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首页> 外文期刊>Life sciences >METHIONINE DEPRIVATION AND METHIONINE ANALOGS INHIBIT CELL PROLIFERATION AND GROWTH OF HUMAN XENOGRAFTED GLIOMAS
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METHIONINE DEPRIVATION AND METHIONINE ANALOGS INHIBIT CELL PROLIFERATION AND GROWTH OF HUMAN XENOGRAFTED GLIOMAS

机译：蛋氨酸的剥夺和蛋氨酸的类似物抑制人异种胶质树胶质细胞的增殖和生长

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Growth of numerous malignant tumors depends on an exogenous methionine (MET) supply, while endogenously synthesized MET supports normal cell proliferation. Because an antitumor effect should be obtained by aggravating the altered MET metabolism in gliomas, MET dependency of human xenografted gliomas was evaluated and a therapeutic approach using MET deprivation or MET analogs to induce MET starvation was applied. In vitro proliferation inhibition of glioma cell lines by MET deprivation and two MET analogs, ethionine (ETH) and trifluoromethylhomocysteine (TFH), was measured. Proliferation of 7 human glioma cell lines tested was inhibited in MET-free medium, and was poorly or not reversed by homocysteine (HCY). ETH or TFH (concentration range: 0.005-2 mg/ml) inhibited proliferation of all cell lines tested. MET analog-induced inhibition was abolished by MET and enhanced by HCY. Cell-cycle alterations due to MET deprivation were optimally assessed after 30 h of culture and bromodeoxyuridine incorporation. In MET(-) medium, cells were arrested in the G1-phase. ETH induced a dramatic accumulation of cells in the G2-phase. ATP contents were reduced by MET analogs only in HCY+ medium, suggesting complementary effects of MET analogs and HCY. Human glioma bearing nude mice were fed an amino acid-substituted MET(-) HCY-supplemented diet (MET(-) HCY+) and/or treated with MET analogs, injected intraperitoneally daily. Using two human xenografted tumors derived from gliomas, antitumor effects were obtained by subjecting tumor-bearing nude mice to MET starvation. TG-1-MA was more sensitive to MET depletion (40% of growth inhibition, P < 0.10) than TG-8-OZ (no growth inhibition). Antitumor effects of a MET(-)HCY(+) diet and 200 mg/kg of ETH were potentiated when co-administered to glioma-bearing mice (77% GI, P < 0.025 and 67%, P < 0.0057 to TG-1-MA and TG-8-OZ respectively). A dose-response effect with no toxicity was obtained when the ETH dose was increased 10 fold. Potentiation of the effects of ETH and a MET-free diet indicates that they probably act on the same pathway but not the same target. In conclusion, experimentally induced MET deprivation and MET-analog treatment retarded the growth of human gliomas. Combination of MET-analog therapy with MET substitution by HCY enhanced their respective effects. [References: 34]
机译：许多恶性肿瘤的生长取决于外源蛋氨酸（MET）的供应，而内源性合成的MET支持正常的细胞增殖。由于应通过加剧胶质瘤中MET代谢的改变来获得抗肿瘤作用，因此对人异种移植神经胶质瘤的MET依赖性进行了评估，并应用了使用MET剥夺或MET类似物诱导MET饥饿的治疗方法。测量了MET剥夺和两种MET类似物乙硫氨酸（ETH）和三氟甲基同型半胱氨酸（TFH）对神经胶质瘤细胞系的体外增殖抑制作用。在无MET的培养基中抑制了测试的7种人类神经胶质瘤细胞系的增殖，并且同型半胱氨酸（HCY）难以逆转或不逆转。 ETH或TFH（浓度范围：0.005-2 mg / ml）抑制所有测试细胞系的增殖。 MET消除了MET类似物诱导的抑制作用，而HCY增强了抑制作用。培养和加入溴脱氧尿嘧啶核苷30小时后，最佳评估了由于MET缺乏引起的细胞周期改变。在MET（-）培养基中，细胞被阻滞在G1期。 ETH诱导G2期细胞大量积聚。仅在HCY +培养基中MET类似物可降低ATP含量，表明MET类似物和HCY具有互补作用。给人类胶质瘤裸鼠喂食氨基酸取代的MET（-）HCY补充饮食（MET（-）HCY +）和/或用MET类似物治疗，每天腹膜内注射。使用两种源自神经胶质瘤的人异种移植肿瘤，通过使荷瘤裸鼠遭受MET饥饿，可获得抗肿瘤作用。 TG-1-MA对MET消耗（40％的生长抑制，P <0.10）比TG-8-OZ（无生长抑制）更敏感。当与含神经胶质瘤的小鼠共同给药时，MET（-）HCY（+）日粮和200 mg / kg ETH的抗肿瘤作用增强（77％GI，P <0.025和67％，P <0.0057对TG-1 -MA和TG-8-OZ）。当ETH剂量增加10倍时，将获得无毒的剂量反应效果。 ETH和无MET饮食的作用增强表明，它们可能作用于相同途径，但作用目标不同。总之，实验诱导的MET剥夺和MET类似物治疗抑制了人类神经胶质瘤的生长。 MET模拟疗法与HCY MET替代疗法的结合可增强其各自的作用。 [参考：34]

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