Irinotecan hydrochloride trihydrate (CPT-11 HCl Trihydrate) keeps DNA from unwinding by inhibiting topoisomerase 1.

在肝脏,胃,十二指肠和结肠中,单剂量的Irinotecan能够显著增加拓扑异构酶I与DNA的共价结合数量.并且与对照组相比,Irinotecan处理组的结肠黏膜细胞中DNA链断裂数量明显较高.在COLO320异种移植物中,Irinotecan诱导92%的最大生长抑制.

在LoVo细胞和HT-29细胞系中,IC50浓度的Irinotecan诱导相似数量的可裂解复合物。SN-38浓度依赖性的诱导可裂解复合物的形成,这在LoVo细胞和HT-29细胞系中没有明显差异。Irinotecan在细胞中的积聚存在显著差异,在HT-29细胞中的水平始终高于LoVo细胞。 在血浆,肠道和肿瘤组织中,Irinotecan被羧酸酯酶活化为SN-38（主要经肝脏活化）,从而可与其靶点,拓扑异构酶I相互作用。在水溶液中Irinotecan的内酯E环和SN-38水解是可逆的,其羧酸盐和内酯形式的互变取决于温度和PH。在肿瘤和正常组织中,对于同一浓度的SN-38葡糖苷酸和Irinotecan,β-葡糖醛酸酶介导的SN-38产率均高于Irinotecan 形成的SN-38产率。在SCLC细胞系中,Irinotecan的活性明显高于NSCLC细胞系,而在组织学分型中并未观察到SN-38有明显的差异。

Exponentially growing cells (LoVo and HT-29 cells) are seeded in 20 cm2 Petri dishes with an optimal cell number for each cell line (2 × 104 for LoVo cells, 105 for HT-29 cells). They are treated 2 days later with increasing concentrations of Irinotecan or SN-38 for one cell doubling time (24 hours for LoVo cells, 40 hours for HT-29 cells). After washing with 0.15 M NaCl, the cells are further grown for two doubling times in normal medium, detached from the support with trypsin-EDTA and counted in a hemocytometer. The IC50 values are then estimated as the Irinotecan or SN-38 concentrations responsible for 50% growth inhibition as compared with cells incubated without Irinotecan or SN-38. (Only for Reference)