Renal cell carcinoma does not express argininosuccinate synthetase and is highly sensitive to arginine deprivation via arginine deiminase

Authors

  • Cheol-Yong Yoon,

    1. Department of Urology, College of Medicine, Korea University, Seoul 136-705, Korea
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    • Cheol-Yong Yoon and Young-Jun Shim contributed equally to this study.

  • Young-Jun Shim,

    1. Department of Pharmacology and BK21 Program for Medical Sciences, College of Medicine, Korea University, Seoul 136-705, Korea
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    • Cheol-Yong Yoon and Young-Jun Shim contributed equally to this study.

  • Eun-Ho Kim,

    1. Department of Pharmacology and BK21 Program for Medical Sciences, College of Medicine, Korea University, Seoul 136-705, Korea
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  • Ju-Han Lee,

    1. Department of Pathology, College of Medicine, Korea University, Seoul 136-705, Korea
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  • Nam-Hee Won,

    1. Department of Pathology, College of Medicine, Korea University, Seoul 136-705, Korea
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  • Jeong-Hun Kim,

    1. Department of Ophthalmology, Seoul National University College of Medicine, Seoul 110-744, Korea
    2. Seoul Artificial Eye Center, Clinical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea
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  • In-Sun Park,

    1. Department of Anatomy, College of Medicine, Inha University, Inchon 400-103, Korea
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  • Duck-Ki Yoon,

    1. Department of Urology, College of Medicine, Korea University, Seoul 136-705, Korea
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  • Bon-Hong Min

    Corresponding author
    1. Department of Pharmacology and BK21 Program for Medical Sciences, College of Medicine, Korea University, Seoul 136-705, Korea
    • 126-1 Anam-dong 5-Ga, Sungbuk-Gu, Seoul 136-705, Korea; Department of Pharmacology and BK21 Program for Medical Sciences, College of Medicine, Korea University

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    • Fax: +82-2-927-9289.


Abstract

Recently, pegylated arginine deiminase (ADI; EC 3.5.3.6) 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.

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