Table of Contents
image Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells
image Vegetable and fruit consumption in relation to prostate cancer risk in Hawaii: A reevaluation of the effect of dietary beta-carotene
image Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer
image Application of molecular epidemiology to lung cancer chemoprevention.
image Antioxidant actions of beta-carotene in liposomal and microsomal membranes: role of carotenoid-membrane incorporation and alpha-tocopherol.
image Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infraction
image Validity of diagnoses of major coronary events in national registers of hospital diagnoses and deaths in Finland.
image Hypertension and borderline isolated systolic hypertension increase risks of cardiovascular disease and mortality in male physicians.
image Demonstration of organotropic effects of chemopreventive agents in multiorgan carcinogenesis models.
image Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance
image Epidemiological evidence for beta-carotene in prevention of cancer and cardiovascular disease.
image Beta-carotene, carotenoids, and disease prevention in humans.
image Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease
image Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease
image Oxidatively modified LDL and atherosclerosis: an evolving plausible scenario.
image Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation.
image Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial.
image Antioxidant defenses in metal-induced liver damage
image Natural killer cell activity in elderly men is enhanced by beta-carotene supplementation
image Prevention of cerebrovascular insults
image Antioxidant status and lipid peroxidation in patients infected with HIV
image Dietary supplementation with orange and carrot juice in cigarette smokers lowers oxidation products in copper-oxidized low-density lipoproteins
image Chemoprevention of oral leukoplakia and chronic esophagitis in an area of high incidence of oral and esophageal cancer.
image Dietary vitamin C, beta-carotene and 30-year risk of stroke: Results from the western electric study.
image Alpha-2 adrenoceptor subtype causing nitric oxide-mediated vascular relaxation in rats.
image Vitamin A and carotene values of institutionalized mentally retarded subjects with and without Down's syndrome.
image [Patients with type-II diabetes mellitus and neuropathy have nodeficiency of vitamins A, E, beta-carotene, B1, B2, B6, B12 and folic acid]
image The age-associated decline in immune function of healthy individuals is not related to changes in plasma concentrations of beta-carotene, retinol, alpha-tocopherol or zinc
image Recommended dietary allowance: support from recent research.
image Critical reappraisal of vitamins and trace minerals in nutritional support of cancer patients.
image Socioeconomic status and lung cancer incidence in men in The Netherlands: Is there a role for occupational exposure?
image [Prevention of cerebrovascular insults]
image The mechanism of apolipoprotein B-100 thiol depletion during oxidative modification of low-density lipoprotein
image The carotenoids beta-carotene, canthaxanthin and zeaxanthin inhibit macrophage-mediated LDL oxidation
image Antioxidant status of hypercholesterolemic patients treated with LDL apheresis
image Oxidized low density lipoproteins in atherogenesis: Role of dietary modification
image Effect of dietary supplementation of beta-carotene on human monocyte -macrophage-mediated oxidation of low density lipoprotein
image The role of free radicals in disease
image Randomized, controlled trial of antioxidant vitamins and cardioprotective diet on hyperlipidemia, oxidative stress, and development of experimental atherosclerosis: The diet and antioxidant trial on atherosclerosis (DATA)
image Effect of vitamin E, vitamin C and beta-carotene on LDL oxidation and atherosclerosis
image Pharmacotherapy in Alzheimer's dementia: Treatment of cognitive symptoms Results of new studies
image Intake of selected micronutrients and the risk of endometrial carcinoma
image New agents for cancer chemoprevention
image Status of antioxidants in patients with diabetes mellitus with and without late complications
image Antioxidants, Helicobacter pylori and stomach cancer in Venezuela.
image Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group.
image Possible immunologic involvement of antioxidants in cancer prevention.
image Synergistic suppression of azoxymethane-induced foci of colonic aberrant crypts by the combination of beta-carotene and perilla oil in rats
image Dietary intake of specific carotenoids and vitamins A, C, and E, and prevalence of colorectal adenomas


The mechanism of apolipoprotein B-100 thiol depletion during oxidative modification of low-density lipoprotein

Archives of Biochemistry and Biophysics (USA), 1997, 341/2 (287-294)

Oxidation of low-density lipoprotein (LDL) is recognized to be a key step in atherogenesis. Previous studies show that LDL contains low-molecular- weight antioxidants such as vitamin E, beta-carotene, and ubiquinol, which can retard oxidative modification. In this report, we have evaluated the antioxidant potential of apolipoprotein B-100 (apo-B) thiols during LDL oxidation. Bath apo-B thiols and vitamin E were depleted concomitantly during the lag phase of Cu2+ -mediated LDL oxidation. The rate of thiol depletion was significantly inhibited by the lipophilic spin trap N-tert-butyl-alpha- phenylnitrone (PBN) but not by the water-soluble spin trap alpha-(4-pyridyl-1- oxide)-N-tert-butylnitrone (POBN). Blocking apo-Bthiols with sulfhydryl modifying agents increased the oxidizability of LDL. As with Cu2+, peroxynitrite also caused depletion of apoB thiols, and again thiol depletion was inhibited by PBN but not by POBN. A PBN/lipid-derived radical adduct was observed by the electron spin resonance technique during oxidation of LDL with peroxynitrite. We conclude that apo-B thiol depletion is mediated by lipid peroxidation, prior to the onset of the propagation phase of LDL oxidation. The implications of apoB thiols as intrinsic antioxidants of LDL are discussed.

The carotenoids beta-carotene, canthaxanthin and zeaxanthin inhibit macrophage-mediated LDL oxidation

FEBS Letters (Netherlands), 1997, 401/2-3 (262-266)

Human monocyte-macrophages were incubated for 24 h in Ham's F-10 medium with human low-density lipoprotein (LDL) in the presence or absence of beta-carotene, canthaxanthin or zeaxanthin, at final concentrations of 2.5, 12.5 and 25 mg/l. LDL oxidation, measured by agarose gel electrophoresis, the thcarotenoids in a concentration-dependent manner. Canthaxanthin was more effective when incorporated into LDL before addition to the cultures whereas beta-carotene and zeaxanthin were more effective when added simultaneously with LDL. The results suggest that dietary carotenoids might help slow atherosclerosis progression.

Antioxidant status of hypercholesterolemic patients treated with LDL apheresis

Cardiovascular Drugs and Therapy (USA), 1996, 10/5 (567-571)

Oxidation of low density lipoprotein is involved in the pathogenesis of atherosclerosis. Epidemiological studies suggest a negative correlation between the occurrence of cardiovascular diseases and blood concentrations of lipophilic antioxidants such as vitamins A and E and beta-carotene. Trace elements, such zymes glutathione peroxidase and superoxide dismutase. The aim of this study was to determine the antioxidant and trace element status of patients with severe hypercholesterolemia who had been treated with dextran-sulphate low-density lipoprotein apheresis in comparison with two control populations, normocholesterolemic subjects and untreated hypercholesterolemic patients. Our results showed that, patients treated with LDL apheresis, compared with normocholesteromic subjects, were not deficient in vitamin E, beta-carotene, and copper, but had low plasma levels of selenium, zinc, and vitamin A. The low selenium and vitamin A levels were due to the LDL apheresis treatment, and the hypercholesterolemia might have provoked the low plasma levels of zinc.This study pointed out the potential benefits of supplemental selenium, zinc, and vitamin A in patients being treated with LDL apheresis.

Oxidized low density lipoproteins in atherogenesis: Role of dietary modification

Annual Review of Nutrition (USA), 1996, 16/- (51-71)

The development of atherosclerosis is a complex and multistep process. There are many determinants in the pathogenesis of this condition, with different factors presumably playing key roles at different times in the evolution of the atherosclerotic plaque. It has been suggested that oxidation of low density lipoproteins (LDL) by cells in the artery wall leads to a proatherogenic particle that may help initiate early lesion formation. For this reason, understanding the determinants of LDL susceptibility to oxidation is essential for developing therapeutic strategies to inhibit this process. Oxidation of LDL begins with the abstraction of hydrogen from polyunsaturated fatty acids; thus, LDL fatty acid composition undoubtedly contributes to the process of LDL oxidation. Since dietary fatty acids influence the fatty acid composition of LDL and cell membranes, the amount and type of fat in the diet may effect susceptibility of LDL and cells to oxidative damage. Additionally, since cell membrane fatty acid composition also influences cellular formation of reactive oxygen species, dietary fatty acids may help determine the prooxidant activity of artery wall cells. Both cells and lipoproteins contain a variety of antioxidants that provide protection against oxidative stress. A major source of these antioxidants is the diet. Enrichment of the diet with foods high in such antioxidants as vitamin E, beta-carotene, or vitamin C, or supplementation of the diet with antioxidant vitamins, may inhibit oxidation and the process of atherosclerosis.

Effect of dietary supplementation of beta-carotene on human monocyte -macrophage-mediated oxidation of low density lipoprotein

Israel Journal of Medical Sciences (Israel), 1996, 32/6 (473-478)

Oxidative modification of low density lipoprotein (LDL), a key step in early atherosclerosis, is protected by the lipoprotein-associated antioxidants. The present study analyzes the effect of beta-carotene in plasma, in LDL and in monocyte-macrophages, on macrophage-mediated oxidation of LDL. We investigated the effect of dietary supplementation of beta-carotene on plasma lipid peroxidation (induced by AAPH (2,2-Azobis-2-amidinopropane hydrochloride)l and on cell-free and cell-mediated oxidation of LDL by human monocyte-derived macrophages (HMDM ) in the presence of CuSO4. Significant enrichment with beta-carotene was noted in plasma (twofold), in LDL (2.6-fold) and in HMDM (1.6-fold) 2 weeks after dietary supplementation with 180 mg/day of beta-carotene. Plasma lipid peroxidation analyzed by conjugated dienes generation decreased by 22% (P < 0.01) and LDL susceptibility to oxidation analyzed by malondialdehyde generation decreased by 40% (P < 0.01). After beta-carotene supplementation, beta-carotene-enrichment of HMDM did not affect HMDM capacity to oxidize native LDL, whereas beta-carotene enrichment of LDL significantly reduced LDL oxidation. In conclusion, then, our results suggest that beta-carotene content of LDL, but not that of the macrophages, is responsible for the inhibition of oxidation of LDL.

The role of free radicals in disease

Australian and New Zealand Journal of Ophthalmology (Australia), 1995, 23/1

Evidence is accumulating that most of the degenerative diseases that afflict humanity have their origin in deleterious free radical reactions. These diseases include atherosclerosis, cancer, inflammatory joint disease, asthma, diabetes, senile dementia and degenerative eye disease. The process of biological ageing might also have a free radical basis. Most free radical damage to cells involves oxygen free radicals or, more generally, activated oxygen species (AOS) which include non-radical species such as singlet oxygen and hydrogen peroxide as well as free radicals. The AOS can damage genetic material, cause lipid peroxidation in cell membranes, and inactivate membrane-bound enzymes. Humans are well endowed with antioxidant defences against AOS; these antioxidants, or free radical scavengers, include ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), beta-carotene, coenzyme Q10, enzymes such as catalase and superoxide dismutase, and trace elements including selenium and zinc. The eye is an organ with intense AOS activity, and it requires high levels of antioxidants to protect its unsaturated fatty acids. The human species is not genetically adapted to survive past middle age, and it appears that antioxidant supplementation of our diet is needed to ensure a more healthy elderly population.

Randomized, controlled trial of antioxidant vitamins and cardioprotective diet on hyperlipidemia, oxidative stress, and development of experimental atherosclerosis: The diet and antioxidant trial on atherosclerosis (DATA)

Cardiovascular Drugs and Therapy (USA), 1995, 9/6

The effects of administration of guava and papaya fruit (100 g/day), vegetables, and mustard oil (5 g/day) (group A); antioxidant vitamins C (50 mg/day) and E (30 mg/day) plus betacarotene (10 mg/day) (group B); a high-fat (5-10 g/day) (group C); or a low-fat (4-5 g/day) diet (group D) were compared over 24 diet weeks in a randomized fashion, while all groups of rabbits (five in each of four groups) received a hydrogenated fat diet (5-10 g/day) for a period of 36 weeks. After 12 weeks on the high fat diet, each group of rabbits had an increase in blood lipoproteins. The fruit and vegetable-enriched prudent diet (group A) caused a significant decline in blood lipids at 24 and 36 weeks, whereas the lipid levels increased significantly in groups C and D. Group A also had a significant rise in vitamin E (2.1 Umol/l), C (10.5 Umol/l), A (0.66 Umol/l), and carotene (0.08 Umol/l) and a decrease in lipid peroxides (0.34 nmol/ml at 36 weeks, whereas the levels were unchanged in groups C and D. Group B rabbits had a significant and greater increase than group A in plasma vitamins E, C, A, and carotene; a rise in HDL cholesterol; and a greater decrease in lipid peroxides after 24 and 36 weeks of treatment. After stimulation of lipid peroxidation in all rabbits, 3 of 5 group C and 2 of 5 group D rabbits died due to coronary thrombosis, whereas in groups A and B there were no deaths, indicating that antioxidant therapy can provide protection against lipid peroxidation and free radical generation. Aortic lipids and sudanophilia, indicating atherosclerosis, were significantly higher in groups C and D than in groups A and B. Fatty streaks and atheromatous and fibrous plaques were noted in all the rabbits in groups C and D. Intimal fibrosis and medial degeneration were also present in the group C rabbits. While group A (36.4 plus or minus 4.4 microm) and group B (37.1 plus or minus 4.2 microm) rabbits had minimal coronary artery plaque sizes, group C (75.4 plus or minus 10.6 microm) and group D rabbits (69.5 plus or minus 6.2 microm) had significantly greater plaque sizes. Aortic plaque sizes were also greater in groups C and D than in groups A and B. It is possible that combined therapy with antioxidant vitamins C, E, and carotene, and a diet rich in antioxidants, could independently inhibit free radical generation and the development of atherosclerosis.

Effect of vitamin E, vitamin C and beta-carotene on LDL oxidation and atherosclerosis

Canadian Journal of Cardiology (Canada), 1995, 11/SUPPL. G (97G-103G)

OBJECTIVE: The oxidative modification of low density lipoprotein (LDL) may be early step in atherogenesis. Furthermore, evidence of oxidized LDL has been found in vivo. The most persuasive evidence shows that supplementation of some animal models with antioxidants slows atherosclerosis. The purpose of this review is to examine the roles that vitamin E, vitamin C and beta-carotene may play in reducing LDL oxidation. DATA SOURCES: English language articles published since 1980, particularly from groups active in this field of research. STUDY SELECTION: In vitro, animal, and human studies on antioxidants, LDL oxidation, and atherosclerosis were selected. DATA SYNTHESIS: Vitamin E has shown the most consistent effects with regard to LDL oxidation. Beta-carotene appears to have only a mild or no effect on oxidizability. Ascorbate, although it is not lipophilic, can also reduce LDL oxidative susceptibility. CONCLUSIONS: LDL oxidizability can be reduced by antioxidant nutrients. However, more research is needed to establish their utility in the prevention of coronary artery disease.

Pharmacotherapy in Alzheimer's dementia: Treatment of cognitive symptoms Results of new studies

Fortschritte der Neurologie Psychiatrie (Germany), 1997, 65/3 (108-121)

Recent investigations have given new insights into pathogenetical determinants of Alzheimer's disease. Amyloid deposition and neurofibrillary tangles are no longer considered to be primary pathological changes. Neurobiological research tries to work out the etiopathogenital cascade that finally causes Alzheimer's disease. So far, several relevant pathogenetical factors have been detected, e.g. pertubated control of glucose breakdown, impairment of oxidative metabolism, impaired neuroprotection due to increased oxidative stress and non-enzymatic protein glycation as well as immunological disturbances. Thus, new strategies for the development of cognition-enhancing drugs are emerging. The authors review reports on agents, that are under investigation for the treatment of cognitive symptomatology in Alzheimer's disease. Some of these agents have already been used for treatment of other medical conditions, e.g. nimodipine, memantine as well as selegiline. Many of them are still experimental. Promising strategies include antioxidative agents (e.g. vitamin E, vitamin C, beta-carotin), acetylcholinesterase-inhibitors with central selectivity (e.g. ENA 713), M1- and M4-muscarinic receptor agonists (milameline) as well as sabeluzole, a benzothazide derivative that shows neurotrophic activities and anti-inflammatory substances like indomethacin.

Intake of selected micronutrients and the risk of endometrial carcinoma

Cancer (USA), 1996, 77/5 (917-923)

BACKGROUND. There is some evidence that dietary habits independent of body mass may influence endometrial carcinoma risk, but the specific aspects of this hypothesis are not yet clear. METHODS. A case-control study was conducted between 1988 and 1994 in the Swiss Canton of Vaud and Northern Italy including 368 patients with histologically confirmed endometrial carcinoma and 713 controls in hospital for acute, nonneoplastic conditions, unrelated to known or potential risk factors for endometrial carcinoma. Multiple logistic regression was used to estimate the odds ratios of carcinoma of the corpus uteri according to quintile of intake of the micronutrients considered, and adjusted for potential confounding factors. RESULTS. Total energy intake was directly related to endometrial carcinoma risk. Adjustment for energy substantially modified the estimated odds ratios. After allowance for calories, the relative risk of endometrial carcinoma in the highest quintile of intake, compared with the lowest quintile of intake, was 1.2 for retinol, 0.5 for beta-carotene, 0.6 for ascorbic acid, 1.8 for vitamin D, 0.9 for vitamin E, 2.9 for methionine, 0.7 for folate, and 1.5 for calcium. Allowance for other micronutrients significantly associated with endometrial carcinoma did not substantially modify the risks estimated for beta-carotene, while associations with ascorbic acid were weaker and nonsignificant. CONCLUSIONS. This study suggests that some micronutrients, including beta-carotene, may have a protective effect against endometrial carcinoma.

New agents for cancer chemoprevention

Nation996, 63/SUPPL. 26 (1-28)

Clinical chemoprevention trials of more than 30 agents and agent combinations are now in progress or being planned. The most advanced agents are well known and are in large Phase III chemoprevention intervention trials or epidemiological studies. These drugs include several retinoids (e.g., retinol, retinyl palmitate, all-trans-retinoic acid, and 13-cis-retinoic acid), calcium, betacarotene, vitamin E, tamoxifen, and finasteride. Other newer agents are currently being evaluated in or being considered for Phase II and early Phase III chemoprevention trials. Prominent in this group are all-trans-N-(4-hydroxy phenyl)retinamide (4-HPR) (alone and in combination with tamoxifen), 2-difluoromethylomithine (DFMO), nonsteroidal antiinflammatory drugs (aspirin, piroxicam, sulindac), oltipraz, and dehydroepiandrostenedione (DHEA). A third group is new agents showing chemopreventive activity in animal models, epidemiological studies, or in pilot clinical intervention studies. They are now in preclinical toxicology testing or Phase I safety and pharmacokinetics trials preparatory to chemoprevention efficacy trials. These agents include S-allyl-l-cysteine, curcumin, DHEA analog 8354 (fluasterone), genistein, ibuprofen, indole-3- carbinol, perillyl alcohol, phenethyl isothiocyanate, 9-cis-retinoic acid, sulindac sulfone, tea extracts, ursodiol, vitamin D analogs, and p-xylyl selenocyanate. A new generation of agents and agent combinations will soon enter clinical chemoprevention studies based primarily on promising chemopreventive activity in animal models and in mechanistic studies. Among these agents are more efficacious analogs of known chemopreventive drugs including novel carotenoids (e.g., alpha-carotene and lutein). Also included are safer analogs which retain the chemopreventive efficacy of the parent drug such as vitamin D3 analogs.Other agents of high interest are aromatase inhibitors (e.g., (+)-vorozole), and protease inhibitors (e.g., Bowman-Birk soybean trypsin inhibitor). Combinations are also being considered, such as vitamin E with l-selenomethionine. Analysis of signal transduction pathways is beginning to yield classes of potentially active and selective chemopreventive drugs. Examples are ras isoprenylation and epidermal growth factor receptor inhibitors.

Status of antioxidants in patients with diabetes mellitus with and without late complications

AKTUEL. ERNAHR.MED. KLIN. PRAX. (Germany), 1994, 19/3 (155-159)

The role of antioxidative vitamins in the therapy of diabetes mellitus is of growing importance. The development of diabetic late complications (cataract, retinopathy, nephropathy and neuropathy and others) is associated with an increased presence of free radicals, and therefore, elevated oxidative stress of the human body. The aim of the present study was the evaluation of the vitamin and selenium status of diabetics. Thirty-eight patients of the age of 35-58 years had been diabetics for 8-27 years and their plasma concentration of haemoglobin was 6.7-7.5%. The diabetics of type I were treated with a functional insulin therapy with dietary restrictions, whereas the type II diabetics received oral antidiabetica (sulfonyl urea, biguanids) and had to comply with a fixed diet. Any supplementation of vitamins was omitted. The nutritional intake was monitored by a weighed record over 7 days. The plasma concentrations of vitamin A, beta-carotone, K and E were determined by reversed-phase-PLC. For the assessment of vitamin C concentrations, a photometric method was used, and selenium concentrations was determined by electrothermal atomic absorption spectrometry. Mean values of plasma concentrations were: vitamin A 36-50 microg/dl, beta-carotene 35-42 microg/dl, vitamin K: 0.5-0.6 ng/ml, vitamin E: 1.1-1.6 mg/dl, selenium: 72-75 microg/l. The values of vitamin C concentration of the diabetics type I without late complications and of type II diabetics were at 0.8 mg/dl and, therefore, at the borderline. Diabetics of type I with late complications showed marginal values of 0.6 plus or minus 0.3 mg/dl. The critical value for the prevention of scorbut has been fixed at 0.4 mg/dl. The results of this confirm the importance and efficiency of vitamins, especially of ascorbic acid. Positive effects of this antioxidative vitamin in respect of the prevention of diabetic side effects and subsequent disease should therefore be expected.

Antioxidants, Helicobacter pylori and stomach cancer in Venezuela.

de Sanjose S; Munoz N; Sobala G; Vivas J; Peraza S; Cano E; Castro D; Sanchez V; Andrade O; Tompkins D; Schorah CJ; Axon AT; Benz M; Oliver W

Servei d'Epidemiologia i Registre del Cancer, Institut Catala d'Oncologia Hospital Duran i Reynals, Barcelona, Spain.

Eur J Cancer Prev (ENGLAND) Feb 1996, 5 (1) p57-62

A randomized chemoprevention trial on precancerous lesions of the stomach is being conducted in Tachira State, Venezuela. The aims of the study are to evaluate the efficacy of vitamin supplementation in preventing the progression rate of precancerous lesions. Here we report on the pilot phase of the study in which two antioxidant preparations were evaluated on their ability to raise antioxidant levels in plasma and in gastric juice. The study aimed also to determine the antibiotic sensitivity profiles of Helicobacter pylori isolates prevalent in the area. Forty-three subjects with precancerous lesions (chronic gastritis, chronic atrophic gastritis, intestinal metaplasia and dysplasia) of the stomach were randomized to one of atments. Treatment 1 (250 mg of standard vitamin C, 200 mg of vitamin E and 6 mg of beta-carotene three times a day) or treatment 2 (150 mg of standard vitamin C, 500 mg of slow release vitamin C, 75 mg of vitamin E and 15 mg of beta-carotene once a day) for 7 days. Blood levels of total vitamin C, beta-carotene and alpha-tocopherol and gastric juice levels of ascorbic acid and total vitamin C were measured before and after treatment on day 8. Both treatments increased the plasma levels of total vitamin C, beta-carotene and alpha-tocopherol/cholesterol but not those of ascorbic acid or total vitamin C in gastric juice. Treatment 1 was the best choice and resulted in a greater increase in the plasma levels of beta-carotene and alpha-tocopherol. H. pylori was cultured from 90% of the gastric biopsies; 35 isolates were identified which were highly resistant to metronidazole, a front-line antibiotic recommended against H. pylori in other settings.

Prevention of esophageal cancer: the nutrition intervention trials in Linxian, China. Linxian Nutrition Intervention Trials Study Group.

Cancer Res. 1994 Apr 1. 54(7 Suppl). P 2029s-2031s

In Linxian China, the esophageal/gastric cardia cancer mortality rates are among the highest in the world. There is suspicion that the population's chronic deficiencies of multiple micronutrients are etiologically involved. We conducted two randomized, placebo-controlled nutrition intervention trials to test the effects of vitamin and mineral supplements in lowering the rates of esophageal/gastric cancer. In the first trial, the dysplasia trial, 3318 adults with a cytological diagnosis of esophageal dysplasia received daily supplementation with 26 vitamins and minerals in doses typically 2-3 times the United States Recommended Daily Allowances, or placebos, for 6 years. The second trial, the general population trial, involved 29,584 adults and used a one-half replicate of a 2(4) factorial experimental design which tested the effects of four combinations of nutrients: A, retinol and zinc; B, riboflavin and niacin; C, vitamin C and molybdenum; and D, beta-carotene, vitamin E, and selenium. Doses for these daily supplements ranged from 1 to 2 times the United States Recommended Daily Allowances, and the different vitamin/mineral combinations or placebos were taken for a period of 5.25 years. As part of the general population trial, and end-of-intervention endoscopy survey was carried out in a small (1.3%) sample of subjects to see if supplementation affected the prevalence of dysplasia and early cancer. Herein we review the methods of these trials and the results of the endoscopic survey. Fifteen esophageal and 16 gastric cancers were identified in endoscopic biopsies from the 391 subjects evaluated from two villages, and nearly all were asymptomatic. No significant reductions in the prevalence of esophageal or gastric dysplasia or cancer were seen with any of the four supplement groups. However, the prevalence of gastric cancer among participants receiving retinol and zinc was 62% lower than those not receiving those supplements (P = 0.09), while participants receiving beta-carotene, vitamin E, and selenium had a 42% reduction in esophageal cancer prevalence (0.34). We have reported separately that cancer mortality over the entire 5.25-year period was significantly reduced among those receiving beta-carotene, vitamin E, and selenium. The findings from the overall trial and the endoscopic sample offer a hopeful sign and should encourage additional studies with these agents in larger numbers of subjects.

Possible immunologic involvement of antioxidants in cancer prevention.

Am J Clin Nutr. 1995 Dec. 62(6 Suppl). P 1477S-1482S

The people of Linxian County, China have one of the world's highest rates of esophageal cancer. Two intervention trials were conducted to determine whether supplementation with specific vitamins and minerals could lower mortality from or incidence of cancer in this population and whether supplementation with multiple vitamins and minerals would reduce esophageal and gastric cardia cancer in persons with esophageal dysplasia. About 30,000 general population (GP) subjects in the GP trial were randomly assigned to one of eight intervention groups according to a one-half replicate of a 2(4) factorial experimental design and were supplemented for 5.25 y with four combinations of micronutrients at doses from one to two times the US recommended dietary allowance (RDA). About 3000 subjects in whom dysplasia was diagnosed in the dysplasia trial were randomly assigned to groups receiving daily supplementation with 14 vitamins and 12 minerals at two to three times the US RDA or placebo for 6 y. Results of the dysplasia trial indicate that in individuals with esophageal dysplasia, micronutrient supplementation had little effect on T lymphocyte responses. In contrast, male participants in the GP trial who were supplemented with beta-carotene, vitamin E, and selenium showed significantly (P < 0.05) higher mitogenic responsiveness of T lymphocytes in vitro than those not receiving these micronutrients.

Synergistic suppression of azoxymethane-induced foci of colonic aberrant crypts by the combination of beta-carotene and perilla oil in rats

Carcinogenesis (United Kingdom), 1996, 17/9 (1897-1901)

The modulating effect of the combined dietary feeding of beta-carotene and perilla oil, which is rich in alpha-linolenic acid, on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) was investigated in male F344 rats. Rats received oral administration of beta-carotene (0, 50 or 200 mg/kg body weight/day) and fed a basal diet containing either 12% olive oil, 3% perilla oil plus 9% olive oil, or 12% perilla oil. A dose-dependent suppressive effect of perilla oil was found. The numbers of ACF were 42.0 and 18.4% of those of the 12% olive oil-fed controls in the rats fed 3% perilla oil plus 9% olive oil and 12% perilla oil, respectively. The development of ACF was also reduced significantly by the addition of dietary beta-carotene in each of the oil-fed groups (P < 0.05, respectively). The suppression by the combination of beta-carotene and perilla oil was synergistic, as the numbers of ACF were 12.9 and 8.9% of those of the 12% olive oil-fed controls in beta-carotene-treated rats fed 3% perilla oil plus 9% olive oil and 12% perilla oil, respectively, beta-carotene plus perilla oil also suppressed the numbers of silver-stained nucleolar organizer regions and the expression of ras mRNA in the colonic mucosa (cell proliferation biomarkers). Following administration of beta-carotene, a significant increase in the concentration of intact beta-carotene molecules was found in the colonic mucosa, livers, and sera. However, no accumulation of retinoids was observed in the colonic mucosa, suggesting that the inhibitory effect may not be related to the provitamin A activity. These results suggest that the combination of beta-carotene and perilla oil may be useful in the prevention of colon cancer.

Dietary intake of specific carotenoids and vitamins A, C, and E, and prevalence of colorectal adenomas

Cancer Epidemiology Biomarkers and Prevention (USA), 1996, 5/3 (147-153)

We determined whether intakes of the main dietary carotenoids (alpha- carotene, beta-carotene, beta-cryptoxanthin, lutein plus zeaxanthin, and lycopene) and of vitamins A, C, and E were associated with the prevalence of colorectal adenomas among male and female members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy (n = 488 matched pairs). Participants, ages 50-74 years, completed a 126-item semiquantitative food- frequency questionnaire and a nondietary questionnaire from 1991 to 1993 In the univariate-matched analysis, alpha-carotene, beta-carotene (with and without supplements), beta-cryptoxanthin, lutein plus zeaxanthin, vitamin A (with and without supplements), and vitamin C (with and without supplements) were associated with a decreased prevalence of colorectal adenomas. After adjustment for intake of calories, saturated fat, folate, fiber, and alcohol, and for current smoking status, body mass index, race, physical activity, and use of nonsteroidal anti-inflammatory drugs, only beta-carotene including supplements was inversely associated with adenomas (odds ratio (OR), 0.6; 95% confidence interval (CI), 0.4-1.1; trend, P = 0.04; ORs compare highest to lowest quartiles); vitamin C showed a weaker inverse association (OR, 0.8; 95% CI, 0.5-1.5; trend, P = 0.08); and the remaining compounds were no longer clearly associated with risk. After including beta-carotene with supplements and vitamin C simultaneously in the multivariate model, the association of beta-carotene with supplements with adenomas was weakened (OR, 0.8; 95% CI, 0.5-1.3; trend P = 0.15), and vitamin C was no longer associated with risk. These data provide only modest support for a protective association of beta- carotene with colorectal adenomatous polyps.