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 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.
Carothers
Adelaide M
AM
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Moran
Amy E
AE
Cho
Nancy L
NL
Redston
Mark
M
Bertagnolli
Monica M
MM
D000236:Adenoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D000068579:Celecoxib; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D015232:Dinoprostone / Q000378:metabolism; D004334:Drug Administration Schedule; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D008084:Lipoxygenase / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D011720:Pyrazoles / Q000008:administration & dosage*; D011982:Receptors, Prostaglandin / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage*
D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; D008084:Lipoxygenase; D000068579:Celecoxib; D015232:Dinoprostone