Changes in antitumor response in C57BL/6J-Min/+ mice during long-term administration of a selective cyclooxygenase-2 inhibitor

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 admini...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2006-06, Vol.66 (12), p.6432-6438
Main Authors: CAROTHERS, Adelaide M, MORAN, Amy E, CHO, Nancy L, REDSTON, Mark, BERTAGNOLLI, Monica M
Format: Article
Language:English
Subjects:
Adenoma - drug therapy
Adenoma - enzymology
Adenoma - metabolism
Animals
Antineoplastic agents
Biological and medical sciences
Celecoxib
Cyclooxygenase 2 Inhibitors - administration & dosage
Dinoprostone - metabolism
Drug Administration Schedule
Intestinal Neoplasms - drug therapy
Intestinal Neoplasms - enzymology
Intestinal Neoplasms - metabolism
Lipoxygenase - biosynthesis
Medical sciences
Mice
Mice, Inbred C57BL
Pharmacology. Drug treatments
Pyrazoles - administration & dosage
Receptors, Prostaglandin - biosynthesis
Signal Transduction - drug effects
Sulfonamides - administration & dosage
Tumors
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Summary: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 (PGE2) 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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-06-0992