用一种新型强效肿瘤代谢抑制剂（3-溴丙酮酸）进行动脉内治疗：在肝癌动物模型中确定治疗剂量和注射方法。

Intraarterial therapy with a new potent inhibitor of tumor metabolism (3-bromopyruvate): identification of therapeutic dose and method of injection in an animal model of liver cancer.

作者信息

Vali Mustafa, Liapi Eleni, Kowalski Jeanne, Hong Kelvin, Khwaja Afsheen, Torbenson Michael S, Georgiades Christos, Geschwind Jean-Francois H

机构信息

Division of Vascular and Interventional Radiology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

出版信息

J Vasc Interv Radiol. 2007 Jan;18(1 Pt 1):95-101. doi: 10.1016/j.jvir.2006.10.019.

DOI:10.1016/j.jvir.2006.10.019

PMID:17296709

Abstract

PURPOSE

A potent new adenosine triphosphate inhibitor--3-bromopyruvate (3-BrPA)--has been shown to have antitumor effects when injected intraarterially in the hepatic artery of rabbits with VX-2 tumors. The authors performed a stepwise study in rabbits to determine the therapeutic dose and method of delivery of 3-BrPA.

MATERIALS AND METHODS

White New Zealand rabbits with VX-2 tumors were used for this study. Eight animals were examined to establish the maximum tolerated dose (2.5 or 5.0 mmol/L of 25-mL 3-BrPA) as a single bolus injection. The 2.5 mmol/L dose was then used to compare three methods of delivery: injection of one bolus, two 12.5-mL serial bolus injections administered 1 hour apart, and continuous infusion of 25 mL for 1 hour. Finally, dose-response analysis was performed by using 10 groups of three animals each, with 1-hour intraarterial infusions of 3-BrPA (25 mL) at incremental doses of 0.25 mmol/L (range, 0.5-2.5 mmol/L) with phosphate buffered saline used for control animals. All animals were sacrificed at 48 hours, and histopathologic analysis was performed. chi2 statistics were used to analyze the data.

RESULTS

The maximum tolerated dose of 3-BrPA was 2.5 mmol/L; however, it caused substantial peripheral liver necrosis. These effects were minimized when 3-BrPA was infused over 1 hour. Complete tumor necrosis was identified in all samples with at least 2.0 mmol/L of 3-BrPA. The 1.75 mmol/L concentration was identified as therapeutic because it caused complete tumor apoptosis and minimal toxicity (P < .001).

CONCLUSIONS

The results identified both the therapeutic dose (1.75 mmol/L) and the method of infusion (1 hour intraarterial infusion) of 3-BrPA. This potent new treatment may prove to be an effective way of treating liver cancer and may become part of a new class of anticancer drugs based on the inhibition of tumor metabolism.

摘要

目的

一种强效的新型三磷酸腺苷抑制剂——3-溴丙酮酸（3-BrPA）——已被证明，当经动脉注射到患有VX-2肿瘤的兔子肝动脉中时具有抗肿瘤作用。作者在兔子身上进行了一项逐步研究，以确定3-BrPA的治疗剂量和给药方法。

材料与方法

本研究使用患有VX-2肿瘤的新西兰白兔。检查了8只动物，以确定作为单次推注注射的最大耐受剂量（25 mL的3-BrPA为2.5或5.0 mmol/L）。然后使用2.5 mmol/L的剂量比较三种给药方法：一次推注、间隔1小时进行两次12.5 mL连续推注以及持续输注25 mL 1小时。最后，通过使用10组每组三只动物进行剂量反应分析，以0.25 mmol/L（范围为0.5 - 2.5 mmol/L）的递增剂量进行1小时的3-BrPA（25 mL）动脉内输注，并用磷酸盐缓冲盐水作为对照动物。所有动物在48小时时处死，并进行组织病理学分析。使用卡方统计分析数据。

结果

3-BrPA的最大耐受剂量为2.5 mmol/L；然而，它导致了大量的外周肝坏死。当3-BrPA在1小时内输注时，这些影响最小化。在所有含有至少2.0 mmol/L 3-BrPA的样本中均发现了完全肿瘤坏死。1.75 mmol/L的浓度被确定为具有治疗作用，因为它导致了完全肿瘤凋亡且毒性最小（P <.001）。