Beretta Giovanni L, Petrangolini Giovanna, De Cesare Michelandrea, Pratesi Graziella, Perego Paola, Tinelli Stella, Tortoreto Monica, Zucchetti Massimo, Frapolli Roberta, Bello Ezia, Manzotti Carla, Fontana Gabriele, Bombardelli Ezio, Battaglia Arturo, Samorì Cristian, Zunino Franco
Department of Experimental Oncology and Laboratories, Istituto Nazionale Tumori, Milan, Italy.
Cancer Res. 2006 Nov 15;66(22):10976-82. doi: 10.1158/0008-5472.CAN-06-2158.
A series of water-soluble camptothecins obtained by linking a spermidine moiety to the 21-position of the open form through an amidic bond have been tested for their biochemical and biological activities. Growth inhibition assay on the human non-small cell lung cancer carcinoma NCI-H460 cell line revealed that the camptothecin analogues were less potent than topotecan and SN38 after 1 hour of treatment. The potency increased after 72 hours of exposure, being similar to that of reference camptothecins. The analysis of topoisomerase I-mediated DNA cleavage using the purified enzyme indicated that the novel camptothecin analogues retained ability to poison topoisomerase I and displayed the same cleavage pattern of SN38. Persistence of the DNA cleavage was comparable with that of SN38. Stabilization of the cleavable complex was not the result of hydrolysis of the N-C bond between polyamine and the drug because no free camptothecin was recovered at the end of DNA cleavage in presence of IDN5174, the analogue selected for detailed studies. IDN5174 exhibited an antitumor activity comparable with that of topotecan and irinotecan against NCI-H460 tumor xenograft. The pharmacokinetics in mice showed a favorable disposition in tumor tissue with low amount of camptothecin detectable in plasma and tumor (around 5-10%), thus supporting the efficacy of intact IDN5174. In conclusion, we found that IDN5174 maintained the biological and antitumor properties, in spite of lack of the closed E ring. The available results support the interpretation that the polyamine linked at the 21-position may allow a favorable drug interaction in the ternary complex.
通过酰胺键将亚精胺部分连接到开环形式的21位得到的一系列水溶性喜树碱，已对其生化和生物活性进行了测试。对人非小细胞肺癌NCI-H460细胞系的生长抑制试验表明，在处理1小时后，喜树碱类似物的效力低于拓扑替康和SN38。暴露72小时后效力增加，与参比喜树碱相似。使用纯化的酶对拓扑异构酶I介导的DNA切割进行分析表明，新型喜树碱类似物保留了使拓扑异构酶I中毒的能力，并显示出与SN38相同的切割模式。DNA切割的持续性与SN38相当。可切割复合物的稳定不是多胺与药物之间N-C键水解的结果，因为在DNA切割结束时，在选择用于详细研究的类似物IDN5174存在下未回收游离喜树碱。IDN5174对NCI-H460肿瘤异种移植瘤表现出与拓扑替康和伊立替康相当的抗肿瘤活性。小鼠体内的药代动力学显示在肿瘤组织中有良好的分布，血浆和肿瘤中可检测到的喜树碱量较低（约5-10%），因此支持完整的IDN5174的疗效。总之，我们发现尽管缺少封闭的E环，IDN5174仍保持生物学和抗肿瘤特性。现有结果支持这样的解释，即连接在21位的多胺可能在三元复合物中允许有利的药物相互作用。
