Suppression of Peutz-Jeghers polyposis by inhibition of cyclooxygenase-2.

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.

• Authors: Lina Udd, Pekka Katajisto, Derrick J Rossi, Anna Lepistö, Anna-Maria Lahesmaa, Antti Ylikorkala, Heikki J Järvinen, Ari P Ristimäki, Tomi P Mäkelä
• Journal: Gastroenterology (Gastroenterology) Vol. 127 Issue 4 Pg. 1030-7 (Oct 2004) ISSN: 0016-5085 [Print] United States
• PMID: 15480979 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Intracellular Signaling Peptides and Proteins
• Isoenzymes
• Membrane Proteins
• Proteins
• Pyrazoles
• Stk11ip protein, mouse
• Sulfonamides
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Protein Serine-Threonine Kinases
• Stk11 protein, mouse
• AMP-Activated Protein Kinases
• Celecoxib

Topics

• AMP-Activated Protein Kinases
• Adaptor Proteins, Signal Transducing
• Animals
• Carrier Proteins
• Celecoxib
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (therapeutic use)
• Disease Models, Animal
• Humans
• Intracellular Signaling Peptides and Proteins
• Isoenzymes (antagonists & inhibitors, genetics, physiology)
• Membrane Proteins
• Mice
• Mice, Inbred C57BL
• Microcirculation (drug effects)
• Peutz-Jeghers Syndrome (drug therapy, enzymology, pathology)
• Prostaglandin-Endoperoxide Synthases (genetics, physiology)
• Protein Serine-Threonine Kinases
• Proteins (genetics)
• Pyrazoles
• Sulfonamides (therapeutic use)