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Recombinant methioninase effectively targets a Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.
- Source :
-
Oncotarget [Oncotarget] 2017 May 30; Vol. 8 (22), pp. 35630-35638. - Publication Year :
- 2017
-
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.
- Subjects :
- Animals
Antimetabolites, Antineoplastic administration & dosage
Antimetabolites, Antineoplastic pharmacokinetics
Biopsy
Carbon-Sulfur Lyases administration & dosage
Carbon-Sulfur Lyases pharmacokinetics
Disease Models, Animal
Humans
Immunohistochemistry
Male
Mice
Mice, Nude
Recombinant Proteins administration & dosage
Recombinant Proteins pharmacokinetics
Sarcoma, Ewing drug therapy
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Antimetabolites, Antineoplastic pharmacology
Carbon-Sulfur Lyases pharmacology
Recombinant Proteins pharmacology
Sarcoma, Ewing pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 8
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 28404944
- Full Text :
- https://doi.org/10.18632/oncotarget.15823