New strategy in cancel therapy with reference tomethionine-depletion

蛋氨酸（Met）是甲基自由基的重要供给者，在DNA复制后甲基化双链以保护DNA不被核酸内切酶酶切。本研究针对恶性肿瘤细胞较正常细胞具有较高的met依赖性，探讨了抗癌治疗的新策略。当使用Met-和/或消耗同型半胱氨酸培养基评估人培养肿瘤细胞时，9株中有7株（78%）是Met依赖的。13例裸鼠人肿瘤异种移植物用去met饮食处理，13株中有4株（31%）对met有依赖性。在多种肿瘤中观察到met依赖性，提示临床癌症的met消耗治疗具有广泛的抗肿瘤谱。此外，与顺铂和5-氟尿嘧啶联合使用耗met疗法也有一定的调节抗肿瘤活性。顺铂的抗肿瘤活性在不依赖met的人乳腺癌异种移植物MX-1上显著增强。在部分依赖met的人胃癌SC-1-NU中，耗met治疗增加了5-氟尿嘧啶对胸苷酸合成酶的抑制作用。在体外和体内研究中，耗met疗法阐明了对met依赖肿瘤的抗肿瘤活性，甚至调节顺铂和5-氟尿嘧啶对met不依赖或部分依赖肿瘤的抗肿瘤活性。耗met疗法在临床治疗人类肿瘤方面有进一步的研究前景。

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.