Research ArticleExperimental Studies

Oral-recombinant Methioninase Converts an Osteosarcoma from Methotrexate-resistant to -sensitive in a Patient-derived Orthotopic-xenograft (PDOX) Mouse Model

YUSUKE AOKI, YASUNORI TOME, QINGHONG HAN, JUN YAMAMOTO, KAZUYUKI HAMADA, NORIYUKI MASAKI, YUTARO KUBOTA, MICHAEL BOUVET, KOTARO NISHIDA and ROBERT M. HOFFMAN
Anticancer Research February 2022, 42 (2) 731-737; DOI: https://doi.org/10.21873/anticanres.15531

Abstract

Background/Aim: Osteosarcoma is the most common bone sarcoma. Although surgery and chemotherapy are initially effective, the 5-year survival is approximately 60% to 80%, and has not improved over three decades. We have previously shown that methionine restriction (MR) induced by oral recombinant methioninase (o-rMETase), is effective against osteosarcoma in patient-derived orthotopic xenograft (PDOX) nude-mouse models. In the present report, the efficacy of the combination of oral o-rMETase and methotrexate (MTX) was examined in an osteosarcoma PDOX mouse model. Materials and Methods: An osteosarcoma-PDOX model was previously established by implanting tumor fragments into the proximal tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups: control; o-rMETase alone; MTX alone; combination of o-rMETase and MTX. The mice were sacrificed after 4 weeks of treatment. Results: The combination of o-rMETase and MTX showed significantly higher efficacy compared to the control group (p=0.04). The combination also showed significantly higher efficacy compared to MTX alone (p=0.04). No significant efficacy of o-rMETase alone or MTX alone compared to control was shown (p=0.21, 1.00, respectively). Only the combination of o-rMETase and MTX reduced the cancer-cell density in the osteosarcoma tumor. Conclusion: rMETase converted an osteosarcoma PDOX from MTX-resistant to MTX-sensitive and thereby shows future clinical potential.

Key Words:

Osteosarcoma is the most common bone sarcoma, with a 5-year survival of approximately 60% to 80%, which has not increased over three decades. First-line therapy for osteosarcoma includes neoadjuvant/adjuvant doxorubicin (DOX), cisplatinum (CDDP), ifosfamide (IFO), and high-dose methotrexate (MTX) (1-5). We have previously established a patient-derived orthotopic xenograft (PDOX) mouse model of osteosarcoma and identified potentially effective drugs and combinations for individual patients (6-23).

Methionine addiction, which is due to a large methionine requirement compared to normal cells (24-30), is a general and fundamental hallmark of cancer and has been termed the Hoffman effect (31, 32). Recombinant methioninase (rMETase), which degrades methionine, arrests methionine-addicted cancer cells in late-S/G2 phase of the cell cycle (33, 34). The efficacy of rMETase has been previously reported on PDOX mouse models of osteosarcoma and other sarcoma PDOX and PDOX models of other cancers, including rMETase administered orally (o-rMETase) (8, 10, 18, 21, 22, 35-46).

o-rMETase has also been shown to prevent obesity, diabetes and fatty liver in mouse models (47-49). o-rMETase has also shown apparent clinical efficacy in advanced prostate cancer (50), reflecting its efficacy in PDOX models of advanced cancers (51-58).

MTX is an inhibitor of dihydrofolate reductase (DHFR) and methylenetetrahydrofolate reductase (MTHFR) (59, 60) and thereby inhibits endogenous methionine synthesis. MTX also inhibits methionine S-adenosyltransferase (MAT) directly (61).

Our hypothesis was that the combination of o-rMETase and MTX may show efficacy, via a synergistic decrease of both exogenous and endogenously-synthesized methionine and transmethylation in an osteosarcoma-PDOX.

Materials and Methods

Mice. Athymic nu/nu nude mice (4-6 weeks) (AntiCancer, Inc., San Diego, CA, USA) were used in the present study. All experiments were performed following the National Institutes of Health (NIH) Guide for the Care and Use of Animals, with Assurance Number A3873-1, as previously described (20-23).

Patient-derived tumor. We previously established an osteosarcoma specimen from a 14-year-old boy, who had osteosarcoma in the pelvis, at the UCLA Medical center (20-23). An informed consent from the patient’s parents and UCLA Institutional Review Board approval (IRB#10-001857) were obtained in advance. The patient did not receive chemotherapy or radiotherapy before surgery.

Osteosarcoma-PDOX mouse model. The osteosarcoma-PDOX model was established as previously reported (23, 62). Briefly, a 1 mm-diameter hole was made in the proximal part of the left tibia, using a 5-mm blade (Medipoint Inc., Mineola, NY, USA). A 1-mm3 osteosarcoma tumor fragment, which was obtained from a subcutaneous tumor in a PDX mouse model, was inserted into the hole. The wound was sutured with 6-0 nylon.

Recombinant methioninase (rMETase) production. The procedure for the production of rMETase from recombinant E. coli was previously reported, and involves fermentation, heat treatment, polyethylene glycol precipitation, and DEAE-Sepharose column chromatography (63).

Treatment and evaluation. We randomized the osteosarcoma-PDOX mouse models into four groups of seven mice per group as follows: G1, control treated with phosphate-buffered saline (PBS) (0.2 ml/day, oral, twice a day); G2, o-rMETase (50 units/mouse, oral, twice a day); G3, MTX [5 mg/kg, intraperitoneal (i.p.) injection, once a week]; G4, combination with o-rMETase (50 units, oral, twice a day) and MTX [5 mg/kg, intraperitoneal (i.p.) injection, once a week] (Figure 1). Treatment was started when the tumor become palpable. Tumor and body-weight measurements were performed twice a week during the 4-week treatment period. Tumor volume was calculated with the following formula: tumor volume (mm3)=length (mm) × width (mm) × width (mm) × 1/2, as previously reported (62). After treatment, all the mice were sacrificed, and tumor tissues were obtained for further pathological evaluations. Data are shown as mean±standard deviation (SD).

Figure 1.
Figure 1.

Treatment schema.

Hematoxylin and eosin (H&E) staining. H&E staining was performed according to standard protocols as previously reported (62).

Statistical analyses. We performed statistical analyses using JMP ver. 15.0.0 (SAS Institute, Cary, NC, USA). For the parametric test to compare between groups, Tukey-Kramer HSD was used. Graphs show the mean, and error bars express SD of the mean. A p-value ≤0.05 was defined to indicate statistically significant difference.

Results

Treatment efficacy on the osteosarcoma-PDOX mouse model. There was no significant difference of tumor volume in the osteosarcoma-PDOX between control and o-rMETase alone or MTX alone (p=0.21, 1.00, respectively), in contrast, the combination of o-rMETase and MTX showed significant efficacy, compared to the control (p=0.04). Moreover, the combination therapy showed significant efficacy compared to MTX alone (p=0.04) (Figure 2 and Figure 3).

Figure 2.
Figure 2.

Efficacy of treatment on the osteosarcoma-PDOX. Relative tumor volume at each time point is shown in line graphs. The relative tumor volume is calculated as the tumor volume at each point divided by the tumor volume at the day of initiation of treatment. n=7 mice/group. *p<0.05. Error bars: ±SD.

Figure 3.
Figure 3.

Representative photographs from each treatment group of osteosarcoma-PDOX mouse models at the end of treatment. (A) Control administered oral PBS. (B) o-rMETase. (C) MTX. (D) Combination of o-rMETase and MTX. Scale bar: 10 mm.

Toxicity of treatment. The body weight of the mice showed no significant reduction in any of the four treatment groups at the end of the experiment (Figure 4). No mice died during the experiment.

Figure 4.
Figure 4.

Toxicity of treatments on the osteosarcoma-PDOX. Mouse body weight at each point is shown in line graphs. Error bars: ±SD.

Histology of osteosarcoma-PDOX. The tumor tissue of the control osteosarcoma-PDOX comprised high-density spindle-shaped cancer cells. The o-rMETase-alone- or MTX-alone-treated osteosarcoma PDOX tissue resembled the control (Figure 5A-C). In contrast the osteosarcoma PDOX treated with the combination of o-rMETase and MTX had a very low density of cancer-cells (Figure 5D).

Figure 5.
Figure 5.

Representative photomicrographs of H & E-stained tissue sections of the untreated and treated osteosarcoma-PDOX. (A) Control administered oral PBS. (B) o-rMETase. (C) MTX. (D) Combination of o-rMETase and MTX. Magnification: 200×. Scale bar: 50 μm.

Discussion

Methionine addiction of cancer cells is the result of increased transmethylation reactions, via S-adenosylmethionine (SAM) (24-30). r-METase effectively degrades external methionine (63). The efficacy of orally-administrated r-METase (o-rMETase) was shown previously shown in many types of cancer in PDOX models (18, 21, 22, 35-46, 51-58). We have also reported the efficacy of rMETase on PDOX models of osteosarcoma including o-rMETase (8, 10, 18, 21, 22).

MTX inhibits dihydrofolate reductase (DHFR), resulting in decrease of tetrahydrofolate and methyl-tetrahydrofolate, eventually depleting the levels of endogenously-synthesized methionine and SAM, which is the main methyl donor in the cell (67). Additionally, there is a previous study reporting that low-dose MTX inhibits SAM synthesis directly (61).

In the present study, o-rMETase converted an osteosarcoma PDOX model from MTX-resistant to MTX-sensitive. This might be because MTX inhibits endogenous MET synthesis and o-rMETase restricts the external supply of methionine, resulting in a synergistic methionine-restriction effect on the osteosarcoma PDOX. The combination of o-rMETase and MTX thus has potential clinical promise

Acknowledgements

This study was funded in part by the Robert M. Hoffman Foundation for Cancer Research. This article is dedicated to the memory of A. R. Moossa, MD, Sun Lee, MD, Professor Li Jiaxi and Masaki Kitajima, MD., and Joseph R. Bertino, MD.

Footnotes

  • Authors’ Contributions

    YA, YT and RMH were involved in study conception and design. YA was involved in acquisition of data. YA, YT, JY, KH NM, YK and RMH analyzed and interpreted data. YA, YT and RMH wrote the manuscript. All Authors reviewed and approved the manuscript.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study. AntiCancer Inc. uses PDOX models for contract research. QH is an employee of AntiCancer Inc. YA, YT, JY, KH, NM, YT, and RMH are or were unsalaried associates of AntiCancer Inc.

  • Received November 22, 2021.
  • Revision received December 30, 2021.
  • Accepted December 31, 2021.

References

  1. ↵
    1. Davis AM,
    2. Bell RS and
    3. Goodwin PJ
    : Prognostic factors in osteosarcoma: a critical review. J Clin Oncol 12(2): 423-431, 1994. PMID: 8113851. DOI: 10.1200/JCO.1994.12.2.423
    OpenUrlAbstract
    1. Messerschmitt PJ,
    2. Garcia RM,
    3. Abdul-Karim FW,
    4. Greenfield EM and
    5. Getty PJ
    : Osteosarcoma. J Am Acad Orthop Surg 17(8): 515-527, 2009. PMID: 19652033. DOI: 10.5435/00124635-200908000-00005
    OpenUrlCrossRefPubMed
    1. Ritter J and
    2. Bielack SS
    : Osteosarcoma. Ann Oncol 21(Suppl 7): vii320-vii325, 2010. PMID: 20943636. DOI: 10.1093/annonc/mdq276
    OpenUrlCrossRefPubMed
    1. Luetke A,
    2. Meyers PA,
    3. Lewis I and
    4. Juergens H
    : Osteosarcoma treatment - where do we stand? A state of the art review. Cancer Treat Rev 40(4): 523-532, 2014. PMID: 24345772. DOI: 10.1016/j.ctrv.2013.11.006
    OpenUrlCrossRefPubMed
  5. ↵
    1. Harrison DJ,
    2. Geller DS,
    3. Gill JD,
    4. Lewis VO and
    5. Gorlick R
    : Current and future therapeutic approaches for osteosarcoma. Expert Rev Anticancer Ther 18(1): 39-50, 2018. PMID: 29210294. DOI: 10.1080/14737140.2018.1413939
    OpenUrlCrossRefPubMed
  6. ↵
    1. Murakami T,
    2. Igarashi K,
    3. Kawaguchi K,
    4. Kiyuna T,
    5. Zhang Y,
    6. Zhao M,
    7. Hiroshima Y,
    8. Nelson SD,
    9. Dry SM,
    10. Li Y,
    11. Yanagawa J,
    12. Russell T,
    13. Federman N,
    14. Singh A,
    15. Elliott I,
    16. Matsuyama R,
    17. Chishima T,
    18. Tanaka K,
    19. Endo I,
    20. Eilber FC and
    21. Hoffman RM
    : Tumor-targeting Salmonella typhimurium A1-R regresses an osteosarcoma in a patient-derived xenograft model resistant to a molecular-targeting drug. Oncotarget 8(5): 8035-8042, 2017. PMID: 28030831. DOI: 10.18632/oncotarget.14040
    OpenUrlCrossRefPubMed
    1. Igarashi K,
    2. Murakami T,
    3. Kawaguchi K,
    4. Kiyuna T,
    5. Miyake K,
    6. Zhang Y,
    7. Nelson SD,
    8. Dry SM,
    9. Li Y,
    10. Yanagawa J,
    11. Russell TA,
    12. Singh AS,
    13. Tsuchiya H,
    14. Elliott I,
    15. Eilber FC and
    16. Hoffman RM
    : A patient-derived orthotopic xenograft (PDOX) mouse model of a cisplatinum-resistant osteosarcoma lung metastasis that was sensitive to temozolomide and trabectedin: implications for precision oncology. Oncotarget 8(37): 62111-62119, 2017. PMID: 28977930. DOI: 10.18632/oncotarget.19095
    OpenUrlCrossRefPubMed
  8. ↵
    1. Igarashi K,
    2. Kawaguchi K,
    3. Kiyuna T,
    4. Miyake K,
    5. Murakami T,
    6. Yamamoto N,
    7. Hayashi K,
    8. Kimura H,
    9. Miwa S,
    10. Tsuchiya H and
    11. Hoffman RM
    : Effective metabolic targeting of human osteosarcoma cells in vitro and in orthotopic nude-mouse models with recombinant methioninase. Anticancer Res 37(9): 4807-4812, 2017. PMID: 28870899. DOI: 10.21873/anticanres.11887
    OpenUrlAbstract/FREE Full Text
    1. Igarashi K,
    2. Kawaguchi K,
    3. Murakami T,
    4. Kiyuna T,
    5. Miyake K,
    6. Nelson SD,
    7. Dry SM,
    8. Li Y,
    9. Yanagawa J,
    10. Russell TA,
    11. Singh AS,
    12. Yamamoto N,
    13. Hayashi K,
    14. Kimura H,
    15. Miwa S,
    16. Tsuchiya H,
    17. Eilber FC and
    18. Hoffman RM
    : Intra-arterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model. Cell Cycle 16(12): 1164-1170, 2017. PMID: 28494180. DOI: 10.1080/15384101.2017.1317417
    OpenUrlCrossRefPubMed
  10. ↵
    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. Kiyuna T,
    4. Miyake K,
    5. Miyake M,
    6. Li Y,
    7. Nelson SD,
    8. Dry SM,
    9. Singh AS,
    10. Elliott IA,
    11. Russell TA,
    12. Eckardt MA,
    13. Yamamoto N,
    14. Hayashi K,
    15. Kimura H,
    16. Miwa S,
    17. Tsuchiya H,
    18. Eilber FC and
    19. Hoffman RM
    : Temozolomide combined with irinotecan regresses a cisplatinum-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) precision-oncology mouse model. Oncotarget 9(8): 7774-7781, 2017. PMID: 29487690. DOI: 10.18632/oncotarget.22892
    OpenUrlCrossRefPubMed
    1. Kiyuna T,
    2. Tome Y,
    3. Miyake K,
    4. Murakami T,
    5. Oshiro H,
    6. Igarashi K,
    7. Kawaguchi K,
    8. Hsu J,
    9. Singh M,
    10. Li Y,
    11. Nelson S,
    12. Bouvet M,
    13. Singh SR,
    14. Kanaya F and
    15. Hoffman RM
    : Eribulin suppressed cisplatinum- and doxorubicin-resistant recurrent lung metastatic osteosarcoma in a patient-derived orthotopic xenograft mouse model. Anticancer Res 39(9): 4775-4779, 2019. PMID: 31519578. DOI: 10.21873/anticanres.13661
    OpenUrlAbstract/FREE Full Text
    1. Higuchi T,
    2. Sugisawa N,
    3. Miyake K,
    4. Oshiro H,
    5. Yamamoto N,
    6. Hayashi K,
    7. Kimura H,
    8. Miwa S,
    9. Igarashi K,
    10. Kline Z,
    11. Belt P,
    12. Chawla SP,
    13. Bouvet M,
    14. Singh SR,
    15. Tsuchiya H and
    16. Hoffman RM
    : Combination treatment with sorafenib and everolimus regresses a doxorubicin-resistant osteosarcoma in a PDOX mouse model. Anticancer Res 39(9): 4781-4786, 2019. PMID: 31519579. DOI: 10.21873/anticanres.13662
    OpenUrlAbstract/FREE Full Text
    1. Higuchi T,
    2. Sugisawa N,
    3. Miyake K,
    4. Oshiro H,
    5. Yamamoto N,
    6. Hayashi K,
    7. Kimura H,
    8. Miwa S,
    9. Igarashi K,
    10. Chawla SP,
    11. Bouvet M,
    12. Singh SR,
    13. Tsuchiya H and
    14. Hoffman RM
    : Sorafenib and palbociclib combination regresses a cisplatinum-resistant osteosarcoma in a PDOX mouse model. Anticancer Res 39(8): 4079-4084, 2019. PMID: 31366491. DOI: 10.21873/anticanres.13565
    OpenUrlAbstract/FREE Full Text
    1. Higuchi T,
    2. Sugisawa N,
    3. Miyake K,
    4. Oshiro H,
    5. Yamamoto N,
    6. Hayashi K,
    7. Kimura H,
    8. Miwa S,
    9. Igarashi K,
    10. Bouvet M,
    11. Singh SR,
    12. Tsuchiya H and
    13. Hoffman RM
    : The combination of olaratumab with doxorubicin and cisplatinum regresses a chemotherapy-resistant osteosarcoma in a patient-derived orthotopic xenograft mouse model. Transl Oncol 12(9): 1257-1263, 2019. PMID: 31299622. DOI: 10.1016/j.tranon.2019.06.002
    OpenUrlCrossRefPubMed
    1. Higuchi T,
    2. Sugisawa N,
    3. Miyake K,
    4. Oshiro H,
    5. Yamamoto N,
    6. Hayashi K,
    7. Kimura H,
    8. Miwa S,
    9. Igarashi K,
    10. Kline Z,
    11. Bouvet M,
    12. Singh SR,
    13. Tsuchiya H and
    14. Hoffman RM
    : Pioglitazone, an agonist of PPARγ, reverses doxorubicin-resistance in an osteosarcoma patient-derived orthotopic xenograft model by downregulating P-glycoprotein expression. Biomed Pharmacother 118: 109356, 2019. PMID: 31545293. DOI: 10.1016/j.biopha.2019.109356
    OpenUrlCrossRefPubMed
    1. Higuchi T,
    2. Miyake K,
    3. Oshiro H,
    4. Sugisawa N,
    5. Yamamoto N,
    6. Hayashi K,
    7. Kimura H,
    8. Miwa S,
    9. Igarashi K,
    10. Chawla SP,
    11. Bouvet M,
    12. Singh SR,
    13. Tsuchiya H and
    14. Hoffman RM
    : Trabectedin and irinotecan combination regresses a cisplatinum-resistant osteosarcoma in a patient-derived orthotopic xenograft nude-mouse model. Biochem Biophys Res Commun 513(2): 326-331, 2019. PMID: 30955860. DOI: 10.1016/j.bbrc.2019.03.191
    OpenUrlCrossRefPubMed
  18. ↵
    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. Igarashi K,
    2. Kawaguchi K,
    3. Yamamoto N,
    4. Hayashi K,
    5. Kimura H,
    6. Miwa S,
    7. Higuchi T,
    8. Taniguchi Y,
    9. Yonezawa H,
    10. Araki Y,
    11. Morinaga S,
    12. Misra S,
    13. Nelson SD,
    14. Dry SM,
    15. Li Y,
    16. Odani A,
    17. Singh SR,
    18. Tsuchiya H and
    19. Hoffman RM
    : A novel anionic-phosphate-platinum complex effectively targets a cisplatinum-resistant osteosarcoma in a patient-derived orthotopic xenograft mouse model. Cancer Genomics Proteomics 17(3): 217-223, 2020. PMID: 32345663. DOI: 10.21873/cgp.20182
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Higuchi T,
    2. Yamamoto J,
    3. Sugisawa N,
    4. Tashiro Y,
    5. Nishino H,
    6. Yamamoto N,
    7. Hayashi K,
    8. Kimura H,
    9. Miwa S,
    10. Igarashi K,
    11. Bouvet M,
    12. Singh SR,
    13. Tsuchiya H and
    14. Hoffman RM
    : PPARγ agonist pioglitazone in combination with cisplatinum arrests a chemotherapy-resistant osteosarcoma PDOX model. Cancer Genomics Proteomics 17(1): 35-40, 2020. PMID: 31882549. DOI: 10.21873/cgp.20165
    OpenUrlAbstract/FREE Full Text
  21. ↵
    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
  22. ↵
    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
  23. ↵
    1. Wu NF,
    2. Yamamoto J,
    3. Aoki Y,
    4. Bouvet M and
    5. Hoffman RM
    : Eribulin inhibits osteosarcoma in a clinically-accurate bone-tumor-insertion PDOX mouse model. Anticancer Res 41(4): 1779-1784, 2021. PMID: 33813382. DOI: 10.21873/anticanres.14943
    OpenUrlAbstract/FREE Full Text
  24. ↵
    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. 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 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
    1. Tan Y,
    2. Xu M and
    3. Hoffman RM
    : Broad selective efficacy of rMETase and PEG-rMETase on cancer cells in vitro. Anticancer Res 30(3): 793-798, 2010. PMID: 20392998.
    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
  30. ↵
    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
  31. ↵
    1. Kaiser P
    : Methionine dependence of cancer. Biomolecules 10(4): 568, 2020. PMID: 32276408. DOI: 10.3390/biom10040568
    OpenUrlCrossRefPubMed
  32. ↵
    1. Lauinger L and
    2. Kaiser P
    : Sensing and signaling of methionine metabolism. Metabolites 11(2): 83, 2021. PMID: 33572567. DOI: 10.3390/metabo11020083
    OpenUrlCrossRefPubMed
  33. ↵
    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
  34. ↵
    1. Hoffman RM and
    2. Jacobsen SJ
    : Reversible growth arrest in simian virus 40-transformed human fibroblasts. Proc Natl Acad Sci 77(12): 7306, 1980. PMID: 6261250. DOI: 10.1073/pnas.77.12.7306
    OpenUrlAbstract/FREE Full Text
  35. ↵
    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. Miyake K,
    2. Kiyuna T,
    3. Li S,
    4. Han Q,
    5. Tan Y,
    6. Zhao M,
    7. Oshiro H,
    8. Kawaguchi K,
    9. Higuchi T,
    10. Zhang Z,
    11. Razmjooei S,
    12. Barangi M,
    13. Wangsiricharoen S,
    14. Murakami T,
    15. Singh AS,
    16. Li Y,
    17. Nelson SD,
    18. Eilber FC,
    19. Bouvet M,
    20. Hiroshima Y,
    21. Chishima T,
    22. Matsuyama R,
    23. Singh SR,
    24. Endo I and
    25. Hoffman RM
    : Combining tumor-selective bacterial therapy with Salmonella typhimurium A1-R and cancer metabolism targeting with oral recombinant methioninase regressed an Ewing’s sarcoma in a patient-derived orthotopic xenograft model. Chemotherapy 63(5): 278-283, 2018. PMID: 30673664. DOI: 10.1159/000495574
    OpenUrlCrossRefPubMed
    1. Hoffman RM,
    2. Han Q,
    3. Kawaguchi K,
    4. Li S and
    5. Tan Y
    : Afterword: Oral methioninase-answer to cancer and fountain of youth? Methods Mol Biol 1866: 311-322, 2019. PMID: 30725426. DOI: 10.1007/978-1-4939-8796-2_24
    OpenUrlCrossRefPubMed
    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 SD,
    12. Russell TA,
    13. Dry SM,
    14. Li Y,
    15. Unno M,
    16. Eilber FC and
    17. Hoffman RM
    : 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, 2017. PMID: 29416666. DOI: 10.18632/oncotarget.23185
    OpenUrlCrossRefPubMed
    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. 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. 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
    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
  46. ↵
    1. Higuchi T,
    2. Han Q,
    3. Miyake K,
    4. Oshiro H,
    5. Sugisawa N,
    6. Tan Y,
    7. Yamamoto N,
    8. Hayashi K,
    9. Kimura H,
    10. Miwa S,
    11. Igarashi K,
    12. Bouvet M,
    13. Singh SR,
    14. Tsuchiya H and
    15. Hoffman RM
    : Combination of oral recombinant methioninase and decitabine arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma patient-derived orthotopic xenograft mouse model. Biochem Biophys Res Commun 523(1): 135-139, 2020. PMID: 31839218. DOI: 10.1016/j.bbrc.2019.12.024
    OpenUrlCrossRefPubMed
  47. ↵
    1. Tashiro Y,
    2. Han Q,
    3. Tan Y,
    4. Sugisawa N,
    5. Yamamoto J,
    6. Nishino H,
    7. Inubushi S,
    8. Higuchi T,
    9. Aoki T,
    10. Murakami M and
    11. Hoffman RM
    : Oral recombinant methioninase prevents obesity in mice on a high-fat diet. In Vivo 34(2): 489-494, 2020. PMID: 32111745. DOI: 10.21873/invivo.11799
    OpenUrlAbstract/FREE Full Text
    1. Tashiro Y,
    2. Han Q,
    3. Tan Y,
    4. Sugisawa N,
    5. Yamamoto J,
    6. Nishino H,
    7. Inubushi S,
    8. Sun YU,
    9. Zhu G,
    10. Lim H,
    11. Aoki T,
    12. Murakami M,
    13. Bouvet M and
    14. Hoffman RM
    : Oral recombinant methioninase inhibits diabetes onset in mice on a high-fat diet. In Vivo 34(3): 973-978, 2020. PMID: 32354882. DOI: 10.21873/invivo.11865
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Tashiro Y,
    2. Han Q,
    3. Tan Y,
    4. Sugisawa N,
    5. Yamamoto J,
    6. Nishino H,
    7. Inubushi S,
    8. Sun YU,
    9. Lim H,
    10. Aoki T,
    11. Murakami M,
    12. Takahashi Y,
    13. Bouvet M and
    14. Hoffman RM
    : Oral recombinant methioninase prevents nonalcoholic fatty liver disease in mice on a high fat diet. In Vivo 34(3): 979-984, 2020. PMID: 32354883. DOI: 10.21873/invivo.11866
    OpenUrlAbstract/FREE Full Text
  50. ↵
    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
  51. ↵
    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
    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
    1. Sugisawa N,
    2. Hamada K,
    3. Han Q,
    4. Yamamoto J,
    5. Sun YU,
    6. Nishino H,
    7. Kawaguchi K,
    8. Bouvet M,
    9. Unno M and
    10. Hoffman RM
    : Adjuvant oral recombinant methioninase inhibits lung metastasis in a surgical breast-cancer orthotopic syngeneic model. Anticancer Res 40(9): 4869-4874, 2020. PMID: 32878774. DOI:10.21873/anticanres.14489
    OpenUrlAbstract/FREE Full Text
    1. Sun YU,
    2. Nishino H,
    3. Sugisawa N,
    4. Yamamoto J,
    5. Hamada K,
    6. Zhu G,
    7. Lim HI and
    8. Hoffman RM
    : Oral recombinant methioninase sensitizes a bladder cancer orthotopic xenograft mouse model to low-dose cisplatinum and prevents metastasis. Anticancer Res 40(11): 6083-6091, 2020. PMID: 33109546. DOI: 10.21873/anticanres.14629
    OpenUrlAbstract/FREE Full Text
    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
    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. Higuchi T,
    2. Han Q,
    3. Sugisawa N,
    4. Yamamoto J,
    5. Yamamoto N,
    6. Hayashi K,
    7. Kimura H,
    8. Miwa S,
    9. Igarashi K,
    10. Bouvet M,
    11. Singh SR,
    12. Tsuchiya H and
    13. Hoffman RM
    : Combination methionine-methylation-axis blockade: a novel approach to target the methionine addiction of cancer. Cancer Genomics Proteomics 18(2): 113-120, 2021. PMID: 33608308. DOI: 10.21873/cgp.20246
    OpenUrlAbstract/FREE Full Text
  58. ↵
    1. Murakami T,
    2. Li S,
    3. Han Q,
    4. Tan Y,
    5. Kiyuna T,
    6. Igarashi K,
    7. Kawaguchi K,
    8. Hwang HK,
    9. Miyake K,
    10. Singh AS,
    11. Nelson SD,
    12. Dry SM,
    13. Li Y,
    14. Hiroshima Y,
    15. Lwin TM,
    16. DeLong JC,
    17. Chishima T,
    18. Tanaka K,
    19. Bouvet M,
    20. Endo I,
    21. Eilber FC and
    22. Hoffman RM
    : Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8(22): 35630-35638, 2017. PMID: 28404944. DOI: 10.18632/oncotarget.15823
    OpenUrlCrossRefPubMed
  59. ↵
    1. Grem JL,
    2. King SA,
    3. Wittes RE and
    4. Leyland-Jones B
    : The role of methotrexate in osteosarcoma. J Natl Cancer Inst 80(9): 626-655, 1988. PMID: 3286880. DOI: 10.1093/jnci/80.9.626
    OpenUrlCrossRefPubMed
  60. ↵
    1. Meyers PA,
    2. Schwartz CL,
    3. Krailo M,
    4. Kleinerman ES,
    5. Betcher D,
    6. Bernstein ML,
    7. Conrad E,
    8. Ferguson W,
    9. Gebhardt M,
    10. Goorin AM,
    11. Harris MB,
    12. Healey J,
    13. Huvos A,
    14. Link M,
    15. Montebello J,
    16. Nadel H,
    17. Nieder M,
    18. Sato J,
    19. Siegal G,
    20. Weiner M,
    21. Wells R,
    22. Wold L,
    23. Womer R and
    24. Grier H
    : Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 23(9): 2004-2011, 2005. PMID: 15774791. DOI: 10.1200/JCO.2005.06.031
    OpenUrlAbstract/FREE Full Text
  61. ↵
    1. Wang YC and
    2. Chiang EP
    : Low-dose methotrexate inhibits methionine S-adenosyltransferase in vitro and in vivo. Mol Med 18: 423-432, 2012. PMID: 22193356. DOI: 10.2119/molmed.2011.00048
    OpenUrlCrossRefPubMed
  62. ↵
    1. Wu NF,
    2. Yamamoto J,
    3. Bouvet M and
    4. Hoffman RM
    : A novel procedure for orthotopic tibia implantation for establishment of a more clinical osteosarcoma PDOX mouse model. In Vivo 35(1): 105-109, 2021. PMID: 33402455. DOI: 10.21873/invivo.12237
    OpenUrlAbstract/FREE Full Text
  63. ↵
    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
    1. Aoki Y,
    2. Yamamoto J,
    3. Tome Y,
    4. Hamada K,
    5. Masaki N,
    6. Inubushi S,
    7. Tashiro Y,
    8. Bouvet M,
    9. Endo I,
    10. Nishida K and
    11. Hoffman RM
    : Over-methylation of histone H3 lysines is a common molecular change among the three major types of soft-tissue sarcoma in patient-derived xenograft (PDX) mouse models. Cancer Genomics Proteomics 18(6): 715-721, 2021. PMID: 34697064. DOI: 10.21873/cgp.20292
    OpenUrlAbstract/FREE Full Text
    1. Wu NF,
    2. Wu J,
    3. Yamamoto J,
    4. Aoki Y,
    5. Hozumi C,
    6. Bouvet M and
    7. Hoffman RM
    : The first mouse model of primary osteosarcoma of the breast. In Vivo 35(4): 1979-1983, 2021. PMID: 34182472. DOI: 10.21873/invivo.12466
    OpenUrlAbstract/FREE Full Text
    1. Masaki N,
    2. Wu NF,
    3. Aoki Y,
    4. Yamamoto J,
    5. Miyazaki J and
    6. Hoffman RM
    : Osteosarcoma of the breast in a patient derived orthotopic xenograft (PDOX) mouse model is arrested by both cisplatinum and eribulin. In Vivo 35(6): 3107-3110, 2021. PMID: 34697141. DOI: 10.21873/invivo.12605
    OpenUrlAbstract/FREE Full Text
  67. ↵
    1. Chan ES and
    2. Cronstein BN
    : Methotrexate – how does it really work? Nat Rev Rheumatol 6(3): 175-178, 2010. PMID: 20197777. DOI: 10.1038/nrrheum.2010.5
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Oral-recombinant Methioninase Converts an Osteosarcoma from Methotrexate-resistant to -sensitive in a Patient-derived Orthotopic-xenograft (PDOX) Mouse Model
YUSUKE AOKI, YASUNORI TOME, QINGHONG HAN, JUN YAMAMOTO, KAZUYUKI HAMADA, NORIYUKI MASAKI, YUTARO KUBOTA, MICHAEL BOUVET, KOTARO NISHIDA, ROBERT M. HOFFMAN
Anticancer Research Feb 2022, 42 (2) 731-737; DOI: 10.21873/anticanres.15531
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

Keywords