title: Pegylated arginine deiminase treatment of patients with unresectable hepatocellular carcinoma: results from phase I/II studies.
abstract: OBJECTIVE
  Recently, we reported that a large number of human hepatocellular cancer (HCC) cell lines were auxotrophic for arginine. Here we report the results obtained with the amino acid-degrading enzyme arginine deiminase (ADI) conjugated to polyethylene glycol (ADI-SS PEG 20,000 mw) as a means of lowering plasma arginine to treat HCC. The study was a cohort dose-escalation phase I/II study.
  
  
  METHODS
  Pharmacodynamic studies indicated an ADI-SS PEG 20,000 mw dose level of 160 U/m(2) was sufficient to lower plasma arginine from a resting level of approximately 130 micromol/L to below the level of detection (< 2 micromol/L) for more than 7 days, a dose later defined as the optimal biologic dose. All patients were to receive three cycles at the optimum biologic dose.
  
  
  RESULTS
  This therapy was well tolerated, even in patients who had no detectable plasma arginine for 3 continuous months of therapy. Of the 19 patients enrolled, two had a complete response, seven had a partial response, seven had stable disease, and three had progressive disease. The median survival for the 19 patients enrolled on this study was 410 days, with four patients still alive at present (> 680 days).
  
  
  CONCLUSIONS
  Elimination of all detectable plasma arginine in patients with HCC was well tolerated and seemed to be effective in the treatment of some patients with HCC. Further testing of ADI-SS PEG 20,000 mw in a larger population of individuals with HCC as well as other human tumors auxotrophic for arginine is warranted.
authors.affiliation: Pascale NAtional Cancer Institute, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Izzo
authors.forename: Paolo
authors.initials: P
authors.lastname: Marra
authors.forename: Gerardo
authors.initials: G
authors.lastname: Beneduce
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Castello
authors.forename: Paolo
authors.initials: P
authors.lastname: Vallone
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Rosa
authors.forename: Franco
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: Holtsberg
authors.forename: John S
authors.initials: JS
authors.lastname: Bomalaski
authors.forename: Mike A
authors.initials: MA
authors.lastname: Clark
authors.forename: Chaan
authors.initials: C
authors.lastname: Ng
authors.forename: Steven A
authors.initials: SA
authors.lastname: Curley
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007273:Injections, Intramuscular; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome
chemical_list: D011092:Polyethylene Glycols; D006867:Hydrolases; C019723:arginine deiminase