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


METHODS
Groups of ten mice were treated for 10 days with increasing doses of erlotinib alone or in combination with cisplatin and/or GLP-2. Weight and length of the gastrointestinal organs were determined and histological 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.
Rasmussen
Andreas Rosén
AR
Department of Biomedical Sciences, The Panum Institute, University of Copenhagen, Copenhagen N, Denmark.
Viby
Niels-Erik
NE
Hare
Kristine Juul
KJ
Hartmann
Bolette
B
Thim
Lars
L
Holst
Jens Juul
JJ
Poulsen
Steen Seier
SS
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001284:Atrophy; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride; D005260:Female; D005759:Gastroenteritis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D047428:Protein Kinase Inhibitors / Q000633:toxicity; D011799:Quinazolines / Q000633:toxicity*
D000970:Antineoplastic Agents; D053767:Glucagon-Like Peptide 2; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D002945:Cisplatin