Dataset Information

Fasting protects against the side effects of irinotecan treatment but does not affect anti-tumour activity in mice.

ABSTRACT:

Background

The main limitation to the use of irinotecan in the treatment of colorectal cancer is the severity of side effects, including neutropaenia and diarrhoea. Here, we explored the effects of 3 days of fasting on irinotecan-induced toxicities, on plasma, liver and tumour pharmacokinetics and on anti-tumour activity in mice.

Experimental approach

Male BALB/c mice received C26 colon carcinoma cells subcutaneously. They were randomized 1:1 into equally sized ad libitum fed and fasted groups after which they were treated with irinotecan. Weight and adverse side effects were recorded daily. At the end of the experiment, tumours were resected and weighed, and concentrations of irinotecan and its active metabolite SN-38 were determined in plasma and tumour.

Key results

Fasting prevented the diarrhoea and visible signs of discomfort induced by irinotecan. Ad libitum fed animals developed leucopenia compared with untreated controls, whereas fasted mice did not. Irinotecan suppressed tumour growth equally in both treated groups, compared with untreated controls. Levels of the active irinotecan metabolite SN-38 9 (calculated as AUC values) were significantly lower in fasted mice in both plasma and liver, but not in tumour tissue.

Conclusions and implications

Fasting protected against irinotecan-induced side effects without interfering with its anti-tumour efficacy. Fasting induced a lower systemic exposure to SN-38, which may explain the absence of adverse side effects, while tumour levels of SN-38 remained unchanged. These data offer important new approaches to improve treatment with irinotecan in patients.

SUBMITTER: Huisman SA

PROVIDER: S-EPMC4761088 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Publications

Fasting protects against the side effects of irinotecan treatment but does not affect anti-tumour activity in mice.

Huisman Sander A SA de Bruijn Peter P Ghobadi Moghaddam-Helmantel Inge M IM IJzermans Jan N M JN Wiemer Erik A C EA Mathijssen Ron H J RH de Bruin Ron W F RW

British journal of pharmacology 20160208 5

<h4>Background</h4>The main limitation to the use of irinotecan in the treatment of colorectal cancer is the severity of side effects, including neutropaenia and diarrhoea. Here, we explored the effects of 3 days of fasting on irinotecan-induced toxicities, on plasma, liver and tumour pharmacokinetics and on anti-tumour activity in mice.<h4>Experimental approach</h4>Male BALB/c mice received C26 colon carcinoma cells subcutaneously. They were randomized 1:1 into equally sized ad libitum fed and ...[more]

PMID: 26332723

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Project description:BackgroundSepsis-induced cardiomyopathy (SIC) is a common severe complication of sepsis that contributes to mortality. SIC is closely associated with excessive inflammatory responses, failed inflammation resolution, and apoptotic damage. Resolvin E1 (RvE1), an omega-3 polyunsaturated fatty acid (PUFA)-derived metabolite, has been reported to exert anti-inflammatory or proresolving activity in multiple animal models of inflammatory disease. However, the therapeutic potential of RvE1 in SIC remains undetermined, which was, therefore, the aim of the present study.MethodsC57BL/6J mice were randomly divided into three groups: control, lipopolysaccharide (LPS), and LPS + RvE1. Echocardiography, Western blotting (WB), quantitative real-time (QRT)-PCR, histological analyses, and flow cytometry were used to evaluate cardiac function, myocardial inflammation, and the underlying mechanisms.ResultsThe RvE1-injected group showed improved left ventricular (LV) function and reduced serum lactate dehydrogenase (LDH) and creatine kinase myocardial bound (CK-MB) levels. Compared to LPS treatment alone, RvE1 treatment inhibited the infiltration of neutrophils and macrophages into the heart and spleen and suppressed the secretion of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein (MCP)-1, in the heart. We also observed that the activation of the mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB signaling pathways was blocked by RvE1 treatment, and this inhibition contributed to the improvement in the inflammatory response induced by LPS. RvE1 inhibited LPS-induced M1 macrophage polarization and promoted macrophage polarization toward the M2-like phenotype in both the heart and spleen. In addition, LPS administration dysregulated cyclooxygenase (COX) and lipoxygenase (LOX) in the heart, which were rectified by RvE1 treatment. RvE1 also reduced myocardial apoptosis rate in response to LPS-induced heart injury.ConclusionRvE1 protects the heart against SIC possibly through the inhibition of the MAPK and NF-κB inflammatory signaling pathways, modulation of macrophage polarization, and reduction in myocardial apoptosis. RvE1 may be a novel lipid mediator for the treatment of SIC.

Dataset Information

Fasting protects against the side effects of irinotecan treatment but does not affect anti-tumour activity in mice.

Background

Experimental approach

Key results

Conclusions and implications

Publications

Fasting protects against the side effects of irinotecan treatment but does not affect anti-tumour activity in mice.

Similar Datasets

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