Prostanoids, ornithine decarboxylase, and polyamines in primary chemoprevention of familial adenomatous polyposis

Abstract

Background & Aims-Familial adenomatous polyposis because of germline mutation of the adenomatous polyposis coli gene is characterized by development of colorectal adenomas and, ultimately, colorectal cancer. The usefulness of colorectal mucosal compounds to predict the effect on adenoma development of primary chemoprevention with the nonsteroidal anti-inflammatory drug sulindac was evaluated.

Prevention of early-onset familial/hereditary colon cancer: New models and mechanistic biomarkers (Review)

“…The APC Min mouse, because of a germ-line mutation in the APC tumor suppression gene, exhibits a high incidence of intestinal adenomas resembling clinical early-onset FAP syndrome (9,10). In recent years, the APC Min model has provided important mechanistic leads for the preventive efficacy of several classes of synthetic pharmacological agents, including non-streroidal anti-inflammatory drugs (NSAIDs), selective enzyme inhibitors, growth factor receptor antagonists and small molecule inhibitors (29,32,(42)(43)(44)(45)(46)(47)(48)(49). These observations have demonstrated a direct correlation between the modulation of pathogenesis and the relevant molecular target for efficacy.…”

Novel cell culture model for prevention of carcinogenic risk in familial adenomatous polyposis syndrome

“…However, these interventional strategies are associated with adverse toxic side effects that compromise patient compliance (29)(30)(31)(32).…”

“…Furthermore, minimally toxic natural dietary components may also modulate the efficacy of toxic chemotherapeutic drugs (35). On the mechanistic level, DFMO functions as a selective inhibitor of ornithine decarboxylase which is an established early response gene and a rate limiting enzyme for the biosynthesis of polyamines (30,31), SUL is a non-selective cyclooxygenase inhibitor (34), EGCG is demonstrated to affect EGF signaling (36), while EPA functions as an inhibitor of lipoxygenase, a critical enzyme for production of leukotrienes (33). All of these targets are known to play important roles in colon carcinogenesis.…”

Inhibitory effect of sulindac on DMBA-induced hamster cheek pouch carcinogenesis and its derived cell line

“…Sulindac inhibits colorectal carcinogenesis in rodent models (9,10) and causes regression of adenomas (2,11) in patients with familial adenomatous polyposis coli. The mechanism by which this activity occurs is unclear, although some correlation has been found between sulindac treatment and reduced levels of prostaglandins in the human colorectal mucosa (12,13). In relation to reduced prostaglandin levels, sulindac treatment was not found to be chemopreventive in all studies (2,13).…”

“…The mechanism by which this activity occurs is unclear, although some correlation has been found between sulindac treatment and reduced levels of prostaglandins in the human colorectal mucosa (12,13). In relation to reduced prostaglandin levels, sulindac treatment was not found to be chemopreventive in all studies (2,13). In addition, several studies indicate that sulindac and its metabolites have demonstrated chemoprotective effects through inhibition of angiogenesis (14,15).…”