聚乙二醇化精氨酸脱亚氨酶可降低丙型肝炎病毒滴度并抑制一氧化氮合成。

Pegylated arginine deiminase lowers hepatitis C viral titers and inhibits nitric oxide synthesis.

作者信息

Izzo Francesco, Montella Maurizio, Orlando Antonio Pio, Nasti Guglielmo, Beneduce Gerardo, Castello Giuseppe, Cremona Francesco, Ensor C Mark, Holtzberg Frederick W, Bomalaski John S, Clark Mike A, Curley Steven A, Orlando Raffaele, Scordino Fabrizio, Korba Brent E

机构信息

National Cancer Institute G Pascale Foundation, Naples, Italy.

出版信息

J Gastroenterol Hepatol. 2007 Jan;22(1):86-91. doi: 10.1111/j.1440-1746.2006.04463.x.

DOI:10.1111/j.1440-1746.2006.04463.x

PMID:17201887

Abstract

BACKGROUND

The arginine-degrading enzyme, arginine deiminase conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw), reduces extracellular arginine, has minimal toxicity, decreases tumor burden and improves liver function in patients with chronic hepatitis C virus infection (HCV) and inoperable hepatocellular carcinoma (HCC). Reduced extracellular arginine inhibits viral replication through unknown mechanisms. It is hypothesized that ADI-SS PEG 20,000 mw reduces HCV viral titers through nitric oxide (NO)-dependent effects.

METHODS

The effects of ADI-SS PEG 20,000 mw (dose, 160 IU/m2; three cycles of four once-weekly i.m. injections) on HCV titers, serum NO and plasma arginine, were evaluated using archived plasma from patients with HCC and HCV and in vitro cell model measurements of HCV replication.

RESULTS

ADI-SS PEG 20,000 mw selectively inhibited HCV replication in vitro (IC50 = 0.027 IU/mL). Fifteen HCC/HCV patients completed treatment. The HCV titers were reduced by up to 99% in five out of 10 (50%) HCV-serotype 1b patients (P = 0.0093). These patients also experienced significant improvements in liver function (P = 0.0091). There were concomitant reductions of plasma arginine and serum NO levels. The HCV titer was not reduced in HCV-type 2c patients.

CONCLUSION

Reduction of extracellular arginine by ADI-SS PEG 20,000 mw in HCC patients reduces HCV viral titers and improves liver function, possibly through suppression of NO.

摘要

背景

与聚乙二醇（ADI-SS PEG 20,000 mw）偶联的精氨酸降解酶——精氨酸脱亚氨酶，可降低细胞外精氨酸水平，毒性极小，能减轻慢性丙型肝炎病毒感染（HCV）和无法手术的肝细胞癌（HCC）患者的肿瘤负担并改善肝功能。细胞外精氨酸水平降低通过未知机制抑制病毒复制。据推测，ADI-SS PEG 20,000 mw通过一氧化氮（NO）依赖性效应降低HCV病毒滴度。

方法

使用来自HCC和HCV患者的存档血浆以及HCV复制的体外细胞模型测量，评估ADI-SS PEG 20,000 mw（剂量为160 IU/m²；三个周期，每周一次肌肉注射，共四次）对HCV滴度、血清NO和血浆精氨酸的影响。

结果

ADI-SS PEG 20,000 mw在体外选择性抑制HCV复制（IC50 = 0.027 IU/mL）。15例HCC/HCV患者完成治疗。10例HCV血清型1b患者中有5例（50%）的HCV滴度降低了99%（P = 0.0093）。这些患者的肝功能也有显著改善（P = 0.0091）。血浆精氨酸和血清NO水平同时降低。HCV 2c型患者的HCV滴度未降低。