Nutrition and Cancer

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Effect of dietary selenium and magnesium on human mammary tumor growth in athymic Nude Mice Lin Yan , L. Mallory Boylan & Julian E. Spallholz To cite this article: Lin Yan , L. Mallory Boylan & Julian E. Spallholz (1991) Effect of dietary selenium and magnesium on human mammary tumor growth in athymic Nude Mice, Nutrition and Cancer, 16:3-4, 239-248, DOI: 10.1080/01635589109514162 To link to this article: http://dx.doi.org/10.1080/01635589109514162

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Effect of Dietary Selenium and Magnesium on Human Mammary Tumor Growth in Athymic Nude Mice Lin Yan, L. Mallory Boylan, and Julian E. Spallholz

Abstract The effect of dietary selenium (Se) supplementation and low dietary magnesium (Mg) on growth of cells of the human mammary tumor cell line (HTB123/DU4475) and the tissue glutathione (GSH) content in female athymic nude mice was studied. Sixty three- to four-week-old female athymic nude mice were randomly divided into six dietary groups of 10 animals. The mice were fed a modified AIN-76A diet with two levels of Mg (100 and 665 mg/kg) and three levels of Se (0.04, 0.2, and 4.0 mg/kg). At the fourth week of dietary treatment, mice were subcutaneously inoculated with 2.5 × 106 viable tumor cells on the dorsal lumbar region and then fed their respective diets for another four weeks. Dietary Se supplementation had no significant effect on tumor growth or tissue GSH content. Low dietary Mg limited both tumor growth and tissue GSH synthesis but raised Mg and GSH levels in tumor tissues. The growth of mice fed the diet containing 100 mg/kg Mg and 4.0 mg/kg Se was significantly retarded. This study demonstrated that neither Se deficiency nor Se supplementation had any effect on mammary tumor growth or tissue GSH content in athymic nude mice. Low dietary Mg did retard tumor growth and inhibited GSH synthesis. Low dietary Mg also resulted in an apparent increase in Se toxicity in these animals. (Nutr Cancer 16, 239-248, 1991)

Introduction Selenium (Se) has been demonstrated to be cytotoxic in vitro to normal (1) and cancer cells (2) and to be antitumorigenic in vivo in some experimental animals bearing different types of tumors (2). Selenocystine, for example, has been used in the treatment of leukemia patients with short-term success (3). Magnesium (Mg) deficiency has been reported to result in regressive tumor growth in patients with malignant tumors (4). The mechanism(s) of the inhibitory effects of dietary Se supplementation and Mg deficiency on tumor growth is not really known. Increases in blood glutathione (GSH) levels have been found in cancer patients (5) and in rats bearing tumors (6). The authors are affiliated with the Center for Food and Nutrition and Institute for Nutritional Sciences, Texas Tech University, Lubbock, TX 79409.

Copyright © 1991, Lawrence Erlbaum Associates, Inc.

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Intracellular GSH is important for normal cell division and proliferation and provides a cellular defense against cytotoxic insults (7). Tumor cells that are resistant to irradiation (8) and alkylating agents (9) have higher intracellular GSH levels than nonresistant cells. These resistant cells regained their sensitivity to treatment after depletion of intracellular GSH. Mg is involved in GSH biosynthesis as a cofactor of both y-glutamylcysteinyl synthetase and GSH synthetase (10). Mg deficiency can induce tumor growth retardation and has been correlated with its inhibition of blood GSH biosynthesis of host animals (6). In vitro studies in this laboratory (1) and in other laboratories (11) have revealed that Se-induced cytotoxicity of cancer cells is accompanied by the oxidation of intracellular GSH. The purpose of this study was to determine the effect of dietary Se supplementation in conjunction with a low and normal dietary Mg intake on the growth of cells of a human mammary tumor cell line (HTB123/DU4475) and the accompanying changes in tissue GSH content in female athymic nude mice. Materials and Methods

Materials Sodium selenite was purchased from Pfaltz and Bauer (Stamford, CT), magnesium oxide, Roswell Park Memorial Institute culture medium 1640 (RPMI1640), penicillin-streptomycin solution, glutathione reductase, /3-nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH), and o-phthadialdehyde were purchased from Sigma Chemical (St. Louis, MO). Iron-supplemented bovine calf serum was obtained from HyClone Laboratories (Logan, UT). Dulbecco's phosphate-buffered saline (DPBS) was purchased from Hazleton Biochemical (Lenexa, KS). Animals and Diets Sixty three- to four-week-old female athymic nude mice from Harlan Sprague-Dawley (Indianapolis, IN) were randomly distributed into six groups of 10 animals each. The animals were fed a modified AIN-76A diet (12,13) with sucrose as the carbohydrate source Table 1. Composition of a Modified Basal AIN-76A Diet Ingredient Casein Sucrose Celufill Methionine Choline bitartrate Corn oil AIN vitamin mixture 76" AIN mineral mixture 76 without Mg and Se6 Total

Percentage 20.0 64.5 5.0 0.3 0.2 5.0 1.0 4.0 100.0

a: Composition of AIN vitamin mixture 76 (US Biochemical, Cleveland, OH) (g/kg mix): 0.6 thiamineHC1; 0.6 riboflavin; 0.7 pyridoxine-HCl; 3 nicotinic acid; 1.6 tf-calcium pantothenate; 0.2 folic acid; 0.02 D-biotin; 0.001 cyanocobalamin; 0.8 retinyl palmitate, premix; 20rf/-a-tocopherylacetate, premix; 0.0025 cholecalciferol; 0.005 menaquionine; 972.9 sucrose. b: Composition of AIN mineral mixture 76 (US Biochemical) (g/kg mix): 500 calcium phosphate, dibasic; 74 sodium chloride; 220 potassium citrate, monohydrate; 52 potassium sulfate; 3.5 manganous carbonate; 6 ferric citrate; 1.6 zinc carbonate; 0.3 cupric carbonate; 0.01 potassium iodate; 0.55 chromium potassium sulfate; 118 sucrose.

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(Table 1), and they were provided deionized water ad libitum. Two dietary levels of Mg as magnesium oxide were adjusted to provide 100 and 665 mg/kg Mg, and three dietary levels of Se as sodium selenite were adjusted to provide 0.04,0.2, and 4.0 mg/kg Se. As determined by fluorometric and atomic absorption analysis, the modified basal AIN-76A diet contained 0.04 ± 0.01 mg Se and 21.68 ± 1.74 mg Mg per kilogram. The deionized water had no detectable Se or Mg. Animals were housed in wire-topped plastic boxes, three to four animals per box, in a laminar flow hood in a pathogen-free room with temperature maintained at 25 ± 1°C and a 12-hour light-dark cycle. Cages, bedding, deionized water, and other materials were autoclaved at 110°C 15 psi for 20 minutes before coming into contact with the mice. Diets were kept at 4°C and were changed every two days. All mice were weighed weekly.

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Analytical Methods Diets and tissues for Se and Mg analysis were digested using a method described by Spallholz and co-workers (14). Se was measured fluorometrically with a fluorescence spectrophotometer (model 650-40, Perkin-Elmer, Norwalk, CT), and Mg was measured with an atomic absorption spectrophotometer (model 5000, Perkin-Elmer). Cellular glutathione peroxidase (GSHPx) activity was determined by a modified method of Paglia and Valentine (15) with 5 mmol H 2 O 2 as substrate by means of a recording spectrophotometer (model 160, Shimadzu UV-VIS, Kyoto, Japan). Enzyme assays were carried out in 50 mmol phosphate buffer (pH 7.0) containing 2.0 mmol GSH, 0.25 mmol NADPH, 1.0 U/ml GSH reductase, and 1.0 mmol NaN3. Liver or tumor tissues were homogenized in 0.25 mol cold sucrose with a Polytron homogenizer and centrifuged at 27,000 g for 20 minutes at 4°C with a Beckman ultracentrifuge (model L8-70). The supernatant was collected and frozen at — 80°C until the analysis of GSHPx activity was performed. Enzyme activity is measured in micromoles of NADPH oxidized per gram of fresh tissue per minute. Tissue GSH was measured using the fluorometric method of Hissin and Hilf (16), taking advantage of the binding of the fluorescent molecule o-phthaldialdehye to reduce GSH at pH 8.0. A portion of tissue, 200-250 mg, was homogenized with phosphate-EDTA buffer (0.1 mol sodium phosphate and 0.005 mol EDTA, pH 8.0) containing 25% cold metaphosphoric acid (vol/vol 4:1) with a Polytron homogenizer. The homogenate was centrifuged at 100,000 g for 30 minutes at 4°C with a Beckman ultracentrifuge (model L8-70) to obtain the supernatant. Fluorescence in the supernatant was determined by excitation at 350 nm and emission at 420 nm by use of a fluorescence spectrophotometer (model 650-40, Perkin-Elmer). GSH standards were prepared just before measurement in phosphate-EDTA buffer. Unless otherwise specified, GSH represents reduced GSH in the present study. Tumor Cell Inoculation The human mammary cancer cell line HTB123/DU4475 was purchased from American Type Culture Collection (Rockville, MD) with a passage number of 168. It is a metastatic cutaneous nodule carcinoma originally derived from a 70-year-old female patient with advanced breast cancer (17). The cells were grown continuously in suspension cultures in a growth medium (pH 7.2) containing 80% RPMI 1640 medium, 20% heat-inactivated iron-supplemented bovine calf serum, and penicillin-streptomycin solution (100 U of penicillin and 100 jig of streptomycin per milliliter of growth medium). The cells were incubated at 37°C in a water-saturated atmosphere of 5% CO2 in air. The growth medium was changed every two days. Tests for Mycoplasma by use of a modified method of Chen (18) were negative. After the experimental diets were fed for four weeks, each nude mouse was subcutane-

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ously inoculated on the dorsal lumbar region with 2.5 x 106 viable tumor cells in a volume of 0.1 ml of sterilized DPBS. Mice were then fed the same experimental diets for another four weeks. Mice were weighed weekly. At the end of the experiment, the mice were killed by cervical dislocation. Tumor, liver, heart, kidneys, and spleen were collected, weighed, washed with 0.25 mol sucrose, blotted, and kept in an Environmental Equipment freezer (Cincinnati, OH) at -80°C until the time of analysis for GSH and/or GSHPx. Statistical Analysis

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Analysis of variance and Duncan's new multiple range test were used for the comparisons among treatments. Student's t test was used for paired comparisons. All the above analyses were performed by the SAS program (19). The level of significance was set at p < 0.05 Results Weight Gain The growth rate of the nude mice fed diets containing the various levels of Se and Mg is shown in Figure 1. At the end of the experimental period, there were no significant differences in body weights of mice among the three Se dietary groups fed the adequate 665 mg/kg Mg diet. Ratios of organ weight to body weight for liver, heart, kidneys, and spleen of these three Se dietary groups of mice were significantly higher than those of the three groups of mice fed the low 100 mg/kg Mg diet (Figure 1 and Table 2). Body weights of the mice fed the diet containing 100 mg/kg Mg and 4.0 mg/kg Se were significantly lower than those of mice fed the other diets. Two mice in this group died at the third week after the experimental diet was fed, another five died two weeks after tumor cell inoculation, and only two mice survived the eight weeks of experimental treatment. D Se0.0/Mg665(mg/kg) 0 Se4.0/Mg665!mg/kg) 1 SeO.2/Mg665(mg/kg> B SeO.O/nglOO(mg/Kg) • Se0.2/Mgl00(mg/Kg> H Se4.0/rigl00tmg/kgl

TIME (WEEK)

242

Figure 1. Effect of dietary selenium (Se) supplementation (0.2 and 4.0 mg) and low dietary magnesium (Mg) (100 mg) after inoculation of human mammary cancer cells (HTB123/DU4475) on weight gain in female athymic nude mice fed a modified AIN-76A diet for 8 wks. Each mouse was inoculated with 2.5 x 106 viable cells on dorsal lumbar region at end of 4 wks. Statistical analysis applied to changes of weight gain on Week 8. Data points with same letters are not significantly different (p > 0.05).

Nutrition and Cancer 1991

Table 2. Body or Tumor Weight and Ratio of Organ or Tumor Weight to Body Weight of Female Athymic Nude Mice Fed Different Experimental Diets for 8 Weeks0-* Se, mg/kg

Mg, mg/kg

Body Wt, g

O/B Ratio,c X100

Tumor Wt,

100

17.8 ± 0.8*

7.32 ± 0.45

0.71 ± 0.22 (6)e 0.32 ± 0.10

0.0

(6)d

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0.2

100

16.6 ± 0.5*

((,)"

6.50 ± 0.21

(8)

(8)

7.15 ± 0.37

g

(8)

4.07 ± 1.35 (6)e 2.05 ± 0.73 (8)

4.0

100

12.5 ± 0.7* (2)

(2)

(2)

(2)

0.0

665

0.2

665

4.0

665

23.6 ± 0.9* (10) 21.5 ± 0.8* (10) 21.0 ± 0.8*

7.99 ± 0.32 (10) 7.64 ± 0.32 (10) 7.42 ± 0.35

1.30 ± 0.32 (10) 1.24 ± 0.48 (10) 1.67 ± 0.28

6.04 ± 2.01 (10) 6.37 ± 2.59 (10) 8.11 ± 1.32

l(X/ 66S7

0.38 ± 0.10

T/B Ratio,c X100

2.97 ± 0.61

(9)

(9)

(9)

(9)

16.8 ± 0.6* (16) 22.0 ± 0.5f (29)

6.89 ± 0.22* (16) 7.80 ± 0.17+ (29)

0.47 ± 0.10* (16) 1.41 ± 0.20* (23)

2.92 ± 0.65* (10) 6.86 ± 1.11* (23)

a: Values are means ± SEM. b: Statistical significance is as follows: values in the same column with the same or no symbol (*, f, t) are not statistically different (p > 0.05). c: Abbreviations are as follows: O/B ratio, ratio of organ wt (pooled wt of liver, heart, spleen, and kidneys) to body wt; T/B ratio, ratio of tumor wt to body wt. d: No. of mice determined. e: No. of mice bearing tumors. /• Pooled data without adjustments for effect of dietary Se.

Tumor Growth Dietary Se supplementation at 0.2 or 4.0 mg/kg Se did not inhibit tumor growth in the mice fed the adequate 665 mg/kg Mg diet or low 100 mg/kg Mg diet as measured by tumor weight or the ratio of tumor weight to body weight (Table 2). The basal diet containing 0.04 mg/kg Se did not enhance tumor growth in the nude mice. Pooled data without adjustment for the effect of dietary Se show that low dietary Mg alone significantly retarded tumor growth and the ratio of tumor weight to body weight compared with tumor weight in mice fed the adequate Mg diet (p < 0.05) (Table 2). At the end of the experiment, all mice fed the low 100 mg/kg Mg diet developed tumors, whereas 87% of the mice fed the adequate 665 mg/kg Mg diet developed tumors. GSHPx Activity GSHPx activity of liver and tumor tissue was measured in all six experimental groups of animals (Table 3). Liver GSHPx activity was significantly higher in mice fed diets containing 0.2 or 4.0 mg/kg Se than in mice fed the basal Se diet. Tumor GSHPx activity was significantly higher in mice fed the diet containing 4.0 mg/kg Se in both dietary Mg treatments than in mice fed the basal Se diet or the diet containing 0.2 mg/kg Se. There were no differences in tumor GSHPx activity between the mice fed the basal Se diet and those fed the diet containing 0.2 mg/kg Se. Neither of the two dietary Mg levels affected GSHPx activity in both liver and tumor tissues (data not shown).

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Table 3. Activity of GSHPx in Liver and Tumor Tissue of Female Athymic Nude Mice Fed Different Experimental Diets for 8 Weeks0-6 Activity of GSHPx,crf NADPH/g fresh tissue/min Se, mg/kg 0.0 0.2

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4.0

Liver

Tumor

11.39 ± 0.92* (16) 21.80 ± 1.39+ (18) 19.60 ± 1.61f (11)

5.11 ± 0.17* (9) 5.35 ± 0.23* (10) 7.07 ± 0.27 f

(9)

a: Values are means ± SEM of no. of determinations per treatment (in parentheses). b: Statistical significance is as follows: values in the same column with the same or no symbol (*, t) are not statistically different (p > 0.05). c: Pooled data without adjustments for effect of dietary Mg. d: Abbreviation: GSHPx, glutathione peroxidase.

GSH Content of Tissues The GSH content of tumor tissues, liver, heart, kidneys, and spleen was determined. None of the three dietary Se levels affected tissue GSH level in mice fed either the low or adequate Mg diet (data not shown). GSH contents in liver, heart, kidneys, and spleen of mice fed the low Mg diet were significantly lower than those of mice fed the adequate Mg diet (Figure 2). Tumor tissue GSH content was significantly higher in animals fed the low Mg diet than in animals fed the adequate Mg diet (Figure 2). MG Content of Tissues Liver Mg content of mice fed the adequate 665 mg/kg Mg diet was significantly (p < 0.05) higher than that of mice fed the low 100 mg/kg Mg diet. However, the tumor Mg content of mice fed the low 100 mg/kg Mg diet was significantly Up < 0.05) higher than that of mice fed the adequate 665 mg/kg Mg diet (Table 4). 2500 _, 100 mg Mg/kg 665 mg Mg/kg 2000 -

1500 .

1000 .

500 .

TUMOR

244

LIVER

HEART

KIDNEY

SPLEEN

Figure 2. Reduced glutathione (GSH) levels in tumor tissue and organs of female athymic nude mice fed low (100 mg/kg) and adequate (665 mg/kg) magnesium (Mg) diets for 8 wks. Values are means ± SEM. Each value represents 16-23 observations. Pairs with an asterisk are significantly different (p < 0.05). Data are pooled without adjustments for effect of dietary selenium.

Nutrition and Cancer 1991

Table 4. Mg Content in Liver and Tumor Tissue of Female Athymic Nude Mice Fed Low and Adequate Mg Diets for 8 Weeks"'6 Mg Content,0 ^g/g fresh tissue Mg, mg/kg 100 665

Liver

Tumor

219.6 ± 3.5*

172.9 ± 8.6*

(8)

(4)

231.3 ± 2.6f

146.1 ± 4.0f

(8)

(4)

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a: Values are means ± SEM of no. of determinations per treatment (in parentheses). b: Statistical significance is as follows: pairs with the same symbols (*, t) are not statistically different (p > 0.05). c: Pooled data without adjustments for effect of dietary Se.

Discussion Our results show that Se supplementation at 0.2 and 4.0 mg/kg exerts no significant inhibitory effect on the growth of HTB123/DU4475 human mammary tumor cells, whereas Se deficiency also has no influence on the growth of the inoculated human mammary tumor cells in athymic nude mice. These results are not correlated with any changes in GSHPx activity or GSH levels in organs and tumor tissues and are in contrast to the studies of the inhibitory effect of dietary Se on chemically induced mammary carcinogenesis (2). Ip and co-workers (20) reported that supplementation of the diet of W/Fu rats with 2 mg/kg Se inhibited the growth of the MT-W9B transplantable rat mammary tumor. Other laboratories have also reported that Se supplements significantly inhibited the in vivo growth of transplantable L1210 leukemic cells (21), Ehrlich ascites tumor cells (22), canine mammary tumor cells (23), and human mammary tumor cells (24) different from that employed in the present study. However, Medina and Shepherd (25) reported that Se supplementation had no effect on the growth of primary mammary tumor transplanted subcutaneously in BALB/c mice. The reason for the discrepancy between our study and the reports described above is not clear. It is possible that different tumor models respond differently to Se treatments. Athymic nude mice accept foreign transplants because they lack functional T lymphocytes (26). At the same time, lack of T lymphocyte immunity in athymic nude mice may alter effects that Se may have on the immune system. It has been reported that Se affects many components of the immune system (27). Both T and natural killer lymphocytes from Se-deficient mice show a significantly decreased capacity to destroy tumor cells in vitro (28), and Se supplementation enhances natural killer cell-mediated tumor cytotoxicity in rats (29). Spallholz and others (30-32) reported that pharmacological levels of Se potentiate immune responses. The lack of effector T lymphocytes in these athymic nude mice may have a more natural tumoricidal effect in animals with T lymphocytes fed a Se-supplemented diet. Other results of this study demonstrate that Mg at the dietary level of 100 mg/kg had no specific effect on the inhibition of tumor growth or GSH metabolism in athymic nude mice. Mills and colleagues (6) reported that Mg deficiency, at a dietary level of 23 mg/kg Mg, retarded tumor growth in rats and limited blood GSH synthesis. Because the growth rate of rats and GSH levels in organs and tumor tissues of rats in their study were not reported, it is difficult to conclude whether the inhibitory effect of Mg deficiency on tumor growth was due to a specific limitation of GSH synthesis or a general Mg malnutrition. Hsu and co-workers (33) studied the role of Mg deficiency in GSH metabolism in rat erythrocytes and reported that Mg deficiency (12 mg/kg Mg in the diet) caused decreased body weight gain and decreased erythrocyte GSH levels but had no effect on organ weights or organ GSH levels. They concluded that erythrocytes appeared to be the primary target of the metabolic

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disturbance during Mg deficiency. In contrast to these previous studies, we observed no such tissue specificity in the low dietary Mg treatment of athymic nude mice. The low dietary Mg intake nonspecifically decreased the growth of mice and organ GSH levels compared with the mice fed the adequate Mg diet. Therefore we conclude that the retardation of tumor growth induced by feeding mice the low 100 mg/kg Mg diet observed in the present study was due, at least in part, to a general Mg malnutrition. A significantly increased Mg and GSH level in the tumor tissue of the mice fed the low 100 mg/kg Mg diet was observed in the present study. The observation of increased Mg levels in tumor tissue of mice fed the low Mg diet is different from the study of Young and Parsons (34). They reported that decreased tumor growth rate in rats fed a diet containing 15 mg/kg Mg was accompanied by a decreased Mg level in tumors compared with control animals fed a diet containing 650 mg/kg Mg. Earlier studies indicated that GSH had an important role in normal cell division and proliferation (6). GSH may provide an important antioxidant defense mechanism for tumors, thereby enhancing their growth (35). Mg is essential for and is involved in the biosynthesis of GSH (10). Increased Mg and GSH levels in tumors of the mice fed the low 100 mg/kg Mg diet suggest that there may be a need for Mg redistribution that fulfills the need for GSH synthesis and cell proliferation of the rapidly growing tumors under a situation of Mg malnutrition. The present study also shows that Mg deficiency enhances Se toxicity. Previous studies in other laboratories demonstrated that only at high dietary levels did Se produce chronic selenosis in either rats (36,37) or mice (38). It has been proposed that the formation of selenodiglutathione by the reaction of selenite and GSH is the first step of selenite detoxification (39). A significant decrease in GSH in organs has been observed in mice fed a low 100 mg/kg Mg diet. This decreased GSH biosynthesis may slow Se metabolism, by which an increase in the toxicity of Se is then expressed. On the other hand, Mg deficiency has been reported to affect both humoral and cellular immunity in laboratory animals (40). Impaired immunity as well as feeding mice a marginally toxic level of dietary Se may make the nude mice less tolerant of both tumor cells and the high dietary Se. This may help explain the early death of the mice fed the low 100 mg/kg Mg and 4 mg/kg Se diets. Acknowledgments and Notes This study was supported in part by a research grant from the Institute for Nutritional Sciences, Texas Tech University and Texas Tech University Health Sciences Center (Lubbock, TX). Present address of Dr. L. Yan is Dept. of Biological Sciences, Rutgers University, Newark, NJ 07102. Address reprint requests to Dr. J. E. Spallholz, Center for Food and Nutrition, Texas Tech University, Lubbock, TX 79409. Submitted 1 February 1991; accepted in final form 19 June 1991.

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36. Palmer, IS, Herr, A, and Nelson, T: "Toxicity of Selenium in Brazil Nuts to Rats." J Food Sci 47, 1595-1597, 1982. 37. Halverson, AW, and Monty, KJ: "An Effect of Dietary Sulfate on Selenium Poisoning in the Rat." J Nutr 70, 100-103, 1960. 38. Jacobs, M, and Frost, C: "Toxicological Effects of Sodium Selenite in Swiss Mice." J Toxicol Environ Health 8, 587-598, 1980. 39. Ganther, HE: "Selenotrisulfides. Formation by the Reaction of Thiols With Selenious Acid." Biochemistry 7, 2898-2905, 1968. 40. Spallholz, JE, and Stewart, JR: "Advances in the Role of Minerals in Immunobiology." Biol Trace Element Res 19, 129-151, 1989.

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Nutrition and Cancer 1991

Effect of dietary selenium and magnesium on human mammary tumor growth in athymic nude mice.

The effect of dietary selenium (Se) supplementation and low dietary magnesium (Mg) on growth of cells of the human mammary tumor cell line (HTB123/DU4...
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