Cheol-Yong Yoon and Young-Jun Shim contributed equally to this study.
Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase
Article first published online: 9 NOV 2006
Copyright © 2006 Wiley-Liss, Inc.
International Journal of Cancer
Volume 120, Issue 4, pages 897–905, 15 February 2007
How to Cite
Yoon, C.-Y., Shim, Y.-J., Kim, E.-H., Lee, J.-H., Won, N.-H., Kim, J.-H., Park, I.-S., Yoon, D.-K. and Min, B.-H. (2007), Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase. Int. J. Cancer, 120: 897–905. doi: 10.1002/ijc.22322
- Issue published online: 27 DEC 2006
- Article first published online: 9 NOV 2006
- Manuscript Accepted: 11 AUG 2006
- Manuscript Received: 9 JAN 2006
- Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea. Grant Number: A050252
- arginine deiminase;
- argininosuccinate synthetase;
- renal cell carcinoma;
- tumor angiogenesis;
- vascular endothelial growth factor
Recently, pegylated arginine deiminase (ADI; EC 126.96.36.199) has been used to treat the patients with hepatocellular carcinoma or melanoma, in which the level of argininosuccinate synthetase (ASS) activity is low or undetectable. The efficacy of its antitumor activity largely depends on the level of intracellular ASS, which enables tumor cells to recycle citrulline to arginine. Thus, we examined the expression levels of ASS in various cancer cells and found that it is low in renal cell carcinoma (RCC) cells, rendering the cells highly sensitive to arginine deprivation by ADI treatment. Immunohistochemical analysis revealed that in biopsy specimens from RCC patients (n = 98), the expression of ASS is highly demonstrated in the epithelium of normal proximal tubule but not seen in tumor cells. Furthermore, RCC cells treated with ADI showed remarkable growth retardation in a dose dependent manner. ADI also exerted in vivo antiproliferative effect on the allografted renal cell carcinoma (RENCA) tumor cells and prolonged the survival of tumor-bearing mice. Histological examination of the tumors revealed that tumor angiogenesis and vascular endothelial growth factor (VEGF) expression were significantly diminished by ADI administration. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of RCC in ways of inhibitions of arginine availability and neovascularization. © 2006 Wiley-Liss, Inc.