Uckun F M, Stewart C F, Reaman G, Chelstrom L M, Jin J, Chandan-Langlie M, Waddick K G, White J, Evans W E
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455, USA.
Blood. 1995 May 15;85(10):2817-28.
Topotecan [(S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SK&F 104864-A, NSC 609699], a water soluble semisynthetic analogue of the alkaloid camptothecin, is a potent topoisomerase I inhibitor. Here we show that topotecan stabilizes topoisomerase I/DNA cleavable complexes in radiation-resistant human B-lineage acute lymphoblastic leukemia (ALL) cells, causes rapid apoptotic cell death despite high-level expression of bcl-2 protein, and inhibits ALL cell in vitro clonogenic growth in a dose-dependent fashion. Furthermore, topotecan elicited potent antileukemic activity in three different severe combined immunodeficiency (SCID) mouse models of human poor prognosis ALL and markedly improved event-free survival of SCID mice challenged with otherwise fatal doses of human leukemia cells at systemic drug exposure levels that can be easily achieved in children with leukemia.
拓扑替康[（S）-9-二甲基氨基甲基-10-羟基喜树碱盐酸盐；SK&F 104864-A，NSC 609699]，一种生物碱喜树碱的水溶性半合成类似物，是一种有效的拓扑异构酶I抑制剂。我们在此表明，拓扑替康可稳定抗辐射的人类B系急性淋巴细胞白血病（ALL）细胞中的拓扑异构酶I/DNA可裂解复合物，尽管bcl-2蛋白高表达，仍可导致快速凋亡性细胞死亡，并以剂量依赖方式抑制ALL细胞的体外克隆生长。此外，拓扑替康在三种不同的人类预后不良ALL的严重联合免疫缺陷（SCID）小鼠模型中引发了强大的抗白血病活性，并且在全身性药物暴露水平下显著提高了接受致命剂量人类白血病细胞攻击的SCID小鼠的无事件生存率，而这种全身性药物暴露水平在白血病儿童中很容易达到。
