Purpose: Irinotecan chemotherapy improves survival for patients with colorectal liver metastasis, but its use is severely limited due to associated diarrhea. In certain cases, the late onset diarrhea can be life threatening and may require a disruption in the treatment schedule and/or a reduction in dosing. Clinical findings also report non-alcoholic fatty liver disease (NAFLD) with irinotecan-based therapy. Despite significant efforts to reduce severity of diarrhea, the effectiveness of current interventions is limited. And at present, there are no interventions to counteract the NAFLD caused by irinotecan. This warrants development of newer approaches to reduce/prevent irinotecan-induced toxicities. Dietary components have shown promise in improving gastrointestinal health and therapeutic outcomes of chemotherapeutic agents by reducing toxicities. We therefore compared the effect of grain-based chow diet containing phytoestrogens and corn/alfalfa as fat source to purified diets containing either animal-derived fat source (lard) or plant-derived fat source (soybean oil) on irinotecan-induced toxicities.
Methods: Adult male C57BL/6J mice were administered intraperitoneally with vehicle or irinotecan (50 mg/kg) for 6 consecutive days. On day 7, following euthanasia, livers and blood were collected. The severity of the diarrhea was monitored each day. Morphological findings in H & E stained liver sections were recorded in a semi-quantitative manner. The serum concentrations of irinotecan and its metabolites, SN-38 (the toxic metabolite) and SN-38G were quantified with LC-MS/MS. The activities of crucial drug metabolizing enzymes (DMEs) involved in irinotecan metabolism were assessed.
Results: Our results show that the chow diet was protective against irinotecan-induced diarrhea and hepatic steatosis. Interestingly, purified diet containing lard caused hepatic steatosis in mice, while chow diet containing corn/alfa-alfa or purified diet with soybean oil did not. Serum levels of SN-38 was significantly higher in mice fed with purified diets compared to the chow-fed, indicating altered irinotecan pharmacokinetics. And this paralleled with diet-specific alteration in the hepatic carboxylesterase, and fecal β-glucuronidase activities in irinotecan-treated mice.
Conclusion: Our study revealed a diet-dependent toxic effect of irinotecan, suggesting that components of grain-based natural diet (presumably phytoestrogens and/or the macronutrients balance) compared to purified diets may have a beneficial effect by controlling the adverse effects of irinotecan in cancer patients.
Pranav Shah– Research Scientist, National Center for Advancing Translational Sciences, Maryland
Michael M Ittmann– Professor and William D. Tigertt Chair in Pathology, Baylor College of Medicine, Houston, Texas, Texas
Romi Ghose– Associate Professor of Pharmaceutics, UNIVERSITY OF HOUSTON, Texas