Brandi Giovanni, Dabard Jean, Raibaud Pierre, Di Battista Monica, Bridonneau Chantal, Pisi Anna Maria, Morselli Labate Antonio Maria, Pantaleo Maria Abbondanza, De Vivo Antonello, Biasco Guido
L.A. Seragnoli Institute of Haematology, Sant'Orsola-Malpighi Hospital, University of Bologna, Italy.
Clin Cancer Res. 2006 Feb 15;12(4):1299-307. doi: 10.1158/1078-0432.CCR-05-0750.
Delayed diarrhea is the most important side effect of irinotecan. The aim of this study was to investigate the role of intestinal microflora on the induction of systemic and intestinal toxicity and diarrhea, studying germ-free and holoxenic mice i.p. injected with irinotecan.
To evaluate the lethal dose, starting with 100 mg/kg/4 d, we treated the holoxenic mice with 100, 80, and 60 mg/kg/4 d and germ-free mice with 60, 80, 100, and 150 mg/kg/4 d. We recorded the percentage of dead animals, diarrhea, and the epithelial damage to the jejunum, ileum, cecum, and colon at optical and scanning electron microscopy.
Germ-free mice were more resistant to irinotecan than the holoxenic group. The lethal dose was between 60 and 80 mg of irinotecan for holoxenic mice and > or =150 mg for the germ-free. The intestinal damage score was higher in holoxenic than germ-free mice at 100 mg and equally diffuse in the small and large bowel. The damage in germ-free mice was less severe (8 of 40 samples) prevailing in the ileum. The differences were significant for all sites (jejunum, P < 0.001; ileum, P = 0.012; cecum, P = 0.001; colon, P < 0.001). No damage was found in germ-free mice at 60 mg. Diarrhea was present in all 100 and 80 mg holoxenic mice and in 19 of 20 cases at 60 mg whereas it was absent in 60 mg or sporadic in 80 and 100 mg germ-free mice.
The intestinal microflora plays a key role in the intestinal toxicity of irinotecan.
延迟性腹泻是伊立替康最重要的副作用。本研究旨在通过对无菌小鼠和普通小鼠腹腔注射伊立替康，研究肠道微生物群在诱导全身和肠道毒性及腹泻中的作用。
为评估致死剂量，从100mg/kg/4天开始，我们对普通小鼠分别给予100、80和60mg/kg/4天的剂量，对无菌小鼠分别给予60、80、100和150mg/kg/4天的剂量。我们记录了死亡动物的百分比、腹泻情况以及在光学显微镜和扫描电子显微镜下空肠、回肠、盲肠和结肠的上皮损伤情况。
无菌小鼠对伊立替康的耐受性高于普通小鼠组。普通小鼠的致死剂量在60至80mg伊立替康之间，而无菌小鼠的致死剂量≥150mg。在100mg剂量时，普通小鼠的肠道损伤评分高于无菌小鼠，且在小肠和大肠中损伤分布相同。无菌小鼠的损伤较轻（40个样本中有8个），主要发生在回肠。所有部位（空肠，P<0.001；回肠，P = 0.012；盲肠，P = 0.001；结肠，P<0.001）的差异均具有统计学意义。60mg剂量时无菌小鼠未发现损伤。所有100mg和80mg的普通小鼠均出现腹泻，60mg剂量时20例中有19例出现腹泻，而60mg剂量的无菌小鼠未出现腹泻，80mg和100mg剂量的无菌小鼠腹泻为偶发。
肠道微生物群在伊立替康的肠道毒性中起关键作用。
