Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase

Kentaro Igarashi, Shukuan Li, Qinghong Han, Yuying Tan, Kei Kawaguchi, Takashi Murakami, Tasuku Kiyuna, Kentaro Miyake, Yunfeng Li, Scott D. Nelson, Sarah M. Dry, Arun S. Singh, Irmina A. Elliott, Tara A. Russell, Mark A. Eckardt, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Hiroyuki TsuchiyaFritz C. Eilber, Robert M. Hoffman

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant ­cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3: G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3; DOX (G2): 329.5 ± 79 mm3, P = 0.670; rMETase (G3): 162.6 ± 51 mm3, P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.

Original languageEnglish
Pages (from-to)3537-3544
Number of pages8
JournalJournal of Cellular Biochemistry
Volume119
Issue number4
DOIs
Publication statusPublished - 2018 Apr

Keywords

  • PDOX
  • doxorubicin
  • patient-derived orthotopic xenograft
  • recombinant methioninase
  • resistant
  • undifferentiated spindle-cell sarcoma

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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