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Chemoprevention of Colorectal Cancer: Dietary and Pharmacologic Approaches

Chemoprevention of Colorectal Cancer: Dietary and Pharmacologic Approaches

ABSTRACT: Colorectal cancer is a major cause of death in the United States, where it accounts for approximately 57,000 deaths per year. Thus, the prevention of this disease would have a significant impact on public health. Chemoprevention is defined as the use of natural or pharmacologic agents to disrupt the process of carcinogenesis. Substances explored as chemopreventive agents in colorectal cancer include: (1) the nonsteroidal anti-inflamma-tory drugs (NSAIDS), which may inhibit the evolution and formation of adenomas by their inhibition of cyclooxygenase and decrease of prostaglandin synthesis; (2) antioxidants, such as vitamin E or C, which may modulate carcinogenic substances; and (3) folate and calcium, which may interfere with tumor cell growth and replication. Dietary intervention can be accomplished by decreasing fat intake and increasing fiber consumption, both of which have been linked to a lower incidence of colon cancer in multiple epidemiologic studies. This field is continuing to evolve. Hopefully, ongoing research efforts will offer a better understanding of the role of these and other substances in chemoprevention. This article summarizes the available data regarding dietary and pharmacologic approaches to colorectal cancer chemoprevention. [ONCOLOGY 1(13):89-98, 1999]

Introduction

Colorectal cancer is the third most prevalent cancer and third most frequent cause of cancer death in the United States.[1] Evidence suggests that colorectal cancer arises from preexisting adenomatous polyps.[2] Many of the current colorectal prevention strategies focus on the identification and removal of these premalignant lesions. Given the morbidity and mortality of colon cancer, as well as the number of individuals at high risk for this cancer (Table 1), chemopreventive interventions directed toward preventing the formation and development of colorectal carcinomas and adenomas could have significant public health benefit.[3]

Cancer development is a continuous process that occurs over several years, during which time damage to numerous regulatory genes eventually may result in premalignant, malignant, and then metastatic disease. Thus, chemoprevention may target various or even multiple stages in the cancer process (Table 2).

This article summarizes much of the available data regarding dietary and pharmacologic approaches to colorectal cancer prevention. Specifically , it addresses the effects of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, dietary fiber and fat, calcium, folate, and vitamins.

Aspirin and NSAIDs

Potential Mechanisms of Cancer-Preventing Effects

Experiments in human and animal models have shown that tumors produce large amounts of prostaglandins (particularly, prostaglandin E2).[4] The synthesis of prostaglandins is limited by cyclooxygenase. Nonsteroidal anti-inflammatory drugs reversibly interrupt prostaglandin synthesis by inhibiting cyclooxygenase. Aspirin works differently from NSAIDs. It acetylates prostaglandin H synthase and thereby irreversibly inactivates cyclooxygenase. Early studies in rodents demonstrated that administration of NSAIDs several weeks after a carcinogen prevented colorectal carcinoma.[5]

Nonsteroidal anti-inflammatory drugs may prevent tumor formation by their actions on prostaglandins, which may have an immune-modulating effect. High levels of prostaglandin E2 may suppress the immune system, which keeps malignant cells in check. Nonsteroidal anti-inflammatory drugs reduce the production of prostaglandin E2.[6] An alternative prostaglandin-based theory suggests that inhibition of cyclo-oxygenase prevents formation of free radicals, which could damage cells and lead to malignant transformation.[7]

Alberts et al[8] studied the effect of different NSAIDs on colon tumor formation and also evaluated prostaglandin E2 levels in an azoxymethane-induced colon carcinogenesis rat model. In this model, a regimen of sulindac and piroxicam reduced the number of tumors per rat. The same investigators also studied a novel agent, sulindac sulfone, that lacks antiprostaglandin synthase activity. Rats treated with sulindac sulfone had a reduced number of tumors. Sulindac and piroxicam decreased levels of prostaglandin E2, as compared with placebo, but sulindac sulfone alone did not. These findings suggested that NSAIDs may also prevent colorectal cancer by prostaglandin-independent pathways.

Other mechanisms that may explain the antiproliferative/antitumor effects of NSAIDs include: interference with membrane-associated processes, such as G-protein signal transduction and transmembrane calcium influx, and inhibition of other enzymes, such as phosphodiesterase, folate-dependent enzymes, and cyclic adenosine 5' monophosphatase–dependent protein kinase, as well as enhancement of immunologic responses and of cellular apoptosis.[6]

Clinical Studies of NSAIDs

Wadell et al[9] detected a decreased number of rectal polyps in patients with familial adenomatous polyposis who took sulindac. The prophylactic effects of this drug were further supported by the subsequent demonstration of reappearance of polyps after therapy was discontinued.

Labayle et al[10] conducted the first randomized, placebo-controlled, double-blind, crossover study using NSAIDs in patients with familial adenomatous polyposis. The results of this study demonstrated a reduced number of polyps in the group receiving sulindac, as compared with the control group. The effect of sulindac disappeared when the therapy was discontinued.

Giardello et al[11] conducted a randomized, double-blind, placebo-controlled trial of oral sulindac vs placebo in 40 patients with familial adenomatous polyposis. Patients in the sulindac group had significantly fewer polyps at 9 months than the control group. In fact, patients in the sulindac group had a 44% decrease in the total polyp number from baseline levels.

Clinical Studies of Aspirin

Human studies evaluating the use of aspirin in colorectal polyp chemoprevention have shown a promising reduction in rates of colorectal cancer as well. In a prospective, cohort study conducted by Giovannucci et al,[12] 51,529 US health professionals 40 to 75 years of age responded to a mailed questionnaire on use of aspirin and other NSAIDs. The regular use of aspirin (ie, more than two times per week) correlated with a lower risk of colorectal cancer (relative risk [RR], 0.68; 95% confidence interval [CI], 0.52 to 0.92).

In another cohort study that followed 121,701 US female registered nurses, Giovannucci et al again demonstrated a statistically significant reduction in colorectal cancer risk among subjects who took aspirin consistently for 20 years.[13] One concern raised about the results of this study was the possibility that the beneficial effect may have been a consequence of earlier detection resulting from aspirin-induced gastrointestinal bleeding.

Thun et al surveyed a cohort of 622,424 adults about medication use from 1982 to 1988. More frequent aspirin use was correlated with a decrease in death from colon cancer.[14]

The Physicians’ Health Study was a prospective, randomized trial assessing the effects of aspirin, 325 mg on alternate days, and beta-carotene vs placebo on the incidence of cardiovascular disease and cancer in 22,000 US male physicians. The study was terminated early because the men in the aspirin group experienced fewer myocardial infarctions than did the men in the control group. The incidence of colorectal tumors in the aspirin group was not decreased. However, the study lasted only 5 years. Therefore, the duration of treatment and follow-up may not have been sufficient to detect an effect on colon cancer incidence.[15]

A recently published follow-up analysis of the study, with a mean follow-up of 12 years, also showed no association between the use of aspirin and the incidence of colorectal cancer.[16]

Clinical Studies of COX-2 Inhibitors

The discovery that overexpression of the gene for cyclooxygenase type 2 (COX-2) is an early, central event in colon carcinogenesis has led to the investigation of COX-2 inhibitors as potential chemopreventive agents.[17] Cyclooxygenase type 2 appears to be distributed only in inflamed tissues and affects cell proliferation, cell adhesion, tumor growth, and immune responsiveness. Some investigators have previously reported increased COX-2 expression in human colorectal adenocarcinomas, as compared with normal adjacent colonic mucosa.[18]

In an experiment evaluating rats for aberrant crypt formation (a commonly accepted preneoplastic lesion), administration of either a COX-2 inhibitor or sulindac significantly suppressed the total number of aberrant crypts, compared to placebo.[19] Other studies using tissue culture support the concept that overexpression of COX-2 leads to increased expression of BCL-2, which can lead to resistance to apoptosis.[20]

The role of COX-2 in intestinal tumorigenesis was also demonstrated in a study comparing mice genetically deficient in both the COX-2 and adenomatous polyposis coli (APC) gene with mice defective in APC alone. The mice with the double defect had a marked diminution in the number of intestinal polyps.[21]

In concordance with these findings, human studies have revealed that colon cancer cell lines have increased amounts of COX-2 messenger RNA.[18] Cyclo-oxygenase type 2 selective inhibitors are particularly promising in that they may prove to be potent chemopreventive agents that have minimal toxicity.

Summary

Overall, these studies support a potential role for aspirin and NSAIDs in the prevention of colorectal carcinoma. At present, the use of aspirin or NSAIDs is not widely recommended for the prevention of colorectal cancer because better information is needed about the duration of therapy, dose, and possible adverse effects. It is also unknown whether a particular NSAID affords better protection than any others.

Perhaps future studies, such as an ongoing Cancer and Leukemia Group B (CALGB) Cooperative Group trial, will help clarify the use of aspirin in colorectal chemoprevention. After curative surgical resection, this phase III trial will randomize approximately 900 patients with a history of colorectal cancer to either aspirin (325 mg) or placebo, one pill daily for 3 to 4 years. The goal of the study is to observe any effect of aspirin on the development of new adenomas and cancer in such patients.

Calcium

Epidemiologic and experimental findings indicate an association between high calcium and vitamin D intake and decreased risk for colorectal cancer.[22,23] Increased levels of calcium in tissue have been shown to decrease cell proliferation and induce normal cell differentiation, whereas low levels of intracellular ionized calcium contribute to cellular proliferation.[24]

Possible Mechanisms of Cancer-Preventing Effects

Several theories exist as to how calcium may decrease the risk of colon cancer. Calcium may act by binding fatty and bile acids. The typical high-fat western diet (100 to 150 g/d of fat) produces hyperproliferative changes in the colonic mucosa of humans and rodents. These hyperproliferative changes are induced, in part, by the toxic effects of increased bile and fatty acids on the colonic epithelium; they may also represent compensatory hyperproliferation by the colonic epithelial cells aimed at providing repair and regeneration.[25] Calcium may inhibit colon cancer by binding to fatty and bile acids in the lumen of the colon, forming insoluble calcium complexes, and by inducing terminal differentiation of colonic epithelial cells.[26]

Studies in humans have shown a possible relationship between calcium supplementation and a decrease in epithelial cell hyperproliferation.[27]

An increased calcium concentration may also directly inhibit the development of malignancy by inhibiting the proliferation of pluripotent stem cells in colonic crypt epithelium.[28] It has been hypothesized that there is a calcium gradient concentration differential along the crypt. This gradient could provide a signal to calcium receptors in colonic cells and trigger different set points in the cell-cycle processes of the colonic crypt cells, as well as providing stability to the cells in the crypt. Therefore, increasing the calcium concentration may arrest and modulate crypt cell proliferation. Disabling or losing calcium receptors along the crypt cells could promote colon carcinogenesis as the responsiveness of cells to the antiproliferative properties of calcium is lost.[29]

Clinical Studies

Clinical trials have not borne out this hypothesis, however. A randomized, double-blind, placebo-controlled trial conducted by Bostick et al failed to detect any difference in epithelial cell proliferation rates between the control and calcium arms.[30] A study done in Norway showed no protective effect of calcium in combination with vitamins on adenoma recurrence or growth.[31] Similarly, Rooney et al noted no effect of calcium on adenoma incidence or mucosal proliferation after 2 years of follow-up.[32]

Summary

At present, the role of calcium in colon carcinoma prevention is unclear. However, additional ongoing studies are evaluating the chemopreventive effects of calcium. These include a randomized, phase III study by Baron (Dartmouth College), which is comparing the effects of 3 years of calcium carbonate (1,200 mg/d) and on colonoscopy-proven polyp recurrence,[33] and a multicenter, randomized, placebo-controlled European study by Faivre et al aimed at testing the efficacy of oral calcium supplementation (2 g/d) in preventing adenoma recurrence.[34]

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