title: Ultrasound-guided direct delivery of 3-bromopyruvate blocks tumor progression in an orthotopic mouse model of human pancreatic cancer.
abstract: 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.
authors.affiliation: 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.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ota
authors.forename: Jean-Francois H
authors.initials: JF
authors.lastname: Geschwind
authors.forename: Manon
authors.initials: M
authors.lastname: Buijs
authors.forename: Joost W
authors.initials: JW
authors.lastname: Wijlemans
authors.forename: Byung Kook
authors.initials: BK
authors.lastname: Kwak
authors.forename: Shanmugasundaram
authors.initials: S
authors.lastname: Ganapathy-Kanniappan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D019344:Lactic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011773:Pyruvates / Q000008:administration & dosage*; D011897:Random Allocation; D018084:Ultrasonography, Interventional / Q000379:methods; D023041:Xenograft Model Antitumor Assays
chemical_list: D019394:Ki-67 Antigen; D011773:Pyruvates; D019344:Lactic Acid; C017092:bromopyruvate; D000255:Adenosine Triphosphate