The intestinotrophic peptide, glp-2, counteracts intestinal atrophy in mice induced by the epidermal growth factor receptor inhibitor, gefitinib.
OBJECTIVE
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been introduced as antitumor agents in the treatment of cancers overexpressing the receptor. The treatment has gastrointestinal side effects which may decrease patient compliance and limit the efficacy. Glucagon-like peptide-2 (GLP-2) is an intestinal hormone with potent intestinotrophic properties and therapeutic potential in disorders with compromised intestinal capacity. The growth stimulation is highly specific to the gastrointestinal tract, and no effects are observed elsewhere. The aim of this study was to examine whether the inhibition of the EGFR induces intestinal atrophy and if this can be counteracted by treatment with GLP-2.


METHODS
Mice were treated for 10 days with either gefitinib orally, GLP-2 as injections, or a combination of both. After sacrifice, the weight and length of the segments of the gastrointestinal tract were determined, and histologic sections were analyzed by morphometric methods.


RESULTS
A significant atrophy of the small-intestinal wall was observed after treatment with gefitinib because both intestinal weight and morphometrically estimated villus height and cross-sectional area were decreased. The same parameters were increased by GLP-2 treatment alone, and when GLP-2 was combined with the gefitinib treatment, the parameters remained unchanged.


CONCLUSIONS
Treatment with an EGFR tyrosine kinase inhibitor in mice results in small-intestinal growth inhibition that can be completely prevented by simultaneous treatment with GLP-2. This suggests that the gastrointestinal side effects elicited by treatment with EGFR tyrosine kinase inhibitors can be circumvented by GLP-2 treatment.
Hare
Kristine Juul
KJ
Department of Anatomy, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Hartmann
Bolette
B
Kissow
Hannelouise
H
Holst
Jens Juul
JJ
Poulsen
Steen Seier
SS
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001284:Atrophy; D001835:Body Weight / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D000077156:Gefitinib; D053767:Glucagon-Like Peptide 2 / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D011799:Quinazolines / Q000633:toxicity*