Subramanian D, Muller M T
Department of Molecular Genetics, Ohio State University, Columbus 43210, USA.
Oncol Res. 1995;7(9):461-9.
Topotecan, a topoisomerase I poison and water-soluble derivative of camptothecin, has shown promise in treating solid tumors; however, the drug is unstable under physiological conditions and converts to an inactive form within 30 minutes. Encapsulating topotecan in liposomes (LIP-TPT) minimizes inactivation. The efficacy of LIP-TPT was examined with a novel in vivo bioassay called ICE for In vivo Complexes of Enzyme. This bioassay uses antibodies to probe DNA for the presence of topoisomerase I covalent complexes and thereby allows direct quantification of topoisomerase I driven DNA adducts in living cells. We report that LIP-TPT was three- to fourfold more effective than free TPT in stabilizing covalent topoisomerase I-DNA intermediates inside tumor cells. These findings reveal that liposomal wrapping permitted effective delivery of camptothecin derivatives to active enzyme in the nucleus of the cell.
拓扑替康是一种拓扑异构酶I抑制剂，也是喜树碱的水溶性衍生物，已显示出治疗实体瘤的潜力；然而，该药物在生理条件下不稳定，30分钟内就会转化为无活性形式。将拓扑替康包裹在脂质体中（LIP-TPT）可最大程度地减少失活。通过一种名为ICE（体内酶复合物）的新型体内生物测定法检测了LIP-TPT的疗效。这种生物测定法使用抗体探测DNA中拓扑异构酶I共价复合物的存在，从而能够直接定量活细胞中拓扑异构酶I驱动的DNA加合物。我们报告称，在稳定肿瘤细胞内的共价拓扑异构酶I-DNA中间体方面，LIP-TPT的效果比游离TPT高三到四倍。这些发现表明，脂质体包裹能够有效地将喜树碱衍生物递送至细胞核中的活性酶。
