Cancer medicine, 8th edition. Hong WK, Bast RC Jr., Hait WN, Kufe DW, Pollock RE, Weichselbaum RR, Holland JF, Frei E III, eds. Shelton, CT: People's Medical Publishing House, 2009 Dec; :225-236
Human chemical carcinogenesis is a multistage process that results from exposures, usually in the form of complex chemical mixtures, often encountered in the environment or through our lifestyle and diet. A prime example is tobacco smoke, which can cause cancers at multiple sites including the lung, the bladder, and the head and neck. Although most chemical carcinogens do not react directly with intracellular components, they are activated to carcinogenic and mutagenic electrophiles by metabolic processes evolutionarily designed to rid the body of toxins and to modify endogenous compounds. Electrophilic chemical species are naturally attracted to nucleophiles like deoxyribonucleic acid (DNA) and protein, and through covalent bonding to DNA genetic damage results. Once internalized, carcinogens are subject to competing processes of metabolic activation and detoxification, although some chemical species can act directly. There is considerable variation among the human population in these competing metabolic processes, as well as the capacity for repair of DNA damage and cellular growth control. This is the basis for inter-individual variation in cancer risk, and is a reflection of gene-environment interactions, which embodies the concept that heritable traits modify the effects of chemical carcinogen exposure. Such variations in constitutive metabolism and DNA repair contribute to the relative susceptibility of individual members of the population to chemical exposures. For example, only 10% of tobacco smokers develop lung cancer, albeit that tobacco use accounts for other fatal conditions, including chronic obstructive pulmonary disease, stroke, and heart disease. Within the conceptual framework of multistage carcinogenesis, the primary genetic change that results from a chemical-DNA interaction is termed tumor initiation. Thus, initiated cells are irreversibly altered and are at a greater risk of malignant conversion than are normal cells. The epigenetic effects of tumor promoters facilitate the clonal expansion of the initiated cells. Selective, clonal growth advantage causes a focus of pre-neoplastic cells to form. These cells are more vulnerable to tumorigenesis because they now present a larger, more rapidly proliferating, target population for the further action of chemical carcinogens, oncogenic viruses, and other cofactors. Additional genetic and epigenetic changes continue to accumulate. The activation of oncogenes, and the inactivation of tumor suppressor and DNA-repair genes, leads to genomic instability or the so-called mutator phenotype and an acceleration in the genetic changes taking place. This scenario is followed by malignant conversion, tumor progression, and metastasis. The underlying molecular mechanisms that govern chemical carcinogenesis are becoming increasingly understood, and the insights generated are assisting in the development of better methods to investigate human cancer risk and susceptibility. The results of such studies are intended to mold strategies for prevention and intervention. Moreover, insights into the normal operations of so-called gatekeeper genes, like the tumor suppressor TP53, have provided an opportunity to develop new, targeted, therapeutic approaches.