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The combination of oral-recombinant methioninase and azacitidine arrests a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft mouse model

  • Takashi Higuchi
  • Norihiko Sugisawa
  • Jun Yamamoto
  • Hiromichi Oshiro
  • Qinghong Han
  • Norio Yamamoto
  • Katsuhiro Hayashi
  • Hiroaki Kimura
  • Shinji Miwa
  • Kentaro Igarashi
  • Yuying Tan
  • Shreya Kuchipudi
  • Michael Bouvet
  • Shree Ram SinghEmail author
  • Hiroyuki TsuchiyaEmail author
  • Robert M. HoffmanEmail author
Original Article

Abstract

Purpose

Cancers are methionine (MET) and methylation addicted, causing them to be highly sensitive to MET restriction. The present study determined the efficacy of restricting MET with oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, azacitidine (AZA) on a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model.

Methods

The osteosarcoma PDOX models were randomized into five treatment groups of six mice: control; doxorubicin (DOX) alone; AZA alone; o-rMETase alone; o-rMETase-AZA combination. Tumor size and body weight were measured during the 14 days of treatment.

Results

We found that tumor growth was arrested only by the o-rMETase–AZA combination treatment, as tumors with this treatment exhibited tumor necrosis with degenerative change.

Conclusion

This study suggests that o-rMETase-AZA combination has clinical potential for patients with chemoresistant osteosarcoma.

Keywords

Osteosarcoma Methionine Recombinant methioninase Patient-derived orthotopic xenograft PDOX 

Notes

Acknowledgements

This paper is dedicated to the memory of Reese Imhoff.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest. AntiCancer Inc. uses PDOX models for contract research. QH and YT are employees of AntiCancer Inc. TH, NS, JY, HO, NY, KH, HK, SM, KI and RMH are or were unsalaried associates of AntiCancer Inc.

Ethical approval

The mouse investigations were carried out using an AntiCancer, Inc. Institutional Animal Care and Use Committee (IACUC) protocol specifically approved for this study as previously described and as per the principles and procedures provided in the National Institutes of Health (NIH) Guide for the Care and Use of Animals under Assurance Number A3873-1 [26, 27].

Informed consent

Written informed consent was obtained from the patient as part of a UCLA Institutional Review Board approved protocol (IRB#10-001857).

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Takashi Higuchi
    • 1
    • 2
    • 3
  • Norihiko Sugisawa
    • 1
    • 2
  • Jun Yamamoto
    • 1
    • 2
  • Hiromichi Oshiro
    • 1
    • 2
  • Qinghong Han
    • 1
  • Norio Yamamoto
    • 3
  • Katsuhiro Hayashi
    • 3
  • Hiroaki Kimura
    • 3
  • Shinji Miwa
    • 3
  • Kentaro Igarashi
    • 3
  • Yuying Tan
    • 1
  • Shreya Kuchipudi
    • 4
  • Michael Bouvet
    • 2
  • Shree Ram Singh
    • 5
    Email author
  • Hiroyuki Tsuchiya
    • 3
    Email author
  • Robert M. Hoffman
    • 1
    • 2
    Email author
  1. 1.AntiCancer, IncSan DiegoUSA
  2. 2.Department of SurgeryUniversity of CaliforniaSan DiegoUSA
  3. 3.Department of Orthopedic Surgery, Graduate School of Medical ScienceKanazawa UniversityKanazawaJapan
  4. 4.Division of Cancer PreventionNational Cancer InstituteRockvilleUSA
  5. 5.Basic Research LaboratoryCenter for Cancer Research, National Cancer InstituteFrederickUSA

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