drinking water to prevent plasmid shedding only in group 3 (29). Tumor volume and body weight were measured every 2 days during the treatment. Tumor volume (mm3) was calculated with the following formula: Tumor volume (mm3)=length (mm) × width (mm) × width (mm) × 1/2.

Stool and tissue collection. Mouse stool was collected before treatment (day 0) and on the evening of day 14. The mice were sacrificed on day 15, and the tumor was removed.

Mouse stool culture. We performed stool culture to examine whether E. coli JM109-rMETase was incorporated into the mouse microbiome or not. The stool was diluted 1:10 by weight into PBS and then homogenized by mechanical disruption. Large debris was pelletized with short centrifugation at 200 × g. Then 100 μl of supernatant was plated onto LB agar with 32 μg/ml TC and incubated overnight at 37°C.

Screening for E. coli JM109-rMETase in mouse stool culture. We performed Gram staining of colonies formed from stool culture. The Gram-negative bacterial colonies were plated on a modified M9 medium with TC (32 μg/ml) and IPTG (0.3 mM) to determine whether these bacteria produced rMETase or not. The modified M9 medium contained 6 g/l disodium hydrogen phosphate, 3 g/l potassium dihydrogen phosphate, 0.5 g/l sodium chloride, 5 g/l L-methionine, 0.24 g/l magnesium sulfate, 0.011 g/l calcium chloride, 2 g/l glucose, 32 μg/ml TC, and 0.3 mM IPTG. Before pouring the plates, phenol red was added to the medium as an indicator for methioninase at a final concentration of 0.007% (w/v) at a pH of 7.0 (59, 60). We determined whether colonies produced rMETase based on the pink color of the colonies because ammonium, produced from methionine by rMETase, makes the colony pink due to phenol red in the modified M9 medium.

Statistics. All statistical analyses were performed with GraphPad Prism 9.4.0 (GraphPad Software, Inc., San Diego). Tukey-Kramer was performed for the parametric test of comparison between groups. All data are displayed as the mean±standard deviation. p-Values ≤0.05 were regarded as significant.

Results

Tolerability of E. coli JM109-rMETase in C57BL/6 mice. Different amounts of E. coli JM109-rMETase administered orally in C57BL/6 mice for 1 week allowed the body weight of mice to be maintained at all amounts tested, indicating E. coli JM109-rMETase was therefore not toxic (Figure 1).

Figure 1.
Figure 1.

Tolerability of C57BL/6 mice to recombinant methioninase (rMETase)-producing Escherichia coli JM109 (E. coli JM109-rMETase) as shown by body weight. CFU: Colony-forming units.

rMETase activity at different E. coli JM109-rMETase cell densities. The rMETase activity of 1011 CFU/ml E. coli JM109-rMETase was 39.7 U/ml compared to 7.9 U/ml for 1010 CFU/ml E. coli JM109-rMETase. Based on these results, the dose of E. coli JM109-rMETase to be used in subsequent experiments was determined to be 1010 CFU/100 μl every morning and evening for 2 weeks.

Antitumor efficacy of oral E. coli JM109-rMETase. E. coli JM109-rMETase significantly inhibited MC-38 tumor growth in C57BL6 mice compared to the untreated control or non-rMETase-producing E. coli JM109 competent cells (control vs. E. coli JM109-rMETase: p=0.0267; E. coli JM109 competent cells vs. E. coli JM109-rMETase: p=0.03) (Figure 2A and B, and Figure 3).

Figure 2.
Figure 2.

Efficacy of recombinant methioninase (rMETase)-producing Escherichia coli JM109 (E. coli JM109-rMETase) on the syngeneic MC38 colon-cancer in the C57BL/6 model. A: Tumor growth curve. B: Tumor size on day 15. C: Body weight change. Data are shown as the mean±standard deviation. *One mouse was dead on day 11.

Figure 3.
Figure 3.

Photographs of tumors excised from mice treated with phosphate-buffered saline (control) (A); Escherichia coli JM109 competent cells (B); or recombinant methioninase-expressing E. coli JM109 cells (C).

Body weight change. Figure 2C shows no significant change in mouse body weight for each group, confirming the tolerability of 1010 CFU/100 μl E. coli.

Stool culture to determine the presence of E. coli JM109-rMETase. Culture of stool bacteria on modified M9 agar resulted in pink colonies of Gram-negative bacilli, consistent with the presence of E. coli JM109-rMETase (Figure 4). Furthermore, after the isolation of these colonies, they were grown to 1011 CFU/ml and examined for rMETase activity. All of the pink colonies had rMETase activity (data not shown).

Figure 4.
Figure 4.

Stool culture on day 15 from six mice treated with recombinant-methioninase-producing Escherichia coli JM109 cells (modified M9 medium with tetracycline).

Discussion

Although we have previously reported the efficacy of oral rMETase in many types of cancer in vivo (40-54, 61-62), this is the first report that shows oral administration of E. coli JM109-rMETase inhibits tumor growth. When E. coli is administered orally, its toxicity to mice should be considered. A tolerability study demonstrated that up to 2×1010 CFU/day of E. coli JM109-rMETase is tolerable. E. coli JM109-rMETase (1011 CFU/ml), after exposure to IPTG, had rMETase activity of 39.7 U/ml, which is about one-tenth of the rMETase we usually use for mice (500 U/ml) (62). The present results indicate that 2×1010 CFU/day of E. coli JM109-rMETase inhibited MC-38 tumor growth in C57BL6 mice.

In the present study, we also found E. coli JM109-rMETase in mouse stool after 2 weeks of oral administration of E. coli JM109-rMETase, indicating it was incorporated into the microbiome.

In conclusion, bacterial therapy using rMETase-producing E. coli JM109 showed growth-inhibitory efficacy against syngeneic MC38 colon cancer in C57BL/6 mice. A previous study showed the anticancer efficacy of asparaginase-producing Salmonella typhimurium (63). Oral methioninase has been shown to be active clinically for prostate cancer (64-66), pancreatic cancer (67), and rectal cancer (68). Future studies will test microbiome-resident rMETase-producing E. coli for multiple cancer types. Recent advances in the manipulation of the gut microbiome indicate the future potential of treating disease as shown in the present report with E. coli JM109-rMETase (69, 70).

Acknowledgements

This paper is dedicated to the memory of A. R. Moossa, MD, Sun Lee, MD, Professor Li Jiaxi, Masaki Kitajima, MD, Shigeo Yagi, PhD, and Jack Geller, MD. The Robert M Hoffman Foundation for cancer research provided funds for this study.

Footnotes

  • Authors’ Contributions

    YK and RMH created the concept and design and wrote the article. YK performed acquisition, analysis, and interpretation of data. QH provided the recombinant methioninase-producing E. coli. KH, YA, NM, KO, AB, MB, and TT reviewed the article.

  • Conflicts of Interest

    The Authors declare no competing interests regarding this work.

  • Received August 18, 2022.
  • Revision received September 8, 2022.
  • Accepted September 13, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Hoffman RM and
    2. Erbe RW
    : High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine. Proc Natl Acad Sci USA 73(5): 1523-1527, 1976. PMID: 179090. DOI: 10.1073/pnas.73.5.1523
    OpenUrlAbstract/FREE Full Text
    1. Coalson DW,
    2. Mecham JO,
    3. Stern PH and
    4. Hoffman RM
    : Reduced availability of endogenously synthesized methionine for S-adenosylmethionine formation in methionine-dependent cancer cells. Proc Natl Acad Sci USA 79(14): 4248-4251, 1982. PMID: 6289297. DOI: 10.1073/pnas.79.14.4248
    OpenUrlAbstract/FREE Full Text
    1. Stern PH,
    2. Mecham JO,
    3. Wallace CD and
    4. Hoffman RM
    : Reduced free-methionine in methionine-dependent SV40-transformed human fibroblasts synthesizing apparently normal amounts of methionine. J Cell Physiol 117(1): 9-14, 1983. PMID: 6311851. DOI: 10.1002/jcp.1041170103
    OpenUrlCrossRefPubMed
    1. Mecham JO,
    2. Rowitch D,
    3. Wallace CD,
    4. Stern PH and
    5. Hoffman RM
    : The metabolic defect of methionine dependence occurs frequently in human tumor cell lines. Biochem Biophys Res Commun 117(2): 429-434, 1983. PMID: 6661235. DOI: 10.1016/0006-291x(83)91218-4
    OpenUrlCrossRefPubMed
    1. Stern PH,
    2. Wallace CD and
    3. Hoffman RM
    : Altered methionine metabolism occurs in all members of a set of diverse human tumor cell lines. J Cell Physiol 119(1): 29-34, 1984. PMID: 6707100. DOI: 10.1002/jcp.1041190106
    OpenUrlCrossRefPubMed
  6. ↵
    1. Tan Y,
    2. Xu M and
    3. Hoffman RM
    : Broad selective efficacy of recombinant methioninase and polyethylene glycol-modified recombinant methioninase on cancer cells In Vitro. Anticancer Res 30(4): 1041-1046, 2010. PMID: 20530407.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Judde JG,
    2. Ellis M and
    3. Frost P
    : Biochemical analysis of the role of transmethylation in the methionine dependence of tumor cells. Cancer Res 49(17): 4859-4865, 1989. PMID: 2503245.
    OpenUrlAbstract/FREE Full Text
    1. Yamamoto J,
    2. Han Q,
    3. Inubushi S,
    4. Sugisawa N,
    5. Hamada K,
    6. Nishino H,
    7. Miyake K,
    8. Kumamoto T,
    9. Matsuyama R,
    10. Bouvet M,
    11. Endo I and
    12. Hoffman RM
    : Histone methylation status of H3K4me3 and H3K9me3 under methionine restriction is unstable in methionine-addicted cancer cells, but stable in normal cells. Biochem Biophys Res Commun 533(4): 1034-1038, 2020. PMID: 33019978. DOI: 10.1016/j.bbrc.2020.09.108
    OpenUrlCrossRefPubMed
    1. Stern PH and
    2. Hoffman RM
    : Elevated overall rates of transmethylation in cell lines from diverse human tumors. In Vitro 20(8): 663-670, 1984. PMID: 6500606. DOI: 10.1007/BF02619617
    OpenUrlCrossRefPubMed
  10. ↵
    1. Wang Z,
    2. Yip LY,
    3. Lee JHJ,
    4. Wu Z,
    5. Chew HY,
    6. Chong PKW,
    7. Teo CC,
    8. Ang HY,
    9. Peh KLE,
    10. Yuan J,
    11. Ma S,
    12. Choo LSK,
    13. Basri N,
    14. Jiang X,
    15. Yu Q,
    16. Hillmer AM,
    17. Lim WT,
    18. Lim TKH,
    19. Takano A,
    20. Tan EH,
    21. Tan DSW,
    22. Ho YS,
    23. Lim B and
    24. Tam WL
    : Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 25(5): 825-837, 2019. PMID: 31061538. DOI: 10.1038/s41591-019-0423-5
    OpenUrlCrossRefPubMed
  11. ↵
    1. Kaiser P
    : Methionine Dependence of Cancer. Biomolecules 10(4): 568, 2020. PMID: 32276408. DOI: 10.3390/biom10040568
    OpenUrlCrossRefPubMed
  12. ↵
    1. Hoffman RM and
    2. Jacobsen SJ
    : Reversible growth arrest in simian virus 40-transformed human fibroblasts. Proc Natl Acad Sci USA 77(12): 7306-7310, 1980. PMID: 6261250. DOI: 10.1073/pnas.77.12.7306
    OpenUrlAbstract/FREE Full Text
    1. Yano S,
    2. Li S,
    3. Han Q,
    4. Tan Y,
    5. Bouvet M,
    6. Fujiwara T and
    7. Hoffman RM
    : Selective methioninase-induced trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity. Oncotarget 5(18): 8729-8736, 2014. PMID: 25238266. DOI: 10.18632/oncotarget.2369
    OpenUrlCrossRefPubMed
  14. ↵
    1. Guo H,
    2. Lishko VK,
    3. Herrera H,
    4. Groce A,
    5. Kubota T and
    6. Hoffman RM
    : Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo. Cancer Res 53(23): 5676-5679, 1993. PMID: 8242623
    OpenUrlAbstract/FREE Full Text
    1. Hoshiya Y,
    2. Guo H,
    3. Kubota T,
    4. Inada T,
    5. Asanuma F,
    6. Yamada Y,
    7. Koh J,
    8. Kitajima M and
    9. Hoffman RM
    : Human tumors are methionine dependent in vivo. Anticancer Res 15(3): 717-718, 1995. PMID: 7645948.
    OpenUrlPubMed
  16. ↵
    1. Yoshioka T,
    2. Wada T,
    3. Uchida N,
    4. Maki H,
    5. Yoshida H,
    6. Ide N,
    7. Kasai H,
    8. Hojo K,
    9. Shono K,
    10. Maekawa R,
    11. Yagi S,
    12. Hoffman RM and
    13. Sugita K
    : Anticancer efficacy in vivo and in vitro, synergy with 5-fluorouracil, and safety of recombinant methioninase. Cancer Res 58(12): 2583-2587, 1998. PMID: 9635582.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Hoffman RM
    : Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey. Expert Opin Biol Ther 15(1): 21-31, 2015. PMID: 25439528. DOI: 10.1517/14712598.2015.963050
    OpenUrlCrossRefPubMed
  18. ↵
    1. Kawaguchi K,
    2. Han Q,
    3. Li S,
    4. Tan Y,
    5. Igarashi K,
    6. Murakami T,
    7. Unno M and
    8. Hoffman RM
    : Efficacy of Recombinant Methioninase (rMETase) on Recalcitrant Cancer Patient-Derived Orthotopic Xenograft (PDOX) Mouse Models: A Review. Cells 8(5): 410, 2019. PMID: 31052611. DOI: 10.3390/cells8050410
    OpenUrlCrossRefPubMed
  19. ↵
    1. Stern PH and
    2. Hoffman RM
    : Enhanced in vitro selective toxicity of chemotherapeutic agents for human cancer cells based on a metabolic defect. J Natl Cancer Inst 76(4): 629-639, 1986. PMID: 3457200. DOI: 10.1093/jnci/76.4.629
    OpenUrlCrossRefPubMed
    1. Hoshiya Y,
    2. Kubota T,
    3. Matsuzaki SW,
    4. Kitajima M and
    5. Hoffman RM
    : Methionine starvation modulates the efficacy of cisplatin on human breast cancer in nude mice. Anticancer Res 16(6B): 3515-3517, 1996. PMID: 9042214.
    OpenUrlPubMed
    1. Tan Y,
    2. Sun X,
    3. Xu M,
    4. Tan X,
    5. Sasson A,
    6. Rashidi B,
    7. Han Q,
    8. Tan X,
    9. Wang X,
    10. An Z,
    11. Sun FX and
    12. Hoffman RM
    : Efficacy of recombinant methioninase in combination with cisplatin on human colon tumors in nude mice. Clin Cancer Res 5(8): 2157-2163, 1999. PMID: 10473100.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Kokkinakis DM,
    2. Hoffman RM,
    3. Frenkel EP,
    4. Wick JB,
    5. Han Q,
    6. Xu M,
    7. Tan Y and
    8. Schold SC
    : Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. Cancer Res 61(10): 4017-4023, 2001. PMID: 11358820.
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Gao X,
    2. Sanderson SM,
    3. Dai Z,
    4. Reid MA,
    5. Cooper DE,
    6. Lu M,
    7. Richie JP Jr.,
    8. Ciccarella A,
    9. Calcagnotto A,
    10. Mikhael PG,
    11. Mentch SJ,
    12. Liu J,
    13. Ables G,
    14. Kirsch DG,
    15. Hsu DS,
    16. Nichenametla SN and
    17. Locasale JW
    : Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572(7769): 397-401, 2019. PMID: 31367041. DOI: 10.1038/s41586-019-1437-3
    OpenUrlCrossRefPubMed
  24. ↵
    1. Durando X,
    2. Thivat E,
    3. Farges MC,
    4. Cellarier E,
    5. D’Incan M,
    6. Demidem A,
    7. Vasson MP,
    8. Barthomeuf C and
    9. Chollet P
    : Optimal methionine-free diet duration for nitrourea treatment: a Phase I clinical trial. Nutr Cancer 60(1): 23-30, 2008. PMID: 18444132. DOI: 10.1080/01635580701525877
    OpenUrlCrossRefPubMed
    1. Thivat E,
    2. Farges MC,
    3. Bacin F,
    4. D’Incan M,
    5. Mouret-Reynier MA,
    6. Cellarier E,
    7. Madelmont JC,
    8. Vasson MP,
    9. Chollet P and
    10. Durando X
    : Phase II trial of the association of a methionine-free diet with cystemustine therapy in melanoma and glioma. Anticancer Res 29(12): 5235-5240, 2009. PMID: 20044642.
    OpenUrlAbstract/FREE Full Text
    1. Durando X,
    2. Farges MC,
    3. Buc E,
    4. Abrial C,
    5. Petorin-Lesens C,
    6. Gillet B,
    7. Vasson MP,
    8. Pezet D,
    9. Chollet P and
    10. Thivat E
    : Dietary methionine restriction with FOLFOX regimen as first line therapy of metastatic colorectal cancer: a feasibility study. Oncology 78(3-4): 205-209, 2010. PMID: 20424491. DOI: 10.1159/000313700
    OpenUrlCrossRefPubMed
  27. ↵
    1. Goseki N,
    2. Yamazaki S,
    3. Shimojyu K,
    4. Kando F,
    5. Maruyama M,
    6. Endo M,
    7. Koike M and
    8. Takahashi H
    : Synergistic effect of methionine-depleting total parenteral nutrition with 5-fluorouracil on human gastric cancer: a randomized, prospective clinical trial. Jpn J Cancer Res 86(5): 484-489, 1995. PMID: 7790321. DOI: 10.1111/j.1349-7006.1995.tb03082.x
    OpenUrlCrossRefPubMed
  28. ↵
    1. Tan Y,
    2. Xu M,
    3. Tan X,
    4. Tan X,
    5. Wang X,
    6. Saikawa Y,
    7. Nagahama T,
    8. Sun X,
    9. Lenz M and
    10. Hoffman RM
    : Overexpression and large-scale production of recombinant L-methionine-alpha-deamino-gamma-mercaptomethane-lyase for novel anticancer therapy. Protein Expr Purif 9(2): 233-245, 1997. PMID: 9056489. DOI: 10.1006/prep.1996.0700
    OpenUrlCrossRefPubMed
  29. ↵
    1. Takakura T,
    2. Ito T,
    3. Yagi S,
    4. Notsu Y,
    5. Itakura T,
    6. Nakamura T,
    7. Inagaki K,
    8. Esaki N,
    9. Hoffman RM and
    10. Takimoto A
    : High-level expression and bulk crystallization of recombinant L-methionine gamma-lyase, an anticancer agent. Appl Microbiol Biotechnol 70(2): 183-192, 2006. PMID: 16012835. DOI: 10.1007/s00253-005-0038-2
    OpenUrlCrossRefPubMed
  30. ↵
    1. Kawaguchi K,
    2. Igarashi K,
    3. Li S,
    4. Han Q,
    5. Tan Y,
    6. Kiyuna T,
    7. Miyake K,
    8. Murakami T,
    9. Chmielowski B,
    10. Nelson S,
    11. Russell T,
    12. Dry S,
    13. Li Y,
    14. Unno M,
    15. Eilber F and
    16. Hoffman R
    : Combination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma in a patient-derived orthotopic xenograft (PDOX) mouse model. Oncotarget 8(49): 85516-85525, 2020. DOI: 10.18632/oncotarget.20231
    OpenUrlCrossRef
    1. Kawaguchi K,
    2. Igarashi K,
    3. Li S,
    4. Han Q,
    5. Tan Y,
    6. Miyake K,
    7. Kiyuna T,
    8. Miyake M,
    9. Murakami T,
    10. Chmielowski B,
    11. Nelson S,
    12. Russell T,
    13. Dry S,
    14. Li Y,
    15. Unno M,
    16. Eilber F and
    17. Hoffman R
    : Recombinant methioninase (rMETase) is an effective therapeutic for BRAF-V600E-negative as well as -positive melanoma in patient-derived orthotopic xenograft (PDOX) mouse models. Oncotarget 9(1): 915-923, 2020. DOI: 10.18632/oncotarget.23185
    OpenUrlCrossRef
    1. Kawaguchi K,
    2. Miyake K,
    3. Han Q,
    4. Li S,
    5. Tan Y,
    6. Igarashi K,
    7. Lwin TM,
    8. Higuchi T,
    9. Kiyuna T,
    10. Miyake M,
    11. Oshiro H,
    12. Bouvet M,
    13. Unno M and
    14. Hoffman RM
    : Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer. Cell Cycle 17(7): 868-873, 2018. PMID: 29623758. DOI: 10.1080/15384101.2018.1445907
    OpenUrlCrossRefPubMed
    1. Igarashi K,
    2. Kawaguchi K,
    3. Kiyuna T,
    4. Miyake K,
    5. Miyake M,
    6. Li S,
    7. Han Q,
    8. Tan Y,
    9. Zhao M,
    10. Li Y,
    11. Nelson SD,
    12. Dry SM,
    13. Singh AS,
    14. Elliott IA,
    15. Russell TA,
    16. Eckardt MA,
    17. Yamamoto N,
    18. Hayashi K,
    19. Kimura H,
    20. Miwa S,
    21. Tsuchiya H,
    22. Eilber FC and
    23. Hoffman RM
    : 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 17(6): 801-809, 2018. PMID: 29374999. DOI: 10.1080/15384101.2018.1431596
    OpenUrlCrossRefPubMed
    1. Igarashi K,
    2. Kawaguchi K,
    3. Li S,
    4. Han Q,
    5. Tan Y,
    6. Gainor E,
    7. Kiyuna T,
    8. Miyake K,
    9. Miyake M,
    10. Higuchi T,
    11. Oshiro H,
    12. Singh A,
    13. Eckardt M,
    14. Nelson S,
    15. Russell T,
    16. Dry S,
    17. Li Y,
    18. Yamamoto N,
    19. Hayashi K,
    20. Kimura H,
    21. Miwa S,
    22. Tsuchiya H,
    23. Eilber F and
    24. Hoffman R
    : Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model. Oncotarget 9(27): 19263-19272, 2020. DOI: 10.18632/oncotarget.24996
    OpenUrlCrossRef
    1. Igarashi K,
    2. Kawaguchi K,
    3. Kiyuna T,
    4. Miyake K,
    5. Miyaki M,
    6. Yamamoto N,
    7. Hayashi K,
    8. Kimura H,
    9. Miwa S,
    10. Higuchi T,
    11. Singh AS,
    12. Chmielowski B,
    13. Nelson SD,
    14. Russell TA,
    15. Eckardt MA,
    16. Dry SM,
    17. Li Y,
    18. Singh SR,
    19. Chawla SP,
    20. Eilber FC,
    21. Tsuchiya H and
    22. Hoffman RM
    : Metabolic targeting with recombinant methioninase combined with palbociclib regresses a doxorubicin-resistant dedifferentiated liposarcoma. Biochem Biophys Res Commun 506(4): 912-917, 2018. PMID: 30392912. DOI: 10.1016/j.bbrc.2018.10.119
    OpenUrlCrossRefPubMed
    1. Igarashi K,
    2. Li S,
    3. Han Q,
    4. Tan Y,
    5. Kawaguchi K,
    6. Murakami T,
    7. Kiyuna T,
    8. Miyake K,
    9. Li Y,
    10. Nelson SD,
    11. Dry SM,
    12. Singh AS,
    13. Elliott IA,
    14. Russell TA,
    15. Eckardt MA,
    16. Yamamoto N,
    17. Hayashi K,
    18. Kimura H,
    19. Miwa S,
    20. Tsuchiya H,
    21. Eilber FC and
    22. Hoffman RM
    : Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase. J Cell Biochem 119(4): 3537-3544, 2018. PMID: 29143983. DOI: 10.1002/jcb.26527
    OpenUrlCrossRefPubMed
    1. Igarashi K,
    2. Kawaguchi K,
    3. Li S,
    4. Han Q,
    5. Tan Y,
    6. Murakami T,
    7. Kiyuna T,
    8. Miyake K,
    9. Miyake M,
    10. Singh AS,
    11. Eckardt MA,
    12. Nelson SD,
    13. Russell TA,
    14. Dry SM,
    15. Li Y,
    16. Yamamoto N,
    17. Hayashi K,
    18. Kimura H,
    19. Miwa S,
    20. Tsuchiya H,
    21. Singh SR,
    22. Eilber FC and
    23. Hoffman RM
    : Recombinant methioninase in combination with doxorubicin (DOX) overcomes first-line DOX resistance in a patient-derived orthotopic xenograft nude-mouse model of undifferentiated spindle-cell sarcoma. Cancer Lett 417: 168-173, 2018. PMID: 29306021. DOI: 10.1016/j.canlet.2017.12.028
    OpenUrlCrossRefPubMed
    1. Murakami T,
    2. Li S,
    3. Han Q,
    4. Tan Y,
    5. Kiyuna T,
    6. Igarashi K,
    7. Kawaguchi K,
    8. Hwang H,
    9. Miyake K,
    10. Singh A,
    11. Nelson S,
    12. Dry S,
    13. Li Y,
    14. Hiroshima Y,
    15. Lwin T,
    16. Delong J,
    17. Chishima T,
    18. Tanaka K,
    19. Bouvet M,
    20. Endo I,
    21. Eilber F and
    22. Hoffman R
    : Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8(22): 35630-35638, 2020. DOI: 10.18632/oncotarget.15823
    OpenUrlCrossRef
  39. ↵
    1. Yamamoto J,
    2. Han Q,
    3. Simon M,
    4. Thomas D and
    5. Hoffman RM
    : Methionine restriction: Ready for prime time in the cancer clinic? Anticancer Res 42(2): 641-644, 2022. PMID: 35093861. DOI: 10.21873/anticanres.15521
    OpenUrlAbstract/FREE Full Text
  40. ↵
    1. Kawaguchi K,
    2. Miyake K,
    3. Han Q,
    4. Li S,
    5. Tan Y,
    6. Igarashi K,
    7. Kiyuna T,
    8. Miyake M,
    9. Higuchi T,
    10. Oshiro H,
    11. Zhang Z,
    12. Razmjooei S,
    13. Wangsiricharoen S,
    14. Bouvet M,
    15. Singh SR,
    16. Unno M and
    17. Hoffman RM
    : Oral recombinant methioninase (o-rMETase) is superior to injectable rMETase and overcomes acquired gemcitabine resistance in pancreatic cancer. Cancer Lett 432: 251-259, 2018. PMID: 29928962. DOI: 10.1016/j.canlet.2018.06.016
    OpenUrlCrossRefPubMed
    1. Sugisawa N,
    2. Yamamoto J,
    3. Han Q,
    4. Tan Y,
    5. Tashiro Y,
    6. Nishino H,
    7. Inubushi S,
    8. Hamada K,
    9. Kawaguchi K,
    10. Unno M,
    11. Bouvet M and
    12. Hoffman RM
    : Triple-methyl blockade with recombinant methioninase, cycloleucine, and azacitidine arrests a pancreatic cancer patient-derived orthotopic xenograft model. Pancreas 50(1): 93-98, 2021. PMID: 33370029. DOI: 10.1097/MPA.0000000000001709
    OpenUrlCrossRefPubMed
    1. Lim HI,
    2. Sun YU,
    3. Han Q,
    4. Yamamoto J and
    5. Hoffman RM
    : Efficacy of oral recombinant methioninase and eribulin on a PDOX model of triple-negative breast cancer (TNBC) liver metastasis. In Vivo 35(5): 2531-2534, 2021. PMID: 34410939. DOI: 10.21873/invivo.12534
    OpenUrlAbstract/FREE Full Text
    1. Park JH,
    2. Zhao M,
    3. Han Q,
    4. Sun Y,
    5. Higuchi T,
    6. Sugisawa N,
    7. Yamamoto J,
    8. Singh SR,
    9. Clary B,
    10. Bouvet M and
    11. Hoffman RM
    : Efficacy of oral recombinant methioninase combined with oxaliplatinum and 5-fluorouracil on primary colon cancer in a patient-derived orthotopic xenograft mouse model. Biochem Biophys Res Commun 518(2): 306-310, 2019. PMID: 31421825. DOI: 10.1016/j.bbrc.2019.08.051
    OpenUrlCrossRefPubMed
    1. Oshiro H,
    2. Tome Y,
    3. Kiyuna T,
    4. Yoon SN,
    5. Lwin TM,
    6. Han Q,
    7. Tan Y,
    8. Miyake K,
    9. Higuchi T,
    10. Sugisawa N,
    11. Katsuya Y,
    12. Park JH,
    13. Zang Z,
    14. Razmjooei S,
    15. Bouvet M,
    16. Clary B,
    17. Singh SR,
    18. Kanaya F,
    19. Nishida K and
    20. Hoffman RM
    : Oral recombinant methioninase overcomes colorectal-cancer liver metastasis resistance to the combination of 5-fluorouracil and oxaliplatinum in a patient-derived orthotopic xenograft mouse model. Anticancer Res 39(9): 4667-4671, 2019. PMID: 31519565. DOI: 10.21873/anticanres.13648
    OpenUrlAbstract/FREE Full Text
    1. Park JH,
    2. Han Q,
    3. Zhao M,
    4. Tan Y,
    5. Higuchi T,
    6. Yoon SN,
    7. Sugisawa N,
    8. Yamamoto J,
    9. Bouvet M,
    10. Clary B,
    11. Singh SR and
    12. Hoffman RM
    : 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. Tissue Cell 61: 109-114, 2019. PMID: 31759402. DOI: 10.1016/j.tice.2019.09.006
    OpenUrlCrossRefPubMed
    1. Sugisawa N,
    2. Higuchi T,
    3. Han Q,
    4. Hozumi C,
    5. Yamamoto J,
    6. Tashiro Y,
    7. Nishino H,
    8. Kawaguchi K,
    9. Bouvet M,
    10. Murata T,
    11. Unno M and
    12. Hoffman RM
    : Oral recombinant methioninase combined with paclitaxel arrests recalcitrant ovarian clear cell carcinoma growth in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Cancer Chemother Pharmacol 88(1): 61-67, 2021. PMID: 33768300. DOI: 10.1007/s00280-021-04261-x
    OpenUrlCrossRefPubMed
    1. Hoffman RM
    Methionine Dependence of Cancer and Aging. Hoffman RM (ed.). Part of: Methods in Molecular Biology (MIMB, volume 1866). New York, Springer Nature, 2019. DOI: 10.1007/978-1-4939-8796-2
    OpenUrlCrossRef
    1. Kawaguchi K,
    2. Higuchi T,
    3. Li S,
    4. Han Q,
    5. Tan Y,
    6. Igarashi K,
    7. Zhao M,
    8. Miyake K,
    9. Kiyuna T,
    10. Miyake M,
    11. Ohshiro H,
    12. Sugisawa N,
    13. Zhang Z,
    14. Razmjooei S,
    15. Wangsiricharoen S,
    16. Chmielowski B,
    17. Nelson SD,
    18. Russell TA,
    19. Dry SM,
    20. Li Y,
    21. Eckardt MA,
    22. Singh AS,
    23. Singh SR,
    24. Eilber FC,
    25. Unno M and
    26. Hoffman RM
    : Combination therapy of tumor-targeting Salmonella typhimurium A1-R and oral recombinant methioninase regresses a BRAF-V600E-negative melanoma. Biochem Biophys Res Commun 503(4): 3086-3092, 2018. PMID: 30166061. DOI: 10.1016/j.bbrc.2018.08.097
    OpenUrlCrossRefPubMed
    1. Higuchi T,
    2. Kawaguchi K,
    3. Miyake K,
    4. Han Q,
    5. Tan Y,
    6. Oshiro H,
    7. Sugisawa N,
    8. Zhang Z,
    9. Razmjooei S,
    10. Yamamoto N,
    11. Hayashi K,
    12. Kimura H,
    13. Miwa S,
    14. Igarashi K,
    15. Chawla SP,
    16. Singh AS,
    17. Eilber FC,
    18. Singh SR,
    19. Tsuchiya H and
    20. Hoffman RM
    : Oral recombinant methioninase combined with caffeine and doxorubicin induced regression of a doxorubicin-resistant synovial sarcoma in a PDOX mouse model. Anticancer Res 38(10): 5639-5644, 2018. PMID: 30275182. DOI: 10.21873/anticanres.12899
    OpenUrlAbstract/FREE Full Text
    1. Higuchi T,
    2. Oshiro H,
    3. Miyake K,
    4. Sugisawa N,
    5. Han Q,
    6. Tan Y,
    7. Park J,
    8. Zhang Z,
    9. Razmjooei S,
    10. Yamamoto N,
    11. Hayashi K,
    12. Kimura H,
    13. Miwa S,
    14. Igarashi K,
    15. Bouvet M,
    16. Chawla SP,
    17. Singh SR,
    18. Tsuchiya H and
    19. Hoffman RM
    : Oral recombinant methioninase, combined with oral caffeine and injected cisplatinum, overcome cisplatinum-resistance and regresses patient-derived orthotopic xenograft model of osteosarcoma. Anticancer Res 39(9): 4653-4657, 2019. PMID: 31519563. DOI: 10.21873/anticanres.13646
    OpenUrlAbstract/FREE Full Text
    1. Higuchi T,
    2. Sugisawa N,
    3. Yamamoto J,
    4. Oshiro H,
    5. Han Q,
    6. Yamamoto N,
    7. Hayashi K,
    8. Kimura H,
    9. Miwa S,
    10. Igarashi K,
    11. Tan Y,
    12. Kuchipudi S,
    13. Bouvet M,
    14. Singh SR,
    15. Tsuchiya H and
    16. Hoffman RM
    : The combination of oral-recombinant methioninase and azacitidine arrests a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft mouse model. Cancer Chemother Pharmacol 85(2): 285-291, 2020. PMID: 31705268. DOI: 10.1007/s00280-019-03986-0
    OpenUrlCrossRefPubMed
    1. Aoki Y,
    2. Tome Y,
    3. Wu NF,
    4. Yamamoto J,
    5. Hamada K,
    6. Han Q,
    7. Bouvet M,
    8. Nishida K and
    9. Hoffman RM
    : Oral-recombinant methioninase converts an osteosarcoma from docetaxel-resistant to -sensitive in a clinically-relevant patient-derived orthotopic-xenograft (PDOX) mouse model. Anticancer Res 41(4): 1745-1751, 2021. PMID: 33813378. DOI: 10.21873/anticanres.14939
    OpenUrlAbstract/FREE Full Text
    1. Lim HI,
    2. Hamada K,
    3. Yamamoto J,
    4. Han Q,
    5. Tan Y,
    6. Choi HJ,
    7. Nam SJ,
    8. Bouvet M and
    9. Hoffman RM
    : Oral methioninase inhibits recurrence in a PDOX mouse model of aggressive triple-negative breast cancer. In Vivo 34(5): 2281-2286, 2020. PMID: 32871751. DOI: 10.21873/invivo.12039
    OpenUrlAbstract/FREE Full Text
  54. ↵
    1. Lim HI,
    2. Yamamoto J,
    3. Han Q,
    4. Sun YU,
    5. Nishino H,
    6. Tashiro Y,
    7. Sugisawa N,
    8. Tan Y,
    9. Choi HJ,
    10. Nam SJ,
    11. Bouvet M and
    12. Hoffman RM
    : Response of triple-negative breast cancer liver metastasis to oral recombinant methioninase in a patient-derived orthotopic xenograft (PDOX) model. In Vivo 34(6): 3163-3169, 2020. PMID: 33144420. DOI: 10.21873/invivo.12151
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Sun X,
    2. Yang Z,
    3. Li S,
    4. Tan Y,
    5. Zhang N,
    6. Wang X,
    7. Yagi S,
    8. Yoshioka T,
    9. Takimoto A,
    10. Mitsushima K,
    11. Suginaka A,
    12. Frenkel EP and
    13. Hoffman RM
    : In vivo efficacy of recombinant methioninase is enhanced by the combination of polyethylene glycol conjugation and pyridoxal 5’-phosphate supplementation. Cancer Res 63(23): 8377-8383, 2003. PMID: 14678999.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    1. Thanassi DG,
    2. Cheng LW and
    3. Nikaido H
    : Active efflux of bile salts by Escherichia coli. J Bacteriol 179(8): 2512-2518, 1997. PMID: 9098046. DOI: 10.1128/jb.179.8.2512-2518.1997
    OpenUrlAbstract/FREE Full Text
  57. ↵
    1. Percie du Sert N,
    2. Ahluwalia A,
    3. Alam S,
    4. Avey MT,
    5. Baker M,
    6. Browne WJ,
    7. Clark A,
    8. Cuthill IC,
    9. Dirnagl U,
    10. Emerson M,
    11. Garner P,
    12. Holgate ST,
    13. Howells DW,
    14. Hurst V,
    15. Karp NA,
    16. Lazic SE,
    17. Lidster K,
    18. MacCallum CJ,
    19. Macleod M,
    20. Pearl EJ,
    21. Petersen OH,
    22. Rawle F,
    23. Reynolds P,
    24. Rooney K,
    25. Sena ES,
    26. Silberberg SD,
    27. Steckler T and
    28. Würbel H
    : Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol 18(7): e3000411, 2020. PMID: 32663221. DOI: 10.1371/journal.pbio.3000411
    OpenUrlCrossRefPubMed
  58. ↵
    1. Corbett TH,
    2. Griswold DP Jr.,
    3. Roberts BJ,
    4. Peckham JC and
    5. Schabel FM Jr.
    : Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure. Cancer Res 35(9): 2434-2439, 1975. PMID: 1149045.
    OpenUrlAbstract/FREE Full Text
  59. ↵
    1. Kotramada Bopaiah BB,
    2. Nanda Kumar DA,
    3. Balan K,
    4. Dehingia L,
    5. Ramanayakanahalli Venkatesh Reddy MK,
    6. Suresh AB and
    7. Nadumane VK
    : Purification, characterization, and antiproliferative activity of L-methioninase from a new isolate of Bacillus haynesii JUB2. J Appl Pharm Sci 10: 54-61, 2020. DOI: 10.7324/JAPS.2020.10106
    OpenUrlCrossRef
  60. ↵
    1. Sundar WA and
    2. Nellaiah H
    : A rapid method for screening of methioninase producing Serratia marcescens species from soil. Int J Pharm Pharm Sci 5: 426-427, 2013.
    OpenUrl
  61. ↵
    1. Yamamoto J,
    2. Miyake K,
    3. Han Q,
    4. Tan Y,
    5. Inubushi S,
    6. Sugisawa N,
    7. Higuchi T,
    8. Tashiro Y,
    9. Nishino H,
    10. Homma Y,
    11. Matsuyama R,
    12. Chawla SP,
    13. Bouvet M,
    14. Singh SR,
    15. Endo I and
    16. Hoffman RM
    : Oral recombinant methioninase increases TRAIL receptor-2 expression to regress pancreatic cancer in combination with agonist tigatuzumab in an orthotopic mouse model. Cancer Lett 492: 174-184, 2020. PMID: 32739322. DOI: 10.1016/j.canlet.2020.07.034
    OpenUrlCrossRefPubMed
  62. ↵
    1. Kawaguchi K,
    2. Han Q,
    3. Li S,
    4. Tan Y,
    5. Igarashi K,
    6. Kiyuna T,
    7. Miyake K,
    8. Miyake M,
    9. Chmielowski B,
    10. Nelson SD,
    11. Russell TA,
    12. Dry SM,
    13. Li Y,
    14. Singh AS,
    15. Eckardt MA,
    16. Unno M,
    17. Eilber FC and
    18. Hoffman RM
    : 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 17(3): 356-361, 2018. PMID: 29187018. DOI: 10.1080/15384101.2017.1405195
    OpenUrlCrossRefPubMed
  63. ↵
    1. Kim K,
    2. Jeong JH,
    3. Lim D,
    4. Hong Y,
    5. Lim HJ,
    6. Kim GJ,
    7. Shin SR,
    8. Lee JJ,
    9. Yun M,
    10. Harris RA,
    11. Min JJ and
    12. Choy HE
    : L-Asparaginase delivered by Salmonella typhimurium suppresses solid tumors. Mol Ther Oncolytics 2: 15007, 2015. PMID: 27119104. DOI: 10.1038/mto.2015.7
    OpenUrlCrossRefPubMed
  64. ↵
    1. Han Q,
    2. Tan Y and
    3. Hoffman RM
    : Oral dosing of recombinant methioninase is associated with a 70% drop in PSA in a patient with bone-metastatic prostate cancer and 50% reduction in circulating methionine in a high-stage ovarian cancer patient. Anticancer Res 40(5): 2813-2819, 2020. PMID: 32366428. DOI: 10.21873/anticanres.14254
    OpenUrlAbstract/FREE Full Text
    1. Han Q and
    2. Hoffman RM
    : Chronic treatment of an advanced prostate-cancer patient with oral methioninase resulted in long-term stabilization of rapidly rising PSA levels. In Vivo 35(4): 2171-2176, 2021. PMID: 34182494. DOI: 10.21873/invivo.12488
    OpenUrlAbstract/FREE Full Text
  66. ↵
    1. Han Q and
    2. Hoffman RM
    : Lowering and Stabilizing PSA levels in advanced-prostate cancer patients with oral methioninase. Anticancer Res 41(4): 1921-1926, 2021. PMID: 33813397. DOI: 10.21873/anticanres.14958
    OpenUrlAbstract/FREE Full Text
  67. ↵
    1. Kubota Y,
    2. Han Q,
    3. Hozumi C,
    4. Masaki N,
    5. Yamamoto J,
    6. Aoki Y,
    7. Tsunoda T and
    8. Hoffman RM
    : Stage IV pancreatic cancer patient treated with FOLFIRINOX combined with oral methioninase: A highly-rare case with long-term stable disease. Anticancer Res 42(5): 2567-2572, 2022. PMID: 35489727. DOI: 10.21873/anticanres.15734
    OpenUrlAbstract/FREE Full Text
  68. ↵
    1. Kubota Y,
    2. Han Q,
    3. Hamada K,
    4. Aoki Y,
    5. Masaki N,
    6. Obara K,
    7. Tsunoda T and
    8. Hoffman R
    : Long-term stable disease in a rectal-cancer patient treated by methionine restriction with oral recombinant methioninase and a low-methionine diet. Anticancer Research 42(8): 3857-3861, 2022. PMID: 35896248. DOI: 10.21873/anticanres.15877
    OpenUrlAbstract/FREE Full Text
  69. ↵
    1. Russell BJ,
    2. Brown SD,
    3. Siguenza N,
    4. Mai I,
    5. Saran AR,
    6. Lingaraju A,
    7. Maissy ES,
    8. Dantas Machado AC,
    9. Pinto AFM,
    10. Sanchez C,
    11. Rossitto LA,
    12. Miyamoto Y,
    13. Richter RA,
    14. Ho SB,
    15. Eckmann L,
    16. Hasty J,
    17. Gonzalez DJ,
    18. Saghatelian A,
    19. Knight R and
    20. Zarrinpar A
    : Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes. Cell 185(17):3263-3277.e15, 2022. PMID: 35931082. DOI: 10.1016/j.cell.2022.06.050
    OpenUrlCrossRefPubMed
  70. ↵
    1. Cheng AG,
    2. Ho PY,
    3. Aranda-Díaz A,
    4. Jain S,
    5. Yu FB,
    6. Meng X,
    7. Wang M,
    8. Iakiviak M,
    9. Nagashima K,
    10. Zhao A,
    11. Murugkar P,
    12. Patil A,
    13. Atabakhsh K,
    14. Weakley A,
    15. Yan J,
    16. Brumbaugh AR,
    17. Higginbottom S,
    18. Dimas A,
    19. Shiver AL,
    20. Deutschbauer A,
    21. Neff N,
    22. Sonnenburg JL,
    23. Huang KC and
    24. Fischbach MA
    : Design, construction, and in vivo augmentation of a complex gut microbiome. Cell 185(19):3617-3636.e19, 2022. PMID: 36070752. DOI: 10.1016/j.cell.2022.08.003
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Oral Installation of Recombinant Methioninase-producing Escherichia coli into the Microbiome Inhibits Colon-cancer Growth in a Syngeneic Mouse Model
YUTARO KUBOTA, QINGHONG HAN, KAZUYUKI HAMADA, YUSUKE AOKI, NORIYUKI MASAKI, KOYA OBARA, ANTON BARANOV, MICHAEL BOUVET, TAKUYA TSUNODA, ROBERT M. HOFFMAN
Cancer Genomics & Proteomics Nov 2022, 19 (6) 683-691; DOI: 10.21873/cgp.20351
Reddit logo Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords