The combination of oral-recombinant methioninase and azacitidine arrests a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft mouse model
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.
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.
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.
This study suggests that o-rMETase-AZA combination has clinical potential for patients with chemoresistant osteosarcoma.
KeywordsOsteosarcoma Methionine Recombinant methioninase Patient-derived orthotopic xenograft PDOX
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.
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].
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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