Rationale and Objectives
3-Bromopyruvate (3-BrPA), an hexokinase II inhibitor, is known to have high necrotic rate in hyperglycolytic liver tumor models without apparent damage to the normal liver parenchyma. The toxicity of intra-arterial delivery of 3-BrPA in various concentrations has not been specifically investigated using a normal rabbit model.
Materials and Methods
Twenty rabbits treated with intra-arterial 3-BrPA were divided into four groups according to its dose and infusion level: 1 mM at the left hepatic artery (group I), 5 mM at the left hepatic artery (group II), 25 mM at the left hepatic artery (group III), and 25 mM at the common hepatic artery (group IV). After selective catheterization, 30 ml of 3-BrPA was infused for 2 minutes. As a control group, five rabbits were treated with normal saline. During 1-week follow-up, toxicities were evaluated with blood laboratory results, mortality, and histopathologic examination.
Results
All 10 rabbits treated with 25 mM 3-BrPA and 2 rabbits treated with 5 mM 3-BrPA died within 3 days after treatment. In 10 of the 12 deaths, hemorrhagic pyloric or duodenal necrosis was noted. Hepatotoxicities on blood laboratory results were dose dependent but transient in the surviving rabbits.
Conclusion
Selective intra-arterial administration of 25 mM 3-BrPA can cause considerable toxicities not only in the liver but also in the gastrointestinal system and are dose dependent and can cause death in high doses.
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and the third most common cause of cancer-related death in the world ( ). Because of the advanced stage of the disease and associated liver cirrhosis at its initial presentation, only a minority of patients are eligible for curative treatments such as surgical excision or local ablation therapies such as radiofrequency ablation and percutaneous ethanol injection ( ). Therefore, transcatheter arterial approach has been widely investigated as a palliative treatment for HCC, which includes hepatic arterial infusion chemotherapy and transcatheter arterial chemoembolization (TACE) ( ). Recently, survival benefit of TACE has been proved by prospective randomized clinical trial ( ). However, the therapeutic efficacy of TACE is still limited and deterioration of liver function is unavoidably associated.
As a new concept for anticancer therapy, blocking of cancer energy metabolism by selective hexokinase II inhibition has been proposed ( ). Hexokinase is the first-step enzyme of glucose metabolism. Among hexokinase isotypes, hexokinase II is overexpressed in tumor cells to produce ATP and cell building blocks for uncontrolled tumor overgrowth. Theoretically, selective inhibition of hexokinase II may lead to tumor necrosis without normal tissue damage ( ).
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Materials and methods
Experimental Animal and Study Design
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Preparation of 3-BrPA Solution
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Procedures for Intra-arterial Administration of 3-BrPA and Normal Saline
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Evaluation of Hepatotoxicity
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Statistical Analysis
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Results
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Discussion
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Conclusion
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