Chemoprevention of Colorectal Cancer: Dietary and Pharmacologic Approaches
Chemoprevention of Colorectal Cancer: Dietary and Pharmacologic Approaches
Colorectal cancer is the third most prevalent
cancer and third most frequent cause of cancer death in the United
States. Evidence suggests that colorectal cancer arises from
preexisting adenomatous polyps. 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.
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.
Potential Mechanisms of Cancer-Preventing Effects
Experiments in human and animal models have shown that tumors produce
large amounts of prostaglandins (particularly, prostaglandin E2).
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.
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.
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.
Alberts et al 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
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'
monophosphatasedependent protein kinase, as well as enhancement
of immunologic responses and of cellular apoptosis.
Clinical Studies of NSAIDs
Wadell et al 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 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 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, 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. 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.
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.
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.
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. 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.
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. 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.
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.
In concordance with these findings, human studies have revealed that
colon cancer cell lines have increased amounts of COX-2 messenger
RNA. Cyclo-oxygenase type 2 selective inhibitors are particularly
promising in that they may prove to be potent chemopreventive agents
that have minimal toxicity.
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.
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.
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. 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.
Studies in humans have shown a possible relationship between calcium
supplementation and a decrease in epithelial cell hyperproliferation.
An increased calcium concentration may also directly inhibit the
development of malignancy by inhibiting the proliferation of
pluripotent stem cells in colonic crypt epithelium. 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.
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. A study
done in Norway showed no protective effect of calcium in combination
with vitamins on adenoma recurrence or growth. Similarly, Rooney
et al noted no effect of calcium on adenoma incidence or mucosal
proliferation after 2 years of follow-up.
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, 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.