TY - JOUR
T1 - Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase
AU - Igarashi, Kentaro
AU - Li, Shukuan
AU - Han, Qinghong
AU - Tan, Yuying
AU - Kawaguchi, Kei
AU - Murakami, Takashi
AU - Kiyuna, Tasuku
AU - Miyake, Kentaro
AU - Li, Yunfeng
AU - Nelson, Scott D.
AU - Dry, Sarah M.
AU - Singh, Arun S.
AU - Elliott, Irmina A.
AU - Russell, Tara A.
AU - Eckardt, Mark A.
AU - Yamamoto, Norio
AU - Hayashi, Katsuhiro
AU - Kimura, Hiroaki
AU - Miwa, Shinji
AU - Tsuchiya, Hiroyuki
AU - Eilber, Fritz C.
AU - Hoffman, Robert M.
N1 - Funding Information:
This study was supported in part by National Cancer Institute grant CA213649.
PY - 2018/4
Y1 - 2018/4
N2 - Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3: G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3; DOX (G2): 329.5 ± 79 mm3, P = 0.670; rMETase (G3): 162.6 ± 51 mm3, P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.
AB - Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3: G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3; DOX (G2): 329.5 ± 79 mm3, P = 0.670; rMETase (G3): 162.6 ± 51 mm3, P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.
KW - PDOX
KW - doxorubicin
KW - patient-derived orthotopic xenograft
KW - recombinant methioninase
KW - resistant
KW - undifferentiated spindle-cell sarcoma
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U2 - 10.1002/jcb.26527
DO - 10.1002/jcb.26527
M3 - Article
C2 - 29143983
AN - SCOPUS:85039770849
VL - 119
SP - 3537
EP - 3544
JO - Journal of Cellular Biochemistry
JF - Journal of Cellular Biochemistry
SN - 0730-2312
IS - 4
ER -