Inhibition of epidermal growth factor receptor tyrosine kinase fails to suppress adenoma formation in ApcMin mice but induces duodenal injury.
A highly selective, p.o. bioavailable irreversible inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, N-[4-(3-chloro4-fluorophenylamino)-quinazolin-6-yl]-ac rylamide (CFPQA), was evaluated for its ability to prevent intestinal adenoma formation in ApcMin mice. Ten-week continuous dietary exposure to CFPQA at doses sufficient to abolish intestinal EGFR tyrosine phosphorylation failed to affect intestinal tumor multiplicity or distribution but induced flat mucosal lesions in the duodenum characteristic of chronic injury. Intestinal trefoil factor, an intestinal peptide that mediates antiapoptotic effects through an EGFR-dependent mechanism, was notably absent in adenomas but was highly expressed in flat duodenal lesions. We conclude that chronic inhibition of EGFR tyrosine kinase by CFPQA does not prevent adenomas in ApcMin mice but may induce duodenal injury.
Ritland
S R
SR
Tumor Biology Program, Mayo Clinic, Scottsdale, Arizona 85259, USA.
Gendler
S J
SJ
Burgart
L J
LJ
Fry
D W
DW
Nelson
J M
JM
Bridges
A J
AJ
Andress
L
L
Karnes
W E
WE
D000178:Acrylamides / Q000097:blood / Q000627:therapeutic use*; D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004379:Duodenal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D017491:Genes, APC / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006133:Growth Substances / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011799:Quinazolines / Q000097:blood / Q000627:therapeutic use*; D015398:Signal Transduction / Q000502:physiology; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3
D000178:Acrylamides; D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D006133:Growth Substances; D009077:Mucins; D009124:Muscle Proteins; C415243:N-(4-(3-chloro-4-fluorophenylamino)quinazolin-6-yl)acrylamide; D009479:Neuropeptides; D010455:Peptides; D011799:Quinazolines; C082495:TFF3 protein, human; C099037:TFF3 protein, rat; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D066246:ErbB Receptors