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


CONCLUSIONS
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.
Izzo
Francesco
F
National Cancer Institute G Pascale Foundation, Naples, Italy. izzo@connect.it
Montella
Maurizio
M
Orlando
Antonio Pio
AP
Nasti
Guglielmo
G
Beneduce
Gerardo
G
Castello
Giuseppe
G
Cremona
Francesco
F
Ensor
C Mark
CM
Holtzberg
Frederick W
FW
Bomalaski
John S
JS
Clark
Mike A
MA
Curley
Steven A
SA
Orlando
Raffaele
R
Scordino
Fabrizio
F
Korba
Brent E
BE
D000328:Adult; D001120:Arginine / Q000097:blood*; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000821:virology; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D006867:Hydrolases / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000821:virology; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000097:blood; D011092:Polyethylene Glycols / Q000494:pharmacology; D012367:RNA, Viral / Q000032:analysis; D018709:Statistics, Nonparametric; D036542:Tomography, Spiral Computed
D012367:RNA, Viral; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C019723:arginine deiminase