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目的重组蛋氨酸酶(rMETase)对于人系外源性蛋白酶,该酶在人肿瘤裸鼠模型中表现出广泛的抑瘤作用。本实验以灵长类动物猕猴为研究对象,测定了rMETase的药动学、免疫原性及系统毒性。方法与结果rMETase单次静脉注射1000u/kg、2000u/kg和4000u/kg时,猕猴血浆蛋氨酸水平在30min内可降低至无法检测的水平(小于0.5μmol/L),且持续4h;给药剂量4000u/kg时,血浆蛋氨酸低于1μmol/L的水平,可维持8h。rMETase在猕猴体内的t1/2为2.49h,给药2000u/kg和4000u/kg时的CL分别为11.28ml/h和30.77ml/h;rMETase以4000u/(kg.8h)重复给药2周时,可使血浆蛋氨酸水平在给药期间维持在2μmol/L以下;重复大剂量给药的主要系统毒性表现为食量减少、体重轻微下降,血浆白蛋白和红细胞水平呈可逆性降低。当rMETase重复给药2周后的28d再次给药时,出现过敏性休克,其中有1只动物死亡;及时给予激素抢救可避免死亡,或给药前给予氢化可的松可预防过敏性休克发生。在实验后的66、86和116d时再次给药,首次给药后抗rMETase抗体水平为10-3,第4次给药后增加到10-6;在以后的2个月内抗体水平降低至10-2。抗rMETase抗体类型主要是IgG,体外检测系中和性抗体;但在体内对rMETase降低血浆蛋氨酸作用的影响较小。结论系统研究表明,rMETase在猕猴模型中能有效地降低血浆中蛋氨酸水平,出现的系统毒性反应很小;rMETase是一具良好前景的广谱抗肿瘤新药,但应重视其免疫原性,如能进行化学修饰或其它处理则可增加药物的作用时间并降低其免疫原性,增加用药安全性。
Purpose Recombinant methioninase (rMETase), a human exogenous protease, exhibits extensive antitumor activity in a human tumor nude mouse model. In this study, primate rhesus monkeys were used as research objects to determine the pharmacokinetics, immunogenicity and systemic toxicity of rMETase. Methods and Results The plasma methionine levels of rMETase could be reduced to undetectable levels (less than 0.5μmol / L) in a single intravenous injection of 1000u / kg, 2000u / kg and 4000u / kg of rMETase for 4h. 4000u / kg, plasma methionine levels below 1μmol / L, can be maintained for 8h. The t1 / 2 of rMETase in rhesus monkeys was 2.49h, the CL was 11.28ml / h and 30.77ml / h respectively at 2000u / kg and 4000u / kg; rMETase was repeatedly administered at 4000u / (kg.8h) for 2 weeks , The plasma methionine level can be kept below 2μmol / L during the administration. The main systemic toxicity of repeated high dose administration is decreased food intake, slight weight loss, and reversibly decreased plasma albumin and red blood cell levels. Anaphylactic shock occurs when rMETase is given again 28 weeks after 2 weeks of repeated administration, with 1 animal being dead; administration of hormonal rescue to avoid death or hydrocortisone administration prior to administration prevents the onset of anaphylactic shock . At 66, 86 and 116 days after the experiment, the drug was administered again, the anti-rMETase antibody level was 10-3 after the first administration, and increased to 10-6 after the fourth administration; the antibody level was reduced to 10-2. The type of anti-rMETase antibody is predominantly IgG and the neutralizing antibody is tested in vitro; however, the effect of reducing the plasma methionine in rMETase is less pronounced in vivo. Conclusions Systematic studies show that rMETase can effectively reduce methionine level in plasma and reduce systemic toxicity. RMETase is a promising broad-spectrum anticancer drug, but its immunogenicity should be emphasized, Chemically modified or otherwise treated can increase the duration of action of the drug and reduce its immunogenicity and increase the safety of the drug.