新一代胸苷酸合成酶抑制剂ZD1694的体内外抗肿瘤作用

Antitumor effects of novel thymidylate synthase inhibitor ZD1694 in vitro and in vivo

目的:观察ZD1694对小鼠体内S180肉瘤生长的抑制作用及其在体外对人胃腺癌SGC7901细胞增殖的影响。方法:采用荷瘤小鼠模型,腹腔注射不同剂量的ZD1694,分单次给药与连续5d分次给药两种方案。处死动物后称取肿瘤组织重量,计算抑瘤率。另外采用MTT比色法及流式细胞仪观察ZD1694对人SGC7901胃腺癌细胞株生长的影响。结果:ZD1694可抑制小鼠体内S180肉瘤的生长,其抑瘤率无论是单次给药组(200、100、50mg·kg-1)还是连续5d给药组(40、20、10mg·kg-1·d-1),均可见剂量依赖性增加。ZD1694(0.001～1000mmol·L-1)对SGC7901人胃腺癌细胞的生长抑制率呈浓度依赖性和时间依赖性增加,可使G0-G1期细胞增多,S期和G2-M期细胞减少。结论:ZD1694对荷瘤小鼠产生明显的抗瘤作用,一次性给药的抑瘤率大于相同剂量分5次给药的抑瘤率。该药在体外可抑制人胃腺癌SGC7901细胞生长,使细胞发生G1期阻滞。

AIM: To observe the inhibitory effects of ZD1694 on the growth of S180 sarcoma cells in mice and investigate the effects of ZD1694 on the proliferation of gastric gland carcinoma SGC-7901 cell lines in vitro. METHODS: The tumor mice models were administered (ip) with ZD1694 at the different dose levels in one day or five consecutive days. The tumor weights were measured after the mice were slaughtered and the antitumor rates were calculated. In addition, MTT assay and flow cytometry were used for testing the effects of ZD1694 on SGC-7901 cell lines. RESULTS: The growth of S180 sarcoma cells in mice was inhibited by ZD1694. The order of the antitumor rates in different groups were listed as 200 mg·kg -1×1 d>100 mg·kg -1×1 d>40 mg·kg -1·d -1×5 d>50 mg·kg -1×1 d>20 mg·kg -1·d -1×5 d>10 mg·kg -1·d -1× 5 d. The inhibitory rate of ZD1694( 0.001- 1 000 mmol·L -1)on SGC-7901 cells were increased in concentration and time-dependent manner. The cell numbers in G_0-G_1 phase in SGC-7901 cells were raised by ZD1694 as well. CONCLUSION: ZD1694 can take obvious antitumor effects on S180-bearing mice. The antitumor rate of ZD1694 is in a dose-dependent manner, and it is higher when the total dosage is administered in one day than that the total dosage was divided into 5 consecutive days. ZD1694 can inhibit the growth of SGC-7901 cells and block the cells in G_1 phase in vitro.