Hall I H, Wong O T, Simlot R, Miller M C, Izydore R A
Division of Medicinal Chemistry and Natural Products, University of North Carolina School of Pharmacy, Chapel Hill 27559.
Anticancer Res. 1992 Sep-Oct;12(5):1355-61.
1-Acyl- and 1,2-diacyl-1,2,4-triazolidine-3,5-diones were found to be potent cytotoxic agents in murine and human cancer cell lines, e.g. L1210, P388, Tmolt3, colon adenocarcinoma, Hela cells and glioma. In vivo activity was demonstrated at 8 mg/kg/day against Ehrlich ascites carcinoma growth. In L1210 cells, 1-acetyl-4-phenyl-1,2,4-triazolidine-3,5-dione, 41, reduced DNA synthesis significantly with moderate reduction in RNA synthesis. Enzyme sites in L1210 cells which were markedly affected were m- and r-RNA polymerase, PRPP amidotransferase, IMP dehydrogenase, dihydrofolate reductase, thymidine, TMP and TDP kinases. Kinetic studies suggest the inhibition of rate limiting enzymes in the purine pathway by 41 was responsible for its cytotoxicity. Acute toxicity studies in mice indicated 41 was safe for therapeutic use at 20, 50, and 100 mg/ky/day.
1-酰基-和1,2-二酰基-1,2,4-三唑烷-3,5-二酮被发现是对小鼠和人类癌细胞系有效的细胞毒性剂，例如L1210、P388、Tmolt3、结肠腺癌、Hela细胞和神经胶质瘤。在8毫克/千克/天的剂量下对艾氏腹水癌生长显示出体内活性。在L1210细胞中，1-乙酰基-4-苯基-1,2,4-三唑烷-3,5-二酮（41）显著降低DNA合成，同时RNA合成有适度降低。L1210细胞中受到显著影响的酶位点是m-和r-RNA聚合酶、PRPP酰胺转移酶、IMP脱氢酶、二氢叶酸还原酶、胸苷激酶、TMP激酶和TDP激酶。动力学研究表明，41对嘌呤途径中限速酶的抑制作用是其细胞毒性的原因。小鼠急性毒性研究表明，41在20、50和100毫克/千克/天的剂量下用于治疗是安全的。
