Overview
Those at increased risk of colon cancer include people
who:
Have a family history of colorectal cancer
Have a
personal history of colorectal cancer, intestinal polyps, or chronic
inflammatory bowel disease
Have familial colorectal cancer syndromes (the
only genetic abnormalities that Have been clearly identified so far
are familial adenomatous polyposis and hereditary nonpolyposis
colorectal cancer); only 5% of colon cancers are due to these
syndromes
Are Jews of Eastern European descent (Ashkenazi
Jews)
Are older than 50 (about 90% of people with
colorectal cancer are more than 50 years old)
Consume a
diet high in foods from animal sources
Are physically
inactive
Are obese
Have diabetes (people with
diabetes have a 30-40% higher risk of developing colon cancer and a
higher mortality rate after diagnosis)
Smoke
Drink
large amounts of alcohol
American Cancer Society. Colorectal
cancer: early detection. www.cancer.org
The development of colon cancer occurs in a series of
steps. Exposure to a carcinogen results in an alteration of the DNA;
current understanding of the process is that it takes several
mutations for a tumor to develop. Post-initiation steps usually
involve changes in signal transduction pathways. Aberrant crypts,
enlarged and elevated compared with normal crypts, are considered to
be preneoplastic structures; they may occur singly or as groups
within a single focus. A small percentage of aberrant crypts will
eventually develop into polyps and then into tumors.
Brady LJ et
al. The role of probiotic cultures in the prevention of colon
cancer. J Nutr 2000;130:410S-414S.
It has been estimated that each cell in the human body
takes 10,000 potentially mutagenic hits to its DNA every day;
therefore, DNA repair is a crucial part of cancer prevention.
Seo YR et al. Selenomethionine induction of DNA repair response
in human fibroblasts. Oncogene 2002;21:3663-3669.
Statistics
Estimates by the American Cancer Society for 2003 are that
there will be approximately 105,500 new cases of colon cancer
(49,000 in men and 56,500 in women) and 42,000 new cases of rectal
cancer (23,800 in men and 18,200 in women) in the U.S., and about
57,100 people will die of colorectal cancer this year.
American
Cancer Society. What are the key statistics for colon and rectum
cancer? www.cancer.org
According to the Centers for Disease Control, colorectal
cancer is the fourth most common type of cancer in men (skin,
prostate, and lung cancers being more common) and in women
(following skin, breast, and lung cancers in frequency).
Centers
for Disease Control. Colorectal cancer: the importance of prevention
and early detection. www.cdc.gov/cancer
Signs, symptoms, and screening
Signs and symptoms of colorectal cancer include blood in
the stool, constipation or diarrhea, weight loss, anemia, abdominal
discomfort or pain, or fullness in the abdomen. Unfortunately, it is
also possible to have colorectal cancer without any signs or
symptoms.
Colon and Rectal Cancer. Clinical Reference
Systems;2001:455.
Screening methods for colorectal cancer include digital
rectal examination; testing the stool for the presence of blood;
flexible sigmoidoscopy; and colonoscopy.
Only rectal
cancer can be detected by digital rectal exam; most colorectal
cancers are in the colon, so the value of this test is limited.
Blood can be present in the stool for reasons other than colorectal
cancer, but positive results need to be followed by more tests.
(Before the test, patients should avoid eating turnips, horseradish,
red meat, vitamin C, iron supplements, or medicines such as aspirin
that irritate the gastrointestinal tract.) Flexible sigmoidoscopy is
used to look at the lower part of the colon; about half of all
colorectal cancers or polyps can be detected by use of this exam.
Colonoscopy can be used to examine most of the colon. Tissue samples
can be removed for biopsy during either sigmoidoscopy or
colonoscopy; sometimes the entire area of abnormality can be removed
during this procedure.
Colorectal Cancer Screening. Clinical
Reference Systems. Annual 2001;457.
The American Cancer Society recommends that men and women
over the age of 50 should follow one of the following five screening
schedules below:
1. Take-home multiple sample fecal occult
blood test every year
2. Flexible sigmoidoscopy every 5
years
3. Fecal occult blood test (as above) every year plus
flexible sigmoidoscopy every 5 years (this is the screening method
recommended by the ACS)
4. Double contrast barium enema
every 5 years
5. Colonoscopy every 10 years
People
with a personal history of polyps, colorectal cancer, or chronic
inflammatory bowel disease, a strong family history of colorectal
cancer (cancer or polyps in a first-degree relative younger than 60
or in two first-degree relatives of any age), or a family history of
hereditary colorectal cancer syndromes should begin screening
earlier and undergo it more often.
American Cancer Society.
Colorectal Cancer: early detection. www.cancer.org
In subjects deemed polyp-free by sigmoidoscopy only, the
actual prevalence of polyps may be 15-17%.
McKelvey W et al. A
case-control study of colorectal adenomatous polyps and consumption
of foods containing partially hydrogenated oils. Cancer Epidemiol
Biomarkers Prev 1999;8:519-524.
Pathology
Most adenomas never become cancerous, but the chances that
they will eventually do so go up with size and
atypia.
Fernandez-Banares F et al. Serum selenium and risk of
large size colorectal adenomas in a geographical area with a low
selenium status. Am J Gastroenterol 2002;97:2103-2108
In more developed countries, adenomas are precursors of
most colorectal cancers, so cancer prevention can, in theory, take
place when an adenoma appears, while it grows, or when it is
transformed into a carcinoma.
Bonithon-Kopp C et al. Calcium and
fibre supplementation in prevention of colorectal adenoma
recurrence: a randomised intervention trial. Lancet
2000;356:1300-1306.
Sugar
Non-insulin-dependent diabetes mellitus is associated with
an increased risk of colorectal cancer. In an Italian study, a
high-glycemic-index diet was also associated with an increased risk
of colorectal cancer, especially among women and particularly for
colon cancer. Fiber from fruits and vegetables appears to reduce the
effects of this type of diet on colorectal cancer
risk.
Franceschi S et al. Dietary glycemic load and colorectal
cancer risk. Ann Oncol 2001;12:1/3-1/8.
Gavage with sucrose solution (20 g/kg) or fructose solution
(10 g/kg) increased colonic proliferation in rat colon fourfold,
measured 16 hours later, compared with water gavage. Sucrose (10
g/kg) also made the colon epithelium more sensitive to azoxymethane
(AOM) when AOM was given immediately after gavage and up to 24 hours
later. Twenty-eight days later, the rats given the sucrose 0 or 14
hours before administration of AOM had three to four times more
aberrent crypt foci than did the rats gavaged with water or glucose;
fructose also significantly increased the sensitivity to AOM, though
to a lesser degree.
Stamp D et al. Sucrose enhancement of the
early steps of colon carcinogenesis in mice. Carcinogenesis
1993;14:777-779.
Results of a case-control study indicated that risks of
colon cancer and rectal cancer both increased with increasing taste
for sugar, as measured by the number of spoonfuls of sugar subjects
normally added to coffee, tea, or other hot drinks. Although the
authors did not inquire about sugar intake from other sources, the
linear relationships between preference for sugar and the risks of
these cancers were both significant, though the link between colon
cancer and taste for sugar was stronger. These results were not
significantly modified when estimates of daily calorie intake were
included in the analysis. The authors concede that it is difficult
to extrapolate information about total sugar intake from these day,
although they note that in Italy, where the study was performed,
artificial sweeteners are not generally used by healthy people and
so the amount of sugar added to beverages is likely to be fairly
representative of a subject’s overall taste for sugar.
La Vecchia
C et al. Refined-sugar intake and the risk of colorectal cancer in
humans. Int J Cancer 1993;55:386-389.
Cyclooxygenase-2 is overexpressed in colon tumors and is
thought to play a role in carcinogenesis; its overexpression is also
believed to increase resistance to apoptosis. Curcumin decreases
activation of nuclear factor kappa beta, a substance that is
required for the induction of expression of the cyclooxygenase-2
gene by tumor necrosis factor alpha. Activation of nuclear factor
kappa beta also blocks apoptosis. The authors suggest that
administration of curcumin may restore susceptibility to apoptosis
because of its inhibitory actions on the activation and expression
of nuclear factor kappa beta and the cyclooxygenase gene.
Plummer
SM et al. Inhibition of cyclo-oxygenase 2 expression in colon cells
by the chemopreventive agent curcumin involves inhibition of NF-?B
activation via the NIK/IKK signalling complex. Oncogene
1999;18:6013-6020.
Risk factors
Alcohol
The authors of this review present hypotheses for the
causes of alcohol’s being a risk factor for liver and other cancers.
Chronic intermittent drinking induces cytochrome P4502E1 activity in
the esophagus, forestomach, and proximal colon; cytochrome P4502E1
is the main cytochrome P450 involved in the catabolism of retinoic
acid. Inhibitors of this enzyme have been demonstrated to protect
the liver from ethanol-induced injury.
Acute ethanol
ingestion may lead to the competitive inhibition of the oxidation of
retinol to retinoic acid in the liver and in other tissues.
Wang
X-D. Retinoids and alcohol-related carcinogenesis. J Nutr
2003;133:287S-290S.
Methylation of DNA at certain sites inhibits transcription, and
hypomethylation, which may be seen with lower-than-normal levels of
S-adenosylmethionine (SAMe), is a consistent feature of colonic
neoplasms. Diets low in methionine and folate (nutrients required
for production of SAMe) or high in alcohol, a methyl group
antagonist, may lead to an imbalance in DNA methylation. The link
between low vegetable and low fruit intakes and an increased risk of
colon cancer may be due in part to low intake of folate from these
sources.
More than 47,000 male health professionals
participated in a study in which colon cancer incidence, methionine
intake, folate intake, aspirin use, and alcohol intake were
determined by use of a questionnaire, which included a food
frequency questionnaire. The incidence of colon cancer increased as
alcohol intake increased; the higher risk was statistically
significant for wine but was pronounced for liquor and beer intake
as well. However, in men in the highest quintile of methionine
intake, colon cancer risk did not increase with alcohol intake; the
same was true for men in the highest quintile of folate intake,
although for men in the four lower quartiles, alcohol intake did
have a positive correlation with risk. Men consuming the lowest
level of methionine were at increased risk of developing colon
cancer; however, total folate intake and folate from foods did not
have significant relationships with risk. Low methionine intake and
high alcohol intake had the greatest influence on colon cancer risk
in men who were not regular users of aspirin.
Giovannucci E et
al. Alcohol, low-methionine-low-folate diets, and risk of colon
cancer in men. J Natl Cancer Inst 1995;87:265-273.
Alcohol is metabolized to acetaldehyde, a carcinogen;
acetaldehyde is in turn oxidized by xanthine oxidase and produces
superoxide radicals that catabolize folates.
The relationships
between folate, methionine, and alcohol intake and cancer risk were
studied in more than 15,000 women and 9,000 men who had a
colonoscopy or sigmoidoscopy during the study period. In the men
consuming 30 g (about two drinks) a day, alcohol intake was
inversely related to erythrocyte folate levels; in women this
relationship was not seen, but few women in the study had that level
of alcohol intake.
Both women and men in the highest
quintile of folate intake had a significantly lower risk of adenoma
than that of those in the lowest quintile. However, folate from
foods decreased the risk of adenoma only weakly and not
statistically significantly.
Women and men who had more
than two drinks a day (whether beer, wine, or liquor) had an
increased risk of adenoma of the distal colon. High alcohol and low
folate intake increased the risk of small adenomas in particular;
when such diets were low in methionine as well, the risk of larger
adenomas was increased.
The authors point out that folate
deficiency is common in many countries with a low incidence of
colorectal cancer, indicating that other factors (e.g., a
high-saturated-fat, low-fiber diet) probably also come into play.
They suggest, however, that because of the strong relationship
between a high-alcohol, low-folate pattern of dietary intake and an
increased risk of colorectal cancer, people who drink should
consider taking a folate supplement.
Giovannucci E et al. Folate,
methionine, and alcohol intake and risk of colorectal adenoma. J
Natl Cancer Inst 1993;85:875-884.
Total lifetime intake of alcohol was positively associated
with rectal cancer risk in men, but not significantly in women, in a
case-control study. The increased risk was noted primarily in those
in the highest quartile of alcohol intake (two to three beers a
day). The authors cite studies in which consumption of stout was
linked to rectal cancer mortality but light beer consumption was
not. Although in this study total alcohol was associated with rectal
cancer risk, the authors point out that beer is high in nitrosamines
and that certain batches of beer may be contain mycotoxins from
contaminated grains and cereals.
Freudenheim JL et al. Lifetime
alcohol intake and risk of rectal cancer in western New York. Nutr
Cancer 1990;13:101-109.
Trans fatty acids
Trans fatty acids (TFAs) may increase the risk of cancer by
altering physical properties of cell membranes or associated
enzymes.
Slattery ML et al. Trans-fatty acids and colon cancer.
Nutr Cancer 2001;39:170-175.
To determine whether intake of TFAs was related to the risk
of developing adenomatous polyps, researchers conducted a
case-control study by administering a food frequency questionnaire
to subjects who had undergone sigmoidoscopy. The incidence of
adenomas and intake of sweetened baked goods were positively
correlated once intake of the latter reached 250 g/day; however, the
lack of association between other TFA-containing foods and adenomas
suggests that the effect is probably not due to the TFA content of
the baked goods but instead to a combination of high sugar, high
fat, and low fiber or other nutrients.
McKelvey W et al. A
case-control study of colorectal adenomatous polyps and consumption
of foods containing partially hydrogenated oils. Cancer Epidemiol
Biomarkers Prev 1999;8:519-524.
Certain subsets of the population seem to be at increased
risk of developing colon cancer if they have a high intake of TFAs.
Overall, there is a weak positive association between TFA intake and
risk in women, but not in men, after adjustment for other risk
factors; however, older subjects did have a somewhat increased risk
with high TFA consumption. Postmenopausal women who were not taking
hormone replacement therapy had an increased risk with high TFA
intake, but postmenopausal women who were taking hormone replacement
therapy were not. In both men and women who did not use NSAIDs,
cancer risk increased with TFA intake; in those who did use these
medications, colon cancer risk did not seem to be affected by TFA
consumption.
Slattery ML et al. Trans-fatty acids and colon
cancer. Nutr Cancer 2001;39:170-175.
Meat consumption
Consumption of either rare or well-done meat increases the
risk of colorectal adenomas; however, in a case-control study, the
increased risk associated with well-done or very well-done meat was
greater (29% per 10 g/day) than that associated with rare or medium
red meat (10% per 10 g/day). Consumption of grilled and pan-fried
red meat also increased risk (by 26% and 15% per 10 g/day,
respectively).
Sinha R et al. Well-done, grilled red meat
increases the risk of colorectal adenomas. Cancer Res
1999;59:4320-4324.
In a case-referent study it was found that total meat
intake, frequent consumption of brown gravy, and a preference for
meat with a heavily browned surface were all independently linked to
the risk of colorectal cancer. Boiled meat increased the risk of
colon cancer by a factor of 1.7 and that of rectal cancer by a
factor of 2.7; for meat with a medium or lightly browned surface the
respective increases in risk were by factors of 0.8 and 1.1 and for
fried meat with a heavily browned surface, the increases were by
factors of 2.8 and 6.0 respectively.
Gerhardsson de Verdier M,
Hagman U, Peters RK, Steineck G, Overvik E. Meat, cooking methods
and colorectal cancer: a case-referent study in Stockholm. Int J
Cancer 1991;49:520-525.
Heterocyclic amines were not linked to increased risk of
colon cancer, rectal cancer, bladder cancer, or kidney cancer in a
population-based case-control study conducted in
Sweden.
Augustsson K et al. Dietary heterocyclic amines and
cancer of the colon, rectum, bladder, and kidney: a population-based
study. Lancet 1999;353:703-707.
Certain people may be more susceptible to the risk of
colorectal cancer incurred by the consumption of meat. Cooking red
meat results in the production of heterocyclic amines, which have
been shown in animal studies to induce various cancers, including
colon cancer. In humans, the risk of colon cancer varies according
to whether or not a person is a rapid acetylator, a metabolic
characteristic determined genetically. The authors of this review
note that four of five studies have found an increased risk of colon
cancer in rapid acetylators, and that in two of these studies this
association was seen only in subjects who ate meat.
Vineis P,
McMichael A. Interplay between heterocyclic amines in cooked meat
and metabolic phenotype in the etiology of colon cancer. Cancer
Causes Control 1996;7:479-486.
The risk of adenoma or of colorectal cancer increases with
meat consumption in fast acetylators but not in slow
acetylators.
Roberts-Thomson IC et al. Diet, acetylator
phenotype, and risk of colorectal neoplasia. Lancet
1996;347:1372-1374.
One reason that has been suggested for the lower incidence
of colorectal cancer in Seventh-Day Adventists, who have a higher
intake of plant sterols than the general population, is that high
intakes of these sterols may result in decreased excretion of bile
acids, which are promoters of colon cancer. However, research
results have been conflicting, though weaknesses in some studies
have made it hard to rule out this possibility.
Normen AL et al.
Plant sterol intakes and colorectal cancer risk in the Netherlands
Cohort Study on Diet and Cancer. Am J Clin Nutr 2001;74:141-148.
The p53 tumor suppressor gene plays many roles, among them
apoptosis and cell cycle arrest. Many, if not most, colon tumors
have alterations in this gene. High-sugar, high-glycemic-load diets,
as well as diets high in red meat, trans-fatty acids, and fast food,
are associated with an increased occurrence of p53 mutations. The
effect on p53 of a high-glycemic-load diet seems to be greater in
women than in men; the fast-food, high-meat, high-trans-fatty acid
diet increases p53 mutation risk men and women over the age of 65
more than in younger subjects.
Slattery ML et al. Diet, activity,
and lifestyle associations with p53 mutations in colon tumors.
Cancer Epidemiol Biomarkers Prev 2002;11:541-548.
Prevention
The chemopreventive agents that protect against colon
cancer exert their effects through a wide variety of probable
mechanisms: inhibition of cellular proliferation; inhibition of the
activity of various enzymes, of gene activation, or of angiogenesis;
prevention of carcinogen-DNA binding; inhibition of the formation of
carcinogens; control of cell cycles; maintenance of a healthy
basement membrane; apoptosis; promotion of differentiation; and
immune support. NSAIDs probably exert their effects through
cyclooxygenase-1 and -2 inhibition, but they also have COX-1 and
–2-independent effects.
In one study, calcium reduced by
20-35% the risk of recurrence in patients who had previously been
diagnosed as having an adenoma; its effects were greater in those
who had had the more advanced lesions. A reduction in recurrence
risk of 19% was seen in a study in which patients took 80 mg aspirin
per day; a higher dose was not more effective. The authors of this
review pointed out that, as of 2002, no clinical trial of calcium,
aspirin, or celecoxib had yet been done to determine the reduction
in colorectal cancer risk in people at only average risk of
developing the disease; however, several trials of various agents
(e.g., celecoxib, aspirin, sulindac) in patients with colorectal
patents are ongoing.
Viner JL et al. Chemoprevention of
colorectal cancer: problems, progress, and prospects. Gastroenterol
Clin 2002;31:[not available]
NSAIDs
Cyclooxygenase-2 (COX-2), unlike COX-1, seems to be present
only in inflamed tissues; its levels are also elevated in tumor cell
lines and in colon cancer cells. The mechanism of its effects on
colon cancer risk is unknown; some research suggests that COX-2
overexpression leads to increased expression of an oncoprotein,
BCL-2, that increases resistance to apoptosis. Many large
case-control and prospective studies indicate that there is an
inverse relationship between NSAID use and risk of colorectal
cancer.
Kahn MJ, Morrison DG. Chemoprevention for colorectal
carcinoma. Hematol/Oncol Clin N Am 1997;11:779-794.
NSAIDs nonselectively inhibit both COX-1 and COX-2, so
although their use seems to decrease colon cancer risk, the side
effects due to inhibition of COX-1, such as ulcers, bleeding, or
renal impairment, may limit some people’s ability to safely use them
at dosages high enough to inhibit COX-2. Mice bred to develop
adenomas within a few months after birth were given the COX-2
inhibitor celecoxib either soon after weaning, at 30 days, or at 55
days, when adenomas were already established. Celecoxib
administration decreased tumor number and size in both groups,
although its effects were greater in the mice who received it
earlier in life.
Jacoby RF et al. The cyclooxygenase-2 inhibitor
celecoxib is a potent preventive and therapeutic agent in the Min
mouse model of adenomatous polyposis. Cancer Res
2000;60:5040-5044.
DuBois et al cite an animal study in which the NSAID sulindac
suppressed carcinogenesis even 14 weeks after administration of a
carcinogen. Sulindac decreases prostaglandin levels in colon tumors;
prostaglandin levels are usually higher in tumors than in
surrounding normal tissue. The effectiveness of NSAIDs in inhibiting
carcinogenesis is generally seen to be correlated with their ability
to inhibit the conversion of arachadonic acid to eicosanoids. Both
controlled and non-controlled studies of patients with familial
polyposis (who develop hundreds of adenomatous polyps by early
adulthood and virtually all of whom develop adenocarcinoma of the
colorectum by their 50s unless they undergo colectomy) have
indicated that sulindac can decrease the number of polyps, as
determined by follow-up examinations; however, the number of polyps
increased again in four of the five patients during the second
(placebo) phase of the trial. In another study, patients with
familial polyposis took sulindac for 9 months; both polyp number and
polyp size decreased, by 44% and 35% respectively, but sulindac did
not completely regress polyps in any of these
patients.
Consistent aspirin use (not defined here)
decreases the risk of polyp recurrence in patients who have already
undergone polypectomy (relative risk, 0.52). It may take up to 10
years of continuous aspirin use for a protective effect of aspirin
on colorectal cancer risk to become apparent.
DuBois RN et al.
Colorectal neoplasia, part I: the scientific basis for current
management: Nonsteroidal anti-inflammatory drugs, eicosanoids, and
colorectal cancer prevention. Gastroenterol Clin
1996;25:773-791.
Researchers used pharmacy and medical records, rather than
patients’ recall, to determine NSAID intake by their study
population. (Because of the hospital population’s socioeconomic
status and the low cost of pharmacy prescriptions, and because of
their clinical experience, the researchers had reason to believe
that these records closely reflected NSAID use, even though
over-the-counter purchase was not quantified.) Length of time a
patient took an NSAID and the cumulative dose were both inversely
related to risk of colorectal cancer. Acetaminophen had no effect on
risk.
Peleg II et al. Aspirin and nonsteroidal anti-inflammatory
drug use and the risk of subsequent colorectal cancer. Arch Intern
Med 1994;154:394-399.
Patients who were regular users of NSAIDs (at least three
times a week for at least one year before the interview) had a lower
risk of colorectal cancer in a case-control study. There were only
slight differences between the risks of developing right- or
left-sided colon cancers. Men who took NSAIDs one or two times a
week for more than 9 years also had a decreased risk of developing
colorectal cancer; this decrease was not observed in the female
subjects. Another difference between the male and female subjects
was that reduction in risk was increased further in men who took
NSAIDs for more than 9 years, whereas women who had taken them for
1-9 years had a decrease in risk that was greater than that in women
who had taken them for more than 9 years. This result may be due to
sampling bias; there were relatively few women who took NSAIDs
regularly.
Muscat JE et al. Nonsteroidal antiinflammatory drugs
and colorectal cancer. Cancer 1994;74:1847-1854.
Administration of various NSAIDs to rats resulted in a
reduction of both incidence of aberrant crypts in the colon and in a
reduced development of multiple-crypt foci. Of the drugs used in the
study, aspirin and piroxicam were the most effective; ibuprofen was
less so, and acetaminophen was not effective. The NSAIDs aspirin,
ibuprofen, and piroxicam are believed to exert their suppressive
effects by inhibiting prostaglandin synthesis, although they may
work through other mechanisms as well. The differentiating agent
13-cis-retinoic acid also inhibited the formation of aberrant
crypts; 4-hydroxyphenretanimide did so too, though to a lesser
extent.
Wargovich MJ et al. Inhibition of aberrant crypt growth
by non-steroidal anti-inflammatory agents and differentiation agents
in the rat colon. Int J Cancer 1995;60:515-519.
Subjects in the Physicians’ Health Study were 22,071 male
physicians who were 40 to 84 years old in 1982 and who were not
current users of NSAIDs (current use being defined as taking an
average of one pill a week or more). The aspirin arm of this study
was terminated early, after an average of 5 years of follow-up,
because the incidence of myocardial infarction was dramatically
lower (reduced by 44%) in the subjects taking aspirin. The data
revealed no significant reduction in colorectal cancer risk in these
subjects; however, the authors suggest that a trial longer than 5
years might have demonstrated an effect. They also note the
possibility that the dose (325 mg every other day) was not high
enough to retard the growth of colorectal cancer, but point out that
there are medical risks associated with using a higher dose.
Gann
PH et al. Low-dose aspirin and incidence of colorectal tumors in a
randomized trial. J Natl Cancer Inst 1993;85:1220-1224.
Although it has been demonstrated in numerous studies that
use of NSAIDs decreases colon cancer risk, the potential for other
compounds to have the same effect by the same means should not be
overlooked. Omega-3 fatty acids, such as docosahexaenoic acid and
eicosapentaenoic acid in fish oil, compete with arachidonic acid in
the cyclooxygenase, lipoxygenase, and monooxygenase pathways, and
may also partially inhibit these pathways as well.
Meletis CD,
Bramwell B. Colon cancer: strategies for prevention. Altern Compl
Ther 2001;April:63-67.
Subjects with familial adenomatous polyposis were given 400
mg celecoxib twice daily, 100 mg twice daily, or placebo. The number
of polyps greater than 2 mm were measured at baseline and after six
months. Subjects taking 400 mg twice a day had significant
reductions in both mean number of colorectal polyps and polyp burden
(the sum of polyp diameters).
Steinbach G et al. The effect of
celecoxib, a cyclooyxgenase-2 inhibitor, in familial adenomatous
polyposis. N Engl J Med 2000;342:1946-1952.
Folate
The finding in a large prospective study that women with a
long history of multivitamin use had a dramatically lower risk of
colon cancer than did nonusers suggests that not only folate but
also the synergistic effects of vitamins and minerals may be
protective.
Meletis CD, Bramwell B. Colon cancer: strategies for
prevention. Altern Compl Ther 2001;April:63-67.
About four-fifths of food folates are polyglutamates; however,
polyglutamates are only about 25% as bioavailable as monoglutamates.
The authors of this prospective study found no significant
difference between the effects of different folate vitamers on
colorectal cancer risk. However, inverse relationships between total
dietary folate and colon cancer risk were found in men and women; an
inverse relationship between total dietary folate and rectal cancer
risk was seen only in men.
Folate deficiency leads to
incorporation of uracil into DNA and to chromosome breaks, and
therefore to initiation of neoplastic transformation. Another effect
of folate deficiency on DNA replication is to lower levels of
S-adenosylmethionine and thereby to lower controls on protooncogene
expression.
Konings EJM et al. Intake of dietary folate vitamers
and risk of colorectal carcinoma: results from The Netherlands
Cohort Study. Cancer 2002;95:1421-1433.
The impact of a family history of colon cancer on a woman’s
likelihood of developing the disease herself can be influenced by
various dietary habits. The age-adjusted relative risk of a woman
without a family history of colon cancer who used multivitamins was
0.84 (i.e., compared with women with no family history who did not
use multivitamins); in women with a family history who used
multivitamins, relative risk was 0.48 (i.e., compared with women
with a family history who did not use multivitamins), suggesting
that women with a family history of colon cancer who use
multivitamins for five or more years may decrease their risk of this
type of cancer by almost 50%. High methionine intake also decreased
risk in women with a family history of colon cancer but not in women
without such a history, and moderate to heavy alcohol intake
increased it.
Fuchs CS et al. The influence of folate and
multivitamin use on the familial risk of colon cancer in women.
Cancer Epidemiol Biomarkers Prev 2002;11:227-234.
Calcium
Supplementation with fiber, in the form of ispaghula husk
(which has been seen to reduce colon cancer risk in animals),
significantly increased the risk of adenoma recurrence compared with
that seen in patients who were given placebo. Patients given calcium
had a nonsignificantly reduced risk of recurrence compared with
those given placebo. However, the increase in risk with ispaghula
was greater in patients who consumed more than the median level of
dietary calcium than in those who consumed less than the median
levels The authors speculate that one possible explanation for this
finding is that the ispaghula fiber binds more strongly to calcium
than to bile acids; the bile acids left free were perhaps then able
to exert their damaging effects on the colonic mucosa. They cite a
previous study in which wheat bran and calcium were less effective
when consumed together than when each was taken
alone.
Bonithon-Kopp C et al. Calcium and fibre supplementation
in prevention of colorectal adenoma recurrence: a randomised
intervention trial. Lancet 2000;356:1300-1306.
Subjects with a history of adenomatous polyps were either
given calcium carbonate supplements (for an average total of 1309 mg
calcium/day, including dietary calcium, up from an average of 642
mg) or consumed a diet high in low-fat dairy foods (for an average
total of 1521 mg calcium per day, up from an average of 644 mg) for
four months, and then crossed over into the other study group. A
rectal biopsy was done at baseline and at the end of each study
period. Proliferation indices (essentially, the proportions and
numbers of cells in the crypt that were proliferating) were similar,
and strikingly less than during baseline (control) conditions, in
the calcium-supplement and low-fat-dairy groups.
Holt PR et al.
Comparison of calcium supplementation or low-fat dairy foods on
epithelial cell proliferation and differentiation. Nutr Cancer
2001;41:150-155.
Patients who had a history of at least one colorectal
carcinoma were given a questionnaire about their intake of vitamins,
minerals, and other supplements. (Amounts and frequency of use were
not recorded.) About half the subjects took at least one supplement;
two-thirds of these took more than one. The authors note that other
researchers may need to take their subjects’ supplement use into
account when designing and analyzing studies.
Sandler RS et al.
Use of vitamins, minerals, and nutritional supplements by
participants in a chemoprevention trial. Cancer
2001;91:1040-1045.
Selenium
The effect of selenium status on the risk of having polyps
or colon cancer may be influenced by age. In a geographic area where
residents tend to have low selenium levels, patients who had
sporadic polyps >1 cm or colon cancer and who were not taking
vitamin, mineral, or fish oil supplements were involved in a
case-control study. For subjects more than 60 years old, there was
no significant difference between the three groups (control, large
adenomatous polyps, and cancer). In younger patients, serum selenium
levels were significantly lower in patients with adenomas than in
control subjects, and were even lower in cancer patients. Serum
selenium level was also lower in older control subjects than in
younger ones. The authors therefore suggest that in a geographic
area with low selenium (where residents tend to have low serum
selenium levels), the preventive effect of selenium against large
adenomas may be limited to people less than 60 years
old.
Fernandez-Banares F et al. Serum selenium and risk of large
size colorectal adenomas in a geographical area with a low selenium
status. Am J Gastroenterol 2002;97:2103-2108
At a concentration (10 µM) easily achievable in vivo
through supplementation, selenomethionine protected DNA in human
fibroblasts from damage due to ultraviolet radiation, to hydrogen
peroxide, or to 4-nitroquinoline. Because of the types of assays and
experiments done, the authors conclude that selenomethionine
protected DNA by promoting the nucleotide excision repair pathway,
and that induction of the activity of selenoenzymes (thioredoxin
reductase and glutathione peroxidase) that scavenge free radicals
was not, at least under these conditions, a major mechanism of
selenomethionine’s effect. They therefore suggest that selenium
supplementation may help prevent carcinogenesis in healthy people,
and also that these findings may be applicable to the treatment of
patients who have modest DNA repair deficits (e.g., those with
xeroderma pigmentosum or Li-Fraumeni syndrome).
Seo YR et al.
Selenomethionine induction of DNA repair response in human
fibroblasts. Oncogene 2002;21:3663-3669.
Undermethylation of DNA is a relatively consistent feature
of carcinogenesis in the colon, and is also seen in the normal areas
of the colonic mucosa of people who have colon cancer, indicating
that it may precede evidence of dysplasia. (Hypermethylation of
cancer suppressor genes is also seen in some cancer cells.) Abnormal
DNA methylation could affect the expression of oncogenes or tumor
suppressor genes or by altering DNA conformation to allow greater
accessibility to damaging agents.
Global hypomethylation
was seen in colon cancer cells grown in a culture deficient in
selenium; diets deficient in selenium also led to global
hypomethylation of DNA in the liver and colon tissues of rats. The
authors suggest that this mechanism may be a possible explanation
for the increased risk of cancer with low selenium diet, although it
does not explain the chemoprotective effect (suggested elsewhere) of
supranutritional intakes of the mineral.
Davis CD et al. Dietary
selenium and arsenic affect DNA methylation in vitro in Caco-cells
and in vivo in rat liver and colon. J Nutr 2000;130:2903-2909.
The authors cite research showing that serum selenium level is
not as clear an indicator of long-term selenium intake as is toenail
selenium level. When they used this measure to assess selenium
status, they found an inverse relationship between selenium levels
and risk of colon cancer in women; when the data from men and women
were combined and analyzed together, the same inverse relationship
was found
No statistically significant relationship was found
between toenail selenium level and risk of breast or colon cancer.
Ghadirian P et al. A case-control study of toenail selenium and
cancer of the breast, colon, and prostate. Cancer Detect Prev
2000;24:305-313.
Vitamin E
In women, the inverse relationship of vitamin E with colon
cancer risk varied strikingly across age groups, being strongest in
the younger subjects (55-59 years old) and weakest in the older ones
(64-69 years old). The authors point out that this finding may be
explained by a decreased risk of colon cancer or by delayed
onset.
Bostick RM et al. Reduced risk of colon cancer with high
intake of vitamin E: the Iowa Women’s Health Study. Cancer Res
1993;53:4230-4237.
Vitamin E succinate (D-a-tocopherol succinate)
dose-dependently increases apoptosis and decreases proliferation of
colon cancer cells in vitro; in vivo, it promotes apoptosis and
decreases metastasis of colon cancer cells. Unfortunately, vitamin E
succinate is cleaved by esterases and does not reach the tumor
intact when administered orally; neither vitamin E nor succinic acid
alone stimulated apoptosis or inhibited proliferation. In a previous
study, the authors found that intraperitoneal injection did result
in delivery of the intact molecule; they did not research whether
the intravenous route would work.
Barnett KT et al. Vitamin E
succinate inhibits colon cancer liver metastases. J Surg Res
2002;106:292-298.
Fiber
Many possible mechanisms for fiber’s beneficial effects
have been suggested:
1. Binding of bile acids, which may be
promoters of neoplasia.
2. Reducing the formation and
availability of secondary bile acids; this may be an especially
important mechanism in people with a high fat
intake.
3. Binding of other mutagens.
4. Diluting of
carcinogens (by increasing stool bulk) and decreasing stool transit
time, so that the mucosa is in contact with tumor initiators or
promoter for a shorter time.
5. Promoting bacterial
fermentation of fiber, diluting carcinogens and promoters by
increasing bacterial mass.
6. Through fermentation,
providing a means by which gut pH is altered and fuel for epithelial
cells is decreased—both of these are involved in preventing
neoplastic transformation.
7. Increasing the concentration
of butyrate, which promotes differentiation of epithelial cells in
the colon.
Not all studies indicate that fiber has a
statistically significant effect on colorectal cancer risk. However,
this may be due at least in part to the failure by some of these
studies’ authors to account for the way in which a high-fat diet can
counteract the benefits of a high-fiber diet.
Kahn MJ, Morrison
DG. Chemoprevention for colorectal carcinoma. Hematol/Oncol Clin N
Am 1997;11:779-794.
Beta-sitosterol
Phytosterols are similar to the cholesterol found in animal
products, but they are not as well absorbed. They have been seen to
inhibit the development of chemically induced colon cancer in vivo
and to normalize hyperproliferation of colon cells in rat and mouse
models. Most phytosterols in roasted peanuts are in the form of
beta-sitosterol, which the authors have shown in previous studies to
have a protective effect against colon, prostate, and breast
cancers. This phytosterol is incorporated in the membranes of tumor
cells and stimulates the sphingomyelin cycle, which may be the
mechanism by which it inhibits tumor growth and stimulates apotosis.
Peanut oil contains more phytosterols, and loses less of them during
refining and processing, than does olive oil.
Awad AB et al.
Peanuts as a source of beta-sitosterol, a sterol with anticancer
properties. Nutr Cancer 2000;36:238-241.
Subjects in a Dutch case-cohort study completed a
semiquantitative food-frequency questionnaire and were followed up
for more than six years in a study designed to determine whether
plant sterol intake had a protective effect against colon cancer.
Intakes of the plant sterols campesterol, ß-sitosterol,
stigmasterol, campestanol, and ß-sitostanol were analyzed
separately.
No overall protective effect of plant sterol
intake was noted in this study, although men in the highest quintile
of stigmasterol intake had a statistically lower risk of colon
cancer, and non-energy-adjusted analysis of ß-sitostanol and
campestanol intakes and colon cancer risk revealed a negative
relationship. However, intake of some individual sterols seemed to
be positively associated with certain types of cancer risk.
ß-sitostanol was positively associated with the risk of distal
cancer in men, and energy-adjusted analysis of the data for
stigmasterol indicated that intake was positively associated with
risk. Camposterol and stigmasterol intakes were positively
associated with the risk of rectal cancer in men; however, except
for ß-sitostanol, intake of plant sterols and stanols tended to have
an inverse relationship with rectal cancer risk, but this
relationship was not linear.
One interesting finding in
this study is that cereal products were an important contributor of
plant sterols to the subjects’ diets. The focus had previously been
on vegetable oils as a main source, because concentrations of plant
sterols in them is so high.
Normen AL et al. Plant sterol
intakes and colorectal cancer risk in the Netherlands Cohort Study
on Diet and Cancer. Am J Clin Nutr 2001;74:141-148.
Bioflavonoids
Cyanidin is one of the most widespread forms of the
polyphenols known as anthocyanidins. It, and its glycosides cyanin
and idaein, are strong antioxidants, but this may not be their only
mechanism of action; an in vitro study was done to see whether they
also inhibit colon cancer cell growth.
Proton extrusion, or
extracellular acidification, is a reflection of the metabolic
activity of cells. In vitro, cyanidin inhibits both neurotensin- and
epidermal growth factor-induced extracellular acidification in a
line of colon cancer cells; its glycosides cyanin and idaein,
however, do not. The concentration of cyanidin at which this effect
was seen was similar to that which could probably be achieved in the
intestinal lumen, even accounting for physiological dilution during
digestion. Anthocyanins are poorly absorbed: most of these chemicals
remain in the intestine when they are consumed in the diet, so their
effects are likely to be most pronounced on the tissues of the
gastrointestinal tract. Foods high in anthocyanins include
blueberries, elderberries, strawberries, currants, grapes, and
cherries.
Briviba K et al. Neurotensin- and EGF-induced metabolic
activation of colon carcinoma cells is diminished by dietary
flavonoid cyanidin but not by its glycosides. Nutr Cancer
2001;41:172-179.
Oral administration of 0.5-2.0% commercial grade curcumin
to mice inhibited tumorigenesis in the forestomachs, duodenums, and
colons of mice (induced by three different carcinogens). Curcumin
led to decreases in the size and number of forestomach papillomas
and squamous cell carcinomas and in the size and number of colon
adenomas and adenocarcinomas whether it was given during the
initiation period or after initiation. The number of duodenal
adenomas and adenocarcinomas per mouse decreased when the curcumin
was given during postinitiation; however, although curcumin
decreased the size of carcinogen-induced adenomas in the duodenum,
there was a tendency for adenocarcinomas to be larger in the mice
given curcumin. In most of the studies, 0.5% curcumin was as
effective at inhibiting carcinogenesis as was the higher
dosages.
It is an antioxidant and free radical scavenger;
it inhibits arachidonic acid metabolism and inflammatory action;
inhibits TPA-induced inflammation and ornithine decarboxylase
activity; and increases levels of hepatic phase I and phase II
enzymes. The authors cite other studies in which colon
carcinogenesis was decreased by anti-inflammatory inhibitors of
arachidonic acid metabolism; curcumin has been seen to exert these
effects in mouse skin through both the cyclooxygenase and
lipoxygenase pathways.
Huang M-T et al. Inhibitory effects of
dietary curcumin on forestomach, duodenal, and colon carcinogenesis
in mice. Cancer Res 1994;54:5841-5847.
Curcumin was fed to Min/+ mice, a model of familial adenomatous
polyposis, to
determine whether it would decrease the
development of adenomas. The mice were fed 0.1%, 0.2%, and 0.5%
curcumin diets from the age of 4 weeks until they were 18 weeks old.
The lowest dosage of curcumin did not affect the development of
intestinal tumors, but the 0.2% and 0.5% diets decreased intestinal
tumor load similarly, by 39% and 40%. The researchers noted that
consumption of curcumin needs to take place for the entire
postweaning period for a chemoprotective effect to be seen; in mice,
curcumin disappears fairly rapidly from the tissues once curcumin
administration is stopped. Another important observation was that
curcumin decreased adenoma-associated bleeding; the authors point
out that many NSAIDs proposed as chemopreventive agents against
colon cancer (aspirin, sulindac, piroxicam) have severe
gastrointestinal side effects.
The equivalent of the 0.2%
dietary curcumin that was effective in this animal model would be
1.6 g/day for humans.
Perkins S et al. Chemopreventive efficacy
and pharmacokinetics of curcumin in the Min/+ mouse, a model of
familial adenomatous polyposis. Cancer Epidemiol Biomarkers Prev
2002;11:535-540.
An herbal formula called Bu-Zhong-Yi-Qi-Tang (BZYQT) inhibits
the proliferation and induces apoptosis of liver cancer cells, but
even at higher concentrations does not seem to affect normal liver
cells. Components of the formula are: Astragalus membranaceus root
(10 parts), Panax ginseng root (3 parts), Angelicae sinensis root (2
parts), Cimicifuga foetida root and rhizome (2 parts), Glycyrrhiza
uralensis root (5 parts), Citrus poonensis pericarp (2 parts),
Bupleurum chinensis root (2 parts), Zingiber officinale root and
rhizome (3 parts), Ziziphus jujuba fruit (3 parts), and Atractylodes
macrocephala root and rhizome (3 parts).
Kao S-T et al. The
Chinese medicine Bu-Zhong-Yi-Qi-Tang inhibited proliferation of
hepatoma cell lines by inducing apoptosis via G0/G1 arrest. Life Sci
2001;69:1485-1496.
Administration of D-limonene at daily doses of 0.5 g/m2 and 1.0
g/m2 led to
stabilization of disease or a decrease in
gastrointestinal tumor growth for 7.5 to 12 months in three patients
(of 32) with advanced cancer who were involved in a study to
determine the safety and toxicity of D-limonene. A patient with
breast cancer also experienced an extended partial remission of her
disease. Doses in excess of the maximum tolerated dose, 8 g/m2 per
day, resulted in reversible gastrointestinal side
effects.
Vigushin DM et al. Phase I and pharmacokinetic study of
D-limonene in patients with advanced cancer. Cancer Chemother
Pharmacol 1998;42:111-117.
Plant phenolics are anticarcinogenic at all stages of tumor
development. They inhibit initiation because they are antimutagenic,
they reduce levels of carcinogen-DNA adducts, and they inhibit Phase
I monoxygenases, thus decreasing the activation of carcinogens. At
the promotion phase, they scavenge free radicals, induce Phase II
detoxifying enzymes, and reduce expression of ornithine
decarboxylase. Finally, they promote cell death or differentiation
and inhibit proliferation.
The plant-derived phenolics
caffeic acid phenethyl ester (CAPE), curcumin, quercetin, and rutin
were administered for 10 weeks to mice that are bred to
spontaneously develop multiple intestinal adenomas, mostly in the
small intestine. CAPE (at 0.15% of the diet) and curcumin (at 0.1%
of the diet) reduced tumor formation by 63%, increased apoptosis
approximately tenfold, and normalized enterocyte
proliferation.
Mahmoud NN et al. Plant phenolics decrease
intestinal tumors in an animal model of familial adenomatous
polyposis. Carcinogenesis 2000;21:921-927.
Fifteen patients with adenocarcinoma of the colon or rectum
for which no further conventional therapies were available were
given Curcuma extract at dosages of 440, 880, 1320, 1760, and 2200
mg per day (equivalent to 36, 72, 108, 144, and 180 mg curcumin) for
up to 4 months. No evidence of toxicity was seen, and the treatment
was well tolerated at all dosages: two patients developed diarrhea
and withdrew from the study, and one developed nausea that resolved
despite continuation of treatment. The purpose of this study was to
determine the safety and metabolic characteristics of orally
administered curcumin, but the authors note that one third of the
patients in the study experienced stability of their disease, as
determined by CT scan, for 3 months or more.
Sharma RA et al.
Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in
patients with colorectal cancer. Clin Cancer Res
2001;7:1894-1900.
Ceramide
Colon cancer cells have approximately half the ceramide
content of normal colon cells from the same patient. In vitro
studies of cell cultures indicated that the presence of ceramide or
ceramidase inhibitors activate the apoptotic pathway in cancer cells
but not in normal cells. When the most potent of the ceramidase
inhibitors tested was administered to murine models of human colon
cancer, tumor growth was completely inhibited and there was no
detectable toxicity. The authors cite a study in which mice given a
diet high in sphingomyelin (which is cleaved into ceramide and
sphingosine) were found to be resistant to carcinogen-induced colon
cancer.
Selzner M et al. Induction of apoptotic cell death and
prevention of tumor growth by ceramide analogues in metastatic human
colon cancer. Cancer Res 2001;61:1233-1240.
Rats bred to develop colon tumors in response to
azoxymethane administration were given diets containing various
concentrations of black raspberries. Aberrant crypt foci
multiplicity (means per treatment group) was significantly lower in
the rats who received black raspberries compared with those that did
not. The reduction in tumor multiplicity, statistically significant
in all groups, was greatest in the rats that received the diet with
the highest black raspberry content; although trends toward
decreased tumor burden and decreased tumor volume with increased
black raspberry consumption were seen, they were not statistically
significant.
Harris GK et al. Effects of lyophilized black
raspberries on azoxymethane-induced colon cancer and
8-hydroxy-2'-deoxyguanosine levels in the Fischer 344 rat. Nutr
Cancer 2001;40:125-133.
Some components of a healthy diet are particularly helpful
in the reduction of colon cancer risk: cereals (to include 20 g/day
of cereal fiber), omega-3 fatty acids (from cold-water fish and from
2000 mg cold-pressed flaxseed oil three times a day),
oligosaccharides (from fruits and vegetables; in addition, a
high-quality probiotic supplement containing Lactobacillus and
Bifidobacterium may be helpful), folic acid (400 µg/day in a
multivitamin), vitamin E (D-a-tocopherol, 400-1200 IU/day), curcumin
(as directed by a health care provider), selenium (200 µg/day), and
calcium (1200 mg/day).
Meletis CD, Bramwell B. Colon cancer:
nutritional strategies for prevention. Altern Compl Ther
2001;April:63-67.
Intestinal integrity
Gut flora
Lactic acid bacteria are thought to exert their effects by
several mechanisms:
1. They stimulate the host’s immune
response, inducing the production ofcytokines that decrease tumor
growth.
2. Their presence leads to reduced absorption of at
least one type of mutagen, and they may affect the ratio of bound to
free toxins in the colon. In addition, lactobacilli have been shown
to degrade nitrosamines.
3. Lactic acid bacteria decrease
the numbers of harmful gut flora that may be involved in the
production of precarcinogens and tumor promoters.
4. Certain
lactic acid bacteria may produce antitumorigenic or antimutagenic
compounds.
5. Intestinal levels of beta-glucoronidase and
other enzymes that hydrolyze detoxified foreign compounds (thus
allowing them to be released in the intestinal tract) have been seen
to decrease following supplementation with Lactobacillus strains.
Continued supplementation seems to be necessary, as a reversal of
this effect has been seen in at least one study following cessation
of Lactobacillus administration.
6. The trend towards a
decreased concentration of soluble bile acids seen in colon cancer
patients after supplementation with Lactobacillus acidophilus may be
indicative of the ability of these bacteria to reduce the cytotoxic
effect of bile acids on the colonic epithelium.
7. In rats,
lactic acid bacteria increase levels of enzymes that are involved in
the metabolism of carcinogens (NADPH-cytochrome P450 reductase and
glutathione S-transferase activity) in the colon.
Hirayama K,
Rafter J. The role of probiotic bacteria in cancer prevention.
Microbes and Infection 2000;2:681-686.
Rats fed diets high in oligofructose or inulin or a control
diet were injected with a colon carcinogen once weekly for 2 weeks.
After 7 weeks, the numbers of aberrant crypt foci were significantly
decreased in both study groups compared with the numbers seen in the
diets receiving the control diet. Crypt multiplicity was also
decreased in the study groups compared with controls. The effects of
inulin were more pronounced than those of oligofructose, but were
significant in both groups. The authors suggest that the inhibition
of aberrant crypt foci formation indicates that these compounds may
be suppressors of colon tumorigenesis.
In another study by
the same authors, Bifidobacterium longum inhibited
carcinogen-induced adenocarcinoma incidence and tumor multiplicity
(i.e., decreased tumors per animal and decreased tumors per
tumor-bearing animal).
In yet another study, B.longum
strongly inhibited the effects of another carcinogen
(2-amino-3-methylimidazo[4,5-f]quinoline, a heterocyclic amine
formed when meat or fish is broiled). Colon and breast tumor
formation was decreased dramatically in rats who were given
lyophilized cultures of this bacteria in addition to the
carcinogen.
Oligofructose and inulin both increase fecal
bifidobacteria and decrease the numbers of bacteriodes, clostridia,
and fusobacteria or gram-positive cocci. The bifidobacteria in turn
lower the intestinal pH to create an environment unfavorable to
enteropathogens; they also may bind carcinogens so these toxins can
be excreted in the feces. Oligofructose and inulin administration
also increase the production by fermentation of short-chain fatty
acids, including butyrate.
Reddy BS. Possible mechanisms by which
pro- and prebiotics influence colon carcinogenesis and tumor growth.
J Nutr 1999;129:1478S-1482S.
Probiotics have been defined as microbial supplements that
benefit the host through their effects on the intestinal tract.
Prebiotics are substances, not digestible by the host, that
stimulate the growth or activate the metabolisms of health-promoting
gut bacteria.
The authors cite several studies in which
administration of probiotics (Bifidobacterium) decreased levels of
ß-glucoronidase, as well as the numbers of aberrant crypts. Numbers
of aberrant crypts have also been seen to be reduced in rats given
prebiotics (oligofructose or inulin); one study of human subjects
has demonstrated that at least 5 grams of fructooligosaccharide per
day is needed to increase numbers of bifidobacteria. They also cite
a study in which Bifidobacterium had no significant effect on
aberrant crypt foci, but Lactobacillus acidophilus and Clostridium
perfringens did.
The authors’ studies in rats do not indicate any
clear relationship between numbers of bifidobacteria present and the
numbers of aberrant crypt foci, although gavage with bifidobacteria
and fructooligosaccharide did tend to decrease aberrant crypt
formation.
Brady LJ et al. The role of probiotic cultures in the
prevention of colon cancer. J Nutr 2000;130:410S-414S.
Rats were fed a prebiotic (an oligofructose enriched
inulin), a probiotic combination (two Lactobacillus strains and
Bifidobacterium lactis), or both for 31 weeks, starting 10 days
before the administration of azoxymethane, a colon carcinogen. There
was a statistically significant decrease in carcinogenesis in the
rats in both groups that were given the prebiotic; rats in both of
the probiotic groups also had fewer cancers, but this decrease did
not reach statistical significance (P=0.079).
Femia AP et
al. Antitumorigenic activity of the prebiotic inulin enriched with
oligofructose in combination with the probiotics Lactobacillus
rhamnosus and Bifidobacterium lactis on azoxymethane-induced colon
carcinogenesis in rats. Carcinogenesis 2002;23:1953-1960.
Consumption of either one of two chicory-derived ß(2-1) fructans,
oligofructose or long-chain inulin, which act as prebiotics,
significantly increased the numbers of apoptotic cells per crypt
when fed for three weeks before administration of a colon
carcinogen. Although ß-glucoronidase activity increased in rats
receiving either type of prebiotic, this increase did not reach the
level of statistical significance
Hughes R, Rowland IR.
Stimulation of apoptosis by two prebiotic chicory fructans in the
rat colon. Carcinogenesis 2001;22:43-47.
The authors provide a table listing the ways in which various
prebiotics and lactic-acid-producing probiotics can have a
protective effect against colon cancer: Administration of probiotics
has been seen, in separate studies, to decrease DNA damage, decrease
procarcinogenic enzyme activity; increase the binding or excretion
of mutagens; or provide immune stimulation. Ingestion of prebiotics
has led to an increase in short-chain fatty acid concentration, a
decrease in pH (shown in some studies to be associated with a
decrease in cancer risk), an increase in the number of probiotics
present, and decreased proliferation and increased apoptosis of
transformed cells.
Different bacteria have different enzyme
activities; bacteroides, clostridia, and enterbacteriaceae have
higher activities of xenobiotic-metabolizing enzymes than do
lactobacilli and bifidobacteria; clostridia and enterobacteria have
particularly high levels of ß-glucuronidase. Toxic compounds that
have been conjugated in the liver may be hydrolyzed and regenerated
by these enzymes, and then return to the enterohepatic circulation,
delaying their excretion.
One of the products of fermentation of
polysaccharides, starch, and fiber by bacteria is butyrate, a
short-chain fatty acid that is an important fuel for colon cells and
one that has other effects on the colon. It may enhance
proliferation and inhibit apoptosis of normal cells and may decrease
proliferation and increase apoptosis of transformed
cells.
Wollowski I et al. Protective role of probiotics and
prebiotics in colon cancer. Am J Clin Nutr
2001;73(suppl):451S-455S.
IMMUNE SUPPORT:
(Tyler Encapsulations) Recancostat
One
manufacturer’s suggested protocol for nutritional support of cancer
patients with reduced glutathione is as follows: for weeks 1-2
(phase 1), 2000 mg/day; for weeks 3-8 (phase 2), 1600 mg/day;
depending on the patient’s condition, begin a maintenance program
(phase 3) of 1200 mg/day, gradually reducing to 800 mg/day as his or
her condition continues to improve, or repeat phase 1 for 4 weeks,
phase 2 for 4 weeks, and then phase 3. Reduced glutathione should be
taken on an empty stomach (at least half an hour before or two hours
after food or medications) with 12-16 ounces of water, in three
divided doses per day.
Tyler Encapsulations. Recancostat
protocol.
The polysaccharides and beta-glucan fractions in certain
mushroom extracts (e.g., those from Coriolus versicolor, also known
as Trametes versicolor, and Grifola frondosa, also known as maitake)
stimulate immune function by increasing the production of
gamma-interferon, interleukin-2, and T-cell proliferation.
Tyler
Encapsulations. Myco Complex.
Reduced glutathione acts as an antioxidant in two ways: it
is a cofactor with glutathione peroxidase, which reduces the
hydrogen peroxide produced during cell respiration, and it is a
non-enzymatic oxidant as well, able to quench free radicals. It is
the main intracellular oxidant responsible for maintaining the redox
balance in cells.
Levels of reduced glutathione decrease as
people age, and lower levels are also seen in people with cancer,
HIV infection, AIDS, liver disease, chronic renal failure,
alcoholism, adult-onset diabetes, cardiovascular disease,
hypertension, and arthritis.
Reduced glutathione has been seen
to reduce the side effects of cancer treatment. Other studies have
suggested that it does so without reducing the effects of
chemotherapy on cancer cells; in fact, in some studies the efficacy
of cisplatin was increased when coadministered with reduced
glutathione.
There is a controversy surrounding the role of
reduced glutathione in drug resistance. Levels of reduced
glutathione are actually elevated in some drug-resistant cancer,s
and in laboratory studies, the presence of buthionine sulfoximine,
which depletes levels of reduced glutathione, led to cancer cells’
becoming sensitized to a drug to which they were previously
resistant. However, this does not mean that exogenous glutathione
increases or causes drug resistance (which is, after all, a
multifactorial phenomenon) in cancer cells, and no such effect has
yet been demonstrated. In fact, reduced glutathione has been
demonstrated to increase apoptosis of cancer cells. Nevertheless,
the use of this compound is contraindicated during a regimen
designed to reduce its level in the body.
Appleton J. Position
statement on glutathione-depleting therapies. Tyler
Encapsulations.
Surgery
There is metastasis to the liver in 20-30% of cases of
colon cancer. A prospective study of 40 patients (a total of 89
metastatic liver tumors) indicated that an anatomic and extensive
liver resection does not necessarily provide the best prognosis for
the treatment of colon cancer metastases to the liver; intrahepatic
metastasis from a metastatic tumor is rare. However, other studies
have reported that survival is reduced and recurrence rate is
increased when tumors are removed with a surgical margin of less
than 10 mm.
Yamamoto J et al. Pathologic support for limited
hepatectomy in the treatment of liver metastases from colorectal
cancer. Ann Surg
1995;221:74-78.
