Carcinogenesis

PROCESS OF CARCINOGENESIS The term chemical carcinogenesis is generally defined to indicate the induction or enhancement of neoplasia by chemicals. A chemical may be identified as a carcinogen based on observations in humans and supported by tests in laboratory animals. Human data may be derived from clinical observations

The relationship between the development of a cancer and the exposure to a chemical is complex There is a long latency, generally in years or decades, between the exposure and the development of the cancer. Humans are exposed to a multiplicity of potentially carcinogenic factors. Exposure of the female parent to chemicals during pregnancy can result in cancer development in offspring without any evidence of cancer in the mother.

MODE OF ACTION Chemical carcinogenesis, as shown in Figure 1, is a multistage process. Carcinogenic chemicals act by initiating certain genetic changes in a cell, promoting the formation of a neoplasm, converting the neoplasm to a cancer, or enhancing the activity of another chemical Carcinogenesis.

Bioactivation Most carcinogenic chemicals are inactive. However, they undergo bioactivation in the body to yield reactive metabolites. A common type of reactive metabolite is epoxide. For example, aflatoxin B1 is converted to aflatoxin-8,9-epoxide.

Interaction with Macromolecules The reactive metabolites bind with macromolecules. Some of them, such as proteins, may not play a critical role in carcinogenesis. However, when DNA is the target, the reaction may lead to point mutation, frame-shift mutation, and others. These changes may not persist: they may be reversed by an error-free DNA repair or disappear when the cell dies.

Initiation If the cell with an altered DNA undergoes mitosis, the alteration will be retained. The cell with the altered DNA is termed an “initiated” cell. Depending on the site of the alteration, the cell may be partially or fully neoplastic. The process generally involves the conversion of proto-oncogenes to oncogenes.

Proto-oncogenes may be converted to oncogenes through translocation to a different chromosomal site, or other mechanisms such as genetic amplification, insertions, and gene mutation

In addition, there are onco suppressor genes; a lack of their expression or an inactivation of their products may also lead to carcinogenesis. One of them, the p53 suppressor gene, is mutated in about half of human cancers

In the case of silica, the generation of reactive oxygen species (ROS) results in activation of nuclear transcription factors, induction of oncogene expression, redox regulation of p53 tumor suppressor gene,and induction of apoptosis.

ROS generation as a step in the pathway of carcinogenesis is also involved in cigarette smoking, radon, and polycyclic aromatic hydrocarbons.

Promotion The initiated tumor cell, with altered genotype and phenotype, may remain dormant for a long period of time before it becomes a tumor through cell proliferation in the presence of promoters. The dormancy is probably due to the suppressant influence of the surrounding normal cells exerted through certain intercellular communication .

The influence can be reduced by programmed cell death (apoptosis), cell killing (e.g., from cytotoxic chemicals), cell removal (e.g., partial hepatectomy), growth factors (e.g., hormones), and other factors.

While initiation is generally considered to be a permanent process, promotion is not .Furthermore, it is reversible. Therefore, for an initiated cell to continue to replicate, it must be exposed to a promoter more or less continuously.

Conversion and Progression These are characterized by biochemical and/or morphological changes in the activity or structures of the genome. The mechanism of action is not fully understood, but may involve activation of the initiated cells by exposure to clastogenic agents or complete carcinogens. During this period, the neoplasm may convert from benign to malignant tumor, which is invasive and metastatic. Similar to initiation, progression is an irreversible process.

CATEGORIES OF CARCINOGENS Carcinogens may also be classified according to their mode of action into genotoxic and non genotoxic carcinogens. Genotoxic Carcinogens Genotoxic carcinogens initiate tumors by producing DNA damage. These are of two types.

Direct-Acting Carcinogens These chemicals are also known as ultimate carcinogens. They are electrophilic and can bind to DNA and other macromolecules. Examples are alkyl and aryl epoxides. Because of their high reactivity, these direct-acting carcinogens are often more active in vitro but less so in vivo.

Pre carcinogens They are also known as pro carcinogens Pre carcinogens They are also known as pro carcinogens. They require conversion through bioactivation to become ultimate carcinogens, either directly or via an intermediary stage, the proximate carcinogens. Most of the presently known chemical carcinogens fall into this class.

Different types of bioactivations(such as formation of epoxides, N -hydroxy derivatives) are involved in their conversion to the direct-acting agents,. These chemicals may also activate proto-oncogene to oncogene and inactivate onco-suppressor genes.

Another type of activation involves the generation of ROS, which subsequently stimulates the multistep sequence resulting in carcinogenesis. As noted above, timely and error-free DNA repair play an important part in the prevention of neoplastic transformation.

Non genotoxic Carcinogens These substances do not damage DNA but enhance the growth of tumors induced by genotoxic carcinogens or induce tumors through other mechanisms. These are briefly described below.

Co-carcinogens These substances enhance the effects of genotoxic carcinogens when given simultaneously. They may act by effecting an increase in the concentration of the initiator, the genotoxic carcinogen itself, or that of the reactive metabolite.

This can be achieved either by an increase of the absorption of the carcinogen, via the gastrointestinal tract or the skin, or by an increase of the bioactivation.

. The same result can also be achieved through a decrease of the elimination of the initiator either by inhibiting the detoxification enzymes or by depleting the endogenous substrates involved in phase Il reactions, such as glutathione

A part from increasing the concentration of the reactive species at the site of action, co-carcinogens may inhibit the rate or fidelity of DNA repair, or they may enhance conversion of DNA lesions to permanent alterations.

Tobacco smoke contains relatively small amounts of genotoxic carcinogens, such as PAH and nitrosamines; its marked carcinogenic effects are perhaps attributed to catechols which act as co-carcinogens.

Promoters These chemicals increase the effects of initiators when given subsequently. The application of the promoters could be delayed for months or even a year without losing the effect. The possible mechanisms of action of promoters include:

1. Stimulation of cell proliferation through cytotoxicity or hormonal effects. 2. Inhibition of intercellular communication, thereby releasing the initiated cells from the restraint exercised by the surrounding normal cells; and 3. Immunosuppression

Hormones such as estradiol and diethylstilbestrol have been shown to produce an increase in tumors in animals (e.g., breast cancer in mice) and in humans (e.g., endometrial cancer in menopausal females maintained on estrogen).

These substances are not genotoxic but act as promoters These substances are not genotoxic but act as promoters. Androgens have little, if any, carcinogenic effect. The herbicide aminotriazole and certain fungicides induce thyroid tumors also through a hormonal mechanism

Immunosuppressive drugs such as cyclosporin A and azathioprine are increasingly being used in conjunction with organ transplantation. They have been shown to produce leukemias and sarcomas in some of these patients and in mice and rats.

The genotoxic agents are likely to be viruses, and the immune suppressive drugs promote the development of the tumors through non genotoxic mechanisms.

Solid-State Carcinogens These are exemplified by asbestos and implanted materials such as plastics, metal, and glass. These substances exert no genotoxic effects, but they produce tumors of mesenchymal origin. Although the precise mode of action is not known,

the tumors they induce are preceded by an exuberant foreign-body reaction including hyperplastic fibrosis with a high frequency of chromosomal changes in the pre neoplastic cells.

In many cases there is concomitant exposure to the substances in cigarette smoke, and the frequency of lung cancer in individuals exposed to asbestos and cigarette smoke is markedly higher than those exposed to asbestos alone.

The absence of tumors in subjects exposed to asbestos alone but the presence of cancer in patients exposed to asbestos and cigarette smoke is a strong indication that asbestos may be acting as an initiator rather than a direct carcinogen .

Metals and Metalloids Arsenic, cadmium, chromium, nickel, uranium, and their compounds are carcinogenic in humans. A number of others such as beryllium, cobalt, and lead are considered to be carcinogens in animals. Arsenic was thought tobe an exception in that it is carcinogenic in humans but not in animals.

The mechanisms underlying metal-induced carcinogenesis are not fully understood, but may involve genotoxic and/or epigenetic activities. .Radon was shown to penetrate bronchial epithelial nuclei resulting in DNA mutation initiation leading to malignant transformation of cells).

Secondary Carcinogens This term has been used to refer to substances that are not directly carcinogenic but can induce cancer following a distinctly noncarcinogenic effect For example, polyoxyethylenemonostearate (Myrj 45), at very high doses, elicited bladder stones that in turn produced bladder tumors. No tumors were observed in any of the animals that had no bladder stones. On the other hand,thisterm has also been used in connection with those genotoxic carcinogens that require bioactivation.