New strategy in cancel therapy with reference tomethionine-depletion

甲硫氨酸(Met)是甲基自由基的重要供给者，复制后可使DNA双链甲基化，防止DNA被核酸内切酶消化。鉴于恶性肿瘤细胞对甲硫氨酸的依赖性比正常细胞高，本研究旨在探索抗癌治疗的新策略。当用甲硫氨酸和/或同型半胱氨酸耗竭介质评估人类培养的肿瘤细胞时，9个菌株中有7个(78%)依赖甲硫氨酸。13株人肿瘤裸鼠移植瘤用去甲硫氨酸饮食治疗，发现4株(31%)依赖甲硫氨酸。甲硫氨酸依赖在多种肿瘤中被观察到，提示甲硫氨酸耗竭治疗临床癌症具有广泛的抗肿瘤作用。此外，还观察到甲硫氨酸耗竭疗法与顺铂和5-氟尿嘧啶联合应用对肿瘤的抑制作用。去甲硫氨酸治疗可显著增强顺铂对甲硫氨酸非依赖型人乳腺癌MX-1移植瘤的抗肿瘤活性。去甲硫氨酸治疗增加5-氟尿嘧啶对甲硫氨酸部分依赖的人胃癌细胞胸苷合成酶的抑制，SC-1-NU。去甲硫氨酸治疗在体内外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，甚至对甲硫氨酸非依赖或部分依赖的肿瘤也是如此。去甲硫氨酸治疗有望为临床人类肿瘤的进一步研究奠定基础。

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.