NUY96H1--PHASE II TRIAL OF 9-AMINO CAMPOTHECIN IN CUTANEOUS T CELL LYMPHOMA

拓扑异构酶诱导蛋白连接的DNA瞬间断裂，从而调节 DNA的结构。拓扑异构酶I(Topo I)诱导单链DNA 允许在显色过程中发生构象变化的中断 组织、有丝分裂、复制和转录。TOPO I能级 在整个细胞周期中保持恒定。然而，拓扑异构酶水平 正常组织和肿瘤组织之间的差异。在人类淋巴瘤中 样本中，Topo I的浓度被发现是5-15倍 高于正常组织。这表明可能存在一种 使用TOPO I抑制剂的治疗窗口。 Campothecins及其类似物9-AC(Topo I)的细胞毒性 抑制物)与形成DNA-蛋白质的能力高度相关 加合物。药物结合是可逆的，细胞毒性细胞周期 依附的。耐药性可能是通过药物的改变来调节的 蓄积、细胞周期持续时间改变或靶细胞变化 酵素。临床前数据表明，药物的长期维持 高于阈值的水平是有益的，而且持续的输液 时间表可能比推注给药更可取。肿瘤，如 同样，生长缓慢的真菌样肉芽肿可能最好的治疗方法是 药物的持续输注。I期研究的毒性主要是 使用72小时输液程序时出现骨髓抑制。这可能会 通过生长因子支持而得到改善。

Topoisomerases induce transient protein linked DNA breaks which modulate the structure of DNA. Topoisomerase I (topo I) induces single strand DNA breaks that allow for conformational changes required during chromatic organization, mitosis, replication, and transcription. Topo I levels remain constant throughout the cell cycle. However, topoisomerase levels differ between normal and neoplastic tissues. In human lymphoma specimens, the concentrations of topo I have been found to be 5-15 fold higher than in normal tissues. This suggests that there may be a therapeutic window to exploit using Topo I inhibitors. The cytotoxicity of campothecins (and the analogue 9-AC) (Topo I inhibitors) is highly correlated with the ability to form DNA-protein adducts. Drug binding is reversible, and cytotoxicity cell cycle dependent. Drug resistance may be mediated through alterations in drug accumulation, altered cell cycle duration, or changes in the target enzyme. Pre-clinical data suggests that prolonged maintenance of drug levels above a threshold is beneficial, and that continuous infusion schedules may be preferable to bolus administration. Neoplasms such as mycosis fungoides with slow growth rates similarly may be best treated by continuous infusions of agents. Toxicity in phase I studies was primarily myelosuppression when a 72 hour infusion schedule was utilized. This could be ameliorated by growth factor support.