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4-甲基哌嗪-1-二硫代甲酸-(3-氰基-3,3-二苯基)丙酯盐酸盐(TM208)是一种新合成的氨基二硫代甲酸酯类化合物,具有良好的体内抗肿瘤作用,且毒性较低。探讨TM208与临床已知抗癌药联用能否提高疗效并降低毒性,可为TM208的临床试验提供依据。本实验通过小鼠肝癌H_(22)移植瘤模型考察了TM208与顺铂(DDP)、环磷酰胺(CTX)、5-氟尿嘧啶(5-Fu)分别联合用药的体内抗肿瘤作用及毒性。体内实验结果证实,5-Fu(5 mg/kg/2d)与TM208(100 mg/kg/d)联用后可显著增强对H_(22)肿瘤的抑制作用(P<0.01),且几乎不增加毒性;而DDP和CTX则不能。进一步研究表明,TM208与5-Fu联用可通过下调cyclin B1,cdc2,cdk7和上调p21,p53的表达引起H_(22)实体瘤细胞发生G_2/M周期阻滞。同时此联合用药方案也可下调cyclin D1,cyclin E的表达,对cdk4,cdk2的表达则没有影响。Cdc2 mRNA的表达与其蛋白表达趋势一致,而cyclin B1mRNA表达在各组间没有差异。总之,TM208与5-Fu联用可提高抗肿瘤疗效,毒性不变,其抗肿瘤作用与细胞周期阻滞及其相关蛋白的表达变化有关。
Methylpiperazine-1-dithioformate- (3-cyano-3,3-diphenyl) propyl ester hydrochloride (TM208) is a newly synthesized aminodithiocarboxylate , Has a good anti-tumor effect in vivo, and less toxic. To investigate whether TM208 combined with clinically known anticancer drugs can improve the curative effect and reduce the toxicity, and provide the basis for the clinical trial of TM208. In this study, we investigated the antitumor effect and toxicity of TM208 combined with cisplatin (DDP), cyclophosphamide (CTX) and 5-fluorouracil (5-Fu) in mice H22 tumor xenografts. In vivo results showed that 5-Fu (5 mg / kg / 2d) combined with TM208 (100 mg / kg / d) significantly enhanced the inhibitory effect on H22 tumors (P <0.01) Increase toxicity; but DDP and CTX can not. Further studies showed that the combination of TM208 and 5-Fu can cause G 2 / M cycle arrest in H 22 tumor cells by down-regulating the expression of cyclin B1, cdc2, cdk7 and up-regulating the expression of p21 and p53. At the same time, this combination regimen can also down-regulate the expression of cyclin D1 and cyclin E, but has no effect on the expression of cdk4 and cdk2. The expression of Cdc2 mRNA was consistent with the trend of its protein expression, while there was no difference in cyclin B1 mRNA expression between the groups. In conclusion, the combination of TM208 and 5-Fu can improve the anti-tumor efficacy and maintain the same toxicity. The anti-tumor effect of TM208 is related to cell cycle arrest and the expression of related proteins.