Selenium and cancer: some nutritional aspects

REVIEW ARTICLE

Selenium and Cancer: Some Nutritional Aspects M. Sanz Alaejos, PhD, F. J. Dı´az Romero, MD, and C. Dı´az Romero, PhD From the Department of Analytical Chemistry, Nutrition and Food Sciences, and the Department of Physical Medicine and Pharmacology, University of La Laguna, La Laguna, Tenerife, Spain The level of selenium in cancer patients is lower than that in control subjects. However, low selenium levels in body fluids can be due to the malnutrition observed in these patients. There is evidence from epidemiologic studies that high dietary selenium intakes and high selenium status in people are associated with lower cancer mortality. However, contradictory information has been found in some prospective studies. The presence of other nutrients in selenium-rich foods can influence the role of the selenium in cancer etiology. Therefore, there are selenium antagonistic elements that inhibit the anticarcinogenic effects of selenium and other antioxidant micronutrients such as ascorbic acid, retinol, ␤-carotene, ␣-tocopherol, and some other elements have a synergistic effect on the prevention of cancer. Nutrition 2000;16:376 –383. ©Elsevier Science Inc. 2000 Key words: selenium, cancer prevention, cancer mortality, interactions with nutrients

INTRODUCTION Selenium (Se), like many other trace elements, has a bimodal effect; its beneficial effects occur in a limited range of daily intake, below which it cannot perform its essential function and above which its effects are toxic. The toxicologic properties of Se were recognized first; its essential nutritional role for animals was discovered in the 1950s and for humans in 1973. Although our understanding of the nutritional significance of Se increases, many questions relating to its roles, requirements, metabolism, and links between dietary intakes and health remain unanswered.1 Selenium participates in processes of detoxification because it forms a part of glutathione peroxidase, but there are other proteins in mammals whose structures require the presence of Se in the form of selenocysteine. Thus, type I iodothyronine deiodinase is an selenoenzyme necessary for proper thyroid function and conversion of thyroxine into triiodothyronine.2 Tamura and Stadtman3 isolated and characterized a new selenoenzyme, thioredoxin reductase, from a human lung adenocarcinoma cell line, which catalyzes the reduction of insulin in the presence of thioredoxin. Selenoprotein P is involved in Se and/or protein transport and in the prevention of free radical pathology.4 Selenoprotein W was isolated from rat muscle. A small portion was associated with membranes, and its function is unknown.5 Humans receive Se as selenoamino acids (selenomethionine, selenocysteine, and selenocystine), and little or none as methylated/non-methylated Se through food Se. Selenoamino acids, in particular selenomethionine, present a higher bioavailability than the inorganic species. Selenium present in cereals, wheat, and most vegetable foods, mainly as selenomethionine, has a higher bioavailability (85–100%) than that observed in dairy products and meats (10 –15%).6 The Se content of fish is high, presenting a relatively high bioavailability (20 –50%).7 Selenate is reduced to selenite; selenite and Se of the selenoamino acids can be converted to selenides.8 Selenides are converted into mono-, di-, and trimethylated species. Whereas the trimethyl Se is excreted through urine and the dimethyl form is exhaled, the monomethylated form is usually released by metabolism of selenomethionine.1,9,10

Correspondence to: F. J. Dı´az Romero, PhD, Department of Analytical Chemistry, Nutrition and Food Sciences, University of La Laguna, 38204 La Laguna, Tenerife, Spain. Nutrition 16:376 –383, 2000 ©Elsevier Science Inc., 2000. Printed in the United States. All rights reserved.

In this review, the literature data of Se levels in body fluids of cancer patients is discussed. Further, the influence of Se intake and other nutritional factors on cancer is discussed, with particular emphasis on the research from mid-1980 to 1997.

SELENIUM STATUS AND CANCER In most papers it has been observed that cancer patients show lower Se levels in body fluids than do control subjects (Table I). However, in a large cohort study,11 no significant associations were observed between toe-nail Se levels and cancer, possibly because toe-nail Se is not a good indicator of Se status. Erythrocytes,12 plasma,12 serum,13–16 and urine Se17 were found to be significantly lower in cancer patients than in matched or unmatched control subjects. Plasma and erythrocyte Se levels were lower only in cases with large tumors.18 However, normal Se levels in whole blood12,19 and serum20 were observed in cancer patients, mainly in populations with low dietary Se intakes.12,20 In most papers (Table I), the reported reduction of Se levels in body fluids of cancer patients in comparison with control subjects ranged between 5% and 35%, but the results of case-control studies are difficult to interpret because of the possible modulation of Se status by prediagnostic cancer.21 According to the data presented in Table I, no clear conclusions can be deduced when considering the different organs and tissues where the cancer had developed. However, if Se protects humans against environmental carcinogens in the same way that it protects mice or rats, then a lower mortality might be expected from cancer in the organ systems concerned with assimilation, metabolism, and excretion of Se.22 This apparent association between low Se status and cancer raises two questions: Is the low Se status a risk factor for cancer? Or, is cancer a cause of low Se status? Low levels of dietary Se do not cause cancer, but decreased levels of Se apparently increase susceptibility to cancer given carcinogenic exposure23 or reduce the ability of the body to withstand cancer-causing stress.24,25 Prospective studies examining the association between Se status and risk of cancer present inconclusive information. Whereas some prospective studies have suggested an overall inverse association between Se levels and cancer,26 –30 other prospective stud0899-9007/00/$20.00 PII S0899-9007(99)00296-8

SELENIUM AND CANCER

377 TABLE I.

SELENIUM CONTENT (mg/L⫺1) IN BODY FLUIDS OF CANCER PATIENTS AND CONTROL SUBJECTS

Subjects Urine Controls Cancer, newly diagnosed Metastatic or undergoing therapy All cases Controls

Geographic location

Greece, Athens Greece

Japan

Year

Analytical method

1985–1988

F

1981

F

Cancer patients Plasma Controls, 30–60 y Cancer patients, 30–60 y Controls, ⬎60 y Cancer patients, ⬎60 y Controls, 30–90 y All cases, 30–90 y Controls, 20–59 y Esophagus, 28–78 y Stomach, 28–78 y Duodenum, 28–78 y Liver, 28–78 y Serum Controls Chronic lymphocytic leukemia Controls, 31–59 y Cancer, 31–59 y Controls Cancer Controls Cancer death Controls Cancer dead, women Controls Cancer dead, men non-smokers Controls Cancer dead, men smokers Controls, 35–64 y All cancer dead, 35–64 y Controls Gastrointestinal cancer Respiratory cancer (lung) Skin and skeletal cancer Urogenital cancer Hematological cancer Others All patients Controls, 42.9 ⫾ 10.9 y Children of patients with primary lung cancer, 42.3 ⫾ 9.9 y Children of adenocarcinoma patients Children of squamous cell patients Children of small cell patients Lung cancer patients, 63.9 ⫾ 11.2 y Adenocarcinoma patients Squamous cell patients Small cell patients Controls Hepatocellular carcinoma Controls Polyps Colon cancer

n

1976–1977

F

USA, New York (Buffalo)

1982–1983

EAAS

Belgium

1987

PIXE

Finland

1972–1978

EAAS

Finland

97

62 25 47 46 109 71 20 12 23 3 5

48 ⫾ 11 38 ⫾ 14 37 ⫾ 10 35 ⫾ 15 43 ⫾ 12 36 ⫾ 14 86.1 53.7 55.6 46.5 60.3

12

98 47 128

97 ⫾ 4 107 ⫾ 5 54.3 ⫾ 1.0 50.5 ⫾ 1.1 54.1 ⫾ 11.3 49.7 ⫾ 10.3 54.5 ⫾ 13.7 47.7 ⫾ 10.3 60.5 59.5 58.4 49.9 63.5 49.3 60.9 ⫾ 1.8 53.7 ⫾ 1.8 55.5 ⫾ 0.6 53.4 ⫾ 3.0 51.5 ⫾ 2.6 52.5 ⫾ 5.4 58.2 ⫾ 3.7 51.9 ⫾ 5.7 65.7 ⫾ 6.5 53.9 ⫾ 1.5 122 ⫾ 14 116 ⫾ 24

1973–1978

87

1974–1978

43

1977–1980

EAAS

21 14 16 51

Finland (rural)

Japan (Sapporo)

1974–1983

EAAS

1986

F

Japan

1989

Spain, Barcelona

1994

EAAS

Reference

25 ⫾ 7 22 ⫾ 4 20 ⫾ 5 21 ⫾ 5 57.9 ⫾ 26.3 (20–113) 26.0 ⫾ 14.0 (10–66)

218 109 65 174 21 23

New Zealand, Otago

Mean or Mean ⫾ SD (min–max)

964 29 38 9 19 8 6 109 56 115 47 45 8 37 14 19 3 124 31 20 22

111 ⫾ 19 120 ⫾ 28 110 ⫾ 24 99 ⫾ 16 96 ⫾ 14 99 ⫾ 16 108 ⫾ 11 124 92.2 64.5 ⫾ 5.1 43.6 ⫾ 2.2 37.2 ⫾ 3.6

98

60

65 13

14

20

86

67 99

(Continued)

378

SELENIUM AND CANCER TABLE I. SELENIUM CONTENT (mg/L⫺1) IN BODY FLUIDS OF CANCER PATIENTS AND CONTROL SUBJECTS (Continued)

Subjects Controls, 45 y Malignancy without hepatic metastases, 61 y Malignancy with hepatic metastases, 65 y Controls, 56.8 ⫾ 7.3 y Cancer, 56.7 ⫾ 7.7 y Controls, ⬍55 y Cancer, ⬍55 y Controls, ⱖ55 y Cancer, ⱖ55 y Controls, blacks Cancer, blacks Controls, whites Cancer, whites Controls, female Cancer, female Controls, male Cancer, male Controls, never smokers Cancer, never smokers Controls, past smokers Cancer, past smokers Controls, current smokers Cancer, current smokers Controls Cancer, ⬍2.5 y to diagnosis Controls Cancer, ⱖ2.5 y to diagnosis Controls, 25–64 y Lung cancer, 25–64 y Controls, 27 ⫾ 6 y, men

Geographic location

Year

Analytical method

USA, Kentucky (Louisville)

1983

RNAA

1973–1979

INAA

USA

n 92 14 12 210 111 43 68 49 60 51 60 50 16 44 42 53

USA, Maryland (Washington County)

1974–1983

INAA

196

HG-AAS

99 140

94.3 ⫾ 2.2 76.7 ⫾ 6.4 66.6 ⫾ 7.2 136 129 135 129 136 129 132 122 139 135 134 132 137 127 136 133 134 134 136 124 134 131 137 129 110 ⫾ 16

Yugoslavia, Zagreb

1988

HG-FAAS

43 13 33

113 ⫾ 18 65 ⫾ 11 (36–89) 44 (37–67) 40 (36–50) 42 (36–52) (43–133) (50–115) (29–75)

China, Beijing

1982

F

Greece, Athens

1985–1988

F

Greece, Athens

1985–1988

F

New Zealand, Otago

1976–1977

F

USA, Oregon (Corvallis)

1982

F

USA, Oregon

1983

F

75 31 41 353 238 90 72 229 177 153 153 113 80 16 52 16 16

123 ⫾ 20 126 ⫾ 30 94 ⫾ 30 88 ⫾ 10 88 ⫾ 20 82 ⫾ 20 62 ⫾ 20 165 ⫾ 33 152 ⫾ 17 174 ⫾ 22 151 ⫾ 18 54 ⫾ 13 50 ⫾ 16 69 112 112 110

Venezuela, Me´rida

Stomach cancer, 43 ⫾ 15 y, men

42

Hepatic cancer, 45 ⫾ 9 y, men

32

Lung cancer, 47 ⫾ 14 y, men

22

Controls, 37–51 y Controls, mastopathy, 37–51 y Breast cancer, 37–51 y Whole Blood Controls Controls, 24 y Controls, 24 y Controls, tin miners Tin miners working above ground Tin miners working underground Lung cancer, tin miners Controls Patients Controls, 56 ⫾ 15 y Patients, 56 ⫾ 15 y Controls, 30–90 y Patients, 30–90 y Seventh-day Adventist non-vegetarians Non-Seventh-day Adventist non-vegetarians Nonvegetarian hormone-dependent cancer Hormone-dependent, women

Mean or Mean ⫾ SD (min–max)

China, Yun-Xi

Reference 100

15

26

37

101

24

97 102 12 19

EAAS, electrothermal atomic absorption spectrometry; F, fluorimetry; HG-AAS, hydride generation atomic absorption spectrometry; INAA, instrumental neutron activation analysis; min–max, minimum–maximum; PIXE, photon-induced X-ray emission; RNAA, radiochemical neutron activation analysis.

SELENIUM AND CANCER ies have failed to confirm this finding.11,20 The protective association with Se seems to be limited to subgroups of the studied population with certain characteristics.15,21,30 –36 Also, in some studies reporting an inverse relation,27,28 it was not possible to rule out that other nutrients or life-style factors covarying with Se intake, and not Se itself, were truly associated with the disease. Most geographic studies have indicated inverse correlations between Se status and cancer mortality.23,25,34,37 Although there are some studies that do not support the hypothesis of a strong inverse relation between dietary Se intake and cancer mortality in humans,38 high negative correlations have been observed between both dietary Se intake and Se levels in whole blood and cancer incidence or cancer mortality patterns in different countries.14,25,26,30,32,34,36 Furthermore, in Finland and New Zealand, countries with low soil Se content, higher rates of cancer were not observed.39,40 Therefore, it is not known which range of Se intake, if any, might be associated with a higher incidence of cancer.38 Kok et al.32 reported that the relative risk of death from cancer among men in the lowest quintile of Se concentration in serum is 2.7-fold higher than those with a higher Se concentration. Similarly, Salonen et al.14 indicated that adjusted risk of death was 5.8-fold in the lowest tertile of Se serum concentration compared with those with higher values. However, the lower cancer mortality in high Se areas could be due to factors other than Se bioavailability, such as lower sun radiation and air pollution.34 Also, the high Se areas tend to be the least industrialized,34 and areas of low Se intake also tend to be areas of greater affluence.41 The cancer incidence observed in the district of Me´rida (Venezuela) with high serum Se content was lower than that in other districts.37 Also, studies from Finland, a country with low Se intake, support an inverse relation between Se status and the risk of cancer.42 There is an upward drift in serum Se levels for both cases and controls between 1972 and 1977, and this was attributed to an increased importation of high-Se grain into Finland during the 1970s.43 In Finland, the mean daily intake of Se has varied from 21 to 56 ␮g in the period from 1941 to 1981, depending on the proportion of imported grain (with high Se content) mixed at milling with domestic grain (with exceptionally low Se content).43 This finding would mean that one serum Se sample taken in 1974 would poorly reflect the average long-term Se status of the individual and, hence, may rank the subject erroneously in Se distribution. In a Finnish cohort, an increased risk was observed only for women in the lowest Se quintile,33 which could suggest the presence of a threshold Se level below which breast cancer is affected.44 The serum Se distributions of the American15 and Finnish13 populations differ to such an extent that the lowest quintile of the American population overlaps with the highest quintile of the Finnish population, which may indicate that serum Se is a non-specific marker of cancer risk.20 The regional distribution of liver cancer was inversely correlated with that of the Se contents of whole blood and local cereal grains in the Jiangsu Province in China, an area of high risk of hepatoma.25

SUPPLEMENTATION OF SELENIUM AND PREVENTION OF CANCER There is great interest in Se because it may be a factor in the prevention of carcinogenesis.9,45–50 An important aspect of Se supplementation is its potential toxicity.51 In general, selenoorganic compounds such as selenomethionine are recognized as being less toxic than inorganic forms of Se such as selenite.52,53 However, acute toxicity of selenate was lower than that found for selenomethionine.54 The chemical form of Se is an important factor to consider in supplementation studies. Forms of Se such as dimethylselenoxide, which are rapidly metabolized to dimethylselenide and trimethylselenonium and excreted, are likely to be a poor choice.55 Thus, in the dimethylbenz(a)anthracene-induced

379 mammary tumor model in rats, the relative efficacy for anticarcinogenic effects of four Se compounds was Se-methylselenocisteyne ⬎ selenite ⬎ selenocystine ⬎ dimethylselenoxide.55 Although not statistically significant, a correlation between male and female serum Se content and soil Se concentrations has been observed.37,56 This observation suggests that the enrichment of fertilizers with Na2SeO3 could be an effective way of increasing the Se intake of people in low-Se areas, with a concomitant decrease in the risk of developing cancer.56 However, additional Se could potentially benefit subjects with low Se levels, but it would not protect against the disease in subjects with moderate to high Se levels.15 A large and recent study carried out between 1983 and 1993 supported the hypothesis that supplemental Se can reduce the incidence of and mortality from carcinomas at several sites. The intervention agent was 200 ␮g Se per day as a 0.5-g high-Se brewer’s yeast tablet. Although the results do not support the hypothesis that Se supplementation reduces the risk of basal and squamous cell carcinomas of the skin, total cancer incidence was 42% lower in the Se group (P ⬍ 0.001) constituted by 1312 patients.49 Also, the long-term study in 113 persons in China who received 200 ␮g Se (organic form) per day for 4 y showed a significantly lower incidence of primary liver cancer than did the placebo group.52 There is, however, increased discussion of a pharmacologic dose of Se, significantly higher than the nutritional dose of the microelement, to treat active conditions.53 Selenium compounds that are able to generate a steady stream of methylated metabolites, in particular the monomethylated species, are likely to have good chemopreventive potential.55 The use of Se supplementation may depend on a number of factors including the amount of Se in the diet, its chemical form, its interactions with other nutrients, and the physiologic state of the host.53

EFFECTS OF INTERACTIONS BETWEEN SELENIUM AND OTHER NUTRIENTS ON CANCER The effect of Se status and supplementation on cancer risk may depend on interactions of Se with primary risk factors (e.g., smoking history, alcohol use, age, gender, and diet).57 Thus, any possible role of dietary Se in the etiology of human cancer could be masked or overcome by the influence of other food constituents.6,20 Low Se status may reflect more specific dietary abnormalities such as high intake of fat and alcohol, related in themselves to the etiology of cancer.20 Also, low risk of large-bowel cancer in Finland is thought to be due to the high consumption of dietary fiber.58 Moreover, the association between low Se levels and risk of cancer may indicate the protective effect of another nutrient present in Se-rich foods.15 A deficient food can produce a low Se intake and, consequently, a low Se status and malnutrition. Thus, in accordance with most studies, it could increase the development of cancer. But the interpretation of these results is complicated because of the fact that the disease process itself may have influenced the food dietary intake and thus the Se status of the patients involved.6,23 Loss of appetite with accompanying malnutrition or redistribution effects caused by sequestration of Se in the tumor tissue are among the mechanisms that might explain the decrease of Se in cancer patients.20,21,59 Therefore, the nutritional state of the patient can significantly influence the Se status.60 Selenium nutrition in chronically ill patients, especially cancer patients, can substantially be impaired, leading to relative Se deficiency.60 However, the results concerning the association between cancer and nutrition are often controversial. Riboli et al.61 suggested four limitations with a direct bearing on the extrapolation of results from foods to food components: 1) measurements of micronutrient intakes through simple dietary questionnaires and current food-composition tables lack precision and specificity; 2) attribution of cancer risk to a single food constituent can be misleading if multicollinearity of dietary variables is not recog-

380 nized; 3) circulating levels of nutrients reflect not only dietary intake but also complex metabolic regulations; and 4) studies have not considered the physical characteristics of foods, which are important determinants of physiologic responses.61 The influence of nutrients and Se on cancer can be divided in two groups. Macronutrients Diets high in fat, saturated fat, and cholesterol have repeatedly been associated with an increased risk of lung cancer, and this effect is not mediated through vegetable and fruit intake.62 A relation between human-blood Se and the consumption of proteinrich foods such as meat, milk, and cereal products has been suggested, but not between vegetarian and non-vegetarian diets.19 Concentrations of Se in plasma from vegetarians did not differ significantly from those in lactovegetarian and omnivorous groups.63 However, it has recently been observed that vegetarians had significantly higher plasma levels of Se than did nonvegetarians.64 Whole-blood Se levels correlated positively with dietary protein.19 Also, Se correlated positively with serum protein and albumin, a recognized parameter of malnutrition.65 A correlation between plasma albumin and plasma Se levels for cancer and for non-cancer patients was established. Similarly in the noncancer group, total protein correlated with plasma Se, which was not the case for the cancer group, because, with a decrease in the serum albumin, there was an increase in the other serum proteins.66 Many cancer patients with low-Se status also had below-normal albumin levels, in particular in association with widespread metastases or a history of poor dietary intake and marked weight loss.12,66 Thus, the lowest serum albumin levels and the lowest Se levels in whole blood (27 ␮g/L) and plasma (16 ␮g/L) were observed in five patients with metastatic cancer and in two patients without cancer.12 These two patients had long histories of inadequate dietary intake with marked weight loss due to inanition in one and an esophageal motility disorder in the other, and they had the lowest plasma Se levels observed in this study.12 Although no correlation was found with the degree of hepatic dysfunction, Se levels were positively correlated with nutritional parameters including serum concentrations of total protein, albumin, and hemoglobin. These results suggest that serum Se concentration may be a useful marker to evaluate the clinical and nutritional status.67 Most (60 – 80%) of the plasma Se has been associated with selenoprotein P in human and rat plasma.68,69 Recently, Hill et al.70 indicated that the concentration of selenoprotein P in human plasma might be a sensitive index of Se nutritional status in humans. Gastrointestinal cancer patients on an adequate diet showed the highest levels of serum Se, with 10% above average. The mean Se level in patients receiving intravenous lipids was 22% below the average observed in the rest of patients.60 Parenteral hyperalimentation practically did not affect Se plasma levels, lowering the mean by only 5%.60 It is possible that the abnormally low Se concentrations found in cancer patients is the result of the intravenous infusion of an amino-acid mixture, which is commonly applied to these patients as a supply of nutrition.71 In contrast, other investigators72 found no significant differences in the total serum protein, albumin, and globulin fractions in cancer patients, although differences were noted in serum Se levels. Selenoproteins in plasma are included in the globulin fraction. The sum globulin fraction in the cancer patients showed a relative increase; nevertheless, Se decreased, which may reflect the degree of lowered Se status in these patients.66 Micronutrients Although the major nutritional emphasis in understanding the etiologies of cancer has been directed toward establishing links with dietary fat, increasing attention is now being given to dietary micronutrients such as vitamins or trace elements, in particular

SELENIUM AND CANCER those that might protect against oxidant damage. Beneficial effects of vegetarian nutritional habits on antioxidative parameters and thus on the reduction of cardiovascular diseases and cancer risk have been found.64 At the most, a two-fold decrease in lung cancer risk with increased vegetable and fruit intake has been suggested.62 However, it is difficult to determine whether the antioxidant nutrients present in vegetables and fruits per se are the sole protective agents or whether other factors associated with foods containing them contribute to the foods’ protective effects.73 The evidence for a protective effect of greater vegetable and fruit consumption is consistent for cancer of the stomach, esophagus, lung, oral cavity and pharynx, endometrium, pancreas, and colon.30,74 The interaction between Se and other micronutrients may affect the biological properties of Se. There is a strong inverse association between Se levels and cancer risk in people with low levels of serum ␣-tocopherol, serum ␤-carotene, and serum retinol.15,32,33 Vitamin C, however, may have the opposite influence on the biological protection offered by some forms of Se in rats.75 It has been postulated that selenite is reduced by vitamin C to elemental Se and is therefore poorly bioavailable.76 Lower serum levels of Se, vitamin E, retinol, and ␤-carotene in future cases of lung cancer as compared with matched control subjects might be biologic markers of preclinical disease. Therefore, asymptomatic lung cancer that was present at time the blood was drawn might be responsible for the lower levels.30 A Chinese trial demonstrated a modest reduction in cancer mortality from a combined intake of ␤-carotene, vitamin E, and Se.77 However, the relevance of the findings to well-nourished populations is uncertain, and any independent effects of the three agents cannot be judged. In contrast, three large-scale random trials of ␤-carotene have recently been carried out, with no significant finding on the effect26,78 or increase in lung cancer79 – 81 in people with ␤-carotene supplementation. However, other investigators30 have found that high serum levels of total carotenoids, ␤-carotene, and ␣-tocopherol are generally related to low risks of oral cancer regardless of the serum levels of other nutrients. But, in contrast to the results from many studies, the risks were higher among individuals with high levels of Se26,30 and retinol30 in each level of the other nutrients. Whether there are anticancer effects of any individual constituents of diet or whether the apparent protection of consuming a diet rich in fruits and vegetables is more likely to be the result of a multifactorial effect of a number of components of these foods remains an open question.82 According to some investigators,14,15 a low serum retinol concentration is associated with an increased risk of some cancers only among people with low values of serum Se and possibly other biological antioxidants. This finding may be related to the antioxidant function of vitamin A. Also, in patients with breast cancer, the inverse association with Se became stronger, but not significant, in those women with a relatively low ␤-carotene intake. However, in women with a relatively low vitamin-C intake, the association with Se became positive.21 Thus, the data do not consistently show that the inverse association with Se is stronger when intake of other antioxidants is low.21 No evidence of a relation between the risk of lung cancer and levels of serum retinol was observed.26 Serum levels of Se and retinol in subjects who died of cancer were lower than those in matched control subjects.14 However, no synergism between serum Se and retinol was demonstrated.15 The association between low serum retinol concentration and an increased risk of cancer exists only among male smokers; no data exist on female smokers.14 A decreased intake of ␤-carotene, retinol, or both seems to contribute to the risk of lung cancer among male smokers with a low intake of Se.14 Serum Se concentration appeared to be independent of the serum retinol concentration but was strongly synergistic with serum ␣-tocopherol, whereas serum ␣-tocopherol alone showed no consistent independent relation to the risk of cancer.14 Willett et al.15 suggested that Se exerts stronger protection in subjects with low serum levels of vitamins A and E. The protective effect of Se

SELENIUM AND CANCER seems to be concentrated in those individuals with a relatively low intake of ␤-carotene and vitamin C.83 Selenium, retinol, and ␣-tocopherol serum concentrations intercorrelated moderately among the cases and weakly among the controls.14 This result could be a consequence of poor nutritional status observed in cancer patients. Low serum levels of vitamin E are related to an increased incidence of any type of lung cancer.26 Although the independent relation of vitamin E with risk of cancer was weak and not significant, vitamin E showed strong synergism with Se on the risk of fatal cancer, so that the impact of Se deficiency on cancer risk seemed to be noticeably greater at low serum vitamin-E concentrations.14,15 Vitamin E reduces the oxidative damage seen in Se deficiency.84,85 The synergism of Se and vitamin E emphasizes the role of the total antioxidative capacity of the body in the etiology of cancer.14 Some epidemiologic studies14,15,34 have shown that a low Se or low vitamin-E concentration in serum increases the risk of human cancer (stomach, esophagus, colon, lung, prostate, and breast). Serum vitamin E was also observed to be significantly associated with the risk of lung cancer but not with Se levels. Healthy family members of lung cancer patients were found to have a trend of lower serum Se levels than the control subjects. Furthermore, in family members of adenocarcinoma patients, serum Se and ␣-tocopherol levels were significantly lower than those in the control subjects. These results suggest that there are familial factors in low serum Se and vitamin-E levels in families of lung cancer patients. These familial factors might be based on two factors: 1) common familial dietary habit and 2) common familial hereditary factors in Se and vitamin-E metabolism.86 An inverse correlation was found between ␣-tocopherol and risk of oral cancer, and the risk was higher with increasing serum levels of ␥-tocopherol.30 Vitamin-E supplementation increases the ability of Se to inhibit development of neoplasia in mice.87 There are many interactions between Se and other trace elements that affect cancer. Selenium is an acceptor of biogenic methyl groups, which is involved in the detoxification of metals and other xenobiotics.88 Thus, Se protects against the toxic effects such as cancer from heavy metals.89 Also, the anticarcinogenic effect of Se can be counteracted by Se antagonists such as arsenic, cadmium, chromium, copper, manganese, and zinc.36,90 Treatment with adriamycin, a potent chemotherapeutic agent used in human neoplastic diseases, did not affect the low Zn and Se concentrations in cancer patients.91 Zinc and Se were the only antioxidants among those studied91 whose concentrations decreased in cancer patients. Selenium inhibits the growth stimulatory effect of cadmium on human prostatic epithelium.92 Lung cancer in smelter workers has been associated with low levels of Se and high levels of cadmium in lung tissue,93 and this increased susceptibility to lung cancer could be explained by the elevated cadmium/Se ratios in their lungs. Arsenic is an Se antagonist because it stimulates the excretion of Se from liver and reduces the anticarcinogenic effect of Se. Arsenite inhibits certain steps in Se methylation to dimethylselenide. Arsenite interferes with the formation of dimethylselenide by inhibiting the microsomal thiol-S-methyltransferase that uses S-adenosylmethionine to methylate H2Se.94 The same enzyme can methylate methylselenol to form dimethylselenide and could possibly methylate the latter to form trimethylselenonium.95 Thus, the partly methylated Se metabolites could be expected to accumulate and exert the anticarcinogenic action.24,95 Arsenic intakes correlate inversely with lung cancer mortalities in men.36 In animal studies, the coadministration of selenobetaine with arsenite enhanced the tumor-suppressive effect of selenobetaine. Arsenic by itself was totally inactive for animals, although is a known carcinogenic for humans.95 However, tin miners frequently exposed to arsenic had significantly lower serum Se levels than did those not exposed.24 Thus, high occupational exposure to tin may increase the Se requirement. If inhaled, as in the case of tin miners, tin may exert its effects directly on lung tissue, thus creating a condition not directly comparable to the effects of orally ingesting

381 large amounts of this element.24 It has recently been observed that low Se status may indirectly predispose those individuals most susceptible to an accompanying thyroid function to postmenopausal breast cancer. Selenium plays a role on the iodide and thyroid hormone metabolism because its deficiency inhibits the activity of the type I iodothyronine deiodinase.2 It is also possible that Se status may influence triiodothyronine levels through changes in the activity of the selenoenzyme type I iodothyronine deiodinase.96

CONCLUSIONS In general, the Se concentration in serum samples from cancer patients is lower than those concentrations in normal people. Further, the low Se status may be due in part to the typical malnutrition observed in cancer patients. Although the information is controversial, one can conclude that relative low Se levels in body fluids are a risk factor for some cancers. Thus, the determination of Se concentration in serum and subsequent comparison with the normal values of the population could be useful for prediagnosing cancer. Selenium supplementation can be used satisfactorily to decrease the incidence of determined cancer, but more studies must be performed to establish the Se efficacy on the different types of cancer and on the dose and the chemical form of Se. The association between cancer and nutrition is well known. Most of the plasma Se is associated with selenoprotein P in humans. Serum Se levels are positively correlated with nutritional parameters such as serum concentrations of total albumin and protein. The Se is associated to the proteins in foods. However, vegetarians present higher plasma levels of Se than do nonvegetarians. This observation is probably due to the higher bioavailability of Se-methionine present in vegetable foods than the bioavailability of Se-cysteine found in animal products. For preventing cancer, a multifactorial disease, many dietary and non-dietary factors must be considered. Among the dietary factors, the micronutrients, especially the antioxidant vitamins and minerals, and Se can play an important role, but it is necessary to develop more research to determine the interactions among the micronutrients.

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