Peutz-Jeghers Syndrome (PJS) is a GI polyposis disorder that is associated with mucocutaneous pigmentation as well as a predisposition to GI polyposis and cancer. The most common clinical manifestations of PJS are acute obstructive complications because of large intestinal polyps. At present the only treatment is surgical resection of clinically significant polyps and follow-up endoscopies. The disease has been shown to be due to inactivating germ-line mutations in the LKB1 gene. This gene appears to be involved in regulating epithelial cell polarity and epithelial cell growth.
Udd and colleagues (2004) in Finland have shown that in mice that are heterozygous for this gene, the polyposis they develop is typically characterized by an elevated level of cyclooxygenase-2 (COX-2). Therefore, these investigators wanted to determine whether inhibition of COX-2 would reduce the tumor burden in heterozygous mice and in PJS patients who also have elevated levels of COX-2 in their polyps and cancers. They therefore investigated the effects of COX-2 inhibition in mice with combined deficiencies in both COX-2 and LKB1 genes whose diet was supplemented with the COX-2 inhibitor celecoxib. In the mice celecoxib treatment initiated before the onset of polyposis reduced the tumor burden by 86%. Late treatment also led to a significant reduction in large polyps.
In a pilot clinical study a subset of PJS patients (2 out of 6) responded favorably to celecoxib with reduced gastric polyposis. These data therefore suggest a pivotal role for COX-2 in promoting Peutz-Jeghers polyposis and in providing the promise of COX-2 inhibition that may benefit PJS patients.
Udd L et al: Suppression of Peutz-Jeghers polyposis by inhibition of cyclooxygenase-2. Gastroenterology 127:1030, 2004