Intestinal microflora and digestive toxicity of irinotecan in mice.

Abstract

Purpose: 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. Experimental Design: To evaluate the lethal dose, starting with 100 mg/kg/4 d, we treated the holoxenic mice with100, 80, and 60 mg/kg/4 d and germ-free mice with 60, 80,100, and150 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. Results: 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 z150 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. Conclusions: The intestinal microflora plays a key role in the intestinal toxicity of irinotecan.

Molecular Insights into Microbialβ-Glucuronidase Inhibition to Abrogate CPT-11 Toxicity

“…A dosing scheme of 50 mg/kg/day, once daily for 9 days, was chosen with the intention of accelerating the onset of diarrhea while preventing death. As outlined previously, 50 mg/kg CPT-11 in mice is roughly equivalent to the 5 mg/kg typical human CPT-11 dose based on differences in body surface area (Brandi et al, 2006;Reagan-Shaw et al, 2008). GI symptoms in group 3 started as early as day 2 and up to day 10 and included decreased appetite, bowel movements, mobility, and body weight.…”

“…It also appears that widespread use of antibiotics may have subtle but serious side effects on human health (Maurice et al, 2013). Additionally, for patients with colorectal cancer, the use of antibiotics to treat CPT-11-induced toxicity may lead to the increased prevalence of subdominant bacterial species with higher overall b-glucuronidase activity in the GI tract and thus, increased toxicity (Brandi et al, 2006). Studies have also shown that the long-term use of neomycin in mice leads to increased serum bilirubin that may interfere with proper hepatic CPT-11 metabolism (Vítek et al, 2005).…”

“…These enzymes, in turn, reactivate SN-38 in situ, resulting in toxic injury to the intestinal epithelial cells (Araki et al, 1993). Indeed, the severity of CPT-11-induced diarrhea is correlated with levels of b-glucuronidase activity in the intestinal lumen, and the intestinal microbiota have been found to play an important role in the development of this toxicity (Takasuna et al, 1996(Takasuna et al, , 1998Mathijssen et al, 2001;Brandi et al, 2006). Although most early-onset diarrhea associated with CPT-11 treatment can be treated with antimotility agents, the delayed GI toxicity associated with SN-38 can be refractory to standard treatments (Saliba et al, 1998).…”

Irinotecan toxicity: genes or intestinal microflora?

“…Irinotecan lethal dose is more than twice higher in the second group, which also exhibited significantly less diarrhoea. Intestinal damage as shown by histological examination reflected bacterial distribution along the gut, in particular it was negligible in germ-free animals treated at 60 mg kg À1 d À1 for 4 days, the lethal dose for holoxenic controls (Brandi et al, 2006).…”

“…Irinotecan lethal dose is more than twice higher in the second group, which also exhibited significantly less diarrhoea. Intestinal damage as shown by histological examination reflected bacterial distribution along the gut, in particular it was negligible in germ-free animals treated at 60 mg kg À1 d À1 for 4 days, the lethal dose for holoxenic controls (Brandi et al, 2006).The poor predictive value for diarrhoea of the genetic loci studied by Rouits et al is therefore not surprising. In humans, intestinal microflora composition is quite stable along life and host-specific, representing a sort of adjunctive fingerprint.…”