Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model
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Takashi Murakami1,2,3, Shukuan Li1, Qinghong Han1, Yuying Tan1, Tasuku Kiyuna1, Kentaro Igarashi1, Kei Kawaguchi1, Ho Kyoung Hwang1, Kentaro Miyake1,2,3, Arun S. Singh4, Scott D. Nelson5, Sarah M. Dry5, Yunfeng Li5, Yukihiko Hiroshima3, Thinzar M. Lwin 2, Jonathan C. DeLong2, Takashi Chishima3, Kuniya Tanaka3, Michael Bouvet2, Itaru Endo3, Fritz C. Eilber6 and Robert M. Hoffman1,2
1 AntiCancer, Inc., San Diego, California, USA
2 Department of Surgery, University of California, San Diego, California, USA
3 Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
4 Division of Hematology-Oncology, University of California, Los Angeles, California, USA
5 Department of Pathology, University of California, Los Angeles, California, USA
6 Division of Surgical Oncology, University of California, Los Angeles, California, USA
Robert M. Hoffman, email:
Fritz C. Eilber, email:
Keywords: recombinant methioninase, patient-derived orthotopic xenograft, Ewing’s sarcoma, recalcitrant cancer, nude mice
Received: December 15, 2016 Accepted: January 11, 2017 Published: March 01, 2017
Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 22.214.171.124]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing’s sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients’outcome. Here we report efficacy of rMETase against Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing’s sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing’s sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing’s sarcoma.
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