title: Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase.
abstract: BACKGROUND
  Some cancers have been shown to lack expression of argininosuccinate synthetase (ASS), an enzyme required for the synthesis of arginine and a possible biomarker of sensitivity to arginine deprivation. Arginine deiminase (ADI) is a microbial enzyme capable of efficiently depleting peripheral blood arginine.
  
  
  METHODS
  Argininosuccinate synthetase expression was assessed in human small cell lung cancer (SCLC) by immunohistochemistry (IHC), with expression also assessed in a panel of 10 human SCLC by qRT-PCR and western blot. Proliferation assays and analyses of apoptosis and autophagy assessed the effect of pegylated ADI (ADI-PEG20) in vitro. The in vivo efficacy of ADI-PEG20 was determined in mice bearing SCLC xenografts.
  
  
  RESULTS
  Approximately 45% of SCLC tumours and 50% of cell lines assessed were negative for ASS. Argininosuccinate synthetase-deficient SCLC cells demonstrated sensitivity to ADI-PEG20, which was associated with the induction of autophagy and caspase-independent cell death. Arginine deiminase-PEG20 treatment of ASS-negative SCLC xenografts caused significant, dose-dependent inhibition of tumour growth of both small and established tumours.
  
  
  CONCLUSIONS
  These results suggest a role for ADI-PEG20 in the treatment of SCLC, and a clinical trial exploring this therapeutic approach in patients with ASS-negative SCLC by IHC has now been initiated.
authors: Ludwig Institute for Cancer Research Ltd, New York Branch of Human Cancer Immunology at Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: M P
authors: MP
authors: Kelly
authors: A A
authors: AA
authors: Jungbluth
authors: B-W
authors: BW
authors: Wu
authors: J
authors: J
authors: Bomalaski
authors: L J
authors: LJ
authors: Old
authors: G
authors: G
authors: Ritter
mesh_terms: D001124:Argininosuccinate Synthase / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D045744:Cell Line, Tumor; D017931:DNA Primers; D020868:Gene Silencing; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D055752:Small Cell Lung Carcinoma / Q000201:enzymology / Q000473:pathology*
chemical_list: D017931:DNA Primers; D034741:RNA, Small Interfering; D006867:Hydrolases; C019723:arginine deiminase; D001124:Argininosuccinate Synthase