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

拓扑异构酶诱导瞬时蛋白质连接的DNA断裂， DNA的结构。拓扑异构酶I诱导单链DNA 断裂允许在染色过程中所需的构象变化， 组织、有丝分裂、复制和转录。Topo I水平 在整个细胞周期中保持不变。然而，拓扑异构酶水平 在正常组织和肿瘤组织之间是不同的。人淋巴瘤 样品，拓扑异构酶I的浓度已被发现是5-15倍 高于正常组织。这表明，可能有一个 使用Topo I抑制剂开发的治疗窗口。 喜树碱（及其类似物9-AC）（Topo I）的细胞毒性 抑制剂）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 依赖。耐药性可能通过药物代谢的改变来介导。 积累，改变细胞周期持续时间，或改变靶点 酵素临床前数据表明， 高于阈值的水平是有益的， 时间表可能比大剂量给药更可取。新教徒，如 类似地，生长速度缓慢的蕈样肉芽肿最好通过以下方法治疗： 连续输注药剂。I期研究中的毒性主要是 使用72小时输注方案时的骨髓抑制。这可能 通过生长因子支持得到改善。

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.