Incidence and distribution of argininosuccinate synthetase deficiency in human cancers - A method for identifying cancers sensitive to arginine deprivation
Incidence and distribution of argininosuccinate synthetase deficiency in human cancers - A method for identifying cancers sensitive to arginine deprivation
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DOI：
10.1002/cncr.20057
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发表时间：
2004-02-15
期刊：
影响因子：
6.2
通讯作者：
Clark, MA
中科院分区：
文献类型：
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作者：
Dillon, BJ;Prieto, VG;Clark, MA
背景精氨酸琥珀酸合成酶（ASS）是将瓜氨酸转化为精氨酸的两种酶中的第一种。这种途径允许细胞从瓜氨酸合成精氨酸，使得这种氨基酸对于大多数哺乳动物细胞的生长不是必需的。先前的研究表明，由于不能表达ASS，几种人类肿瘤细胞系是精氨酸营养缺陷型的。从这些肿瘤动物的循环中选择性消除精氨酸是一种潜在有效的抗癌治疗方法。这些实验的目的是确定ASS缺陷和精氨酸营养缺陷型在各种人类恶性肿瘤中的频率。作者用单克隆抗体通过免疫组织化学分析了ASS在各种人类肿瘤活检组织中的表达。他们发现，ASS缺乏症的发生率随肿瘤类型和起源组织的不同而变化很大。黑色素瘤、肝细胞癌和前列腺癌最常缺乏ASS。一些人类癌症几乎总是ASS阳性（例如，肺癌和结肠癌）。然而，其他人类癌症，包括肉瘤、浸润性乳腺癌和肾细胞癌，有时也缺乏ASS。这些数据表明，ASS的免疫组化检测可能被证明是一种有效的手段，用于确定ASS缺陷的恶性人类肿瘤，并确定患者最有可能响应精氨酸剥夺治疗。基于这些结果，已经启动了使用精氨酸降解酶疗法治疗晚期黑色素瘤或肝细胞癌患者的人体临床试验。(C)2004年美国癌症协会。
BACKGROUND. Argininosuccinate synthetase (ASS) was the first of two enzymes to convert citrulline to arginine. This pathway allowed cells to synthesize arginine from citrulline, making this amino acid nonessential for the growth of most mammalian cells. Previous studies demonstrated that several human tumor cell lines were auxotrophic for arginine due to an inability to express ASS. Selective elimination of arginine from the circulation of animals with these tumors is a potentially effective anticancer treatment. The purpose of these experiments was to determine the frequency of ASS deficiency and arginine auxotrophy in a variety of human malignant tumors.METHODS. The authors analyzed the expression of ASS by immumohistochemistry with a monoclonal antibody in a variety of human tumor biopsies. They found that the incidence of ASS deficiency varied greatly with the tumor type and tissue of origin.RESULTS. Melanoma, hepatocellular carcinoma, and prostate carcinoma were most frequently deficient in ASS. Some human cancers were almost always positive for ASS (e.g., lung and colon carcinomas). However, other human cancers, including sarcomas, invasive breast carcinoma, and renal cell carcinoma, also were sometimes ASS deficient.CONCLUSIONS. These data indicated that immunohistochemical detection of ASS may prove an effective means for determining ASS deficiency in malignant human tumors and for identifying patients most likely to respond to arginine deprivation therapy. Based on these results, human clinical trials using arginine-degrading enzyme therapy to treat patients with advanced melanoma or hepatocellular carcinoma have been initiated. (C) 2004 American Cancer Society.