Kokkinakis D M, Schold S C, Hori H, Nobori T
Department of Neurology, University of Texas Southwestern Medical Center at Dallas 75235-9036, USA.
Nutr Cancer. 1997;29(3):195-204. doi: 10.1080/01635589709514624.
Depletion of plasma methionine is expected to inhibit or reverse growth of methionine-dependent tumors; however, modulation of methionine and other sulfur amino acids is not a trivial task in experimental animals. L-Methioninase from Pseudomonas putida at 1,000 U/kg causes acute reduction of plasma methionine by 80% in mice, but recovery occurs within 14 hours. Restriction of dietary choline and replacement of dietary methionine with homocystine results in 50% chronic reduction of plasma methionine. A > 70% reduction can be accomplished with a diet deficient in methionine, homocystine, and choline, but ultimately this diet is lethal. Plasma methionine can be lowered to a steady state of < 5 microM in mice with a combination of dietary restriction of methionine, homocysteine, and choline and synchronous treatments with intraperitoneal injections of 1,000 U/kg L-methioninase and 25-50 mg/kg homocystine, each administered at 12-hour intervals. Modulation of plasma methionine by this means causes no weight loss or pathologies in liver or pancreas, and it does not markedly alter levels of cysteine, homocysteine, or glutathione in plasma or in hepatic tissue. When this procedure is applied to athymic mice bearing human medulloblastoma (Daoy) tumors subcutaneously, tumor growth is inhibited. Methionine deprivation arrests mitosis by blocking the cell cycle in G2 and induces apoptosis. Tumor stasis was achieved in 100% of treated animals within 4 days of treatment, and regression was seen in one-third of animals after a 10-day period. These data strongly support the use of methionine-depleting regimens for tumor treatments.
血浆蛋氨酸的消耗有望抑制或逆转依赖蛋氨酸的肿瘤生长；然而，在实验动物中调节蛋氨酸和其他含硫氨基酸并非易事。恶臭假单胞菌的L-蛋氨酸酶以1000 U/kg的剂量可使小鼠血浆蛋氨酸急性降低80%，但14小时内即可恢复。限制饮食中的胆碱并用同型半胱氨酸替代饮食中的蛋氨酸可使血浆蛋氨酸慢性降低50%。蛋氨酸、同型半胱氨酸和胆碱缺乏的饮食可使血浆蛋氨酸降低>70%，但最终这种饮食是致命的。通过限制饮食中的蛋氨酸、同型半胱氨酸和胆碱，并同步腹腔注射1000 U/kg的L-蛋氨酸酶和25 - 50 mg/kg的同型半胱氨酸（均每隔12小时给药一次），可使小鼠血浆蛋氨酸降至<5 microM的稳态水平。通过这种方式调节血浆蛋氨酸不会导致体重减轻，也不会引起肝脏或胰腺的病变，并且不会显著改变血浆或肝组织中半胱氨酸、同型半胱氨酸或谷胱甘肽的水平。当将此方法应用于皮下接种人髓母细胞瘤（Daoy）肿瘤的无胸腺小鼠时，肿瘤生长受到抑制。蛋氨酸剥夺通过阻断细胞周期的G2期来阻止有丝分裂并诱导细胞凋亡。在治疗后4天内，100%的治疗动物实现了肿瘤停滞，10天后三分之一的动物出现肿瘤消退。这些数据有力地支持了使用消耗蛋氨酸的方案进行肿瘤治疗。
