Hori H, Takabayashi K, Orvis L, Carson D A, Nobori T
Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla 92093-0663, USA.
Cancer Res. 1996 May 1;56(9):2116-22.
Methionine dependency has been reported in cancer cell lines and primary tumors. Thus, L-methionine deprivation might have potential value for the treatment of human cancers with a methionine requirement. L-Methionine-alpha-deamino-gamma-mercaptomethane-lyase has been reported to decrease plasma methionine levels and to inhibit tumor growth in experimental animals but has not been studied extensively because sufficient homogeneous enzyme was not available. In this study, we cloned the L-methioninase gene from Pseudomonas putida and isolated pure and abundant recombinant enzyme. Both L-methionine and L-cysteine in culture medium were completely degraded by 1 unit/ml purified enzyme. Two hundred and fifty units/kg L-methioninase administered i.v. to mice yielded 0.7 unit/ml of plasma concentration and lowered total plasma sulfur-containing amino acids by more than 75%. Although sensitivity to enzymatic methionine depletion differed among cell lines, leukemia cell lines were generally more sensitive than solid tumor cell lines. The availability of pure recombinant L-methioninase will allow in vivo studies on the antitumor activity and the potential toxicity of enzymatic methionine depletion.
在癌细胞系和原发性肿瘤中已报道有甲硫氨酸依赖性。因此，L-甲硫氨酸剥夺对于治疗有甲硫氨酸需求的人类癌症可能具有潜在价值。据报道，L-甲硫氨酸-α-脱氨基-γ-巯基甲烷裂解酶可降低实验动物的血浆甲硫氨酸水平并抑制肿瘤生长，但由于缺乏足够的纯酶，尚未得到广泛研究。在本研究中，我们从恶臭假单胞菌中克隆了L-甲硫氨酸酶基因，并分离出了纯的且大量的重组酶。每毫升纯化酶可完全降解培养基中的L-甲硫氨酸和L-半胱氨酸。给小鼠静脉注射250单位/千克的L-甲硫氨酸酶，血浆浓度可达0.7单位/毫升，并使血浆中总含硫氨基酸降低超过75%。尽管不同细胞系对酶促甲硫氨酸消耗的敏感性不同，但白血病细胞系通常比实体瘤细胞系更敏感。纯重组L-甲硫氨酸酶的可得性将使我们能够对酶促甲硫氨酸消耗的抗肿瘤活性和潜在毒性进行体内研究。
