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

• DOI: 10.21873/anticanres.12899
• Publication Date: 2018-10-01T21:49:35Z
• Authors: 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
• Keywords: Male; 0301 basic medicine; Antibiotics, Antineoplastic; Administration, Oral; Mice, Nude; Middle Aged; Combined Modality Therapy; Xenograft Model Antitumor Assays; Recombinant Proteins; 3. Good health; Carbon-Sulfur Lyases; Mice; Sarcoma, Synovial; 03 medical and health sciences; Doxorubicin; Drug Resistance, Neoplasm; Caffeine; Tumor Cells, Cultured; Animals; Humans; Central Nervous System Stimulants

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.