TY - JOUR
T1 - Changes in antitumor response in C57BL/6J-Min/+ mice during long-term administration of a selective cyclooxygenase-2 inhibitor
AU - Carothers, Adelaide M.
AU - Moran, Amy E.
AU - Cho, Nancy L.
AU - Redston, Mark
AU - Bertagnolli, Monica M.
PY - 2006/6/15
Y1 - 2006/6/15
N2 - Selective cyclooxygenase-2 (COX-2) inhibitors are widely prescribed for severe arthritis and are currently under study in human chemoprevention trials. Recently, long-term use of these agents has come under scrutiny due to reports of treatment-associated cardiovascular toxicity. On short-term administration, the selective COX-2 inhibitor celecoxib inhibits adenoma growth in animal tumor models, including the C57BL/6J-Min/+ (Min/+) mouse. With uninterrupted long-term celecoxib administration, intestinal tumors in Min/+ mice initially regressed and then recurred to levels comparable with untreated controls. Celecoxib treatment initially suppressed COX-2 and prostaglandin E2 (PGE 2) expression, but long-term use produced significantly higher levels of these molecules and reactivated PGE2-associated growth factor signaling pathways in tumor and normal tissues. These results indicate that COX-2 is an important chemoprevention target and that inhibition of this enzyme alters a paracrine enterocyte regulatory pathway. Chronic uninterrupted celecoxib treatment, however, induces untoward effects that enhance early progression events in intestinal tumorigenesis and may contribute to treatment toxicity.
AB - Selective cyclooxygenase-2 (COX-2) inhibitors are widely prescribed for severe arthritis and are currently under study in human chemoprevention trials. Recently, long-term use of these agents has come under scrutiny due to reports of treatment-associated cardiovascular toxicity. On short-term administration, the selective COX-2 inhibitor celecoxib inhibits adenoma growth in animal tumor models, including the C57BL/6J-Min/+ (Min/+) mouse. With uninterrupted long-term celecoxib administration, intestinal tumors in Min/+ mice initially regressed and then recurred to levels comparable with untreated controls. Celecoxib treatment initially suppressed COX-2 and prostaglandin E2 (PGE 2) expression, but long-term use produced significantly higher levels of these molecules and reactivated PGE2-associated growth factor signaling pathways in tumor and normal tissues. These results indicate that COX-2 is an important chemoprevention target and that inhibition of this enzyme alters a paracrine enterocyte regulatory pathway. Chronic uninterrupted celecoxib treatment, however, induces untoward effects that enhance early progression events in intestinal tumorigenesis and may contribute to treatment toxicity.
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U2 - 10.1158/0008-5472.CAN-06-0992
DO - 10.1158/0008-5472.CAN-06-0992
M3 - Article
C2 - 16778222
AN - SCOPUS:33745728135
SN - 0008-5472
VL - 66
SP - 6432
EP - 6438
JO - Cancer Research
JF - Cancer Research
IS - 12
ER -