TY - JOUR
T1 - Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer
AU - Kawaguchi, Kei
AU - Miyake, Kentaro
AU - Han, Qinghong
AU - Li, Shukuan
AU - Tan, Yuying
AU - Igarashi, Kentaro
AU - Lwin, Thinzar M.
AU - Higuchi, Takashi
AU - Kiyuna, Tasuku
AU - Miyake, Masuyo
AU - Oshiro, Hiromichi
AU - Bouvet, Michael
AU - Unno, Michiaki
AU - Hoffman, Robert M.
N1 - Publisher Copyright:
© 2018 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely-used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance. A pancreatic cancer obtained from a patient was grown orthotopically in the pancreatic tail of nude mice to establish the PDOX model. Five weeks after implantation, 40 pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); GEM (100 mg/kg, i.p., once a week for 5 weeks, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); GEM+rMETase (GEM: 100 mg/kg, i.p., once a week for 5 weeks, rMETase: 100 units, i.p., 14 consecutive days, n = 10). Although GEM partially inhibited PDOX tumor growth, combination therapy (GEM+rMETase) was significantly more effective than mono therapy (GEM: p = 0.0025, rMETase: p = 0.0010). The present study is the first demonstrating the efficacy of rMETase combination therapy in a pancreatic cancer PDOX model to overcome first-line therapy resistance in this recalcitrant disease.
AB - Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely-used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance. A pancreatic cancer obtained from a patient was grown orthotopically in the pancreatic tail of nude mice to establish the PDOX model. Five weeks after implantation, 40 pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); GEM (100 mg/kg, i.p., once a week for 5 weeks, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); GEM+rMETase (GEM: 100 mg/kg, i.p., once a week for 5 weeks, rMETase: 100 units, i.p., 14 consecutive days, n = 10). Although GEM partially inhibited PDOX tumor growth, combination therapy (GEM+rMETase) was significantly more effective than mono therapy (GEM: p = 0.0025, rMETase: p = 0.0010). The present study is the first demonstrating the efficacy of rMETase combination therapy in a pancreatic cancer PDOX model to overcome first-line therapy resistance in this recalcitrant disease.
KW - Gemcitabine
KW - Methionine dependence
KW - Nude mice
KW - Orthotopic
KW - Pancreatic cancer
KW - Patientderived orthotopic xenograft (PDOX)
KW - Precision therapy
KW - Recombinant methioninase
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UR - http://www.scopus.com/inward/citedby.url?scp=85047212373&partnerID=8YFLogxK
U2 - 10.1080/15384101.2018.1445907
DO - 10.1080/15384101.2018.1445907
M3 - Article
C2 - 29623758
AN - SCOPUS:85047212373
VL - 17
SP - 868
EP - 873
JO - Cell Cycle
JF - Cell Cycle
SN - 1538-4101
IS - 7
ER -