Yoon Cheol-Yong, Shim Young-Jun, Kim Eun-Ho, Lee Ju-Han, Won Nam-Hee, Kim Jeong-Hun, Park In-Sun, Yoon Duck-Ki, Min Bon-Hong
Department of Urology, College of Medicine, Korea University, Seoul 136-705, Korea.
Int J Cancer. 2007 Feb 15;120(4):897-905. doi: 10.1002/ijc.22322.
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.
最近，聚乙二醇化精氨酸脱亚氨酶（ADI；EC 3.5.3.6）已被用于治疗精氨琥珀酸合成酶（ASS）活性水平低或检测不到的肝细胞癌或黑色素瘤患者。其抗肿瘤活性的疗效很大程度上取决于细胞内ASS的水平，这使得肿瘤细胞能够将瓜氨酸循环转化为精氨酸。因此，我们检测了各种癌细胞中ASS的表达水平，发现其在肾细胞癌（RCC）细胞中较低，这使得细胞对ADI治疗导致的精氨酸剥夺高度敏感。免疫组织化学分析显示，在98例RCC患者的活检标本中，ASS的表达在正常近端小管上皮中高度表达，但在肿瘤细胞中未见。此外，用ADI处理的RCC细胞以剂量依赖的方式表现出显著的生长迟缓。ADI对同种异体移植肾细胞癌（RENCA）肿瘤细胞也具有体内抗增殖作用，并延长了荷瘤小鼠的生存期。对肿瘤的组织学检查显示，给予ADI后肿瘤血管生成和血管内皮生长因子（VEGF）表达显著减少。因此，这些发现表明，ADI导致的精氨酸剥夺可以通过抑制精氨酸供应和新血管形成，为RCC的治疗提供一种有益的策略。
