The intestinotrophic peptide, GLP-2, counteracts the gastrointestinal atrophy in mice induced by the epidermal growth factor receptor inhibitor, erlotinib, and cisplatin

TY - JOUR

T1 - The intestinotrophic peptide, GLP-2, counteracts the gastrointestinal atrophy in mice induced by the epidermal growth factor receptor inhibitor, erlotinib, and cisplatin

AU - Rasmussen, Andreas Rosén

AU - Viby, Niels-Erik

AU - Hare, Kristine Juul

AU - Hartmann, Bolette

AU - Thim, Lars

AU - Holst, Jens Juul

AU - Poulsen, Steen Seier

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Purpose Erlotinib, an epidermal-growth-factor receptor inhibitor, belongs to a new generation of targeted cancer therapeutics. Gastrointestinal side-effects are common and have been markedly aggravated when erlotinib is combined with cytostatics. We examined the effects of erlotinib alone and combined with the cytostatic, cisplatin, on the gastrointestinal tract and examined whether glucagon-like peptide- 2 (GLP-2), an intestinal hormone with potent intestinotrophic properties, might counteract the possible damaging effects of the treatments. Experimental Design Groups of ten mice were treated for 10 days with increasing doses of erlotinib alone or incombination with cisplatin and/or GLP-2. Weight and length of the gastrointestinal organs were determined andhistological sections were analyzed with morphometric methods as well as BrdU- and ApopTag-staining to determine mitotic and apoptotic activity. Results Erlotinib was found to induce small-intestinal and colonic growth inhibition through an increased apoptotic activity but had no effect on mitotic activity. The combined treatment with cisplatin synergistically aggravated the intestinal growth inhibition. Erlotinib, and especially the combination therapy, increased the weight of the stomach contents considerably. Concomitant treatment with GLP-2 counteracted the intestinal mucosal atrophy induced both by erlotinib alone and combined with cisplatin through a reduction of the apoptotic activity. There was no influence on the mitotic activity. Conclusions The findings demonstrate that the intestinal mucosal damage induced by erlotinib alone and in combination with cisplatin can be counteracted by GLP-2 treatment, which might suggest a role for GLP-2 in the treatment of the gastrointestinal side-effects caused by these cancer therapeutics.

AB - Purpose Erlotinib, an epidermal-growth-factor receptor inhibitor, belongs to a new generation of targeted cancer therapeutics. Gastrointestinal side-effects are common and have been markedly aggravated when erlotinib is combined with cytostatics. We examined the effects of erlotinib alone and combined with the cytostatic, cisplatin, on the gastrointestinal tract and examined whether glucagon-like peptide- 2 (GLP-2), an intestinal hormone with potent intestinotrophic properties, might counteract the possible damaging effects of the treatments. Experimental Design Groups of ten mice were treated for 10 days with increasing doses of erlotinib alone or incombination with cisplatin and/or GLP-2. Weight and length of the gastrointestinal organs were determined andhistological sections were analyzed with morphometric methods as well as BrdU- and ApopTag-staining to determine mitotic and apoptotic activity. Results Erlotinib was found to induce small-intestinal and colonic growth inhibition through an increased apoptotic activity but had no effect on mitotic activity. The combined treatment with cisplatin synergistically aggravated the intestinal growth inhibition. Erlotinib, and especially the combination therapy, increased the weight of the stomach contents considerably. Concomitant treatment with GLP-2 counteracted the intestinal mucosal atrophy induced both by erlotinib alone and combined with cisplatin through a reduction of the apoptotic activity. There was no influence on the mitotic activity. Conclusions The findings demonstrate that the intestinal mucosal damage induced by erlotinib alone and in combination with cisplatin can be counteracted by GLP-2 treatment, which might suggest a role for GLP-2 in the treatment of the gastrointestinal side-effects caused by these cancer therapeutics.

KW - Animals

KW - Antineoplastic Agents

KW - Atrophy

KW - Body Weight

KW - Cisplatin

KW - Dose-Response Relationship, Drug

KW - Drug Interactions

KW - Female

KW - Gastroenteritis

KW - Gastrointestinal Tract

KW - Glucagon-Like Peptide 2

KW - Mice

KW - Mice, Inbred Strains

KW - Protein Kinase Inhibitors

KW - Quinazolines

U2 - 10.1007/s10620-009-1104-x

DO - 10.1007/s10620-009-1104-x

M3 - Journal article

C2 - 20112065

SN - 0163-2116

VL - 55

SP - 2785

EP - 2796

JO - Digestive Diseases and Sciences

JF - Digestive Diseases and Sciences

IS - 10

ER -