Oral Recombinant Methioninase Combined with Caffeine and Doxorubicin Induced Regression of a Doxorubicin-resistant Synovial Sarcoma in a PDOX Mouse Model

Author:

Higuchi, Takashi

Kawaguchi, Kei

Miyake, Kentaro

Han, Qinghong

Tan, Yuying

Oshiro, Hiromichi

Sugisawa, Norihiko

Zhang, Zhiying

Razmjooei, Sahar

Yamamoto, Norio

Hayashi, Katsuhiro

Kimura, Hiroaki

Miwa, Shinji

Igarashi, Kentaro

Chawla, Sant P

Singh, Arun S

Eilber, Frederick C

Singh, Shree Ram

Tsuchiya, Hiroyuki

Hoffman, Robert M
Author Address

AntiCancer, Inc., San Diego, CA, U.S.A., Department of Surgery, University of California, San Diego, CA, U.S.A., Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan., Sarcoma Oncology Center, Santa Monica, CA, U.S.A., Division of Hematology-Oncology, University of California, San Diego, CA, U.S.A., Division of Surgical Oncology, University of California, San Diego, CA, U.S.A., Basic Research Laboratory, National Cancer Institute, Frederick, MD, U.S.A. all@anticancer.com all@anticancer.com tsuchi@med.kanazawa-u.ac.jp singhshr@mail.nih.gov., Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan all@anticancer.com all@anticancer.com tsuchi@med.kanazawa-u.ac.jp singhshr@mail.nih.gov., AntiCancer, Inc., San Diego, CA, U.S.A. all@anticancer.com all@anticancer.com tsuchi@med.kanazawa-u.ac.jp singhshr@mail.nih.gov.,

Abstract:

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. 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. 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. 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. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

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