Oral recombinant methioninase combined with caffeine and doxorubicin induced regression of a doxorubicin-resistant synovial sarcoma in a PDOX mouse model

Takashi Higuchi, Kei Kawaguchi, Kentaro Miyake, Qinghong Han, Yuying Tan, Hiromichi Oshiro, Norihiko Sugisawa, Zhiying Zhang, Sahar Razmjooei, Norio Yamamoto, Katsuhiro Hayashi, Hiroaki Kimura, Shinji Miwa, Kentaro Igarashi, Sant P. Chawla, Arun S. Singh, Frederick C. Eilber, Shree Ram Singh, Hiroyuki Tsuchiya, Robert M. Hoffman

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Background/Aim: Synovial sarcoma (SS) is a recalcitrant neoplasm with low chemosensitivity. We recently reported that recombinant methioninase (rMETase) inhibited SS growth in a patient-derived orthotopic xenograft (PDOX) mouse model and was more effective when administered in combination with the first-line drug doxorubicin (DOX). Caffeine enhances the efficacy of anticancer drugs by overcoming drug-induced cell-cycle arrest and increasing subsequent apoptosis. Here, we determined the efficacy of oral recombinant methioninase (o-rMETase) in combined with caffeine on an SS-PDOX model. Materials and Methods: Mice bearing SS-PDOX tumors were randomized into four treatment groups of six: Untreated control; o-rMETase alone; o-rMETase with caffeine; DOX plus o-rMETase with caffeine. Tumor size and body weight were measured during the treatment and plasma L-methionine (MET) levels were measured at the end of treatment. Results: All treatments significantly inhibited SS-PDOX tumor growth. Combining caffeine with o-rMETase was more effective than o-rMETase alone. DOX combined with o-rMETase and caffeine led to regression of SS-PDOX. Plasma MET levels were reduced with o-rMETase treatment. Conclusion: These results suggest that combining o-rMETase and caffeine along with first-line chemotherapy can be highly effective for SS and has clinical potential for this recalcitrant disease.

Original languageEnglish
Pages (from-to)5639-5644
Number of pages6
JournalAnticancer research
Volume38
Issue number10
DOIs
Publication statusPublished - 2018 Oct
Externally publishedYes

Keywords

  • Caffeine
  • Doxorubicin
  • Oral rMETase
  • PDOX
  • Regression
  • Synovial sarcoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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