AntiCancer, Inc., San Diego, CA 92111, USA.
Anticancer Res. 2010 Apr;30(4):1041-6.
Elevated dependence on methionine of cancer cells is a cancer-specific metabolic defect. Recombinant L-methionine alpha,gamma-lyase (rMETase), an L-methionine depleting enzyme cloned from Pseudomonas putida, was shown to have efficacy on a broad series of cancer cell lines. Twenty-one different human tumor cell lines (4 lung, 4 colon, 4 kidney, 4 melanoma, 3 CNS, and 2 prostate) from the NCI Human Tumor Cell Line Screen and 7 human normal cell strains were treated with rMETase in vitro. We showed that rMETase had a mean IC(50) (units rMETase/ml) for the following cancer cell types: renal, 0.07; colon, 0.04; lung, 0.12; prostate, 0.01; melanoma, 0.19; and CNS, 0.195, which was approximately one order of magnitude lower than that for normal cell strains: skin fibroblasts, 4; aortic smooth muscle cells, 0.88; aortic endothelial cells, 0.8; keratinocytes, 0.75; and bronchial epithelial cells, 0.75. rMETase was also conjugated with polyethylene glycol (PEG). PEG-rMETase also had high cancer cell-killing activity. In vitro studies, animal studies and clinical trials have now shown that methionine restriction is an effective anticancer strategy. Cells from many different types of cancer are methionine dependent. The most effective strategy to deplete methionine is with the use of rMETase. PEG-rMETase offers additional advantages of increasing the circulating half-life and reducing the immunogenicity of rMETase which is a bacterial protein. The results of the current study demonstrate the broad clinical potential for rMETase and PEG-rMETase for cancer treatment.
癌细胞对蛋氨酸的依赖性增加是一种癌症特异性代谢缺陷。从恶臭假单胞菌克隆的重组 L-蛋氨酸 α，γ-裂合酶（rMETase）是一种 L-蛋氨酸耗竭酶，对广泛的一系列癌细胞系具有疗效。21 种不同的人肿瘤细胞系（4 种肺癌、4 种结肠癌、4 种肾癌、4 种黑色素瘤、3 种中枢神经系统肿瘤和 2 种前列腺癌）来自 NCI 人肿瘤细胞系筛选，以及 7 种人正常细胞株，在体外用 rMETase 进行处理。我们表明，rMETase 对以下癌症细胞类型的平均 IC50（单位 rMETase/ml）为：肾，0.07；结肠，0.04；肺，0.12；前列腺，0.01；黑色素瘤，0.19；中枢神经系统，0.195，这大约比正常细胞株低一个数量级：皮肤成纤维细胞，4；主动脉平滑肌细胞，0.88；主动脉内皮细胞，0.8；角质形成细胞，0.75；和支气管上皮细胞，0.75。rMETase 也与聚乙二醇（PEG）缀合。PEG-rMETase 也具有很高的癌细胞杀伤活性。目前的研究表明，在体外研究、动物研究和临床试验中，限制蛋氨酸是一种有效的抗癌策略。来自许多不同类型癌症的细胞依赖于蛋氨酸。耗尽蛋氨酸最有效的策略是使用 rMETase。PEG-rMETase 提供了增加循环半衰期和降低 rMETase 的免疫原性的额外优势，rMETase 是一种细菌蛋白。目前的研究结果表明，rMETase 和 PEG-rMETase 具有广泛的临床应用潜力，可用于癌症治疗。
