Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase.
Arginine deiminase PEG20 inhibits growth of small cell lung cancers lacking expression of argininosuccinate synthetase.
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DOI：
10.1038/bjc.2011.524
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发表时间：
2012-01-17
影响因子：
8.8
通讯作者：
Ritter G
中科院分区：
文献类型：
--
作者：
Kelly MP;Jungbluth AA;Wu BW;Bomalaski J;Old LJ;Ritter G
一些癌症被证明缺乏精氨酸琥珀酸合成酶(ASS)的表达，精氨酸琥珀酸合成酶是合成精氨酸所需的酶，也可能是对精氨酸缺乏敏感的生物标志物。精氨酸脱亚胺酶(ADI)是一种能够有效消耗外周血精氨酸的微生物酶。用免疫组织化学(IHC)法检测了10例小细胞肺癌(SCLC)组织中精氨酸琥珀酸合成酶的表达，并用qRT-PCR和Western印迹方法检测了10例小细胞肺癌组织中精氨酸琥珀酸合成酶的表达。体外细胞增殖实验、细胞凋亡和自噬分析评价了聚乙二醇化ADI(ADI-PEG20)的作用。检测ADI-PEG20对小鼠小细胞肺癌移植瘤的体内疗效。大约45%的小细胞肺癌肿瘤和50%的细胞株评估为ASS阴性。精氨酸琥珀酸合成酶缺陷的SCLC细胞对ADI-PEG20表现出敏感性，这与诱导自噬和caspase非依赖性细胞死亡有关。精氨酸脱亚胺酶-PEG20治疗ASS阴性的小细胞肺癌移植瘤可显著抑制小肿瘤和已建立肿瘤的生长，且呈剂量依赖关系。这些结果提示ADI-PEG20在小细胞肺癌治疗中的作用，现在已经启动了一项临床试验，探索IHC对ASS阴性小细胞肺癌患者的这种治疗方法。
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. 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. 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. 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.
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