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New strategy in cancel therapy with reference tomethionine-depletion

参考蛋氨酸消耗的取消治疗新策略

基本信息

批准号：
07671329
负责人：
KUBOTA Tetsuro
金额：
$ 1.6万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1997
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07671329/
关键词：
Methionine dependency cultured human tumor cells nude mouse enzyme 新鮮手術材料 G2ブロック

项目摘要

Methionine (Met) is an important supplier of methyl radicals which will methylate double strand of DNA after replication to protect from DNA digestion by endonuclease. The present study was investigated the new strategy in anticancer therapy in reference to the higher Met-dependency of malignant tumor cells comparing with normal cells. When human culture tumor cells were assessed using Met- and/or homocysteine-depleting medium, 7 of 9 (78%) strains were Met-dependent. Thirteen human tumor xenografts in nude mice were treated with Met-depleting diet, and 4 of 13 (31%) strains were found to be Met-dependent. The Met-dependency was observed in a various kind of tumors, suggesting a wide antitumor spectrum of Met-depleting therapy for clinical cancer. In addition, some modulating antitumor activity of Met-depleting therapy was observed in combination with cisplatin and 5-fluorouracil. The antitumor activity of cisplatin was significantly enhanced by the Met-depleting therapy on Met-independent human breast carcinoma xenograft, MX-1. Met-depleting therapy increased the thymidylate synthetase inhibition by 5-fluorouracil in Met-partly dependent human gastric cancer, SC-1-NU.Met-depleting therapy elucidated antitumor activity on Met-dependent tumors in vitro and in vivo, and modulated the antitumor activity of cisplatin and 5-fluorouracil even on Met-independent or -partial dependent tumors. Met-depleting therapy is promising for further investigation for clinical human tumors.

蛋氨酸（Met）是甲基自由基的重要提供者，其将DNA复制后的双链甲基化以保护DNA免受内切酶的消化。本研究针对恶性肿瘤细胞对蛋氨酸的依赖性高于正常细胞的特点，探讨了抗肿瘤治疗的新策略。当使用Met和/或同型半胱氨酸消耗培养基评估人培养肿瘤细胞时，9种菌株中有7种（78%）是Met依赖性的。13个人肿瘤裸鼠移植瘤用Met耗竭饮食处理，发现13个菌株中有4个（31%）是Met依赖性的。在多种肿瘤中观察到Met依赖性，表明Met耗竭疗法对临床癌症具有广泛的抗肿瘤谱。此外，在与顺铂和5-氟尿嘧啶联合使用时，观察到Met耗竭疗法的一些调节抗肿瘤活性。顺铂的抗肿瘤活性显着增强的Met-消耗治疗的Met-非依赖性人乳腺癌异种移植，MX-1。去甲硫氨酸治疗增加了5-氟尿嘧啶对部分甲硫氨酸依赖的人胃癌SC-1-NU中胸苷酸合成酶的抑制作用。去甲硫氨酸治疗在体外和体内阐明了对甲硫氨酸依赖的肿瘤的抗肿瘤活性，并调节顺铂和5-氟尿嘧啶的抗肿瘤活性，即使对甲硫氨酸非依赖或部分依赖的肿瘤也是如此。甲硫氨酸耗竭疗法有望用于临床人类肿瘤的进一步研究。