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Review
Background
The field of
investigation of the role of nutrition in the cancer process is very
broad. It is becoming clearer as research continues that nutrition plays a
major role in cancer. It has been estimated by the American Institute for
Cancer Research and the World Cancer Research Fund that 30 --40 percent of
all cancers can be prevented by appropriate diets, physical activity, and
maintenance of appropriate body weight 1]. It is likely to be higher than
this for some individual cancers.
Most of the research on nutrition and cancer has been reductionist;
that is, a particular food or a nutrient has been studied in relation to
its impact on tumor formation/regression or some other end point of cancer
at a particular site in the body. These studies are very helpful in seeing
the details of the mechanisms of disease. However, they do not help give
an overall picture of how to prevent cancer on a dietary level. Even less,
they tell little of how to eat when a person already has a cancer and
would like to eat a diet that is favorable to their recovery.
This review will focus on those dietary factors which has been shown to
be contribute to increased risk of cancer and then on those additional
protective dietary factors which reduce cancer risk. Finally, some
whole-diet studies will be mentioned which give a more complete picture of
how these individual factors work together to reduce cancer risk.
Over Consumption of Energy
(Calories) Eating too much food is one of the main risk factors for
cancer. This can be shown two ways: (1) by the additional risks of
malignancies caused by obesity, and (2) by the protective effect of eating
less food.
Obesity has reached epidemic proportions in the United States.
Sixty-four percent of the adult population is overweight or obese 2].
About 1 in 50 are now severely obese (BMI > 40 kg/m2) 3]. Mokdad et al
4] found that poor diet and physical inactivity was the second leading
cause of death (400,000 per year in the USA), and would likely overtake
tobacco as the leading cause of death.
It was estimated in a recent study, from a prospective cancer
prevention cohort, that overweight and obesity accounted for 14 percent of
all cancer deaths in men and 20 percent of those in women 5]. Significant
positive associations were found between obesity and higher death rates
for the following cancers: esophagus, colon and rectum, liver,
gallbladder, pancreas, kidney, stomach (in men), prostate, breast, uterus,
cervix, and ovary 5]. The authors estimated that over 90,000 cancer deaths
per year could be avoided if the adult population all maintained a normal
weight (BMI < 25.0) 5]. Clearly, obesity is a major risk factor for
cancer.
On the other side, careful menu planning brings about an approach
entitled CRON-Calorie Restriction with Optimal Nutrition. The basic idea
is to eat a reduced amount of food (about 70 --80 percent of the amount
required to maintain "normal" body weight) while still consuming all of
the necessary amounts of vitamins, minerals, and other necessary
nutrients. The only restriction is the total amount of energy (calories)
that is consumed. While being difficult to practice, this approach has a
lot of scientific merit for being able to extend average life spans of
many species of animals including rats, mice, fish, and possibly primates
(currently being tested). Along with this life span extension is a
reduction in chronic diseases that are common to mankind, reviewed in
Hursting et al 6]. A recent meta-analysis of 14 experimental studies found
that energy restriction resulted in a 55% reduction in spontaneous tumors
in laboratory mice 7]. Calorie restriction inhibited induced mammary
tumors in mice 8] and suppressed implanted tumor growth and prolonged
survival in energy restricted mice 9]. Among Swedish women who had been
hospitalized for anorexia nervosa (definitely lower caloric intake, but
not adequate nutrition) prior to age 40, there was a 23% lower incidence
of breast cancer for nulliparous women and a 76% lower incidence for
parous women 10]. So, too many calories is definitely counter-productive,
and slightly less than normal is very advantageous.
Glucose Metabolism
Refined sugar is
a high energy, low nutrient food -- junk food. "Unrefined" sugar (honey,
evaporated cane juice, etc) is also very concentrated and is likely to
contribute to the same problems as refined sugar. Refined wheat flour
products are lacking the wheat germ and bran, so they have 78 percent less
fiber, an average of 74 percent less of the B vitamins and vitamin E, and
69 percent less of the minerals (USDA Food database, data not shown).
Concentrated sugars and refined flour products make up a large portion of
the carbohydrate intake in the average American diet. One way to measure
the impact of these foods on the body is through the glycemic index.
The glycemic index is an indication of the blood sugar response of the
body to a standardized amount of carbohydrate in a food. The glycemic load
takes into account the amount of food eaten. An international table of the
glycemic index and glycemic load of a wide variety of foods has been
published 11].
Case-control studies and prospective population studies have tested the
hypothesis that there is an association between a diet with a high
glycemic load and cancer. The case control studies have found consistent
increased risk of a high glycemic load with gastric 12], upper aero
digestive tract 13], endometrial 14], ovarian 15], colon or colorectal
cancers 16,17]. The prospective studies' results have been mixed. Some
studies showed increased risk of cancer in the whole cohort with high
glycemic load 18-20]; some studies found only increased risk among
subgroups such as sedentary, overweight subjects 21-24]; other studies
concluded that there was no increased risk for any of their cohort 25-28].
Even though there were no associations between glycemic load and
colorectal, breast, or pancreatic cancer in the Nurses' Health Study there
was still a strong link between diabetes and colorectal cancer 29].
Perhaps the dietary glycemic load is not consistently related to
glucose disposal and insulin metabolism due to individual's different
responses to the same glycemic load. Glycated hemoglobin
(HbA1c) is a time-integrated measurement of glucose control,
and indirectly, of insulin levels. Increased risk in colorectal cancer was
seen in the EPIC-Norfolk study with increasing HbA1c; subjects
with known diabetes had a three-fold increased risk of colorectal cancer
30]. In a study of a cohort in Washington county, Maryland, increased risk
of colorectal cancer was seen in subjects with elevated HbA1c,
BMI > 30 kg/m2, or who used medications to control diabetes
31]. However, glycated hemoglobin was not found to be associated with
increased risk of colorectal cancer in a small nested case-control study
within the Nurses' Health Study 32]. Elevated fasting glucose, fasting
insulin, 2 hour levels of glucose and insulin after an oral glucose
challenge, and larger waist circumference were associated with a higher
risk of colorectal cancer 33]. In multiple studies diabetes has been
linked with increased risk of colorectal cancer 34-37], endometrial cancer
38], and pancreatic cancer 35,39]. It is clear that severe dysregulation
of glucose metabolism is a risk factor for cancer. Foods which contribute
to hyperinsulinemia, such as refined sugar, foods containing refined
sugar, and refined flour products should be avoided and eliminated from a
cancer protective diet.
Low Fiber
Unrefined plant foods
typically have an abundance of fiber. Dairy products, eggs, and meat all
have this in common -- they contain no fiber. Refined grain products also
have most of the dietary fiber removed from them. So, a diet high in
animal products and refined grains (a typical diet in the USA) is low in
fiber. In prospective health studies low fiber was not found to be a risk
for breast cancer 25]. It is possible that fiber measurements are just a
surrogate measure for unrefined plant food intake. Slattery et al 40]
found an inverse correlation between vegetable, fruit and whole grain
intake plant food intake and rectal cancer, while refined grains were
associated with increased risk of rectal cancer. A threshold of about 5
daily servings of vegetables was needed to reduce cancer risk and the
effect was stronger among older subjects 40]. Many other nutrients are
co-variants with fiber, including folic acid, which is covered in detail
below.
Red Meat
Red meat has been
implicated in colon and rectal cancer. A Medline search in February 2003
uncovered 26 reports of human studies investigating the link between diet
and colon or colorectal cancer. Of the 26 reports, 21 of them reported a
significant positive relationship between red meat and colon or colorectal
cancer 17,41-64]. A recent meta-analysis also found red meat, and
processed meat, to be significantly associated with colorectal cancer 65].
Meat, and the heterocyclic amines formed in cooking, have been correlated
to breast cancer in a case-control study in Uruguay as well 66].
Omega 3:6 Ratio Imbalance
Omega 3
fats (alpha-linolenic acid, EPA, DHA) have been shown in animal studies to
be protect from cancer, while omega 6 fats (linoleic acid, arachidonic
acid) have been found to be cancer promoting fats. Now there have been
several studies that have tested this hypothesis in relation to breast
cancer, summarized in Table 1. Except for the study by London et al 67],
all of these studies found an association between a higher ratio of N-3 to
N-6 fats and reduced risk of breast cancer. Long chain N-3 and N-6 fats
have a different effect on the breast tumor suppressor genes BRCA1 and
BRCA2. Treatment of breast cell cultures with N-3 fats (EPA or DHA)
results in increased expression of these genes while arachadonic acid had
no effect 68]. Flax seed oil and DHA (from an algae source) both can be
used to increase the intake of N-3 fat, with DHA being a more efficient,
sure source.
Flax seed
Flax seed provides all of
the nutrients from this small brown or golden hard-coated seed. It is an
excellent source of dietary fiber, omega 3 fat (as alpha-linolenic acid),
and lignans. The lignans in flax seed are metabolized in the digestive
tract to enterodiol and enterolactone, which have estrogenic activity. In
fact, flax seed is a more potent source of phytoestrogens than soy
products, as flax seed intake caused a bigger change in the excretion of
2-hydroxyestrone compared to soy protein 69].
Ground flax seeds have been studied for its effect on cancer, including
several excellent studies by Lilian Thompson's research group at the
University of Toronto. In one study the flax seed, its lignan fraction, or
the oil were added to the diet of mice who had previously been
administered a chemical carcinogen to induce cancer. All three treatments
reduced the established tumor load; the lignan fraction containing
secoisolariciresinol diglycoside (SDG) and the flax seed also reduced
metastasis 70]. In another study the flax lignan SDG was fed to mice
starting 1 week after treatment with the carcinogen
dimethylbenzanthracene. The number of tumors per rat was reduced by 46%
compared to the control in this study 71]. Flax or its lignan (SDG) were
tested to see if they would prevent melanoma metastasis. The flax or
lignan fraction were fed to mice two weeks before and after injection of
melanoma cells. The flax treatment (at 2.5, 5, or 10% of diet intake)
resulted in a 32, 54, and 63 percent reduction in the number of tumors,
compared to the control 72]. The SDG, fed at amounts equivalent to the
amount in 2.5, 5, or 10% flax seed, also reduced the tumor number, from a
median number of 62 in the control group to 38, 36, and 29 tumors per
mouse in the SDG groups, respectively 73].
More recently Thompson's research group studied mice that were injected
with human breast cancer cells. After the injection the mice were fed a
basal diet (lab mouse chow) for 8 weeks while the tumors grew. Then one
group continued the basal diet and another was fed a 10% flax seed diet.
The flax seed reduced the tumor growth rate and reduced metastasis by 45%
74].
Flax seed has been shown to enhance mammary gland morphogenesis or
differentiation in mice. Nursing dams were fed the 10% flax seed diet (or
an equivalent amount of SDG). After weaning the offspring mice were fed a
regular mouse chow diet. Researchers then examined the female offspring
and found an increased number of terminal end buds and terminal ducts in
their mammary glands with more epithelial cell proliferation, all
demonstrating that mammary gland differentiation was enhanced 75]. When
these female offspring were challenged with a carcinogen to induce mammary
gland tumors there were significantly lower incidence of tumors (31% and
42% lower in the flax seed and SDG groups, respectively), significantly
lower tumor load (51% and 62% lower in the flax seed and SDG groups,
respectively), significantly lower mean tumor size (44% and 68% lower in
the flax seed and SDG groups, respectively), and significantly lower tumor
number (47% and 45% lower in the flax seed and SDG groups, respectively)
76]. So, flax seed and its lignan were able to reduce tumor growth (both
in number and size of tumors), prevent metastasis, and even cause
increased differentiation of mouse mammary tissue in suckling mice, making
the offspring less susceptible to carcinogenesis even when not consuming
any flax products.
Other researchers have tested flax seed and prostate cancer. In an
animal model using mice, Lin et al 77] found that a diet supplemented with
5% flax inhibited the growth and development of prostate cancer in their
experimental mouse model. A pilot study of 25 men who were scheduled for
prostatectomy surgery were instructed to eat a low-fat diet (20% or less
of energy intake) and to supplement with 30 g of ground flaxseed per day.
During the follow-up of an average of 34 days there were significant
changes in serum cholesterol, total testosterone, and the free androgen
index 78]. The mean proliferation index of the experimental group was
significantly lower and apoptotic indexes higher compared to historical
matched controls. Ground flax seed may be a very beneficial food for men
battling prostate cancer. However, a meta-analysis of nine cohort and
case-control studies revealed an association between flax seed oil
intake or high blood levels of alpha-linolenic acid and prostate
cancer risk 79]. It is quite likely that the lignans in flax seed are a
major component of flax's anti-cancer effects so that flax oil without the
lignans is not very beneficial. Some brands of flax seed oil retain some
of the seed particulate because of the beneficial properties of the
lignans.
Fruits and Vegetables
One of the
most important messages of modern nutrition research is that a diet rich
in fruits and vegetables protects against cancer. (The greatest message is
that this same diet protects against almost all other diseases, too,
including cardiovascular disease and diabetes.) There are many mechanisms
by which fruits and vegetables are protective, and an enormous body of
research supports the recommendation for people to eat more fruits and
vegetables.
Block et al 80] reviewed about 200 studies of cancer and fruit and
vegetable intake. A statistically significant protective effect of fruits
and vegetables was found in 128 of 156 studies that gave relative risks.
For most cancers, people in the lower quartile (1/4 of the population) who
ate the least amount of fruits and vegetables had about twice the risk of
cancer compared to those who in the upper quartile who ate the most fruits
and vegetables. Even in lung cancer, after accounting for smoking,
increasing fruits and vegetables reduces lung cancer; an additional 20 to
33 percent reduction in lung cancers is estimated 1].
Steinmetz and Potter reviewed the relationship between fruits,
vegetables, and cancer in 206 human epidemiologic studies and 22 animal
studies 81]. They found "the evidence for a protective effect of greater
vegetable and fruit consumption is consistent for cancers of the stomach,
esophagus, lung, oral cavity and pharynx, endometrium, pancreas, and
colon." Vegetables, and particularly raw vegetables, were found to be
protective; 85% of the studies that queried raw vegetable consumption
found a protective effect. Allium vegetables, carrots, green vegetables,
cruciferous vegetables, and tomatoes also had a fairly consistent
protective effect 81]. Allium vegetables (garlic, onion, leeks, and
scallions) are particularly potent and have separately been found to be
protective for stomach and colorectal cancers 82,83] and prostate cancer
84].
There are many substances that are protective in fruits and vegetables,
so that the entire effect is not very likely to be due to any single
nutrient or phytochemical. Steinmetz and Potter list possible protective
elements: dithiolthiones, isothiocyanates, indole-32-carbinol, allium
compounds, isoflavones, protease inhibitors, saponins, phytosterols,
inositol hexaphosphate, vitamin C, D-limonene, lutein, folic acid, beta
carotene (and other carotenoids), lycopene, selenium, vitamin E,
flavonoids, and dietary fiber 81].
A joint report by the World Cancer Research Fund and the American
Institute for Cancer Research found convincing evidence that a high fruit
and vegetable diet would reduce cancers of the mouth and pharynx,
esophagus, lung, stomach, and colon and rectum; evidence of probable risk
reduction was found for cancers of the larynx, pancreas, breast, and
bladder 1].
Many of the recent reports from prospective population-based studies of
diet and cancer have not found the same protective effects of fruits and
vegetables that were reported earlier in the epidemiological and
case-control studies reviewed in 85]]. One explanation is that people's
memory of what they ate in a case-cohort study may have been tainted by
their disease state. Another problem might be that the food frequency
questionnaires (FFQ) used to measure food intake might not be accurate
enough to detect differences. Such a problem was noted in the EPIC study
at the Norfolk, UK site. Using a food diary the researchers found a
significant correlation between saturated fat intake and breast cancer,
but using a FFQ there was no significant correlation 86]. So, inaccurate
measurement of fruit and vegetable intake might be part of the explanation
as well.
It must be noted that upper intakes of fruits and vegetables in these
studies are usually within the range of what people on an American
omnivorous diet normally eat. In the Nurses Health Study the upper
quintiles of fruit and vegetable intake were 4.5 and 6.2 servings/day,
respectively 87]. Similarly, the upper quintiles of fruit and vegetable
intake in the Health Professionals Follow-up Study were 4.3 and 5.4
serving/day for fruits and vegetables, respectively 87]. Intakes of fruits
and vegetables on the Hallelujah Diet are much higher, with median
reported intakes of six servings of fruits (646 g/day) and eleven servings
of vegetables per day (971 g/day) 88] in addition to a green powder from
the juice of barley leaves and alfalfa that is equivalent to approximately
another 100 g/day of fresh dark greens. So, it is very possible that the
range of intakes in the prospective population based studies do not have a
wide enough intake on the upper end to detect the true possible impact of
a very high intake of fruits and vegetables on cancer risk.
Cruciferous Vegetables
Cruciferous
vegetables (broccoli, cauliflower, cabbage, Brussels sprouts) contain
sulforophane, which has anti-cancer properties. A case-control study in
China found that intake of cruciferous vegetables, measured by urinary
secretion of isothiocyanates, was inversely related to the risk of breast
cancer; the quartile with the highest intake only had 50% of the risk of
the lowest intake group 89]. In the Nurses' Health Study a high intake of
cruciferous vegetables (5 or more servings/week vs less than two
servings/week) was associated with a 33% lower risk of non-Hodgkin's
lymphoma 90]. In the Health Professionals Follow-up Study bladder cancer
was only weakly associated with low intake of fruits and vegetables, but
high intake (5 or more servings/week vs 1 or less servings/wk) of
cruciferous vegetables was associated with a statistically significant 51%
decrease in bladder cancer 91]. Also, prostate cancer risk was found to be
reduced by cruciferous vegetable consumption in a population-based
case-control study carried out in western Washington state. Three or more
servings per week, compared to less than one serving of cruciferous
vegetables per week resulted in a statistically significant 41% decrease
in prostate cancer risk 92]. Similar protective effects of cruciferous
vegetables were seen in a multi-ethnic case-control study 93]. A
prospective study in Shanghai, China found that men with detectable
amounts of isothiocyanates in their urine (metabolic products that come
from cruciferous vegetables) had a 35% decreased risk of lung cancer.
Among men that had one or two genetic polymorphisms that caused them to
eliminate these isothiocyanates slower there was a 64% or 72% decreased
risk of lung cancer, respectively 94].
Broccoli sprouts have a very high concentration of sulforophane since
this compound originates in the seed and is not made in the plant as it
grows 95,96]. One sprout contains all of the sulforophane that is present
in a full-grown broccoli plant. So, if sulforophane is especially
cancer-protective, it would seem reasonable to include some broccoli
sprouts in an anti-cancer diet.
Selenium
Selenium is a mineral with
anti-cancer properties. Many studies in the last several years have shown
that selenium is a potent protective nutrient for some forms of cancer.
The Arizona Cancer Center posted a selenium fact sheet listing the major
functions of selenium in the body 97]. These functions are as follows:
1. Selenium is present in the active site of many enzymes, including
thioredoxin reductase, which catalyze oxidation-reduction reactions. These
reactions may encourage cancerous cells to under apoptosis.
2. Selenium is a component of the antioxidant enzyme glutathione
peroxidase.
3. Selenium improved the immune systems' ability to respond to
infections.
4. Selenium causes the formation of natural killer cells.
5. P450 enzymes in the liver may be induced by selenium, leading to
detoxification of some carcinogenic molecules.
6. Selenium inhibits prostaglandins that cause inflammation.
7. Selenium enhances male fertility by increased sperm motility.
8. Selenium can decrease the rate of tumor growth.
A serendipitous randomized, double-blind, controlled trial of a
200mu]g/day selenium supplement in the southeastern region of the USA
(where soil selenium levels are low) found that the primary endpoints of
skin cancer were not improved by the selenium supplement, but that other
cancer incidence rates were decreased by selenium 98,99]. There was a
significant reduction in total cancer incidence (105 vs 137 cases, P =
0.03), prostate cancer (22 vs 42 cases, P = 0.005), a marginally
significant reduction in colorectal cancer incidence (9 vs 19 cases, P =
0.057), and a reduction in cancer mortality, all cancer sites (40 vs 66
deaths, P = 0.008) (selenium versus control group cases reported,
respectively) 98]. The selenium supplement was most effective in
ex-smokers and for those who began the study with the lowest levels of
serum selenium. Several prospective studies have also examined the role of
selenium in cancer prevention, particularly for prostate cancer,
summarized in Table 2.
Overall, it appears that poor selenium levels, especially for men, are
a cancer risk. If a person has low selenium levels and other antioxidant
defenses are also low the cancer risk is increased even further. Women do
not appear to be as sensitive to selenium, as breast cancer has not been
found to be influenced by selenium status in several studies 100-104],
although both men and women were found to be protected by higher levels of
selenium from colon cancer 100] and lung cancer 105,106]. Good vegetarian
sources of selenium are whole grains and legumes grown in selenium-rich
soil in the western United States, brazil nuts (by far the most dense
source of selenium), nutritional yeast, brewers yeast, and sunflower
seeds.
Chlorophyll
All green plants also
contain chlorophyll, the light-collecting molecule. Chlorophyll and its
derivatives are very effective at binding polycyclic aromatic hydrocarbons
(carcinogens largely from incomplete combustion of fuels), heterocyclic
amines (generated when grilling foods), aflatoxin (a toxin from molds in
foods which causes liver cancer), and other hydrophobic molecules. The
chlorophyll-carcinogen complex is much harder for the body to absorb, so
most of it is swept out with the feces. The chemoprotective effect of
chlorophyll and its derivatives has been tested in laboratory cell
cultures and animals 107,108]. There is so much compelling evidence for
anti-carcinogenic effects of chlorophyll that a prospective randomized
controlled trial is being conducted in Qidong, China to see if
chlorophyllin can reduce the amount of liver cancer cases, which arise
from aflatoxin exposure in their foods (corn, peanuts, soy sauce, and
fermented soy beans). A 55% reduction in aflatoxin-DNA adducts were found
in the group that took 100 mg of chlorophyllin three times a day 109]. It
was supposed that the chlorophyllin bound up aflatoxins, but there were
chlorophyllin derivatives also detected in the sera (which had a green
tint to it) of the volunteers who took the supplement, indicating a
possible role in the body besides binding carcinogens in the gut 110].
Protective Vitamins
Vitamin B-12
Vitamin B-12 has not
been proven to be an anti-cancer agent, but there is some evidence
indicating that it could be beneficial. The form of administered vitamin
B-12 may be important.
Some experimental cancer studies have been carried out with various
forms of vitamin B-12. Methylcobalamin inhibited tumor growth of SC-3
injected into mice 111], and caused SC-3 mouse mammary tumor cells to
undergo apoptosis, even when stimulated to grow by the presence of
growth-inducing androgen 112]. Methylcobalamin, but not cyanocobalamin,
increased the survival time of mice bearing implanted leukemia tumor cells
113]. 5'-deoxyadenosylcobalamin and methylcobalamin, but not
cyanocobalamin, were shown to be effective cytotoxic agents 114].
Methylcobalamin also was able to increase survival time and reduce tumor
growth in laboratory mice 115].
Laboratory mechanistic evidence for the effects of vitamin B12 were
seen in a laboratory study with vitamin B-12 deficient rats. Choi et al
116] found that the colonic DNA of the B-12 deficient rats had a 35%
decrease in genomic methylation and a 105% increase in uracil
incorporation, both changes that could increase risk of carcinogenesis. In
two prospective studies (one in Washington Country, Maryland and the
Nurses' Health Study) a relation between lower vitamin B12 status (but not
deficiency) and statistically significant higher risk of breast cancer was
found 117,118]. So, there is evidence from laboratory studies, prospective
cohort studies, and mechanistic studies showing that vitamin B-12 is an
important nutrient for genetic stability, DNA repair, carcinogenesis, and
cancer therapy.
Folic Acid
Folic acid is the dark
green leafy vegetable vitamin. It has an integral role in DNA methylation
and DNA synthesis. Folic acid works in conjunction with vitamin B-6 and
vitamin B-12 in the single carbon methyl cycle. If insufficient folic acid
is not available uracil is substituted for thymidine in DNA, which leads
to DNA strand breakage. About 10% of the US population (and higher
percentages among the poor) has low enough intakes of folic acid to make
this a common problem 119]. As shown in Tables 3 and 4, many studies have
found a significant reduction in colon, rectal, and breast cancer with
higher intakes of folic acid and their related nutrients (vitamin B-6 and
B-12). Alcohol is an antagonist of folate, so that drinking alcoholic
beverages greatly magnifies the cancer risk of a low-folate diet. Genetic
polymorphisms (common single DNA base mutations resulting in a different
amino acid encoded into a protein) in the methylenetetrahydrofolate
reductase and the methionine synthase genes which increase the relative
amount of folate available for DNA synthesis and repair also reduces the
risk of colon cancer 120-123]. Cravo et al 124] used 5 mg of folic acid a
day (a supraphysiological dose) in a prospective, controlled, cross-over
study of 20 patients with colonic adenoma polyps. They found that the
folic acid could reverse DNA hypomethylation in 7 of 12 patients who had
only one polyp.
Folate may be more important for rapidly dividing tissue, like the
colonic mucosa. Therefore, the cancer risk associated with low folate
intake is probably higher for colon cancer than for breast cancer. Most of
the breast cancer studies only found a protective effect of folate among
women who consumed alcohol (see Table 4). However, among women residents
of Shanghai who consumed no alcohol, no vitamin supplements and ate
unprocessed, unfortified foods there was a 29% decreased risk of breast
cancer among those with the highest intake of folate 125]. So, there may
be a true protective effect that is masked in the western populations by
so many other risk factors. Two studies showed that the risk of cancer due
to family history can be modified by high folate intake, so a prudent
anti-cancer diet would be high in dark green leafy vegetables. The mean
intake of folic acid on the Hallelujah Diet was 594mu]g/day for men and
487mu]g/day for women 88].
Vitamin D
Vitamin D is produced
primarily from the exposure of the skin to sunshine. Even casual exposure
of the face, hands, and arms in the summer generates a large amount of
vitamin D. In fact, simulated sunshine, equivalent to standing on a sunny
beach until a slight pinkness of the skin was detected, was equivalent to
a 20,000 IU oral dose of vitamin D2 126]. (Note that the RDA is
400 IU for most adults.) It has been estimated that 1,000 IU per day is
the minimal amount needed to maintain adequate levels of vitamin D in the
absence of sunshine 126], and that up to 4,000 IU per day can be safely
used with additional benefit 127].
The concentration of the active hormonal form of vitamin D is tightly
regulated in the blood by the kidneys. This active hormonal form of
vitamin D has the potent anti-cancer properties. It has been discovered
that various types of normal and cancerous tissues, including prostate
cells 128], colon tissue 129], breast, ovarian and cervical tissue 130],
pancreatic tissue 131] and a lung cancer cell line 132] all have the
ability to convert the major circulating form of vitamin D, 25(OH)D, into
the active hormonal form, 1,25(OH)2D. So, there is a local
mechanism in many tissues of the body for converting the form of vitamin D
in the body that is elevated by sunshine exposure into a hormone that has
anticancer activity.
Indeed, 25(OH)D has been shown to inhibit growth of colonic epithelial
cells 133], primary prostatic epithelial cells 134], and pancreatic cells
131]. So, the laboratory work is confirming what had been seen some time
ago in ecological studies of populations and sunshine exposure.
The mortality rates for colon, breast, and ovary cancer in the USA show
a marked north-south gradient 135]. In ecological studies of populations
and sunlight exposure (no individual data) sunlight has been found to have
a protective effect for prostate cancer 136], ovarian cancer 137], and
breast cancer 138]. Recently Grant found that sunlight was also protective
for bladder, endometrial, renal cancer, multiple myeloma, and Non-Hodgkins
lymphoma in Europe 139] and bladder, esophageal, kidney, lung, pancreatic,
rectal, stomach, and corpus uteri cancer in the USA 140]. Several
prospective studies of vitamin D and cancer have also shown a protective
effect of vitamin D (see Table 5). It could be that sunshine and vitamin D
are protective factors for cancers of many organs that can convert 25(OH)D
into 1,25(OH)D2.
Antioxidants
Carotenoids have been studied vigorously to see if these
colorful compounds can decrease cancer risk. In ecological studies and
early case-control studies it appeared thatbeta]-carotene was a
cancer-protective agent. Randomized controlled trials ofbeta]-carotene
found that the isolated nutrient was either neutral 141] or actually
increased risk of lung cancer in smokers 142,143]. Beta-carotene may be a
marker for intake of fruits and vegetables, but it does not have a
powerful protective effect in isolated pharmacological doses.
However, there is a large body of literature that indicates that
dietary carotenoids are cancer preventative (See Table 6). Alpha-carotene
has been found to be a stronger protective agent than its well-known
isomerbeta]-carotene. Studies tend to agree that overall intake of
carotenoids is more protective than a high intake of a single carotenoid.
So, a variety of fruits and vegetables is still a better anti-cancer
strategy than just using a single vegetable high in a specific
carotenoid.
The richest source ofalpha]-carotene is carrots and carrot juice, with
pumpkins and winter squash as a second most-dense source. There is
approximately onemu]g ofalpha]-carotene for every twomu]g ofbeta]-carotene
in carrots. The most common sources ofbeta]-cryptoxanthin are citrus
fruits and red sweet peppers.
Lycopene
Of the various carotenoids
lycopene has been found to be very protective, particularly for prostate
cancer. The major dietary source of lycopene is tomatoes, with the
lycopene in cooked tomatoes being more bioavailable than that in raw
tomatoes. Several prospective cohort studies have found associations
between high intake of lycopene and reduced incidence of prostate cancer,
though not all studies have produced consistent results 144,145]. Some
studies suffer from a lack of good correlation between lycopene intake
assessed by questionnaire and actual serum levels, and other studies
measured intakes among a population that consumed very few tomato
products. The studies with positive results will be reviewed here.
In the Health Professionals Follow-up Study there was a 21% decrease in
prostate cancer risk, comparing the highest quintile of lycopene intake
with the lowest quintile. Combined intake of tomatoes, tomato sauce,
tomato juice, and pizza (which accounted for 82% of the lycopene intake)
were associated with a 35% lower risk of prostate cancer. Furthermore,
lycopene was even more protective for advanced stages of prostate cancer,
with a 53% decrease in risk 146]. A more recent follow-up report on this
same cohort of men confirmed these original findings that lycopene or
frequent tomato intake is associated with about a 30 --40% decrease in
risk of prostate cancer, especially advanced prostate cancer 147].
In addition to the two reports above a nested case control study from
the Health Professional Follow-up Study with 450 cases and controls found
an inverse relation between plasma lycopene and prostate cancer risk (OR
0.48) among older subjects (>65 years of age) without a family history
of prostate cancer 148]. Among younger men high plasmabeta]-carotene was
associated with a statistically significant 64% decrease in prostate
cancer risk. So, the results for lycopene have been found for dietary
intakes as well as plasma levels.
In a nested case-control study from the Physicians' Health Study
cohort, a placebo-controlled study of aspirin andbeta]-carotene, there was
a 60% reduction in advanced prostate cancer risk (P-trend = 0.006) for
those subjects in the placebo group with the highest plasma lycopene
levels, compared to the lowest quintile. Thebeta]-carotene also had a
protective effect, especially for those men with low lycopene levels
149].
In addition to these observational studies, two clinical trials have
been conducted to supplement lycopene for a short period before radical
prostatectomy. In one study 30 mg/day of lycopene were given to 15 men in
the intervention group while the 11 men were in the control group were
instructed to follow the National Cancer Institute's recommendations to
consume at least 5 servings of fruits and vegetables daily. Results showed
that the lycopene slowed the growth of prostate cancer. Prostate tissue
lycopene concentration was 47% higher in the intervention group. Subjects
that took the lycopene for 3 weeks had smaller tumors, less involvement of
the surgical margins, and less diffuse involvement of the prostate by
pre-cancerous high-grade prostatic intraepithelial neoplasia 150]. In
another study before radical prostatectomy surgery 32 men were given a
tomato sauce-based pasta dish every day, which supplied 30 mg of lycopene
per day. After 3 weeks serum and prostate lycopene levels increaed 2-fold
and 2.9-fold, respectively. PSA levels decreased 17%, as seen also by
Kucuk et al 150]. Oxidative DNA damage was 21% lower in subjects'
leukocytes and 28% lower in prostate tissue, compared to non-study
controls. The apoptotic index was 3-fold higher in the resected prostate
tissue, compared to biopsy tissue 151]. These intervention studies raise
the question of what could have been done in this intervention was longer
and combined synergistically with other effective intervention methods,
such as flax seed, increased selenium and possibly vitamin E, in the
context of a diet high in fruits and vegetable?
Vitamin C
Vitamin C, or ascorbic
acid, has been studied in relation to health and is the most common
supplement taken in the USA. Low blood levels of ascorbic acid are
detrimental to health (for a recent article see Fletcher et al 152]) and
vitamin C is correlated with overall good health and cancer prevention
153]. Use of vitamin C for cancer therapy was popularized by Linus
Pauling. At high concentrations ascorbate is preferentially toxic to
cancer cells. There is some evidence that large doses of vitamin C, either
in multiple divided oral doses or intravenously, have beneficial effects
in cancer therapy 154-156]. Oral doses, even in multiple divided doses,
are not as effective as intravenous administration. Vitamin C at a dose of
1.25 g administered orally produced mean peak plasma concentrations of 135
plus minus] 21mu]mol/L compared with 885 plus minus] 201mu]mol/L for
intravenous administration 154].
While vitamin C is quite possibly an effective substance, the amounts
required for these therapeutic effects are obviously beyond dietary
intakes. However, intravenous ascorbate may be a very beneficial adjuvant
therapy for cancer with no negative side effects when administered
properly.
Other Antioxidants
There are many
more substances that will have some benefit for cancer therapy. Most of
these substances are found in foods, but their effective doses for therapy
are much higher than the normal concentration in the food. For example,
grape seed extract contains proanthocyanidin, which shows anticarcinogenic
properties (reviewed by Cos et al \ 157]. Also, green tea contains a
flavanol, epigallocatechin-3-gallate (EGCG), which can inhibit
metalloproteinases, among several possible other mechanisms 158]. And
there are claims for various other herbal substances and extracts that
might be of benefit, which are beyond the scope of this review.
Probiotics
The bacteria that reside
in the intestinal tract generally have a symbiotic relationship with their
host. Beneficial bacteria produce natural antibiotics to keep pathogenic
bugs in check (preventing diarrhea and infections) and produce some B
vitamins in the small intestine where they can be utilized. Beneficial
bacteria help with food digestion by providing extra enzymes, such as
lactase, in the small intestine. Beneficial bacteria help strengthen the
immune system right in the gut where much of the interaction between the
outside world and the body goes on. Beneficial bacteria can help prevent
food allergies. They can help prevent cancer at various stages of
development. These good bacteria can improve mineral absorption,
maximizing food utilization.
However, the balance of beneficial and potentially pathogenic bacteria
in the gut is dependent on the diet. Vegetable fiber encourages the growth
of beneficial bacteria. A group of Adventist vegetarians was found to have
a higher amount of beneficial bacteria and lower amount of potentially
pathogenic bacteria compared to non-vegetarians on a conventional American
diet 159]. Differences in bacterial populations were seen between patients
who recently had a colon polyp removed, Japanese-Hawaiians, North American
Caucasians, native rural Japanese, and rural native Africans.
Lactobacillus species and Eubacterium aerofaciens, both
producers of lactic acid, were associated with the populations with the
lower risk of colon cancer, while Bacteroides and
Bifidobacterium species were associated with higher risk of colon
cancer 160]
There is a solid theoretical basis for why probiotics should help
prevent cancer, especially colon cancer, and even reverse cancer.
Probiotics produce short chain fatty acids in the colon, which acidify the
environment. Lower colon pH is associated with lower incidence of colon
cancer. Probiotic bacteria reduce the level of procarcinogenic enzymes
such as beta-glucuronidase, nitroreductase, and azoreductase 161].
L. casei was used in two trials of patients with superficial
bladder cancer. In the first trial, the probiotic group had a 50% disease
free time of 350 days, compared to 195 days for the control group 162].
The second trial also showed that the probiotics worked better than the
placebo, except for multiple recurring tumors 163].
Except for the two studies noted above, most of the research of
probiotics and cancer has been done in animals. Studies have looked at
markers of tumor growth or at animals with chemically induced tumors.
Studies in rats have shown that probiotics can inhibit the formation of
aberrant crypt foci, thought to be a pre-cancerous lesion in the colon.
Some of the best results were obtained with a probiotic strain consumed
with inulin, a type of fructooligosaccharide. Total aberrant crypt foci,
chemically induced, were reduced 74% by the treatment of rats with inulin
and B. longum, but only 29 and 21% by B. longum and inulin
alone, respectively 164]. There was a synergistic effect in using both
products together. Similar synergy was seen in rats with
azoxymethane-induced colon cancer in another study. Rats fed Raftilose, a
mixture of inulin and oligofructose, or Raftilose with Lactobacilli
rhamnosus (LGG) and Bifidobacterium lactis (Bb12) had a
significantly lower number of tumors compared to the control group 165]. A
probiotic mixture, without any prebiotic, given to rats fed azoxymethane
reduced colon tumors compared to the control (50% vs 90%), and also
reduced the number of tumors per tumor-bearing rat 166].
In lab mice bred to be susceptible to colitis and colon cancer, a
probiotic supplement, Lactobacillus salivarium ssp. Salivarius
UCC118, reduced fecal coliform levels, the number of potentially
pathogenic Clostridium perfringens, and reduced intestinal
inflammation. In this small study two mice died of fulminant colitis and 5
mice developed adenocarcinoma in the control group of 10 mice, while there
was no colitis and only 1 mouse with adenocarcinoma in the probiotic test
group 167].
The research on probiotics and disease is still an emerging field.
There is a high degree of variation of health benefits between different
strains of bacteria. As new methods for selecting and screening probiotics
become available, the field will be able to advance more rapidly.
Oral Enzymes
Many people diagnosed
with cancer have digestion or intestinal tract disorders as well. Impaired
digestion will greatly hinder a nutritional approach to treating cancer.
If the nutrients cannot be released from the food and taken up by the
body, then the excellent food provided by the Hallelujah Diet will go to
waste. Digestive enzyme supplements are used to ensure proper and adequate
digestion of food. Even raw foods, which contain many digestive enzymes to
assist in their digestion, will be more thoroughly digested with less of
the body's own resources with the use of digestive enzymes. So, the
enzymes taken with meals do not have a direct effect upon a tumor, but
assist the body in getting all of the nutrition out of the food for
healing and restoring the body to normal function. Recently, an in vitro
system was used to test the use of supplemental digestive enzymes. The
digestive enzymes improved the digestibility and bioaccessibility of
proteins and carbohydrates in the lumen of the small intestine, not only
under impaired digestive conditions, but also in healthy human digestion
168].
There is evidence that indicates the presence of an enteropancreatic
circulation of digestive enzymes 169]. Digestive enzymes appear to be
preferentially absorbed into the bloodstream and then reaccumulated by the
pancreas for use again. There appears to be a mechanism by which digestive
enzymes can reach systemic circulation.
Enzymes, especially proteases, if they reach systemic circulation, can
have direct anti-tumor activity. Wald et al 170] reported on the
anti-metastatic effect of enzyme supplements. Mice inoculated with the
Lewis lung carcinoma were treated with a proteolytic enzyme supplement,
given rectally (to avoid digestion). The primary tumor was cut out, so
that the metastatic spread of the cancer could be measured. After surgical
removal of the primary tumor (day 0), 90% of the control mice died by day
18 due to metastasized tumors. In the first group, which received the
rectal enzyme supplement from the time of the tumor-removal surgery, 30%
of the mice had died from metastasized cancer by day 25. In the second
group, which received the enzymes from 6 days prior to removal of the
primary tumor, only 10% of the animals showed the metastatic process by
day 15. In the third group, which received the enzyme treatment since the
initial inoculation of the Lewis lung carcinoma, no metastatic spread of
the tumor was discernible. One hundred day-survival rates for the control,
first, second, and third groups were 0, 60%, 90%, and 100%.
In a similar experiment, an enzyme mixture of papain, trypsin, and
chymotrypsin, as used in the preparation Wobe-Mugos E, was rectally given
to mice that were inoculated with melanoma cells. Survival time was
prolonged in the test group (38 days in the enzyme group compared to 24
days in the control mice) and 3 of the 10 enzyme-supplemented mice were
cured. Again, a strong anti-metastatic effect of the proteolytic enzymes
was seen 171].
Further evidence of the efficacy of oral enzyme supplementation is
available from clinical trials in Europe. Two different studies have
demonstrated that two different oral proteolytic enzyme supplements were
able to reduce high levels of transforming growth factorbeta], which may
be a factor in some cancers 172,173]. In the Slovak Republic an oral
enzyme supplement was tested in a placebo-controlled trial of multiple
myeloma. For stage III multiple myeloma, control group survival was 47
months, compared to 83 months (a 3 year gain) for patients who took the
oral enzymes for more than 6 months 174].
Enzyme supplements have also been shown to reduce side effects of
cancer therapy. Enzyme supplementation resulted in fewer side effects for
women undergoing radiation therapy for carcinomas of the uterine cervix
175], for patients undergoing radiation therapy for head and neck cancers
176], and for colorectal cancer patients undergoing conventional cancer
treatments 177]. In a large multi-site study in Germany women undergoing
conventional cancer therapy were put into a control group or a group that
received an oral enzyme supplement. Disease and therapy related symptoms
were all reduced, except tumor pain, by the enzyme supplement. Also,
survival was longer with less recurrence and less metastases in the enzyme
group 178]. In all of these studies the oral enzyme supplements were well
tolerated, with only a small amount of mild to moderate gastrointestinal
symptoms.
Even though these few studies don't give a lot of evidence of the
effectiveness of oral enzyme supplementation, it is clear that there are
some circumstances that will be helped by enzyme supplementation, with
very little danger of negative side effects. At the least, enzymes will
improve digestion and lessen the digestive burden on the body, leaving
more reserves for disease eradication. However, as the research indicates,
the effect may be much greater than that, with the potential for direct
anti-tumor activity.
Whole Diet Studies
A diet-based
cancer therapy, the Gerson Therapy, was used to treat melanoma cancer. The
five-year survival rates from their therapy compared very favorably to
conventional therapy reported in the medical literature, especially for
more advanced stages of melanoma 179] (see Table 7).
An Italian cohort of 8,984 women was followed for an average of 9.5
years, with 207 incident cases of breast cancer during that time. Their
diets were analyzed by patterns -- salad vegetables (raw vegetables and
olive oil), western (potatoes, red meat, eggs and butter), canteen (pasta
and tomato sauce), and prudent (cooked vegetables, pulses, and fish). Only
the salad vegetable diet pattern was associated with a significantly lower
risk of breast cancer, about 35% lower. For women of normal weight (BMI
<25) the salad vegetable pattern was even more protective, about a 61%
decreased risk of breast cancer 180]. The overall dietary pattern does
make a very significant difference.
In US-based studies the "prudent" diet has been shown to be protective
for colon cancer, while the "western" diet has been shown to be
detrimental. The "western" dietary pattern, with its higher intakes of red
meat and processed meats, sweets and desserts, French fries, and refined
grains, was associated with a 46% increase relative risk of colon cancer
in the Nurses' Health Study 45]. Slattery et al 17] found a two-fold
increase in relative risk of colon cancer associated with a "western"
dietary pattern, and a 35 --40% decrease in relative risk associated with
the "prudent" pattern, especially among those diagnosed at an earlier age
(<67 years old). The "salad vegetable" pattern is still more likely to
be protective compared to the prudent dietary pattern, but this pattern
did not exist in this study population.
In an analysis of the colon cancer data from the Health Professionals
Follow-up Study, Platz et al 56] found that there was a 71% decrease in
colon cancer risk when men with none of six established risk factors were
compared to men with at least one of these risk factors (obesity, physical
inactivity, alcohol consumption, early adulthood cigarette smoking, red
meat consumption, and low intake of folic acid from supplements). So, if
all men had the same health profile as these healthier 3% of the study
population, colon cancer rates would have been only 29% of what they
measured.
A plant-based dietary pattern in being currently tested in the Women's
healthy Eating and Living (WHEL) Study. About 3,000 women who were treated
for an early stage of breast cancer have been randomized into two groups.
The dietary goals for the test group of the study are 5 servings of
vegetables, 16 oz of vegetable juice, 3 servings of fruit, 30 g of fiber,
and <20% of energy from fat. No guidelines were given for animal
product intake, and initial results seem to confirm, since there were no
changes in body weight, total cholesterol, or LDL cholesterol 181], which
would be affected by animal protein intake. However, over the first year
of follow-up vegetable intake did increase to seven servings/day, fruit
intake increased to 3.9 servings/day, energy from fat decreased from 28%
to 23%. Also, plasma carotenoid concentrations increased significantly in
the intervention group, but not in the control group.alpha]-Carotene
increased 223%,beta]-carotene increased 87%, lutein increase 29%, and
lycopene increased 17% 182], indicating that a substantial dietary change
had been made by these women. It will be very interesting to follow the
results of this study.
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