Ferguson L R, van Zijl P, Baguley B C
Cancer Research Laboratory, University of Auckland Medical School, New Zealand.
Mutat Res. 1988 Feb;204(2):207-17. doi: 10.1016/0165-1218(88)90091-2.
The mutagenicity of CI-921, the 4-methyl-5-(N-methyl)carboxamide derivative of the clinical antileukaemia agent, amsacrine, has been assessed using both bacterial and mammalian cells. CI-921 is distinguished from amsacrine in its high activity against some experimental tumours and is currently undergoing phase I clinical trial. Like 9-aminoacridine and amsacrine, CI-921 is mutagenic to the Salmonella typhimurium frameshift tester strain TA1537, but shows no sign of inducing base pair changes in strain TA100. In Chinese hamster cell culture, however, it differs from 9-aminoacridine in causing extensive chromosomal aberrations and an increase in mutations at the hypoxanthine-guanine phosphoribosyltransferase locus. It induces the formation of tightly packed and multilayered colonies in treated cultures of C3H/10T1/2 cells, but its action differs from that of benzo[a]pyrene, which induces type III fibroblastic multilayered colonies. Side-by-side comparison of the mutagenic properties of CI-921 and amsacrine showed no substantial differences at similar toxicity, suggesting that the increased lipophilicity and DNA-binding affinity of CI-921, which are thought to contribute to its increased antitumour activity, do not concomitantly increase the efficiency of in vitro mutagenesis or cell transformation.
临床抗白血病药物安吖啶的4-甲基-5-（N-甲基）甲酰胺衍生物CI-921的致突变性已通过细菌和哺乳动物细胞进行了评估。CI-921与安吖啶的区别在于其对某些实验性肿瘤具有高活性，目前正在进行I期临床试验。与9-氨基吖啶和安吖啶一样，CI-921对鼠伤寒沙门氏菌移码测试菌株TA1537具有致突变性，但在TA100菌株中未显示出诱导碱基对变化的迹象。然而，在中国仓鼠细胞培养中，它与9-氨基吖啶不同，会导致广泛的染色体畸变，并增加次黄嘌呤-鸟嘌呤磷酸核糖基转移酶位点的突变。它在C3H/10T1/2细胞的处理培养物中诱导紧密堆积和多层菌落的形成，但其作用与苯并[a]芘不同，苯并[a]芘诱导III型成纤维细胞多层菌落。CI-921和安吖啶致突变特性的并排比较表明，在相似毒性下没有实质性差异，这表明CI-921增加的亲脂性和DNA结合亲和力被认为有助于其增加的抗肿瘤活性，但并不会同时增加体外诱变或细胞转化的效率。
