新型鸟苷代谢核苷抑制剂作为抗肿瘤药物

Novel nucleoside inhibitors of guanosine metabolism as antitumor agents.

作者信息

Smejkal R M, Page T T, Boyd V L, Nyhan W L, Jacobsen S J, Mangum J H, Robins R K

出版信息

Adv Enzyme Regul. 1984;22:59-68. doi: 10.1016/0065-2571(84)90008-6.

Abstract

A detailed study of the inhibition of DR and TR in the SkLu-1 line of human lung adenocarcinoma has shown that TR significantly inhibits this tumor line, probably via inhibition of IMP dehydrogenase by the corresponding TAD analog of NAD. DR exhibited a similar degree of inhibition in this cell line. In a system devised to detect the inhibition of cloning efficiency of the SkLu cells, DR showed a 50% inhibition at 4 X 10(-3) M and TR at 1 X 10(-4) M. When DR and TR were used in combination, the ID50 was decreased to 3 X 10(-5) M. The study of DR in a number of human carcinoma cell lines revealed that de novo purine biosynthesis was significantly inhibited; however, in the SkLu-1 lung carcinoma cells this inhibition was not observed. The synergism observed in this cell line is presently viewed as potentially due to both agents acting on IMP dehydrogenase at different sites.

摘要

对人肺腺癌细胞系SkLu-1中DR和TR抑制作用的详细研究表明，TR显著抑制该肿瘤细胞系，可能是通过相应的NAD的TAD类似物抑制IMP脱氢酶实现的。DR在该细胞系中表现出相似程度的抑制作用。在一个设计用于检测SkLu细胞克隆效率抑制情况的系统中，DR在4×10⁻³ M时显示出50%的抑制率，TR在1×10⁻⁴ M时显示出50%的抑制率。当DR和TR联合使用时，半数抑制浓度降至3×10⁻⁵ M。对多种人类癌细胞系中DR的研究表明，从头嘌呤生物合成受到显著抑制；然而，在SkLu-1肺癌细胞中未观察到这种抑制作用。目前认为在该细胞系中观察到的协同作用可能是由于两种药物作用于IMP脱氢酶的不同位点。