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The stigma that cancer equals death, originating in the experiences of Hippocrates, Galen, and Celsus, was attached to the disease for centuries. It led to the long-respected dictum that doctors should not inform their patients of the diagnosis to avoid agony. In view of progress in surgery, which allowed the removal of some tumors, the American Cancer Society was formed in 1913 to educate the public about the warning symptoms of cancer and to reduce their fatalistic fears. The increased public health awareness was helpful whenever carcinogenic mechanisms were identified and the need for lifestyle changes was publicized. The insight that malignancy may be caused by the influence of damaging agents forms the basis of the noxious theory of carcinogenesis. Among the influences that may cause cancer are chemicals, radiation, and viruses.

Chemical carcinogenesis. In 1775, chemical carcinogenesis was observed by the English surgeon Sir Percival Pott, who related the cause of scrotal skin cancer in a number of his patients to a common history of occupational exposure to large amounts of coal soot as chimney sweepers when they were boys. The connection between soot and cancer was confirmed in 1915 by the first controlled experimental induction of cancer in laboratory animals by Katsusaburo Yamagiwa. The experiment established chemical carcinogenesis, and specifically occupational exposure, as one possible cause for malignant growths. An unrelated form of occupational exposure was documented in the mid-19th century in silver miners from St. Joachimsthal, Bohemia (today Czech Republic). Silver had been extracted there since the mid-16th century and was manufactured into the Joachimsthaler silver coins that were predecessors of the German currency "Thaler" and later the American currency "dollar." These miners had a high incidence of lung cancer, which was otherwise extremely rare at that time. The cause was traced to their occupational exposure (Table 1.3.A).

Archeological evidence suggests that the Mayans smoked tobacco leaves as early as the 1st century bc.

Table I.3.A. Occupational cancers. Certain occupations are associated with high levels of exposure to specific carcinogenic influences. These agents cause DNA damage through physical or chemical effects. Accordingly, the types of cancers induced by these carcinogens have a higher than normal incidence among exposed workers

Agent

Occupation

Site of cancer

X-rays

Ultraviolet radiation

Polycyclic hydrocarbons (soot, tar)

Asbestos

Radon

Bis(chloromethyl)ether

Mustard gas

Tobacco smoke

Naphthylamine

4-aminobiphenyl

Vinyl chloride

Benzene

Radium

Arsenic

Radiologists, radiographers Farmers, sailors

Chimney sweepers, manufacturers of coal gas Insulation workers, shipyard workers Underground miners for uranium or fluorspar Ion-exchange resin manufacturers Poison gas manufacturers Flight attendants, bar tenders Rubber workers, manufacturers of coal gas Chemical workers PVC manufacturers Workers with glues or varnishes Luminous dial painters Sheep dip makers, gold miners, vineyard workers, ore smelters

Skin Skin

Skin, bronchus, scrotum

Bronchus, pleura, peritoneum

Bronchus

Bronchus

Bronchus, larynx

Lung

Bladder

Bladder

Liver (angiosarcoma) Bone marrow (leukemia) bone

Epidermoid and basal cells, bronchus, liver, bladder

Only in 1761, John Hill published a treatise that warned of unusual tumors of the nose consecutive to sniffing tobacco. By 1949, Ernst Wynder had conducted a survey of 684 lung cancers, which indicated a substantially elevated risk in smokers compared to nonsmokers. It was followed 6 months later by a similar analysis, authored by Richard Doll. About 188 years after the publication by John Hill, a connection between lifestyle choices and cancer risk was established. During the following years of the 20th century, chemical carcinogenesis by tobacco products became a major cause for an increasing incidence of lung cancers. (Table 1.3.B).

In Italy, Bernardino Ramazzini associated breast cancer with reproductive factors. He reported in 1713 the virtual absence of cervical cancer and relatively high incidence of breast cancer in nuns and suggested that this was in some way related to their celibate lifestyle. The key observations by Pott, Hill, and Ramazzini laid the foundation for the field of cancer epidemiology. This area of research was given another foundation between 1930 and 1932, when Fisher, Haldane, and Wright established the principles of population genetics. In the United States, the first hospital registry for cancer was established in 1926 at Yale-New Haven Hospital in Connecticut. In 1935 and 1946, the first central cancer registries were initiated in Connecticut and California. In 1941, the United States National Cancer Institute published a survey of 696 chemical compounds, 169 of which were found to be carcinogenic in animals. During the 1960s, environmental movements became prominent in most of the Western societies. Rachel Carson believed that the long-term ecological effects of synthetic chemical pesticides were not being researched adequately. Her book "Silent Spring" pointed to the pathogenic potential of environmental toxins, and the concept of carcinogens entered popular consciousness. In 1964, Rachel Carson succumbed to cancer at the age of 56. The National Cancer Act of 1971 (declared "war on cancer" by President Richard Nixon) mandated the collection, analysis, and dissemination of all data useful in the prevention, diagnosis, and treatment of cancer. It resulted in the establishment of the National Cancer Program, under which the Surveillance, Epidemiology, and End Results (SEER) Program was developed in 1973.

Over the years, the susceptibility to various cancers has been associated with nutritional habits. In 1981, Doll and Peto [1981] estimated that 35% of cancer deaths in the United States were attributable to dietary factors. The Western European diet is rich in meat and correlates with a high incidence of colon cancer. Nasopharyngeal cancer is among the most widespread tumors in Southeast Asia, possibly supported by the ingestion of salted fish. Esophageal cancer typically occurs in conjunction with alcoholism. The growing health conscience in the late years of the 20th century, combined with insights into the potential carcinogenic properties of reactive oxygen intermediates prompted multiple studies into cancer preventive capacities of antioxidants as nutrition supplements. It was soon found that while

Table 1.3.B. Chemical carcinogens. While all chemical carcinogens share the property of damaging DNA, various compounds cause the formation of tumors in diverse organs. Among many mechanisms, this may reflect the site of exposure (skin, lungs), the site of metabolism (liver), or the site of accumulation during excretion (bladder)

Chemical Compounds Cancer

Pro-carcinogen

Polycyclic aromatic hydrocarbons

3,4-Benzopyrene Lung and pancreas cancer

3-Methylcholanthrene Lung carcinoma Benzanthracene Bladder and skin cancer 7,12-Dimethylbenzanthracene Mammary carcinoma Aromatic amines and azo dyes 2-Naphthylamine Benzidine

2-Acetylaminofluorene

4-Dimethylaminoazobenzene Mycotoxins Aflatoxins Mitomycin C Metals Arsenic Chromium

(hexavalent compounds) Cadmium Nickel

N-nitroso compounds Nitrosamines N-nitroso-piperidin Nitrosourea

Other pro-carcinogens Chlordane Carbon tetrachloride Direct-acting carcinogens

Alkylating agents Cyclophosphamide Busulfan

Chlorambucil P-Propiolactone Bis(chloromethyl)ether Acetylating agents 1-Acetylimidazole Promoters

12-Tetradecanoyl phorbol-13-

acetate (TPA, PMA) Dichlorodiphenyl- Breast cancer trichloroethane (DDT) Phenobarbital Liver cancer

2,3,7,8-Tetrachloro-p-dioxin Lymphoma Cyclosporin Squamous cell carcinoma

Unknown function

Vinyl carbamate Lung cancer

4-(Methylnitroamino)-1- Lung cancer

(3-pyridyl)-1-butanone the intake of some foods can increase the risk for specific malignancies, others - such as retinoids -can act in a chemopreventive [Sporn et al. 1976] fashion (Figure 1.3.A).

From their studies of oral cancer, Slaughter, Southwick, and Smejkal derived the concept of car-cinogenesis as a process of field cancerization (field carcinogenesis, condemned mucosa syndrome). The repeated exposure of a region's entire tissue area to carcinogenic insult increases the risk for developing multiple independent premalignant and malignant foci in that tissue [Slaughter et al. 1953]. Increasingly, molecular mechanisms have been identified to link certain toxins to specific cancers. In 1975, Bruce Ames at the University of California in Berkeley developed a test for the mutagenicity of chemical compounds, which was used to confirm that carcinogens are mutagens. Further mechanistic insight was gained with the demonstration that afla-toxin causes the mutation G249T in p53, which is associated with hepatoma [Bressac et al. 1991]. Ultraviolet (UV) light induces pyrimidine dimers, which cause mutations in p53 that lead to skin cancer [Brash et al. 1991; Pierceall et al. 1991].

The double-edged sword of mutagens became evident when their possible benefit in the treatment of neoplasias was discovered. Mustard gas had been used as a chemical warfare agent during World War I and was studied further in World War II. In 1917, Krumbhaar, a Captain in the US Medical Corps, noted the development of profound leukopenia in individuals who survived a gas attack for several days [Krumbhaar 1919]. Following up on this observation, a group of the US Office of Scientific Research and Development (OSRD) at Yale Medical School secretly studied the effects of nitrogen mustard on lymphomata. There, Lindskog successfully treated a radioresistant lymphosarcoma that compressed the patient's trachea with the injection of nitrogen mustard in December 1942. None of this was made public until 1946. During a military operation in World War II, allied ships in Bari harbor, Italy, were sunk in an air assault (2 December 1943). At the center of the destruction was the vessel John Harvey, laden with ammunition, supplies, and 2,000 mustard gas bombs. A large number of military personnel were accidentally exposed to mustard gas and were later found to have abnormally low white blood cell counts. It was reasoned that an agent, which damaged the rapidly growing white blood cells, might have a similar effect on cancer. Cornelius P. Rhoads served as chief of

Bladder carcinoma Bladder carcinoma Bladder, kidney, and liver cancer Liver tumors

Hepatocellular carcinoma

Skin cancer, lung cancer Lung cancer

Sarcomas, testicular cancer Lung cancer

Liver cancer

Liver cancer, esophagus cancer Intestinal cancer, squamous skin cancer

Liver cancer Liver cancer

Bladder cancer, skin cancer Leukemia, kidney cancer, uterine cancer

Skin cancer, stomach cancer Lung cancer

Lung cancer

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