Carcinogens And Carcinogenesis Notes

Carcinogens And Carcinogens

Carcinogenesis or oncogenes is or tumorigenesis means mechanism of induction of tumors (pathogenesis of cancer); agents which can induce tumors are called carcinogens (etiology of cancer).

Since the time first-ever carcinogen was identified, there has been an ever-increasing list of agents implicated in the etiology of cancer.

There has been still greater accumulation in volumes of knowledge on the pathogenesis of cancer, especially due to tremendous strides made in the field of molecular biology and genetics in recent times as discussed above.

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Based on implicated causative agents, etiology and pathogenesis of  Chemical carcinogens and chemical carcinogenic

Chemical Carcinogens

The first-ever evidence of any cause for neoplasia came from the observation of Sir Percival Pott in 1775 that there was higher incidence of cancer of the scrotal skin in boys engaged in sweeping industrial chimneys in London than in the general population. This inspired the law-makers in

London to pass a ruling that these workers should bathe daily and this simple public health measure lowered the cancer incidence of scrotum in these workers.

Similar other observations in occupational workers who have skin soaked in industrial oils and reporting a higher incidence of cancer of the skin invoked wide interest in soot and coal tar and its constituents as possible carcinogenic agents.

The first successful experimental induction of cancer was produced by two Japanese workers (Yamagata and Ichikawa) in 1914 in the rabbit’s skin by repeatedly painting with coal tar.

Since then the list of chemical carcinogens which can experimentally induce cancer in animals and have epidemiological evidence in causing human neoplasia is ever-increasing.

Stages In Chemical Carcinogenic

The induction of cancer by chemical carcinogens occurs after a delay—weeks to months in the case of experimental animals, and often several years in humans.

Other factors that influence the induction of cancer are the dose and mode of administration of carcinogenic chemicals, individual susceptibility, and various predisposing factors.

Chemical carcinogenesis occurs by the induction of mutations in the proto-oncogenes (to become growth-promoting oncogenes) and in tumor-suppressor genes.

The phenomena of cellular transformation by chemical carcinogens (as also other carcinogens) is a progressive process involving 3 sequential stages

1. Initiation
2. Promotion
3. Progression

1. Initiation Of Carcinogenesis:

Initiation is the first stage in carcinogenesis induced by initiator chemical carcinogens. The change can be produced by a single dose of the initiating agent for a short time, though a larger dose for a longer duration is more effective.

The change so induced is sudden, irreversible, and permanent.

Chemical carcinogens acting as initiators of carcinogenesis can be grouped into 2 categories:

1. Direct-acting carcinogens: These are a few chemical substances (for example, alkylating agents, alkylating agents) that can induce cellular transformation without undergoing any prior metabolic activation.
2. Indirect-acting carcinogens or procarcinogens: These require metabolic conversion within the body so as to become ‘ultimate’ carcinogens having carcinogenicity for example, Polycyclic aromatic hydrocarbons, aromatic amines, azo dyes, naturally-occurring products, and others.

In either case, the following steps are involved in transforming ‘the target cell’ into ‘the initiated cell’:

• Metabolic activation:   The vast majority of chemical carcinogens are indirect-acting or procarcinogens which require metabolic activation, while direct-acting carcinogens do not require this activation.
  • The indirect-acting carcinogens are activated in the liver by the mono-oxygenases of the cytochrome P-450 system in the endoplasmic reticulum.
  • In some circumstances, the procarcinogen may be detoxified and rendered metabolically inactive.

Important chemical carcinogens:

• • In fact, the following 2 requirements determine the carcinogenic potency of a chemical:
    1. The balance between activation and inactivation reaction of the carcinogenic chemical.
    2. Genes that code for cytochrome P-450-dependent enzymes involved in metabolic activation for example, Genotype carrying susceptibility gene CYP1A1 for the enzyme system have far higher incidence of lung cancer in light-smokers as compared to those not having this permissive gene.
    3. In addition, factors such as age, sex, and nutritional status of the host also play some role in determining the response of the individual to chemical carcinogens.
• Reactive electrophiles: While direct-acting carcinogens are intrinsically electrophilic, indirect-acting substances become electron-deficient after metabolic activation i.e. they become reactive electrophiles.
  • Following this step, both types of chemical carcinogens behave alike, and their reactive electrophiles bind to electron-rich portions of other molecules of the cell such as DNA, RNA, and other proteins.
• Target molecules: The primary target of electrophiles is DNA, producing mutagenesis. The change in DNA may lead to ‘the initiated cell’, or cellular enzymes may be able to repair the damage in DNA.
  • The classic example of such a situation occurs in xeroderma pigmentosum, a precancerous condition, in which there is a hereditary defect in the DNA repair mechanism of the cell, and thus such patients are prone to develop skin cancer.
  • Any gene may be the target molecule in the DNA for the chemical carcinogen.
  • However, on the basis of chemically-induced cancers in experimental animals and epidemiologic studies in human beings, it has been observed that the most frequently affected growth-promoting oncogene is the RAS mutation and the tumor-suppressor gene is the p53 mutation.
• The initiated cell: The unrepaired damage produced in the DNA of the cell becomes permanent and fixed only if the altered cell undergoes at least one cycle of proliferation.
  • This results in transferring the change to the next progeny of cells so that the DNA damage becomes permanent and irreversible, which are the characteristics of the initiated cell, vulnerable to the action of promoters of carcinogenesis.
  • The stimulus for proliferation may come from the regeneration of surviving cells, dietary factors, hormone-induced hyperplasia, viruses, etc.
  • Examples are hepatocellular carcinoma in cases of viral hepatitis, an association of endometrial hyperplasia with endometrial carcinoma, the effect of. Estrogen in breast cancer.

2. Promotion of Carcinogenesis:

Promotion is the next sequential stage in chemical carcinogenesis. Promoters of carcinogenesis are substances such as phorbol esters, phenols, hormones, artificial sweeteners, and drugs like phenobarbital.

The following features distinguish promoters from initiators:

• They do not produce sudden change.
• They require application or administration, following initiator exposure, for sufficient time and in sufficient doses.
• The change induced may be reversible.
• They do not damage the DNA per se and are, thus, not mutagenic but instead, enhance the effect of direct-acting carcinogens or procarcinogens.
• Tumor promoters act by further clonal proliferation and expansion of initiated (mutated) cells, and have reduced the requirement of growth factor, especially after RAS gene mutation.

It may be mentioned here that persistent and sustained application/exposure of the cell to the initiator alone without a subsequent application of promoter may also result in cancer.

But vice versa does not hold true since either application of promoter alone, nor its application prior to exposure to initiator carcinogen would result in transformation of the target cell.

3. Progression of Carcinogenesis:

Progression of cancer is the stage when mutated and proliferated cells show phenotypic features of malignancy that include morphological, biochemical, and molecular characteristics.

Such phenotypic features appear only when the initiated cells proliferate rapidly, and during the process, acquire additional multiple mutations. The new progeny of cells developed after such repetitive proliferation inherits genetic and biochemical characteristics of malignancy.