A novel human tumor necrosis factor a mutant showed potent antitumor activity and reduced toxicity in vivo  

一种新型人肿瘤坏死因子α突变体具有高抑瘤活性及低体内毒性<英文>

作　　者：卢芳[1] 陈拯民[2] 刘全海[3] 陈常庆[1] 

机构地区：[1]中国科学院上海生命科学研究院上海生物工程研究中心,上海中国200233 [2]天津药物研究院,天津中国300193 [3]上海医药工业研究院,上海中国200437

出　　处：《Acta Pharmacologica Sinica》2001年第7期45-49,共5页中国药理学报（英文版）

基　　金：Project supported by China 863 High Technology Foundation,No 863-103-01-04

摘　　要：AIM: To study the antitumor activity and systemic toxic-ity of human tumor necrosis factor α (hTNFα) mutant M2 ( R2K-N30S-R32W-L157F-hTNFα ). METHODS: Mouse sarcoma S180 tumors and hepatoma HAC tumors were implanted into mice, and human urocyst carcinoma CP-3 tumors were implanted into nude mice. The xenografted mice were injected with wild-type hTNFa and its mutant M2 at different doses. After 7 d (mice) or 10 d (nude mice) of injection, the tumor weight was measured to calculate the inhibition rate of hTNFa and M2. Systemic toxicity experiments were done on Rhesus monkeys by injecting them with wild-type hTNFa and mutant M2 respectively for 10 consecutive d. Observations were made on the monkeys both before and after the injection. RESULTS: For mice implanted with sarcoma S180 and hepatoma HAC tumors, the inhibition rate of M2 was similar to that of wild-type hTNFa at the dose of 0.025 mg/kg, while for nude mice implanted with human urocyst carcinoma CP-3, the inhibition rate of M2 (45.5 % ) was much higher than that of wild-type hTNFa (15.5 %). When the dose came to 0.25 and 2.5 mg/kg respectively, however, the inhibition rate of M2 greatly increased (the highest was 75.9 %). The tests of systemic toxicity of hTNFa and its mutant M2 in monkeys proved that M2 presented lower toxicity than wild-type hTNFα did. CONCLUSION: hTNFa mutantM2 not only presented higher antitumor activity than wild-type hTNFa did on mouse tumor (S180 and HAC)-and human tumor (CP-3)-implanted mice, but also showed lower systemic toxicity in the Rhesus monkey.目的:研究人肿瘤坏死因子α(hTNFα)新型突变体M2(R2K-N30S-R32W-L157F-hTNFα)的动物体内抑瘤效应及毒性。方法:将小鼠肉瘤S180及肝癌HAC实体瘤细胞分别植入小鼠,并将人膀胱癌瘤株CP-3植入裸鼠体内,再对它们分别注射不同剂量的野生型hTNFα以及突变体M2。连续注射7d(小鼠)或10d(裸鼠)后称实体瘤重量,据此计算野生型hTNFα和M2的抑瘤率。对恒河猴进行为期10d的多次注射野生型hTNFα及其突变体M2的毒性实验,并观察注射前后动物的生理状况,检查体重及血液生化指标。结果:对于小鼠移植瘤S180和HAC,在0.025mg/kg的给药浓度下,突变体M2表现出与野生型hTNFα相似的抑瘤效应,而在这一浓度下,M2 对移植到裸鼠的人膀胱癌CP-3肿瘤的抑瘤率为45.5％,明显高于野生型hTNFα的15.5％。此外,当M2的给药浓度提高到0.25及2.5mg/kg时,其抑瘤率明显升高,其中最高可达75.9％。恒河猴体内毒性实验结果证明,hTNFα突变体M2的毒性要小于野生型hTNFα。结论:hTNFα新型突变体M2相对于野生型hTNFα不仅在小鼠肿瘤(S180和HAC)和人肿瘤(CP-3)移植的小鼠中具有更高的抑瘤活性,而且在恒河猴体内表现较低的毒性。

关 键 词：tumor necrosis factor experimental implants antineoplastic agents toxicity tests nude mice macaca mulatta 

分 类 号：R96[医药卫生—药理学]