Pii: b978-0-12-088393-6.50084-

Dietary Supplements in Cancer Prevention MARY FRANCES PICCIANO, BARBARA E. COHEN, AND PAUL R. THOMAS must be taken to determine the circumstances under whichdietary supplements may have beneficial health effects on Dietary supplements are regulated in the United States by cancer or on any other disease or medical disorder. Special the Food and Drug Administration (FDA) under authority of attention must be given to the circumstances that could influ- the Federal Food, Drug, and Cosmetic Act (FFDCA). An ence the effects of dietary supplements, including the timing amendment to the FFDCA, the Dietary Supplement Health of supplement use, dose and dose–response, the role of and Education Act of 1994 (DSHEA), defines a dietary sup- specific supplement components, and the impact of interac- plement as a product that is intended to supplement the diet tive factors. This chapter addresses these issues with and contains at least one or more of certain dietary ingredi- selected examples. Although it is beyond the scope of this ents, such as a vitamin, mineral, herb or other botanical, or chapter to address these issues for all supplements, the an amino acid. These products may not be represented as points made here are relevant to almost all categories of conventional foods and are marketed in forms that include capsules, tablets, gelcaps, softgels, and powders. Althoughmanufacturers are required to have evidence to support theirclaims of a dietary supplement’s safety and efficacy, FDA approval is not required before a product is marketed.
The passage of DSHEA played a role in increasing the use of supplements in the United States by ensuring consumer access to a wide range of such products (U.S.
As many people are motivated to change their food- Congress, 1994). The legislation also created the Office of intake behaviors with the hope of improving their health, Dietary Supplements within the National Institutes of Health they also are using a variety of alternative strategies (NIH) with the mission “to strengthen knowledge and under- including the consumption of vitamin, mineral, herbal, standing of dietary supplements by evaluating scientific and botanical supplements (Halsted, 2003). The following information, stimulating and supporting research, dissemi- two subsections present the most recent data on the preva- nating research results, and educating the public to foster an lence of and reasons for dietary supplement use, first in the enhanced quality of life and health for the U.S. population” general population and then among people diagnosed with (Office of Dietary Supplements, 2004).
Dietary supplements are commonly purchased and con- sumed in the United States even though they may not have proven benefits for the general population and, for some, may have harmful effects. However, the possibility that sup-plements help to prevent cancer development, progression, Data from the latest National Health and Nutrition Exam- or reoccurrence attracts many people. A rigorous approach ination Survey (NHANES) indicate that 52% of the U.S.
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adult population took some sort of dietary supplement in garlic and lecithin (Radimer et al., 2000). In 2003, the top- 1999–2000, most commonly a multivitamin and multimin- selling herbals were weight-loss blends with and without eral supplement (35%) (Radimer et al., 2004). The 1987 ephedra and glucosamine/chondroitin sulfate (Nutrition National Health Interview Survey (NHIS), conducted by the Business Journal, 2004). It is interesting that many dietary Centers for Disease Control and Prevention, found that supplement users report that they do not discuss their 51.1% of U.S. adults used a vitamin or mineral supplement, supplement use with their physicians because they believe but only 23.1% on a daily basis (Subar and Block, 1990).
that physicians are biased against, and not knowledgeable The daily use of vitamin or mineral supplements increased enough about, supplements (Hensrud et al., 1999).
to 33.9% in the 2000 NHIS, and 6% of the respondentsreported using nonvitamin or nonmineral supplements (Millen et al., 2004). The 2002 NHIS indicated that 38.2 million American adults (~19%) use nonvitamin nonmineralsupplements, primarily botanical products (Barnes et al., Given the prevalence and usage trends of dietary supple- 2004). Market data show that in 2004 the sale of vitamins, ments in the general population, it is not surprising to see herbs and botanicals, sports nutrition supplements, minerals, similar trends among people who have been diagnosed with meal supplements, and other specialty supplements totaled cancer. However, the majority of prevalence studies do not $20.33 billion, representing a $4.27 billion (26.6%) increase collect data on supplement use before cancer diagnosis but since 1999 (Nutrition Business Journal, 2005). The 2004 only provide information on supplement use after diagnosis.
sales of vitamins and minerals, in either a multivitamin- This disallows inferences to be made on the role of a cancer multimineral or single-nutrient form, were 42% of all sales diagnosis as a motivator for dietary supplement use. In general, motivators for supplement use among cancer Data from NHANES and other research efforts have patients include maintenance of health, increased well- also been useful in identifying characteristics of supplement being, prevention of recurrence, and alleviation of symp- users and the reasons for supplement use. These findings toms. Tables 1, 2, and 3 summarize studies published since indicate that the highest usage of vitamin and mineral sup- 2000 that provide prevalence data on dietary supplement use plements is associated with being female, having an educa- among people with cancer. Table 1 summarizes studies with tion beyond high school, having a higher income, being data from pools of cancer patients, generally adults. The non-Hispanic white, and being older (Steward et al., 1985; range of any supplement use in this set of studies is between Koplan et al., 1986; Medeiros et al., 1989; Moss et al., 1989; 29 and 80%. Multivitamins were the most frequently used Subar and Block, 1990; Bender et al., 1992; Slesinski et al., supplement; vitamins A, B, C, and E were the most fre- 1995; Lyle et al., 1998; Newman et al., 1998). This profile quently used single vitamins; calcium and selenium were the is similar to that for people using herbal supplements, with most frequently used single minerals; garlic, ginseng, and a few exceptions. Herbal use does not increase with age, and soy were the most frequently used botanicals; and shark although those with health insurance are more likely to use cartilage, hydrazine sulfate, and coenzyme Q10 (CoQ10) the vitamins or minerals, those without health insurance are most frequently used nonbotanical dietary supplements.
more likely to use herbs (Fennell, 2004). Nationally repre- However, the list of other supplements used by any propor- sentative data from NHANES indicate that although an tion of the study samples is extensive. Table 2 focuses on increase in the use of supplements has occurred since the studies with data from people with specific cancer diagnoses passage of DSHEA, usage patterns among various demo- (in which the range of supplement use is between 35 and graphic groups are similar to those reported by researchers 64%), and Table 3 presents two studies published on pedi- using nonrepresentative population samples.
Reasons cited for usage of dietary supplements by Among studies on the general adult cancer patient popu- various subgroups suggest that a large segment of people lation, two compared dietary supplement usage by people living in the United States is adopting a health-promotion with cancer to people not diagnosed with cancer. The first strategy that includes seeking alternative forms of medicine of these analyzed data from the NHIS in 1987 and 1992 (Slesinski et al., 1995; Eliason et al., 1997; Eisenberg et al., (McDavid et al., 2001). Among both populations in this 1998; Patterson et al., 1998; Gilbert, 1999; Hensrud et al., nationally representative survey, multivitamins were more 1999; Radimer et al., 2000; Greger, 2001). Supplements are commonly used than other supplements (taken by 75%), used to improve nutrition, make up for nutrients missing in although ~50% of both groups reported taking vitamin C. It the diet, decrease susceptibility to or severity of disease, is important to note that this is not necessarily daily use, but increase energy (vitality), or improve performance. Herbal any use during the period for which data were collected.
and botanical preparations are frequently used to supple- Unfortunately, the small sample size of the cancer cohort ment conventional medical treatments. Those most com- (689 people) provided little power to test differences monly used by the general population before 1995 were between this group and those not reporting a diagnosis of Prevalence of Dietary Supplement Use among People Diagnosed with Cancer Reference
Type of study
Location
Population
among women (34.9%) than men (13.8%), and vitaminA use was higher among men (9.0%) than women (7.6%) high-dose vitamin C [at >10 g/day] and vitamin E), 34% took herbal supplements (23identified), and 16% took othersupplements (such as shark cartilage and hydrazine sulfate);admitting use of unconventionaltherapies increased from 7% to 40% when patients directlyqueried used botanical supplements(typically garlic, ginseng, soy, ginkgo, and echinacea), and67 used individual minerals(calcium, followed by iron andselenium) 57.5% had high use (two or more per day) of vitamin andmineral supplements, and 16.0% and 20.7% had high use of herbal and specialty supplements; strongest positive associations were found for cranberry pills with bladder cancer, zinc with ovarian cancer, soy with prostate cancer,melatonin with cervical cancer, and vitamin D with thyroid cancer 42.7% of women took any herbal or other type of supplement; conclusion: men and women “differ considerably”in their use of complementaryand alternative medicine,including use of dietarysupplements improved health and energy;38% did not disclose supplementuse to their physicians Prevalence of Dietary Supplement Use by Diagnosis of Breast, Prostate, and Colorectal Cancer Reference
Type of study
Location
Population
herbs; more than half did nottake supplements beforediagnosis, and majoritydiscussed supplement use withdoctor 29 used an herbal supplement(most commonly lycopene andsaw palmetto); many believedsupplements helped cure their cancer and helped them to feelbetter ≥500mg/day), 42% vitamin C(24% at intakes ≥1000 mg/day), 11% vitamin A and carotenoids,and ~10% antioxidant mixtures;trend toward use of multi-ingredient products containingherbs; supplements commonlyused for general health and “to feel better” cancer. The second such study offering comparative statis- study design and outcome indicators (Metz et al., 2001; tics was the Vitamins and Lifestyle (VITAL) study, com- Kumar et al., 2002; Hedderson et al., 2004; Jazieh et al., posed of a self-selected sample of adults in western Washington State, most of whom took at least one vitamin The differences in results reported in Table 2 also reflect supplement at the start (Greenlee et al., 2004). This study, the variation in study design, sample selection, and out- which focused on supplement use at least five times weekly, come variables. Patterson et al. (2003) only report on new showed little difference among cancer patients and those supplements taken after a diagnosis of breast, prostate, and without cancer with respect to both multivitamin, single colorectal cancer and do not include usual supplements vitamin or mineral supplement, and herbal supplement use.
taken before and after diagnosis. Hall et al. (2003) limited Differences among prevalence rates reported in these their study to men with prostate cancer, and Lengacher et al.
and the remaining four studies in Table 1 reflect variation in (2002) and Salminen et al. (2004) limited their studies to Prevalence of Dietary Supplement Use among Pediatric Cancer Patients Reference
Type of study
Location
Population
cartilage), herbal supplements(14), single-nutrient supplements (13), vitamin C (7), andechinacea (6); majority usedsupplements to maintain health or to treat noncancer symptoms like cold and flu reasons: improve health,supplement diet, and prevent disease; supplements werediscontinued within past year by one third of parents women with breast cancer. Rock et al. (2004) presented these supplements for people with different types of cancers, comparative data from a study conducted with breast undergoing different types of treatments, and at varying cancer patients and one with the general population.
Reported multivitamin use in women with a history of early-stage breast cancer in the Women’s Healthy Eating and Living (WHEL) Study (n = 3,088) was 58%, with 42% usingvitamin C.
Any recommendations for supplementation must be The two studies of children with cancer (Table 3) also use based on scientific evidence that the supplements are both different outcome measures. Ball et al. (2005) reported on effective and safe. Ideally, a rigorous systematic research the prevalence of dietary supplement use separately for chil- approach (Table 4) is carried out and the results are evalu- dren with leukemia and solid tumors (42% and 50%, respec- ated to assess the health benefits of a dietary supplement and tively, used vitamins; 10% and 16% used minerals; and 18% whether its use is recommended. The review begins with and 24% used botanicals). Neuhouser et al. (2001b) did not preclinical (in vitro and in vivo studies) and epidemiologi- differentiate by type of cancer and reported 29% use of cal evidence. Although these lines of evidence may provide single vitamin supplements, 15% use of vitamin and mineral insight into anticipated outcomes, it is important that mixtures, and 35% use of herbal supplements. Most parents research be taken to the next level of clinical trials. Before of the children in this study reported perceived improvement the conduct of human clinical trials, however, all available from single vitamin use (76.9%) and herbal supplement use evidence must be reviewed thoroughly and objectively to (85.7%). Motivators for dietary supplement use included determine whether data on efficacy and safety justify pro- treating side effects or symptoms of cancer or cancer treat- ceeding to clinical trials. Such evidence-based reviews differ ment (47.2%), preventing recurrence or spread of cancer from traditional opinion-based narrative reviews in that they (33.3%), preventing or treating noncancer symptoms such systematically attempt to reduce bias by the comprehen- as a cold or flu (51.4%), and maintaining general good health siveness and reproducibility of the search for and selection of articles for review. Systematic reviews also assess the Despite the variations in populations, study design, methodological quality of the included studies and evaluate sample size, and outcome variables, it is clear that signifi- the overall strength of the body of evidence (Agency for cant proportions of people who have been diagnosed with Healthcare Research and Quality [AHRQ], 2002). When the cancer are using dietary supplements. This underscores the body of evidence on safety and efficacy justifies proceeding need for additional information on the efficacy and safety of to clinical trials, the trials are usually conducted in three and safety of the supplement of interest and to make recommendations for supplementation.
Two evidence-based reviews have been conducted on the effect of specific supplements on cancer prevention. The (In vitro experiments and in vivo animal experiments) first was a review by the U.S. Preventive Services Task Force (PSTF) on routine vitamin supplementation to prevent HUMAN OBSERVATIONAL EPIDEMIOLOGICAL STUDIES(Identify possible links between dietary supplements and cancer cancer and cardiovascular disease. For cancer, the PSTF recommended against the use of β-carotene supplements,either alone or in combination, and concluded that insuffi- cient evidence exists either for or against the use of supple- (Evaluation of existing laboratory and epidemiological evidence on ments of vitamins A, C, or E, multivitamins with folic acid, dietary supplement safety and effectiveness: as related to cancer or antioxidant combinations for the prevention of cancer (PSTF, 2003). The second systematic review by the AHRQ on the use of the antioxidant vitamins C and E and CoQ10 supported the PSTF recommendations for vitamins C and E and determined that the literature does not support the use of CoQ10 supplements to help prevent or treat cancer (AHRQ, 2003). The AHRQ recognized that a few individ- ual trials did report benefits in patients with bladder cancer (Identify adverse side effects: safe dosage: and potential interactions) and that other trials reported beneficial intermediate out- comes, such as colonic crypt cell proliferation with vitamin (Measure supplement effectiveness at various safe doses) Although clinical trials provide a wealth of information, various interactions must be accounted for when interpret- LARGE-SCALE: DOUBLE-BLIND: PLACEBO-CONTROLLED: ing the results and developing public health recommenda- tions. These factors include a person’s stage of life, general (Test whether supplementation has the hypothesized human health health status, genetic makeup, and health and lifestylebehaviors. Each may influence the absorption, useful- ness, and need for any particular dietary supplement. For example, the results of a large randomized clinical trial, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention(ATBC) study conducted in Finland suggested a substantialbenefit of vitamin E in reducing prostate cancer (Heinonen phases: human safety trials, small efficacy trials (usually in et al., 1998). However, almost all the participants were defined target groups), and large-scale trials that are essen- tial in moving from basic and observational science to Another major concern associated with clinical trials evidence-based public health recommendations that have designed to evaluate the health effects of dietary supple- ments is that participants might take additional supplements, The large-scale, double-blind, randomized, placebo- which could influence trial outcomes. In the Prostate Cancer controlled clinical trial, which is designed to eliminate all Prevention Trial (PCPT) of the drug finasteride, for example, possible bias, is considered the gold standard of scientific almost half of the participants reported using a multivitamin intervention research. In such trials, some people receive the supplement, about a third used single supplements of either substance being tested and some receive an inactive placebo.
vitamin C or E, and one in five used calcium supplements.
These trials may not be possible in all circumstances, Limitations to the study included the lack of control for however, because of ethical issues that make it inappropri- dosage amount, frequency of intake, type of supplement, ate to withhold the substance being tested from any trial par- and the limited data on micronutrient intake from fortified ticipants. For example, after it was observed that low folate foods (Neuhouser et al., 2001a). Very little evidence is avail- intake by pregnant women was linked to neural tube defects, able about how individual micronutrients might interact a placebo-controlled intervention trial to test the validity of with one another to influence health outcomes. The Sele- this association would not have been ethical. In such cases, nium and Vitamin E Prevention Trial (SELECT) is expected all available evidence from in vitro laboratory research and to help clarify the association of dietary supplement use in vivo animal studies, as well as epidemiological studies with prostate and other cancers. SELECT is a randomized, and surveys, must be reviewed systematically and objec- prospective, double-blind study designed to determine tively to draw conclusions about the possible effectiveness whether selenium and vitamin E reduce the risk of prostate Role of Dietary Supplements in Cancer Prevention and During Therapy cancer in healthy men (Klein et al., 2003). The vitamin E Timing with the Framework of a Day:
supplement will be a higher dose than that used in the ATBC The Example of Calcium
study (400 vs 50 mg), and final results are expected in 2013.
Calcium has been investigated for its role in cancer The following section explores the relationship of these prevention because it participates in multiple molecular interactive factors with respect to the role of dietary sup- signaling pathways and alterations of gene expression associated with cancer and for its role in many other keybiological processes, such as bone formation and properfunctioning of the nervous system (NIH Consensus Confer- ence, 1994; Patton et al., 2003). However, the time of sup- plementation may influence its impact. Ingesting calcium supplements between meals supports calcium bioavailabil-ity because some foods contain compounds such as oxalates To understand the potential role of dietary supplements that reduce calcium absorption (NIH Consensus Conference, in the prevention of cancer, scientists have developed 1994). Also, high intakes of calcium from foods or sup- models of molecular mechanisms through which nutrient plements taken with meals may inhibit nonheme iron and nonnutrient supplements might affect metabolic pro- absorption and negatively affect the redox and antioxidant cesses that lead to cancer. Potential mechanisms include availability of iron (NIH Consensus Conference, 1994; inhibiting carcinogen uptake, inhibiting the formation or activation of carcinogens, and preventing dietary carcinogenbinding to DNA (American Institute for Cancer Research,2000). Different supplements use different pathways to Timing with the Lifespan:
influence carcinogenesis. For example, antioxidants neutral- The Example of Phytoestrogens
ize free radicals, preventing them from damaging other mol-ecules, which over time may lead to cancer. In addition to Another example of timing is exposure during different the well-known antioxidants (vitamin C, vitamin E, and β- periods of life. Throughout the lifespan, estrogens increase carotene), other substances such as mistletoe extract exhibit mammary cell proliferation, but other factors, such as hor- antioxidant properties. Calcium inhibits carcinogen uptake monal levels, may influence estrogens’ ability to induce most often in conjunction with vitamin D. Folic acid helps differentiation or affect mammary growth by other means.
to synthesize and repair DNA, potentially preventing cancer Thus, estrogens can have a different impact on the breast if development. Phytoestrogens, the most common of which the exposure occurs in utero; during childhood, puberty, or (genistein and daidzein) come from soy products, may pregnancy; premenopausally; or during postmenopause inhibit the growth of estrogen receptor (ER)-positive and (Hilakivi-Clarke and Clarke, 1998). There is evidence that ER-negative breast cancer cells (Jennings, 1995; Peterson genistein also has different effects on the breast depending and Barnes, 1996). These are only a few supplement-related on the timing of exposure. For example, studies in rats mechanisms that have been or are being studied.
have shown that prepubertal exposure to genistein protects Researchers have also investigated additional factors that against chemically induced mammary tumors, possibly might influence the involvement of dietary supplements in because genistein increases cellular differentiation at early the prevention of cancer. They include the timing of sup- stages of mammary development (Lamartiniere et al., 2002).
plement use, the effect of dose and dose–response, the role During the reproductive years, genistein increases mammary of specific supplement components, and the impact of inter- gland proliferation, as has been shown in both animal and active factors. Each factor is discussed in the following human studies (Petrakis et al., 1996; Hsieh et al., 1998; McMichael-Phillips et al., 1998). Differences have beennoted in the effect of genistein premenopausally and post-menopausally. Although there is no evidence that genistein promotes breast cancer in premenopausal women, animal The issue of timing in dietary supplement use with studies suggest that it may play a role in the growth of cancer respect to cancer prevention and treatment reflects on the cells in postmenopausal women (Hsieh et al., 1998; Trock age of the person and the time within the course of the et al., 2000). It is possible that the different impact of genis- disease that supplements are taken. A better understanding tein on premenopausal and postmenopausal women re- of these issues may help explain some of the conflicting flects the increased likelihood that postmenopausal women results from epidemiological and clinical studies on dietary already have malignant cells in their breasts and that genis- supplement use. Calcium and the soy isoflavone genistein tein, acting as an estrogenic agent, proliferates mammary provide examples of the importance of timing in supple- cell growth, be it healthy or malignant cells (Bouker and independent of antioxidant activity. Dose–response studiesshow that growth-inhibitory doses of tocotrienols are five to Because dietary supplements are ingested to add to or six times lower than their corresponding lethal doses, sug- replace dietary factors generally found in food products, gesting that different mechanisms control their antiprolifer- issues of dose and bioavailability are important in discus- ative and cytotoxic effects (Sylvester and Shah, 2005).
sions of their efficacy and safety. Often, the dose of a dietarysupplement is greater than the amount normally found infood and may equal or exceed recommended levels of Folic Acid
intake. For example, the recommendation for vitamin C is Epidemiological studies suggest that dose and dose– 75 mg/day for adults older than 18 years, but an average dose response are important factors in folate supplementation to of a vitamin C supplement is 500 mg. Although dietary re- reduce cancer risk, especially for colon cancer and colorec- commendations suggest the value of eating large amounts of tal adenoma. A 35–40% risk reduction was observed in those fruits and vegetables, which contain vitamin C and other with the highest folate intake compared with those with the antioxidants, research is necessary to determine the levels of lowest intake (Kim, 1999). A randomized study of patients specific nutrient or nonnutrient components of these foods, with recurrent polyps reported that supplementation with 2 which when used as supplements will have an impact on mg of folate significantly decreased colonic mucosal-cell proliferation in the treatment group compared with controls(no supplementation) (Khosraviani et al., 2002).
Vitamin A and b-Carotene
For example, both the α-Tocopherol, β-Carotene Cancer Calcium and Vitamin D
Prevention (ATBC) Study and the β-Carotene and Retinol Calcium, which has the potential to reduce the risk Efficacy Trial (CARET) reported that the use of β-carotene of colon cancer, also has been shown to exhibit a supplements in smokers may promote lung cancer (ATBC dose–response relationship (Wu et al., 2002). Data from the Study Group, 1994; Omenn et al., 1996). Among the expla- Nurses’ Health Study (Martínez et al., 1996) and Health Pro- nations for these results is that the dose of β-carotene in the fessionals Follow-up Study (Kearney et al., 1996) indicate trial was 5–10 times greater than that supplied by a healthy that higher calcium intake is associated with a reduced risk diet; this higher dose may have inhibited the absorption of distal colon cancer. The incremental benefit of additional of other antioxidants with cancer-preventive properties calcium intake >700 mg/day was minimal. Interestingly, it (Greenwald, 2003). In addition, tissues of trial participants has been shown that the relationship between calcium and supplemented with β-carotene showed a 50-fold higher vitamin D is important in their associations with cancer concentration than those of individuals who consumed large risk (Milner et al., 2001). Results of the Calcium Polyp amounts of fruits and vegetables (Borrás et al., 2003).
Prevention Study show that vitamin D status strongly influ- Dose–response to vitamin A also is dependent on the enced the impact of calcium supplementation on adenoma vitamin A status of cells. Vitamin A circulates in the body recurrence (Grau et al., 2003). Calcium supplements only after binding to a retinol-binding protein (RBP), which is lowered the risk of adenoma in subjects with 25- accumulated in the liver, and homeostasis results in extra hydroxyvitamin D levels above the median. Similarly, 25- retinol being stored for future use. When cells are deficient hydroxyvitamin D was associated with reduced risk only in vitamin A, the liver accumulates large amounts of RBP among those supplemented with calcium. It was concluded in anticipation of future availability of the vitamin (Russell, that vitamin D and calcium supplements appear to act 2000). Ingesting vitamin A through the diet or by supple- together, not separately, on colorectal carcinogenesis.
ment in a vitamin A–deficient state causes a rapid large risein serum retinol that is short-lived. Vitamin A ingestion Interactive Impacts: Environment, Gender, when cells are not deficient results in a slower and smallerrise in serum retinol, with extra amounts being stored for Environmental, genetic, and other differences may deter- mine whether benefit or harm is derived from the use ofdietary supplements in healthy individuals, populations at Vitamin E and Its Constituents
risk for certain diseases, and patients undergoing disease The two subgroups of vitamin E are tocopherols and therapy. Selenium, folate, genistein, and zinc are examples tocotrienols. Tocotrienols have been shown to have potent of dietary supplements that have been investigated for anticancer activity at doses that do not appear to affect their association with environmental, genetic, and hormonal normal cell growth or function. Their antitumor activity is Role of Dietary Supplements in Cancer Prevention and During Therapy Environmental Factors
phism were at reduced risk of colorectal cancer. Interest-ingly, alcohol consumption reversed this association—pos- Epidemiological studies suggest an increase in colon sibly by depletion of the dietary methyl supply and folate cancer in areas where selenium levels are low in the soil breakdown by acetaldehyde—and suggests that individuals (Clark et al., 1991). Because the amount of selenium pro- with this genotype may be more susceptible to the carcino- vided by the diet is dependent on the amount found in the genic effects of alcohol (Greenwald et al., 2001).
soil used to grow food products, the level of intake among Epidemiological studies report that zinc deficiency is populations is varied, especially when most food consumed associated with an increased risk of esophageal squamous comes from a single geographic source. Clinical trial results cell carcinoma in high incidence areas of China and Iran from Linxian, China, an area characterized by epidemic (Fong et al., 2003). Abnormalities in the p53 tumor sup- rates of squamous esophageal and adenomatous gastric- pressor gene, which causes a loss of function leading to cardia cancers, indicated a significant inverse association of increased tumor proliferation and decreased apoptosis, has serum selenium levels with these cancers when the highest- been studied in zinc-deficient mice exposed to the carcino- to-lowest quartiles of serum selenium were compared (Mark gen N-nitromethylbenzylamine (NMBA). An investiga- et al., 2000). Selenium supplementation has been associated tion of esophageal NMBA-induced tumor proliferation in with a reduction in prostate, lung, and colorectal cancers p53−/− zinc-deficient mice suggests that zinc modulates genetic susceptibility to cancer caused by p53 inactivation(Fong et al., 2003).
Genetic Factors
Genetic variability and selenium intake may both play Hormonal Factors
important roles in reducing cancer risk. A large randomizedphase III trial, The Selenium and Vitamin E Cancer Pre- The relationship between genistein and hormones in the vention Trial (SELECT), is investigating the effect of sup- lifespan of women was described in the section “Timing plementation with selenium and vitamin E, alone or in with the Lifespan: The Example of Phytoestrogens.” In men, combination, on prostate cancer incidence. A nested case- epidemiological and experimental evidence suggests that control study within SELECT will assess genetic polymor- genistein may inhibit prostate tumor growth through various phisms of four genes (androgen receptor [AR], 5α-reductase mechanisms, including cell proliferation and increased type II [SRD5A2], cytochrome P450c 17α [CYP17], and apoptosis (Greenwald et al., 2002). In a study in LNCaP β-hydroxysteroid dehydrogenase [HSD3β2]) on prostate prostate cancer cells, genistein completely inhibited expres- cancer incidence (Hoque et al., 2001). CYP17 is of particu- sion of prostate-regulated transcript 1 (PART-1), an andro- lar interest because previous studies have suggested that the gen-induced gene that may represent a novel tumor marker A1/A1 genotype confers a significantly higher serum andro- for prostate cancer (Yu et al., 2003). In a small study of gen level than is found in men with either the A1/A2 or the patients with prostate cancer, a dietary supplement of red- clover isoflavones, including genistein, was administered Folate provides another example of genetic differences before surgery. After prostatectomy, apoptosis in cells from that can influence the potential benefits of supplementation.
treated patients was significantly higher than in cells from Methylenetetrahydrofolate reductase (MTHFR) is a critical controls, specifically in regions of low- to moderate-grade enzyme that regulates the metabolism of folate by convert- ing 5,10-methylenetetrahydrofolate (methyleneTHF) to 5-methyltetrahydrofolate (methylTHF), the major form of circulating folate in plasma. A common polymorphism ofthe MTHFR gene (677C→T) results in an alanine→valine Just as there are many mechanisms through which dietary substitution in the enzyme and, subsequently, in significantly supplements influence the prevention of cancer, so are there decreased activity (Greenwald et al., 2002). This results in a variety of ways in which they influence cancer treatment.
increased methyleneTHF, which results in reduced incorpo- The following highlights some of the mechanisms that have ration of uracil in DNA, which leads to fewer chromosome an impact on the efficacy of treatment and its side effects.
breaks and possibly reduced cancer risk (Greenwald et al., This is not meant to be a complete list of all influential factors, but a highlight of examples of potential interactions.
Studies of data from the Health Professionals Follow-Up Study and the Physician’s Health Study on the 677→6T Antioxidants
MTHFR polymorphism and dietary intake of folate in col-orectal tumorigenesis found that when the dietary methyl Chemotherapeutic agents include alkylating agents supply was high, individuals with the MTHFR polymor- (cyclophosphamides), anthracycline antibiotics (doxoru- bicin), platinum compounds (cisplatin), mitotic inhibitors system and drug-transporting P glycoprotein. Studies have (vincristine), antimetabolites (5-fluorouracil), camptothecin found that St. John’s wort reduces levels of drugs such derivatives (topotecan), biological response modifiers (inter- as cyclosporine and indinavir, as well as levels of the feron), and hormonal therapies (tamoxifen). Anticancer active metabolite of irinotecan, a chemotherapeutic agent therapies that may potentially be influenced by antioxidants (Mathijssen et al., 2002; Weiger et al., 2002).
include: alkylating agents (cyclophosphamide and iphos-phamide), platinum compounds (cisplatin), antibiotics (doxorubicin and bleomycin), topoisomerase II inhibitors (etoposide), and radiation (Conklin, 2000). However, theevidence with respect to the impact of antioxidants on Despite varied results with respect to specific foods and chemotherapy or radiation is controversial. Studies show specific cancers, results of observational, ecological, and both that antioxidants are safe and effective enhancers of clinical studies provide strong evidence that diets high in chemotherapy and that they interfere with the oxidative vegetables, fruits, and plant-based foods and low in animal breakdown of cellular DNA and cell membranes needed for fats lower the risk for cancer. The specific agents responsible the chemotherapy to be effective (Norman et al., 2003).
for cancer protection are unknown (World Cancer Research Although most clinical trials have not shown significant Fund, 1997). At best, the evidence is mixed that dietary sup- impacts of antioxidant supplementation on chemotherapy or plements taken for health promotion and disease prevention radiation, some have reported either the potentiation or the actually provide the benefits expected by consumers and inhibition of these therapies by antioxidants (Weiger et al., patients. However, given the high rate of dietary supplement 2002). Three clinical trials indicate that melatonin (an use among the general population and those diagnosed antioxidant) enhances the efficacy of radiation therapy and with cancer, a better understanding of possible differences chemotherapy (Lissoni et al., 1996, 1997, 1999). Animal between a dietary factor in food and the same factor as a studies indicate that the impact of antioxidants may depend supplement is necessary. As new molecular and technological on dosage and timing of administration with respect to radi- approaches are developed to study the nutritional sciences, investigations can be designed to elucidate the mechanismsof action of dietary factors in both forms. Experimental andanimal models must be developed to help assess the safety Phytoestrogens
and efficacy of the multitude of vitamins, minerals, and As was discussed in the section “Timing with the Life- botanicals in the marketplace. Also, identification and use span: The Example of Phytoestrogens,” soy isoflavonoids, of intermediate outcomes as endpoints in future clinical particularly genistein and daidzein, have both positive and research could provide a more cost-effective method for negative estrogenic effects on breast tissue. In a review of gauging the efficacy of dietary supplements. Furthermore, 26 animal studies, soy was found to have a positive effect attention should be directed toward possible confounding in most cases (Messina et al., 1994). However, other animal effects of supplement use by participants in clinical trials for studies suggest the need for concern that soy supplementa- cancer prevention and control. From a broader research per- tion in women with breast cancer, particularly with ER- spective, there is a need to investigate dietary supplement use positive tumors, may cause a proliferation of the cancerous in the context of health disparities and cultural, ethnic, and cells (Weiger et al., 2002). A review addressed this dichoto- demographic determinants. A better understanding of supple- mous role and concluded that the data are not strong enough ment timing, dose and dose–response, and vulnerability of on either side to support the use or nonuse of soy supple- specific populations is essential for providing scientifically ments (Messina and Loprinzi, 2001). Additional effects of sound information on the use of dietary supplements.
soy on cancer treatments have also been examined. Animal Important issues to be addressed in research aimed at study data indicate that genistein can negate the inhibitory determining the effects of dietary supplements on cancer effect of tamoxifen on breast cancer growth (Ju et al., 2002).
include developing better methods to measure the contribu- Given its antioxidant activity, there is also concern with tion of dietary supplements for various population groups respect to the use of soy supplementation during radiation and to monitor these usage trends over time. Although data are available on the prevalence of dietary supplement useamong people with cancer, the data collection is not sys-tematic and the data are not collected both before and after Other Supplements
cancer diagnosis. The majority of information is collected Supplements that are neither antioxidants nor phyto- on people who have been diagnosed with cancer. This makes estrogens also may affect treatment. Blood levels of med- inferences to the role of supplements in cancer prevention ications may be influenced by the use of St. John’s wort.
difficult, if not impossible. Although some of the nationally This herb is an inducer of the cytochrome P450 enzyme representative survey data provide comparisons between cancer patients and individuals not diagnosed with cancer, the number of cancer patients is too small, limiting the Agency for Healthcare Research and Quality. 2002. Systems to rate the strength of the comparative results. Additionally, although strength of scientific evidence. Agency for Healthcare Research and some studies collect data on new supplement use (post Quality, Rockville, MD. Evidence Report/Technology Assessment No.
diagnosis), most do not ask about length of time for which Agency for Healthcare Research and Quality. 2003. Effect of the supple- mental use of antioxidants vitamin C, vitamin E, and coenzyme Q10 The systematic collection of prevalence data could for the prevention and treatment of cancer. Agency for Healthcare include the development of a set of core prevalence indica- Research and Quality, Rockville, MD. Evidence Report/Technology tors that include definitions of cancer patient or survivor, Assessment No. 75. AHRQ Publication No. 03-E047.
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