Combination of oral recombinant methioninase and decitabine arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma patient-derived orthotopic xenograft mouse model

Takashi Higuchi; Qinghong Han; Kentaro Miyake; Hiromichi Oshiro; Norihiko Sugisawa; Yuying Tan; Norio Yamamoto; Katsuhiro Hayashi; Hiroaki Kimura; Shinji Miwa; Kentaro Igarashi; Michael Bouvet; Shree Ram Singh; Hiroyuki Tsuchiya; Robert M Hoffman

doi:10.1016/j.bbrc.2019.12.024

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. 2020 Feb 26;523(1):135-139. doi: 10.1016/j.bbrc.2019.12.024. Epub 2019 Dec 12.

Authors

Affiliations

¹ AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
² AntiCancer, Inc., San Diego, CA, USA.
³ AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA.
⁴ Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
⁵ Department of Surgery, University of California, San Diego, CA, USA.
⁶ Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA. Electronic address: singhshr@mail.nih.gov.
⁷ Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan. Electronic address: tsuchi@med.kanazawa-u.ac.jp.
⁸ AntiCancer, Inc., San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA. Electronic address: all@anticancer.com.

PMID: 31839218
DOI: 10.1016/j.bbrc.2019.12.024

Abstract

Cancer cells are methionine (MET) and methylation addicted and are highly sensitive to MET restriction. The present study determined the efficacy of oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, decitabine (DAC) on restricting MET in an undifferentiated-soft tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) nude-mouse model. The USTS PDOX models were randomized into five treatment groups of six mice: Control; doxorubicin (DOX) alone; DAC alone; o-rMETase alone; and o-rMETase-DAC combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested only in the o-rMETase-DAC condition. Tumors treated with the o-rMETase-DAC combination exhibited tumor necrosis with degenerative changes. This study demonstrates that the o-rMETase-DAC combination could arrest the USTS PDOX tumor suggesting clinical promise.

Keywords: DNA methylation; Decitabine; Methionine addiction; PDOX; Recombinant methioninase; Undifferentiated soft-tissue sarcoma.

Published by Elsevier Inc.

MeSH terms

Administration, Oral
Animals
Antimetabolites, Antineoplastic / administration & dosage
Antimetabolites, Antineoplastic / pharmacology*
Carbon-Sulfur Lyases / administration & dosage
Carbon-Sulfur Lyases / metabolism*
Combined Modality Therapy
Decitabine / administration & dosage
Decitabine / pharmacology*
Disease Models, Animal*
Drug Resistance, Neoplasm / drug effects*
Female
Humans
Mice
Mice, Nude
Middle Aged
Muscle Neoplasms / drug therapy*
Muscle Neoplasms / pathology
Muscle Neoplasms / surgery
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / pathology
Neoplasms, Experimental / surgery
Recombinant Proteins / administration & dosage
Recombinant Proteins / metabolism
Sarcoma / drug therapy*
Sarcoma / pathology
Sarcoma / surgery

Substances

Antimetabolites, Antineoplastic
Recombinant Proteins
Decitabine
Carbon-Sulfur Lyases
L-methionine gamma-lyase