Gibson Rachel J, Bowen Joanne M, Inglis Mark R B, Cummins Adrian G, Keefe Dorothy M K
Department of Medical Oncology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.
J Gastroenterol Hepatol. 2003 Sep;18(9):1095-100. doi: 10.1046/j.1440-1746.2003.03136.x.
Irinotecan (CPT-11) is a chemotherapeutic drug for cancer that causes severe diarrhea by an uncertain mechanism. The aim of the present study was to investigate the time-course of apoptosis and whole intestinal damage after irinotecan to further elucidate the mechanism behind the diarrhea.
Groups of breast cancer-bearing dark agouti (DA) rats were treated with 100, 150 or 200 mg/kg doses of irinotecan or vehicle control daily for two days, and killed at 6, 24, 72 or 96 h after treatment. Apoptosis and morphometry were examined in both the small and large intestines. Histopathology and goblet cell numbers were recorded. Data were analyzed using the Peritz' F-test.
Irinotecan increased apoptosis and caused villous atrophy and crypt hypoplasia in the small intestine, and increased apoptosis, crypt hypoplasia, crypt dilation and mucus secretion in the large intestine. Irinotecan at 100 and 150 mg/kg caused crypt hypoplasia at 6 and 24 h, with rebound hyperplasia at 72 and 96 h. At 200 mg/kg, irinotecan caused a more pronounced crypt hypoplasia earlier and all animals died by 96 h. Apoptosis peaked at 6 h and remained elevated over the remainder of the time-points. This was not dose-dependent. Irinotecan at all doses altered colonic, but not jejunal, goblet cells. Irinotecan increased colonic mucus secretion.
We conclude that irinotecan causes diarrhea by inducing apoptosis and hypoproliferation in both the small and large intestines, and causes colonic damage with changes in goblet cells and mucin secretion.
伊立替康（CPT - 11）是一种用于治疗癌症的化疗药物，其导致严重腹泻的机制尚不明晰。本研究旨在探究伊立替康给药后细胞凋亡和全肠道损伤的时间进程，以进一步阐明腹泻背后的机制。
将荷乳腺癌的黑褐大鼠分组，每天分别给予100、150或200 mg/kg剂量的伊立替康或赋形剂对照，连续给药两天，并在给药后6、24、72或96小时处死。对小肠和大肠进行细胞凋亡和形态学检测。记录组织病理学和杯状细胞数量。数据采用Peritz' F检验进行分析。
伊立替康增加了细胞凋亡，导致小肠绒毛萎缩和隐窝发育不全，并增加了大肠的细胞凋亡、隐窝发育不全、隐窝扩张和黏液分泌。100和150 mg/kg的伊立替康在6和24小时导致隐窝发育不全，在72和96小时出现反弹增生。200 mg/kg时，伊立替康更早引起更明显的隐窝发育不全，所有动物在96小时前死亡。细胞凋亡在6小时达到峰值，并在其余时间点保持升高。这与剂量无关。所有剂量的伊立替康均改变了结肠杯状细胞，但未改变空肠杯状细胞。伊立替康增加了结肠黏液分泌。
我们得出结论，伊立替康通过诱导小肠和大肠的细胞凋亡和增殖减少导致腹泻，并通过杯状细胞和黏蛋白分泌的改变引起结肠损伤。
