Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer

被引:27
作者
Ota, Shinichi [1 ]
Geschwind, Jean-Francois H. [1 ]
Buijs, Manon [1 ]
Wijlemans, Joost W. [1 ,2 ]
Kwak, Byung Kook [1 ,3 ]
Ganapathy-Kanniappan, Shanmugasundaram [1 ]
机构
[1] Johns Hopkins Univ, Div Vasc & Intervent Radiol, Russell H Morgan Dept Radiol & Radiol Sci, Sch Med, Baltimore, MD 21287 USA
[2] Univ Med Ctr Utrecht, Dept Radiol, NL-3584 CX Utrecht, Netherlands
[3] Chung Ang Univ Hosp, Dept Radiol, Seoul, South Korea
关键词
Pancreatic cancer; 3-Bromopyruvate; Glycolysis; Ultrasound; CELLS; CHEMOTHERAPY; INJECTION; THERAPY; GEMCITABINE; METABOLISM; RESISTANCE; CARCINOMA; TRIAL;
D O I
10.1007/s11523-013-0273-x
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Studies in animal models of cancer have demonstrated that targeting tumor metabolism can be an effective anticancer strategy. Previously, we showed that inhibition of glucose metabolism by the pyruvate analog, 3-bromopyruvate (3-BrPA), induces anticancer effects both in vitro and in vivo. We have also documented that intratumoral delivery of 3-BrPA affects tumor growth in a subcutaneous tumor model of human liver cancer. However, the efficacy of such an approach in a clinically relevant orthotopic tumor model has not been reported. Here, we investigated the feasibility of ultrasound (US) image-guided delivery of 3-BrPA in an orthotopic mouse model of human pancreatic cancer and evaluated its therapeutic efficacy. In vitro, treatment of Panc-1 cells with 3-BrPA resulted in a dose-dependent decrease in cell viability. The loss of viability correlated with a dose-dependent decrease in the intracellular ATP level and lactate production confirming that disruption of energy metabolism underlies these 3-BrPA-mediated effects. In vivo, US-guided delivery of 3-BrPA was feasible and effective as demonstrated by a marked decrease in tumor size on imaging. Further, the antitumor effect was confirmed by (1) a decrease in the proliferative potential by Ki-67 immunohistochemical staining and (2) the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphospate nick end labeling staining. We therefore demonstrate the technical feasibility of US-guided intratumoral injection of 3-BrPA in a mouse model of human pancreatic cancer as well as its therapeutic efficacy. Our data suggest that this new therapeutic approach consisting of a direct intratumoral injection of antiglycolytic agents may represent an exciting opportunity to treat patients with pancreas cancer.
引用
收藏
页码:145 / 151
页数:7
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