Direct-Acting Carcinogens

Alkylating Agents

-Propiolactone

Dimethyl sulfate

Diepoxybutane

Anticancer drugs (cyclophosphamide, chlorambucil, nitrosoureas, and others)

Acylating Agents

1-Acetyl-imidazole

Dimethylcarbamyl chloride

Procarcinogens That Require Metabolic Activation

Polycyclic and Heterocyclic Aromatic Hydrocarbons

Benz(a)anthracene

Benzo(a)pyrene

Dibenz(a,h)anthracene

3-Methylcholanthrene

7,12-Dimethylbenz(a)anthracene

Aromatic Amines, Amides, Azo Dyes

2-Naphthylamine (-naphthylamine)

Benzidine

2-Acetylaminofluorene

Dimethylaminoazobenzene (butter yellow)

Natural Plant and Microbial Products

Aflatoxin B1

Griseofulvin

Cycasin

Safrole

Betel nuts

Others

Nitrosamine and amides

Vinyl chloride, nickel, chromium

Insecticides, fungicides

Polychlorinated biphenyls

of promoters leads to proliferation and clonal expansion of initiated (mutated) cells. Initiated cells respond differently to promoters than do normal cells and hence expand selectively. Such cells (especially after RAS activation) have reduced growth factor requirements and may also be less responsive to growth inhibitory signals in their extracellular milieu. Forced to proliferate, the initiated clone of cells suffers additional mutations, developing eventually into a malignant tumor. Thus, the process of tumor promotion includes multiple steps: Proliferation of preneoplastic cells, malignant conversion, and eventually tumor progression, which depends on changes in tumor cells and the tumor stroma.

The initiation-promotion sequence of chemical carcinogenesis raises an important question: Since promoters are not mutagenic, how do they contribute to tumorigenesis? Although the effects of tumor promoters are pleiotropic, induction of cell proliferation is a sine qua non of tumor promotion. TPA (tetradecanoyl phorbol-13 acetate), a phorbol ester tumor promoter, is a powerful activator of protein kinase C (see Chapter 3 ), an enzyme that phosphorylates several substrates involved in signal transduction pathways, including those activated by growth factors. The promoting effect of phenobarbital in liver carcinogenesis has been linked to stimulation of cell proliferation associated with blockage of the TGF-pathway.[154]

The concept that sustained cell proliferation increases the risk of mutagenesis and hence neoplastic transformation is also applicable to human carcinogenesis. For example, pathologic hyperplasia of the endometrium ( Chapter 22 ) and increased regenerative activity that accompanies chronic liver cell injury ( Chapter 18 ) are associated with the development of cancer in these organs.

Carcinogenic Chemicals

Before closing this discussion of chemical carcinogenesis, we briefly describe some initiators (see Table 7-11 ) and promoters of chemical carcinogenesis, with special emphasis on those that have been linked to cancer development in humans.[155]

Date: 2016-04-22; view: 935