title: Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.
abstract: 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 4.4.1.11]). 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.
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.|Department of Surgery, University of California, San Diego, California, USA.|Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Murakami
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.
authors.forename: Shukuan
authors.initials: S
authors.lastname: Li
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Han
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Tan
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Kiyuna
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawaguchi
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.
authors.forename: Ho Kyoung
authors.initials: HK
authors.lastname: Hwang
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.|Department of Surgery, University of California, San Diego, California, USA.|Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Division of Hematology-Oncology, University of California, Los Angeles, California, USA.
authors.forename: Arun S
authors.initials: AS
authors.lastname: Singh
authors.affiliation: Department of Pathology, University of California, Los Angeles,California, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Nelson
authors.affiliation: Department of Pathology, University of California, Los Angeles,California, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Dry
authors.affiliation: Department of Pathology, University of California, Los Angeles,California, USA.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Hiroshima
authors.affiliation: Department of Surgery, University of California, San Diego, California, USA.
authors.forename: Thinzar M
authors.initials: TM
authors.lastname: Lwin
authors.affiliation: Department of Surgery, University of California, San Diego, California, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: DeLong
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Chishima
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Kuniya
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Department of Surgery, University of California, San Diego, California, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Endo
authors.affiliation: Division of Surgical Oncology, University of California, Los Angeles, California, USA.
authors.forename: Fritz C
authors.initials: FC
authors.lastname: Eilber
authors.affiliation: AntiCancer, Inc., San Diego, California, USA.|Department of Surgery, University of California, San Diego, California, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001706:Biopsy; D013437:Carbon-Sulfur Lyases / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000473:pathology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000964:Antimetabolites, Antineoplastic; D011994:Recombinant Proteins; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase
keywords: Ewing’s sarcoma; methionine dependence; nude mice; patient-derived orthotopic xenograft; recalcitrant cancer; recombinant methioninase