title: Pegylated arginine deiminase lowers hepatitis C viral titers and inhibits nitric oxide synthesis.
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.
  
  
  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.
authors.affiliation: National Cancer Institute G Pascale Foundation, Naples, Italy. izzo@connect.it
authors.forename: Francesco
authors.initials: F
authors.lastname: Izzo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Montella
authors.forename: Antonio Pio
authors.initials: AP
authors.lastname: Orlando
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Nasti
authors.forename: Gerardo
authors.initials: G
authors.lastname: Beneduce
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castello
authors.forename: Francesco
authors.initials: F
authors.lastname: Cremona
authors.forename: C Mark
authors.initials: CM
authors.lastname: Ensor
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Holtzberg
authors.forename: John S
authors.initials: JS
authors.lastname: Bomalaski
authors.forename: Mike A
authors.initials: MA
authors.lastname: Clark
authors.forename: Steven A
authors.initials: SA
authors.lastname: Curley
authors.forename: Raffaele
authors.initials: R
authors.lastname: Orlando
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Scordino
authors.forename: Brent E
authors.initials: BE
authors.lastname: Korba
mesh_terms: 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
chemical_list: D012367:RNA, Viral; D009569:Nitric Oxide; D011092:Polyethylene Glycols; D001120:Arginine; D006867:Hydrolases; C019723:arginine deiminase