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. Much of this research was performed in a chronic disease prevention institution--created by Dr. Wynder--the American Health Foundation. There were outreach programs to educate people about proper lifestyles to secure disease prevention, including beginning health education in children.

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. with an aqueous solution of 15 mg/kg azoxymethane (AOM) on day 50 and day 57, and a group was also injected i.p with 0.5 mg melatonin in 0.5 ml of 10% ethanol solution 5 times per week beginning at age 47 days. Foci and multiplicity of aberrant crypts were determined after 8 weeks. These groups of animals were kept in light daily from 4∶30 to 16∶30. RESULTS: In the group receiving AOM and the melatonin injections, there were fewer foci of aberrant crypts in the colon and the average number of crypts was lower after 8 weeks, compared to the group on AOM alone. CONCLUSIONS: Melatonin inhibited the formation of foci of aberrant crypts in the descending colon of rats. Also, it reduced the number of aberrant crypts per focus from foci with 3 and more aberrant crypts.

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. The mechanisms are categorized into 5 groups. 1) Tea polyphenols are powerful antioxidants. They decrease the oxidation of LDL cholesterol and lower the risk of heart disease, and also inhibit action of reactive oxygen species mediating the oxidation of DNA associated with carcinogenesis 2) Tea polyphenols induce detoxifying enzymes, glucuronosyl transferases, eliminating active forms of carcinogens and other toxicants, accounting for the lower cancer risk. 3) Tea polyphenols lower duplication rates of cancer cells and inhibit the growth of cancer, increase apoptosis and lower angiogenesis. 4) Tea polyphenols alter the intestinal bacterial flora, suppressing undesirable bacteria and favoring growth of beneficial bacteria. 5) Aging phenomena, and diseases associated with the formation of reactive oxygen species (ROS) are inhibited.

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. Individuals in the Mediterranean area present with a lower risk of several important chronic diseases, including coronary heart disease and a number of types of cancer associated with nutritional traditions, such as breast, colon, and prostate cancer. Vegetables and fruits in general and cooked tomatoes, together with olive oil, appear to be the nutritional traditions that account for this lower risk. These results lead to public health recommendations to consume more vegetables and, especially, cooked tomatoes with olive oil.

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. Also, at that time, a possible pesticide, 2-aminofluorene, was tested for chronic toxicity, revealing that it rapidly induced cancers in several organs of rodents. This led to investigations on the mode of action of this class of chemicals, including their metabolic conversion. Biochemical activation to more reactive N-hydroxy compounds was found to occur, mostly in the liver, through what is now known as the cytochrome p450 enzyme systems, and also through prostaglandin synthetases. There were species differences. Guinea pigs were resistant to carcinogenesis because of the low titer of the necessary activating enzymes. In target tissues, a second essential reaction was necessary, namely acylation or sulfate ester formation. The reactive compounds produced display attributes of genotoxicity in appropriate test systems. Interest in this class of compounds increased when of Sugimura and colleagues discovered the formation of mutagens at the surface of cooked meat or fish, that were identified as heterocyclic amines (HCAs). These compounds undergo the same type of activation reactions, as do other arylamines. Epidemiological data suggest that meat eaters may have a higher risk of breast and colon cancer. HCAs induced cancer in rats in these organs and also in the prostate and the pancreas. In addition, there is some evidence that they affect the vascular system. The formation of HCAs during cooking can be decreased by natural and synthetic antioxidants, by tryptophan or proline, or by removing the essential creatine through brief microwave cooking prior to frying or broiling. The amounts of HCAs in cooked foods are small, but other components in diet such as omega-6-polyunsaturated oils have powerful promoting effects in target organs of HCAs. On the other hand, the action of HCAs may be decreased by foods containing antioxidants, such as vegetables, soy, and tea. Some constituents in foods also induce phase II enzymes that detoxify reactive HCA metabolites. Additional mechanisms involved decreased growth of neoplasms by intake of protective foods. Possibly, the carcinogenic effect of HCAs is accompanied by the presence of reactive oxygen species (ROS), which are also inhibited by antioxidants. World-wide, there have been many contributors to knowledge in this field. Adequate information may permit now to adjust lifestyle and lower the risk of human disease stemming from this entire class of aryl and HCA.

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. The key difference between the results of Dunning and the NCI Bioassay Program was that her animals were retired breeders, whereas the NCI studies utilized virgin rats. The question of breeding was, therefore, examined as a possible protective factor. Groups of male F344 CDF/Crl rats were kept as virgin animals, or permitted access to bilaterally tube ligated female F344/Crl rats that were replaced twice over a 52-week period. At that time, all males from both groups were housed three per cage to 85 weeks when they were killed in a CO(2) atmosphere and necropsied. Sections were prepared from the fixed tissues, stained and studied by histopathology. The results were evaluated by appropriate statistical methods. Virgin and sexually active F344 rats displayed monolateral or bilateral Leydig cell tumors. There was no statistical difference between the two groups. Despite the early difference between breeding and virgin F344 rats, a control experiment failed to disclose an effect of sexual activity on the occurrence of Leydig cell cancers. This disease displays some difference in incidence in various parts of the world, with the higher socioeconomic groups having a greater incidence. Etiological factors on the occurrence of this disease in animals and in humans remain to be discovered.

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. Application of tea polyphenols, polyphenon 60 from green tea, and polyphenon B from black tea, to both surfaces of ground beef before cooking inhibits the formation of the mutagens in a dose-related fashion. This procedure is simple and effective, and utilizes inexpensive tea, a product that deserves consideration for practical use.