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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。
OBJECTIVE: To study the antitumor effect and toxicity of an animal model of human tumor necrosis factor alpha (hTNFα) mutant M2 (R2K-N30S-R32W-L157F-hTNFα). Methods: Mouse sarcoma S180 and hepatocellular carcinoma HAC solid tumor cells were implanted into mice respectively. Human bladder carcinoma tumor cell line CP-3 was implanted into nude mice. Different doses of wild-type hTNFα and mutant M2 . After 7 days (mice) or 10 days (nude mice) injection, the weight of solid tumor was calculated, and the inhibition rates of wild-type hTNFα and M2 were calculated. The rhesus monkeys were injected with wild-type hTNFα and its mutant M2 for 10 days. The physiological status of the animals was observed before and after injection, and body weight and blood biochemical parameters were examined. Results: For mouse xenografts S180 and HAC, mutant M2 showed similar antitumor effects as wild-type hTNFα at a concentration of 0.025 mg / kg, and at this concentration, Of human bladder cancer CP-3 tumor inhibition rate was 45.5%, significantly higher than the wild-type hTNFα 15.5%. In addition, when the concentration of M2 was increased to 0.25 and 2.5mg / kg, the tumor inhibition rate was significantly increased, of which up to 75.9%. In vivo toxicity studies in rhesus monkeys demonstrated that the toxicity of hTNFα mutant M2 was less than that of wild-type hTNFα. Conclusions: The novel hTNFα mutant M2 has higher antitumor activity than the wild-type hTNFα in mice transplanted with both mouse tumors (S180 and HAC) and human tumors (CP-3), but also in vivo in rhesus monkeys Lower toxicity.