Can dietary beta-carotene materially reduce human cancer rates?
TL;DR: If dietary β-carotene is truly protective—which could be tested by controlled trials—there are a number of theoretical mechanisms whereby it might act, some of which do not directly involve its ‘provitamin A’ activity.
Abstract: Human cancer risks are inversely correlated with (a) blood retinol and (b) dietary beta-carotene. Although retinol in the blood might well be truly protective, this would be of little immediate value without discovery of the important external determinants of blood retinol which (in developed countries) do not include dietary retinol or beta-carotene. If dietary beta-carotene is truly protective--which could be tested by controlled trials--there are a number of theoretical mechanisms whereby it might act, some of which do not directly involve its 'provitamin A' activity.
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TL;DR: No reduction in the incidence of lung cancer among male smokers is found after five to eight years of dietary supplementation with alpha-tocopherol or beta carotene, and this trial raises the possibility that these supplements may actually have harmful as well as beneficial effects.
Abstract: Background. Epidemiologic evidence indicates that diets high in carotenoid-rich fruits and vegetables, as well as high serum levels of vitamin E (alpha-tocopherol) and beta carotene, are associated with a reduced risk of lung cancer. Methods. We performed a randomized, double-blind, placebo-controlled primary-prevention trial to determine whether daily supplementation with alpha-tocopherol, beta carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers 50 to 69 years of age from southwestern Finland were randomly assigned to one of four regimens: alpha-tocopherol (50 mg per day) alone, beta carotene (20 mg per day) alone, both alpha-tocopherol and beta carotene, or placebo. Follow-up continued for five to eight years. Results. Among the 876 new cases of lung cancer diagnosed during the trial, no reduction in incidence was observed among the men who received alpha-tocopherol (change in incidence as compared with those who did not, -2 percent; 95 percent confidence interval, -14 to 12 percent). Unexpectedly, we observed a higher incidence of lung cancer among the men who received beta carotene than among those who did not (change in incidence, 18 percent; 95 percent confidence interval, 3 to 36 percent). We found no evidence of an interaction between alpha-tocopherol and beta carotene with respect to the incidence of lung cancer. Fewer cases of prostate cancer were diagnosed among those who received alpha-tocopherol than among those who did not. Beta carotene had little or no effect on the incidence of cancer other than lung cancer. Alpha-tocopherol had no apparent effect on total mortality, although more deaths from hemorrhagic stroke were observed among the men who received this supplement than among those who did not. Total mortality was 8 percent higher (95 percent confidence interval, 1 to 16 percent) among the participants who received beta carotene than among those who did not
4,357 citations
TL;DR: Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
Abstract: Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
3,646 citations
TL;DR: After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.
Abstract: Background Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. Methods We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial — the Beta-Carotene and Retinol Efficacy Trial — involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. Results A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P = 0.02), as compared with the placebo group. There were no statistically significant ...
3,417 citations
TL;DR: It would appear that major public health benefits could be achieved by substantially increasing consumption of fruit and vegetable consumption, and in particular in cancers of the esophagus, oral cavity, and larynx, for which 28 of 29 studies were significant.
Abstract: Approximately 200 studies that examined the relationship between fruit and vegetable intake and cancers of the lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary are reviewed. A statistically significant protective effect of fruit and vegetable consumption was found in 128 of 156 dietary studies in which results were expressed in terms of relative risk. For most cancer sites, persons with low fruit and vegetable intake (at least the lower one-fourth of the population) experience about twice the risk of cancer compared with those with high intake, even after control for potentially confounding factors. For lung cancer, significant protection was found in 24 of 25 studies after control for smoking in most instances. Fruits, in particular, were significantly protective in cancers of the esophagus, oral cavity, and larynx, for which 28 of 29 studies were significant. Strong evidence of a protective effect of fruit and vegetable consumption was seen in cancers of the pancreas and stomach (26 of 30 studies), as well as in colorectal and bladder cancers (23 of 38 studies). For cancers of the cervix, ovary, and endometrium, a significant protective effect was shown in 11 of 13 studies, and for breast cancer a protective effect was found to be strong and consistent in a meta analysis. It would appear that major public health benefits could be achieved by substantially increasing consumption of these foods.
3,250 citations
TL;DR: Dietary intake of natural antioxidants could be an important aspect of the body's defense mechanism against these agents of cancer and other age-related diseases.
Abstract: The human diet contains a great variety of natural mutagens and carcinogens, as well as many natural antimutagens and anticarcinogens. Many of these mutagens and carcinogens may act through the generation of oxygen radicals. Oxygen radicals may also play a major role as endogenous initiators of degenerative processes, such as DNA damage and mutation (and promotion), that may be related to cancer, heart disease, and aging. Dietary intake of natural antioxidants could be an important aspect of the body’s defense mechanism against these agents. Many antioxidants are being identified as anticarcinogens. Characterizing and optimizing such defense systems may be an important part of a strategy of minimizing cancer and other age-related diseases.
2,924 citations
References
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Book•
01 Jan 1971
TL;DR: Introduction biology and pathophysiology of skin disorders presenting in the skin and mucous membranes dermatology and internal medicine diseases due to microbial agents therapeutics paediatric and geriatric dermatology.
Abstract: Introduction biology and pathophysiology of skin disorders presenting in the skin and mucous membranes dermatology and internal medicine diseases due to microbial agents therapeutics paediatric and geriatric dermatology.
4,333 citations
Journal Article•
TL;DR: It is shown how diminished enzyme activities along with radical production may lead to many of the observed properties of cancer cells.
Abstract: Diminished amounts of manganese-containing superoxide dismutase have been found in all the tumors examined to date. Lowered amounts of the copper-zinc-containing superoxide dismutase have been found in many, but not all, tumors. At the same time, tumors have been shown to produce superoxide radicals. It is shown how diminished enzyme activities along with radical production may lead to many of the observed properties of cancer cells. The apparent exploitation of the differences between normal and cancer cell superoxide dismutase activity in the treatment of cancer is discussed.
1,011 citations
TL;DR: The development of liver tumours, in animals fed five structually diverse hypolipidaemic compounds, supports the hypothesis that potent hepatic peroxisome proliferators as a class are carcinogenic.
Abstract: Several drugs, including clofibrate (ethyl-a-p-chlorophenoxyisobutyrate)1, are now available for the treatment of hyperlipidaemias2,3 and others are in the process of preclinical or clinical evaluation4,5. Clofibrate, the most widely used hypo-lipidaemic drug in Europe and the US2, as well as other potent hypolipidaemic agents, cause massive hepatomegaly when administered to rats6–8, mice7,8 or hamsters (J.K.R., unpublished). This hepatomegaly is characteristically associated with a marked increase of peroxisomes (Fig. 1) in the liver cells of all three species6–8. These ubiquitous cytoplasmic organelles9,10contain catalase, several hydrogen peroxide-generating oxi-dases, carnitine acetyltransferase11 as well as enzymes involved in the β-oxidation of long-chain fatty acids12. The activities of these enzymes in liver are elevated in association with peroxisome proliferation8,13. As hepatomegaly and peroxisome proliferation persist for as long as these drugs are administered to the animals, we initiated chronic toxicity studies with selected hepatic peroxisome proliferators in CSb mice and F344 rats. Liver tumours were observed in both rats and mice fed nafeno-pin (2-methyl-2[p-(l,2,3,4-tetrahydro-l-naphthyl)phenoxy]-propionic acid)14–16 or Wy-14,643 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid)17, two structurally unrelated compounds (Fig. 2, compounds 2 and 3) which are several times more potent than clofibrate in inducing peroxisome proliferation and hypolipidaemia8. Recent evidence indicates that clofibrate (Fig. 2, compound 1) is also carcinogenic when fed to rats at a concentration of 0.5% in the diet18,19. We report here that BR-931 ([4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-β-hydroxyethyl)-acetamide])20 and tibric acid(2-chloro-5-(3,5-dimethylpiperidinosulphonyl)benzoic acid)8, two potent hypolipidaemic hepatic peroxisome proliferators (Fig. 2, compounds 4 and 5) induce hepatocellular carcinomas in CSb mice and/or F344 rats. Thus, the development of liver tumours, in animals fed five structually diverse hypolipidaemic compounds (Fig. 2) supports our hypothesis that potent hepatic peroxisome proliferators as a class are carcinogenic.
822 citations
01 Jan 1976
784 citations