Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

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one of the most important host responses for controlling the growth of tumor cells. The finding of tumor-reactive antibodies in the serum of people with cancer supports the role of the B lymphocyte as a member of the immune surveillance team. Antibodies cause destruction of can- cer cells through complement-mediated mechanisms or through antibody-dependent cellular cytotoxicity, in which the antibody binds the cancer cell to another effector cell, such as the NK cell, that does the actual killing of the cancer cell. NK cells do not require antigen recognition and can lyse a wide variety of target cells. Chemical Carcinogens A carcinogen is an agent capable of causing cancer. The role of environmental agents in causation of cancer was first noted in 1775 by Sir Percivall Pott, a English physi- cian who related the high incidence of scrotal cancer in chimneysweeps to their exposure to coal soot. 2,3 Coal tar has since been found to contain potent polycyclic aromatic hydrocarbons. Since then, many chemicals have been suspected of being carcinogens. Some have been found to cause cancers in animals, and others are known to cause cancers in humans (Chart 7-1). Chemical carcinogens can be divided into two groups: (1) direct-reacting agents, which do not require

activation in the body to become carcinogenic, and (2) indirect-reacting agents, called procarcinogens or initiators, which become active only after metabolic conversion. 2,3 Direct- and indirect-acting initiators form highly reactive species (such as free radicals) that bind with residues on DNA, RNA, or cellular proteins. They then prompt cell mutation or disrupt protein synthesis in a way that alters cell replication and interferes with cell regulatory controls. The carcinogenicity of some chemicals is augmented by agents called promoters that, by themselves, have little or no cancer-causing ability. It is believed that promoters, in the presence of these car- cinogens, exert their effect by altering gene expression, increasing DNA synthesis, enhancing gene amplification (i.e., number of gene copies that are made), and altering intercellular communication. Exposure to many carcinogens, such as those con- tained in cigarette smoke, is associated with a lifestyle risk for development of cancer. Cigarette smoke con- tains both procarcinogens and promoters. It is directly associated with lung and laryngeal cancer and has been linked with cancers of the mouth, nasal cavities, phar- ynx, esophagus, pancreas, liver, kidney, uterus, cervix, and bladder and myeloid leukemias. Not only is the smoker at risk, but others passively exposed to cigarette smoke are at risk. Chewing tobacco increases the risk of cancers of the oral cavity and esophagus. Occupational exposure to industrial chemicals is another significant risk factor for cancer. These include polycyclic aromatic hydrocarbons, which are metabo- lized in the liver. 5 For example, long-term exposure to vinyl chloride, the simple two-carbon molecule that is widely used in the plastics industry, increases the risk for hepatic angiosarcoma. 3 There is also strong evidence that certain elements in the diet contain chemicals that contribute to cancer risk. Most known dietary carcinogens occur either naturally in plants (e.g., aflatoxins) or are produced during food preparation. 2 The polycyclic aromatic hydrocarbons are of particular interest because they are produced during several types of food preparation, including frying foods in animal fat that has been reused multiple times; grill- ing or charcoal-broiling meats; and smoking meats and fish. Nitrosamines, which are powerful carcinogens, are formed in foods that are smoked, salted, cured, or pick- led using nitrites or nitrates as preservatives. Formation of these nitrosamines may be inhibited by the presence of antioxidants such as vitamin C found in fruits and vegetables. Cancer of the colon has been associated with high dietary intake of fat and red meat and a low intake of dietary fiber. 28 A high-fat diet is thought to be car- cinogenic because it increases the flow of primary bile acids that are converted to secondary bile acids in the presence of anaerobic bacteria in the colon, producing carcinogens or promoters. Heavy or regular alcohol consumption is associ- ated with a variety of cancers. The first and most toxic metabolite of ethanol is acetaldehyde, a known car- cinogen that interferes with DNA synthesis and repair and that causes point mutations in some cells. 28,29 The carcinogenic effect of cigarette smoke can be enhanced

CHART 7-1

Major Chemical Carcinogens 2,3

Direct-Acting Alkylating Agents

■■ Anticancer drugs (e.g., cyclophosphamide, cisplatin, busulfan) Polycyclic and Heterocyclic Aromatic Hydrocarbons

■■ Tobacco combustion (cigarette smoke) ■■ Animal fat in broiled and smoked meats

■■ Benzo(a)pyrene

■■ Vinyl chloride Aromatic Amines and Azo Dyes ■■ β -Naphthylamine ■■ Aniline dyes Naturally Occurring Carcinogens

■■ Aflatoxin B1 ■■ Griseofulvin

■■ Betel nuts Nitrosamines and Amides

■■ Formed in gastrointestinal tract from nitro-stable amines and nitrates used in preserving processed meats and other foods Miscellaneous Agents

■■ Asbestos

■■ Chromium, nickel, and other metals when volatilized and inhaled in industrial settings

■■ Insecticides, fungicides ■■ Polychlorinated biphenyls