Suppression of Peutz—Jeghers polyposis by inhibition of cyclooxygenase-2
L Udd, P Katajisto, DJ Rossi, A Lepistö, AM Lahesmaa… - Gastroenterology, 2004 - Elsevier
L Udd, P Katajisto, DJ Rossi, A Lepistö, AM Lahesmaa, A Ylikorkala, HJ Järvinen…
Gastroenterology, 2004•ElsevierBackground & 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 …
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 …
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 × 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.
Elsevier