低叶酸条件下可提高trifluorothymidine之间的相互作用与抗结肠癌细胞。

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Temmink哦,Hoogeland MF,福岛M,彼得斯GJ

低叶酸条件下可提高trifluorothymidine之间的相互作用与抗结肠癌细胞。

癌症Chemother杂志。2006年1月;57 (2):171 - 9。Epub 2005年7月12日。

PubMed ID

16010590 (在PubMed

]

文摘

目的:Trifluorothymidine (TFT)是一个fluoropyrimidine小说的一部分组合代谢物助教- 102,TFT的结合是一个有力的胸苷磷酸化酶抑制剂(TPI)。助教- 102是目前测试作为口服化疗剂在不同的时间表在第一阶段的研究。一磷酸的形式,TFT可以抑制thymidylate合成酶(TS)活动绑定后TS-nucleotide结合位点导致dTTP损耗,和三磷酸形成TFT纳入DNA,最终导致DNA损伤。在体外研究中,我们调查了TFT是否能加强细胞毒性的antifolate-based TS抑制剂AG337 (Nolatrexed) ZD1694 (Raltitrexed)和GW1843;和增加TS抑制或DNA损伤是否与此相关的结果。方法:研究了药物组合在结肠癌细胞株生长在低或高叶酸的条件。多重药物效应分析后进行测量时生长抑制药物组合(MTT试验)和表达为组合指数(CI), CI在< 0.9表示合作,CI = 0.9 - -1.1表示相加性和CI > 1.1表示对立。药物目标分析都使用了TS原位抑制试验和FADU dna损伤分析。细胞暴露于药物单独或组合来确定影响TS活动和DNA损伤诱导,分别。结果:三个实验程序被用来测试药物的相互作用:任何一种药物的浓度保持在一个常数(IC25)或两种药物被添加在1:1 IC50-based摩尔比。 The combinations of TFT with one of the antifolates in which one of the drugs was kept at a constant concentration were synergistic for all antifolates in WiDr/F cells, which grow in low folate medium (CI=0.6-0.8), but only additive to antagonistic for the cell lines growing in high folate medium: TFT-AG337: CI=0.9-2.3; TFT-ZD1694: CI=0.9-1.3; TFT-GW1843: CI=0.8-1.7. The procedure in which the two drugs were added in a 1:1 IC50-based molar ratio showed antagonism for all three combinations in all cell lines (CI>2.7). TS inhibition (14.3%) and DNA damage (8%) were more pronounced than expected (P<0.05) when TFT was combined with GW1843 in WiDr/F cells, in contrast to AG337 and ZD1694, which showed inhibiting effects as expected (additive). CONCLUSIONS: The combination of TFT with the antifolates AG337, ZD1694 and GW1843 is mainly additive when the drugs are given simultaneously and this is mediated by an additive TS inhibition and DNA damage. The drug interaction may partly be dependent on the folate homeostasis since WiDr/F cells growing at low folate conditions show pronounced synergism in growth inhibition, two-sided TS inhibition and DNA damage, especially when TFT is combined with the tight-binding TS inhibitor GW1843.

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药物靶点

药物	目标	类	生物	药理作用	行动
Trifluridine	DNA	核苷酸	人类	是的	其他/未知	细节
Trifluridine	Thymidylate合酶	蛋白质	人类	是的	抑制剂	细节