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首页> 美国卫生研究院文献>Elsevier Public Health Emergency Collection >Inhibition of ribonucleotide reductase and growth of human colon carcinoma HT-29 cells and mouse leukemia L1210 cells by N-hydroxy-N′-aminoguanidine derivatives
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Inhibition of ribonucleotide reductase and growth of human colon carcinoma HT-29 cells and mouse leukemia L1210 cells by N-hydroxy-N′-aminoguanidine derivatives

机译：N-羟基-N-氨基胍衍生物对核糖核苷酸还原酶的抑制作用及对人结肠癌HT-29细胞和小鼠白血病L1210细胞的生长

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A series of -hydroxy- ′-aminoguanidine (HAG) derivatives were studied and compared for their effects on ribonucleotide reductase activity in cell-free extracts; on nucleic acid synthesis and the growth of human colon carcinoma HT-29 cells; and on mouse leukemia L1210 cells in culture. The HAG derivatives [RCHNNHC(NH)NHOH-tosylate] studied could be grouped as; (1) hydroxy-benzylidines; (2) methoxybenzylidines; and (3) nitrobenzylidines substituted at the R position. 2′-Hydroxybenzylidine-HAG, the lead compound, was relatively active in both HT-29 cells and L1210 cells (20 ± 5 and 13 ± 4 M for 50% inhibition of HT-29 and L1210 cell growth respectively). The monohydroxybenzylidene compounds were generally more active than the dihydroxy- and trihy-droxybenzylidene-HAG derivatives. The methoxybenzylidene-HAGs were as active as the monohy-droxybenzylidene-HAGs. 2′-Hydroxy-4′-methoxybenzylidene-HAG was much more active than 2′,4′-dihydroxybenzylidene-HAG. The mononitrobenzylidene-HAGs were more active than the dinitro-benzylidene-HAG compound. In general, L1210 cells were more sensitive to the effects of the HAG compounds than were HT-29 cells. There was good agreement between the concentration of drug required to inhibit the growth of HT-29 cells and that required to inhibit the growth of L1210 cells. There was also good correlation between the ability of HAG derivatives to inhibit ribonucleotide reductase activity and to inhibit tumor cell growth. Some derivatives, such as 2′,3′,4′- and 3′,4′,5′-trihydroxybenzylidene-HAG inhibited L1210 cell growth by 50% at lower concentrations (7.8 and 11.9 μM respectively) than the concentrations needed for 50% inhibition of HT-29 cell growth (196 and 234 μM respectively) and ribonucleotide reductase activity (122 and 188 μM respectively). The studies of nucleic acid synthesis in L1210 cells using [ H]cytidine as a precursor showed that 2′,3′,4′-trihy-droxybenzylidine-HAG inhibited DNA synthesis at a lower concentration (29 μM for 50% inhibition) than was needed for the inhibition of RNA synthesis and formation of [ H]deoxycytidine nucleotides in the acid-soluble fraction (320 and 820 μM for 50% inhibition respectively). These results indicate that 2′,3′,4′-trihydroxybenzylidine-HAG inhibits DNA synthesis in L1210 cells through other mechanisms rather than exclusively through the inhibition of ribonucleotide reductase activity.
机译：研究了一系列的-羟基-'-氨基胍（HAG）衍生物，并比较了它们对无细胞提取物中核糖核苷酸还原酶活性的影响。对人结肠癌HT-29细胞的核酸合成及其生长的影响以及对小鼠白血病L1210细胞的培养。研究的HAG衍生物[RCHNNHC（NH）NHOH-甲苯磺酸酯]可以归类为： （1）羟基苄基; （2）甲氧基苄基; （3）在R位置取代的硝基苄基。前导化合物2'-羟基苄基-HAG在HT-29细胞和L1210细胞中均具有相对活性（分别为20±5和13±4 M，分别抑制HT-29和L1210细胞的生长）。一羟基亚苄基化合物通常比二羟基-和三-羟基苄基-HAG衍生物更具活性。甲氧基亚苄基-HAG与一元-羟基苄基-HAG一样有活性。 2'-羟基-4'-甲氧基亚苄基-HAG比2'，4'-二羟基亚苄基-HAG具有更高的活性。单硝基亚苄基-HAG比二硝基亚苄基-HAG化合物更具活性。通常，L1210细胞对HAG化合物的作用比HT-29细胞更为敏感。抑制HT-29细胞生长所需的药物浓度与抑制L1210细胞生长所需的药物浓度之间有很好的一致性。 HAG衍生物抑制核糖核苷酸还原酶活性和抑制肿瘤细胞生长的能力之间也存在良好的相关性。一些衍生物，例如2'，3'，4'-和3'，4'，5'-三羟基亚苄基-HAG在低于50所需浓度的浓度（分别为7.8和11.9μM）下抑制L1210细胞生长50％。抑制HT-29细胞生长的百分比（分别为196和234μM）和核糖核苷酸还原酶活性（分别为122和188μM）。以[H]胞苷为前体的L1210细胞核酸合成研究表明，2'，3'，4'-三氢-苯甲基苄基-HAG抑制DNA合成的浓度比抑制浓度低（29μM，抑制50％）。需要抑制酸合成级分中的RNA合成和[H]脱氧胞苷核苷酸的形成（分别为320和820μM，抑制50％）。这些结果表明2'，3'，4'-三羟基苄基-HAG通过其他机制而不是仅通过抑制核糖核苷酸还原酶活性来抑制L1210细胞中的DNA合成。

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