Division of Vascular and Interventional Radiology, Russell H. Morgan Department of Radiology and Radiological Sciences, School of Medicine, Johns Hopkins University, 600 North Wolfe Street, Blalock 545, Baltimore, MD 21287, USA.
Target Oncol. 2013 Jun;8(2):145-51. doi: 10.1007/s11523-013-0273-x. Epub 2013 Mar 26.
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.
在癌症的动物模型研究中已经证实，靶向肿瘤代谢可能是一种有效的抗癌策略。此前，我们表明，通过丙酮酸类似物 3-溴丙酮酸（3-BrPA）抑制葡萄糖代谢，在体外和体内都能诱导抗癌作用。我们还记录到，3-BrPA 瘤内给药会影响肝癌皮下肿瘤模型中的肿瘤生长。然而，这种方法在临床相关的原位肿瘤模型中的疗效尚未报道。在这里，我们研究了超声（US）引导下在人胰腺癌细胞的原位小鼠模型中递送 3-BrPA 的可行性，并评估了其治疗效果。在体外，用 3-BrPA 处理 Panc-1 细胞导致细胞活力呈剂量依赖性下降。活力的丧失与细胞内 ATP 水平和乳酸产生的剂量依赖性下降相关，证实了能量代谢的破坏是这些 3-BrPA 介导的作用的基础。在体内，US 引导下递送 3-BrPA 是可行且有效的，这可通过成像上肿瘤大小的显著减小得到证明。此外，通过 Ki-67 免疫组织化学染色减少增殖潜能和末端脱氧核苷酸转移酶介导的脱氧尿苷 5-三磷酸缺口末端标记染色诱导细胞凋亡证实了其抗肿瘤作用。因此，我们在人胰腺癌细胞的小鼠模型中证明了 US 引导下肿瘤内注射 3-BrPA 的技术可行性及其治疗效果。我们的数据表明，这种由直接瘤内注射抗糖酵解剂组成的新治疗方法可能为治疗胰腺癌患者提供一个令人兴奋的机会。
