Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase

Br J Cancer. 2012 Jan 17;106(2):324-32. doi: 10.1038/bjc.2011.524. Epub 2011 Dec 1.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Argininosuccinate Synthase / genetics*
  • Base Sequence
  • Blotting, Western
  • Cell Line, Tumor
  • DNA Primers
  • Gene Silencing
  • Humans
  • Hydrolases / metabolism*
  • Immunohistochemistry
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / pathology*
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Small Cell Lung Carcinoma / enzymology
  • Small Cell Lung Carcinoma / pathology*

Substances

  • DNA Primers
  • RNA, Small Interfering
  • Hydrolases
  • arginine deiminase
  • Argininosuccinate Synthase