Suppression of Peutz-Jeghers polyposis by inhibition of cyclooxygenase-2.
Gastroenterology
; 127(4): 1030-7, 2004 Oct.
Article
in En
| MEDLINE
| ID: mdl-15480979
ABSTRACT
BACKGROUND & AIMS:
Peutz-Jeghers syndrome (PJS) is typically manifested as severe gastrointestinal polyposis. Polyps in PJS patients and in Lkb1(+/-) mice that model PJS polyposis are frequently characterized by elevated cyclooxygenase-2 (COX-2). This study was designed to determine whether COX-2 inhibition would reduce tumor burden in Lkb1(+/-) mice or Peutz-Jeghers patients.METHODS:
Genetic interactions between Cox-2 and Lkb1 in polyp formation were analyzed in mice with combined deficiencies in these genes. Pharmacologic inhibition of COX-2 was achieved by supplementing the diet of Lkb1(+/-) mice with 1500 ppm celecoxib between 3.5-10 and 6.5-10 months. In PJS patients, COX-2 was inhibited with a daily dose of 2 x 200 mg celecoxib for 6 months.RESULTS:
Total polyp burden in Lkb1(+/-) mice was significantly reduced in a Cox-2(+/-) (53%) and in a Cox-2(-/-) (54%) background. Celecoxib treatment initiating before polyposis (3.5-10 months) led to a dramatic reduction in tumor burden (86%) and was associated with decreased vascularity of the polyps. Late treatment (6.5-10 months) also led to a significant reduction in large polyps. In a pilot clinical study, a subset of PJS patients (2/6) responded favorably to celecoxib with reduced gastric polyposis.CONCLUSIONS:
These data establish a role for COX-2 in promoting Peutz-Jeghers polyposis and suggest that COX-2 chemoprevention may prove beneficial in the treatment of PJS.
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Database:
MEDLINE
Main subject:
Sulfonamides
/
Peutz-Jeghers Syndrome
/
Proteins
/
Carrier Proteins
/
Cyclooxygenase Inhibitors
/
Protein Serine-Threonine Kinases
/
Isoenzymes
Language:
En
Journal:
Gastroenterology
Year:
2004
Type:
Article
Affiliation country:
Finland