High Efficacy of Pazopanib on an Undifferentiated Spindle-Cell Sarcoma Resistant to First-Line Therapy Is Identified With a Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model.
Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer. Our laboratory pioneered the patient-derived orthotopic xenograft (PDOX) nude mouse model with the technique of surgical orthotopic implantation (SOI). In the present study, we evaluated the efficacy of standard first-line chemistry of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. A high-grade USCS from a striated muscle of the patients was grown orthotopically in the right biceps femoris muscle of nude mice to establish the PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, GEM (100 mg/kg, i.p., weekly, for 2 weeks) combined with DOC (20 mg/kg, i.p., once); G4, PAZ (100 mg/kg, p.o., daily, for 14 days). All treatments except DOX significantly inhibited tumor growth compared to untreated control on day 14 after treatment initiation. Tumor sizes were as fallows: control (G1): 332.0 ± 58.7 mm3; DOX (G2): 316.9 ± 55.9 mm3, P = 0.605; GEM + DOC (G3): 228.9 ± 39.8 mm3, P = 0.001; PAZ (G4): 173.8 ± 23.3 mm3, P < 0.0001. PAZ showed significantly more efficacy compared to other therapies evaluated: DOX (P < 0.0001), GEM + DOC (P = 0.006). There were no animal deaths in any group and body weight of treated mice was not significantly different in each group. The present results demonstrate that the PDOX model of USCS can identify a promising novel agent with significantly greater efficacy than first-line therapy for this recalcitrant disease. J. Cell. Biochem. 118: 2739-2743, 2017. © 2017 Wiley Periodicals, Inc.
AntiCancer, Inc., San Diego, California.|Department of Surgery, University of California, San Diego, California.|Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
Kentaro
K
Igarashi
AntiCancer, Inc., San Diego, California.|Department of Surgery, University of California, San Diego, California.
Kei
K
Kawaguchi
AntiCancer, Inc., San Diego, California.|Department of Surgery, University of California, San Diego, California.
Takashi
T
Murakami
AntiCancer, Inc., San Diego, California.|Department of Surgery, University of California, San Diego, California.
Tasuku
T
Kiyuna
AntiCancer, Inc., San Diego, California.|Department of Surgery, University of California, San Diego, California.
Kentaro
K
Miyake
Division of Hematology-Oncology, University of California, Los Angeles, California.
Arun S
AS
Singh
Department of Pathology, University of California, Los Angeles, California.
Scott D
SD
Nelson
Department of Pathology, University of California, Los Angeles, California.
Sarah M
SM
Dry
Department of Pathology, University of California, Los Angeles, California.
Yunfeng
Y
Li
Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
Norio
N
Yamamoto
Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
Katsuhiro
K
Hayashi
Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
Hiroaki
H
Kimura
Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
Shinji
S
Miwa
Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan.
Hiroyuki
H
Tsuchiya
Division of Surgical Oncology, University of California, Los Angeles, California.
Fritz C
FC
Eilber
AntiCancer, Inc., San Diego, California.|Department of Surgery, University of California, San Diego, California.
Robert M
0000-0002-0049-0041
RM
Hoffman
D000368:Aged; D000818:Animals; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D064593:Heterografts; D006801:Humans; D007191:Indazoles; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology*; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib
DOCETAXEL; DOXORUBICIN; EFFICACY; GEMCITABINE; INDIVIDUALIZED THERAPY; NUDE MICE; PAZOPANIB; PDOX; PRECISION MEDICINE; RESISTANCE; SPINDLE-CELL SARCOMA