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- Title
Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase.
- Authors
Kelly, M P; Jungbluth, A A; Wu, B-W; Bomalaski, J; Old, L J; Ritter, G
- 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.
- Subjects
ARGININE deiminase; SMALL cell lung cancer; CANCER treatment; IMMUNOHISTOCHEMISTRY techniques; ARGININOSUCCINATE synthetase; AUTOPHAGY
- Publication
British Journal of Cancer, 2012, Vol 106, Issue 2, p324
- ISSN
0007-0920
- Publication type
Article
- DOI
10.1038/bjc.2011.524