Contributions of Ernst L. Wynder to chronic disease control worldwide and to preventive medicine.

Ernst L. Wynder is internationally known for his important discoveries in the field of human chronic disease causation, that is the underlying mechanisms, studied in various animal models, as a foundation for recommendations on the prevention of these diseases. These include coronary heart disease, and the main human cancers including cancer of the lung, caused by traditional smoking habits, and the nutritionally linked cancers, namely cancer of the breast, prostate, colon, pancreas, and urinary bladder.

Effect of melatonin on the induction of foci of aberrant crypts in the colon by azoxymethane in rats.

Objective: A program of research was established on the question whether melatonin played a chemopreventive role in the development of foci of aberrant crypts in the intestinal tract of male rats. Male F344 rats were injected i.p.

Antimutagens, anticarcinogens, and effective worldwide cancer prevention.

Cancer is the eventual outcome of the transformation of normal cells by DNA-reactive, genotoxic carcinogens and the growth promotion of mutated cells by enhancing factors. It is important to discriminate between genotoxic carcinogens and nongenotoxic chemicals because their mechanisms of action are quite distinct. Their dose-response curves, reversibility, and organ- and species-specificity are also quite distinct.

Lifestyle, health and disease prevention: the underlying mechanisms.

International studies in geographic pathology provide background information that a disease may have a quite different incidence and resulting mortality as a function of area of residence. Investigations in animals can model fairly precisely what is learned through such international research, and provide the basis for examining relevant hypotheses and, more importantly, possible mechanisms of action. These approaches can yield public health recommendations and health promotion activities.

Prevention of coronary heart disease and cancer by tea, a review.

Biomedical research has uncovered the mechanisms whereby tea promotes good health and lowers the risk of major chronic diseases, such as heart disease and many types of cancer. The active components in tea are polyphenols, epigallocatechin gallate in green tea, theaflavins and thearubigins in black tea. Green and black tea and the polyphenols have similar beneficial effects.

Lycopene and tomato products in health promotion.

International research through epidemiological techniques has provided information on risk factors and preventive approaches in chronic disease. Causation complementing this base of knowledge with laboratory research on associated markers for each disease has outlined the possible mechanisms whereby risk factors and preventive conditions operate. Furthermore, laboratory research in animal models and cell cultures has expanded the appropriate elements associated with each condition.

Comments on the history and importance of aromatic and heterocyclic amines in public health.

The carcinogenic risk of aromatic amines in humans was first discovered when a physician related the occurrence of urinary bladder cancer to the occupation of his patients. They were employed in the dyestuff industry, chronically exposed to large amounts of intermediate arylamines. Laboratory investigations disclosed that rats and mice administered specific azo dyes arylamines or derivatives developed cancer, primarily in the liver.

Mechanisms of chronic disease causation by nutritional factors and tobacco products and their prevention by tea polyphenols.

The beverage tea, from the top leaves of the plant Camellia sinensis is one of the most widely used beverages in the world, second only to water. Black and green tea have mostly similar actions. The active components are polyphenols, mainly epigallocatechin gallate in green tea, and the tea leaf polyphenol oxidase mediated oxidation to oolong and black tea, yielding other polyphenols, theaflavin and thearubigins.

On the occurrence of Leydig cell tumors in the F344 rat.

Dunning began inbreeding, what is now the Fischer F344 rat, in 1931. Because of her publications showing a low incidence of spontaneous tumors to 35 months of age, we selected the F344 rat for most of the studies in the National Cancer Institute (NCI) Bioassay Program, beginning in 1964. We were surprised by the finding that untreated male F344 rats displayed a high incidence of Leydig cell tumors of the testes beginning at about 17 months of age.

Induction of UDP-glucuronosyltransferase 1 (UDP-GT1) gene complex by green tea in male F344 rats.

Tea is one of the most frequently consumed beverages in the world, second only to water. Epidemiological studies have associated the consumption of green tea with a lower risk of several types of cancers, including stomach, oral cavity, esophagus, and lung. This paper deals with the mechanism of action of tea as an effective chemopreventive agent for toxic chemicals and especially carcinogens.

Tea polyphenols inhibit the formation of mutagens during the cooking of meat.

Powerful mutagens are formed during the broiling or frying of meat. These mutagens cause specific cancers in animal models, and epidemiological studies suggest that they increase the risk of breast and colon cancer. It is important, therefore, to inhibit the formation of these mutagens.

Differential effects of CYP2E1 status on the metabolic activation of the colon carcinogens azoxymethane and methylazoxymethanol.

Methylazoxymethanol (MAM) and its chemical and metabolic precursor, azoxymethane (AOM), both strong colon carcinogens in rodents, can be metabolically activated by CYP2E1 in vitro. Using CYP2E1-null mice, we found that CYP2E1 deficiency differentially affects the activation of AOM and MAM, as reflected in DNA guanine alkylation in the colon and in the formation of colonic aberrant crypt foci (ACF). Male and female inbred 129/SV wild-type (WT) and CYP2E1-null (null) mice were treated with 189 micromol/kg of either AOM or methylazoxymethyl acetate (MAMAc), and 7-methylguanine (7-MeG) and O(6)-methylguanine (O(6)-MeG) were measured in the DNAs of various organs.

Chemopreventive effects of cocoa polyphenols on chronic diseases.

We have explored the causes of the major chronic diseases prevailing in the world and the relevant mechanisms as a sound basis for recommendations for their prevention. Research shows that the cocoa bean, and tasty products derived from the cocoa bean such as chocolate, and the beverage cocoa, popular with many people worldwide, is rich in specific antioxidants, with the basic structure of catechins and epicatechin, and especially the polymers procyanidins, polyphenols similar to those found in vegetables and tea. Metabolic epidemiological studies indicate that regular intake of such products increases the plasma level of antioxidants, a desirable attribute as a defense against reactive oxygen species (ROS).

Antimutagenesis and anticarcinogenesis, from the past to the future.

Observations on cancer causation are some 150 years old, but actual detailed research on elements bearing on cancer started at the beginning of the twentieth century. Rapid progress, however, is only some 40 years old. Studies in humans documented certain lifestyle related factors to lead to cancer, and research in animal models strengthened this information.

Urinary excretion of N-OH-2-amino-3-methylimidazo[4,5-f]quinoline-N-glucuronide in F344 rats is enhanced by green tea.

The effects of green tea on the metabolism of the food carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) with emphasis on the formation of the detoxified glucuronides was studied. Two groups of 20 adult male and female Fischer 344 rats consumed 2% green tea or water for 6 weeks before being administered a single dose of 40 mg/kg body weight of [2-14C]IQ by oral gavage. Major metabolites in 24 h urine samples were separated by high-performance liquid chromatography (HPLC), including N-OH-IQ-N-glucuronide, 5-OH-IQ glucuronide and sulfate, IQ sulfamate and IQ itself.

Investigation of commercial Mitolife as an antioxidant and antimutagen.

Coronary heart disease and many types of cancer are important diseases in the world and especially in Western countries. There are biochemical activation processes for low-density lipoprotein cholesterol and genotoxic carcinogens to reactive products. In part, these also involve the generation of active oxygen and reactive oxygen species.

Green tea and the metabolism of 2-amino-3-methylimidazo.

The effects of green tea intake on the metabolism of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in the rat was studied. IQ belongs to a new class of mutagens and carcinogens, heterocyclic arylamines, formed during cooking through browning meats and fish, thus, in the food chain of most non-vegetarians. Ten adult male and female Fischer 344 rats were placed on a 2% solution of green tea and 10 control rats were on water for 6 weeks.

Prevention of cancer and other chronic diseases worldwide based on sound mechanisms.

The transformation of normal cells by DNA reactive, genotoxic carcinogens and the growth promotion and development of mutated cells by enhancing factors is involved in the overall basic mechanism of cancer induction. Thus, discrimination between genotoxic carcinogens and nongenotoxic chemicals is essential. The dose-response curves, reversibility, and organ-and species specificity are distinct.

Eat to live, not live to eat.

Most of the prevailing chronic diseases in the world have an important nutritional component by directly causing a specific disease, enhancing the risk through phenomena of promotion, exerting a beneficial effect in decreasing risk, or preventing the disease. International studies in geographic pathology have shown that a given disease may have vastly different incidence and mortality as a function of residence. Laboratory research in animal models can reproduce fairly accurately what is learned through international research and provide the basis for examining relevant hypotheses and, more importantly, proposed mechanisms of action.

Approaches for chronic disease prevention based on current understanding of underlying mechanisms.

Much progress has been achieved by exploring the causes of the main human cancers and of cardiovascular and cerebrovascular diseases. Even more important has been the knowledge acquired about the mechanisms underlying the development of these diseases. In many parts of the world, particularly in the West, the major cancers associated with dietary habits involve the postmenopausal breast, distal colon, prostate, pancreas, ovary, and endometrium.