Letters to the Editor

Sulindac in familial adenomatous polyposis

Like adenomatous polyps in familial adenomatous polyposis, some sporadic colorectal polyps have been reported to regress in response to sulindac administration. However, a rapidly growing invasive rectal cancer developed in one of 15 patients with sulindac-treated sporadic adenomatous colorectal polyps 16 months after sulindac treatment. In this patient, both the adenomatous polyp that responded partially to sulindac and the rectal cancer developing after sulindac therapy showed immunostaining for cyclooxygenase-2. Although short term sulindac therapy seems to be able to cause some adenomatous colorectal polyps to regress, 4 months of sulindac therapy may not reliably prevent colorectal cancer development in these patients.

We investigated whether the therapeutic action of sulindac, used for the treatment of familial adenomatous polyposis, desmoid tumors, and against colon cancer, could be mediated by its active metabolite, sulindac sulfide, in cell growth and apoptosis on cell lines derived from abdominal neoplasms. Sulindac sulfide actions on cell growth and apoptosis were evaluated in epithelial human colon tumor 8 (HCT8) cell line and mesenchymal cell lines (bovine bone endothelial (BBE) cell line, desmoid tumor-derived cells, human colorectal cancer-derived fibroblasts). Sulindac sulfide (0.1–60 μg/ml) induced a dose-dependent inhibition of cell proliferation of all cell lines tested. Apoptosis was induced at doses of 20 and 40 μg/ml, respectively, in BBE and HCT8 cells with no effect on desmoid tumor cells and colorectal cancer-derived fibroblasts. Since mesenchymal cells respond to clinically effective concentrations of the compound, its preferential action on the stromal compartment of intestinal polyps, desmoid tumors and colon cancer can be proposed, with consequent regression of the tumor.

Several studies have shown that persons on a high fat diet with a sedentary life-style have an increased risk for developing cancer of the large intestine, the etiology of colorectal cancer. Several reports indicate an association between an intake of nonsteroidal anti-inflammatory drugs (NSAIDs) and a decreased risk for developing colorectal cancer. Research indicates that a link between NSAID use and colorectal cancer may exist. Epidemiologic studies indicate a 40-50% reduction in mortality from colorectal cancer in individuals taking NSAIDs (such as aspirin) compared to those not taking these agents. Second, familial adenomatous polyposis (FAP) patients who take sulindac have a significant reduction in adenoma size and number. Third, in animal models of colorectal carcinogenesis, several different NSAIDs exhibit chemoprotective effects, causing a reduction in the frequency and number of premalignant and malignant lesions. The aim of this chapter is to carefully examine these studies and attempt to offer insight concerning the molecular basis for the chemoprotective effect of NSAIDs. The chapter discusses the adenoma-carcinoma sequence, prevention of colon cancer in animal models, treatment of familial adenomatous polyposis (FAP) patients with NSAIDs, and the relationship between NSAID use and colorectal neoplasia. There is discussion on NSAlDs and the prevention of colon cancer, retrospective case control studies, prospective cohort studies examining the effect of aspirin on the incidence or mortality of colon cancer, the clinical trials on sulindac on sporadic polyps, and the effects of aspirin in preventing myocardial infarction and β-carotene in preventing cancer. There is note on the molecular targets of NSAIDs. NSAIDs were designed by pharmaceutical companies primarily to inhibit prostaglandin production by inhibiting the enzyme, prostaglandin endoperoxide synthase. NSAIDs at high concentrations can directly induce programmed cell death in cultured cells. This chapter is a concise review of the on the risk of colorectal cancer among NSAID users.