Carcinogens: what is it and what are they?

The emergence of tumors is the result of the interaction of carcinogenic factors and the body. According to the World Organization (WHO) estimates, cancer is 80-90% associated with environmental factors. Carcinogens constantly affect the human body throughout his life.

Representations of specific agents that cause tumors initially originated in the field of occupational pathology. They developed gradually and went through a significant evolution. Initially, during the period of the domination of R.Virkhov's ideas about the role of irritation in the development of cancer, various factors of chronic damage, both mechanical and chemical, were attributed to them. However, since the beginning of the XX century. As the development of experimental oncology, chemistry, physics, virology and thanks to systematic epidemiological studies, clear concrete ideas about carcinogenic agents emerged.

The WHO Expert Committee gave the following definition of the concept of a carcinogen: "Carcinogens are agents that can cause or accelerate the development of a neoplasm, regardless of its mechanism of action or the degree of specificity of the effect. Carcinogens are agents that, due to their physical or chemical properties, can cause irreversible changes or damage in those parts of the genetic apparatus that carry out homeostatic control of somatic cells "(WHO, 1979).

It is now firmly established that tumors can cause chemical, physical or biological carcinogens.

[1], [2], [3], [4], [5],

Chemical carcinogens

Experimental studies on the experimental induction of tumors by various agents in animals, begun in the early XX century. K. Yamaghiva and K. Ichikawa (K. Yamagiwa and K. Ichikawa, 1918), led to the discovery of a significant number of chemical compounds of various structures, collectively called blastomogenic, or carcinogenic, substances.

One of the outstanding researchers of this problem was E. Kennaway, who singled out in the 1930s. Benz (a) pyrene - the first of the now known chemical environmental carcinogens. In the same years, T. Yoshida and R. Kinosita discovered a group of carcinogenic aminoazo compounds, and W. Heuper first showed the carcinogenicity of aromatic amines. In the 1950s. P. Magee and J. Barnes, followed by G. Druckrey et al. Revealed a group of carcinogenic N-nitroso compounds. At the same time, the carcinogenicity of some metals was shown, carcinogenic properties of individual natural compounds (aflatoxins) and drugs were revealed. These experimental studies confirmed the results of epidemiological observations of the occurrence of tumors in humans.

At present, all known chemical carcinogens are divided into classes according to the chemical structure.

1. Polycyclic aromatic hydrocarbons (PAHs).
2. Aromatic azo compounds.
3. Aromatic amino compounds.
4. Nitroso compounds and nitramines.
5. Metals, metalloids and inorganic salts.

Depending on the nature of the action on the body, chemical carcinogens are divided into three groups:

1. carcinogens that cause tumors primarily at the site of application;
2. carcinogens of distant selective action, causing a tumor in one or another organ;
3. carcinogens of multiple action, provoking the development of tumors of different morphological structure and in various organs.

The International Agency for Research on Cancer (Lyon, France), which is the specialized body of WHO, conducted a synthesis and analysis of information on carcinogenic factors. More than 70 volumes published by the agency contain data that indicate that of approximately 1 000 suspicious agents for carcinogenicity, only 75 substances, production hazards and other factors have been proven to cause cancer in humans. The most reliable evidence is the results of many years of epidemiological observations of large groups of people conducted in many countries, which showed that contact with substances in the production environment caused the formation of malignant tumors. However, evidence of the carcinogenicity of hundreds of other substances in the occurrence of cancer in humans is not direct, but indirect. For example, chemicals such as nitrosamines or benz (a) pyrene cause cancer in many species of animals. Under their influence, normal human cells cultivated in an artificial environment can turn into malignant cells. Although this evidence is not supported by a statistically significant number of observations of people, the carcinogenic risk of such compounds is beyond doubt.

The International Agency for Research on Cancer has compiled a detailed classification of carcinogenicity-related factors. In accordance with this classification, all chemicals are divided into three categories. The first category is substances that are carcinogenic for humans and animals (asbestos, benzene, benzidine, chromium, vinyl chloride, etc.). The second category is probable carcinogens. This category is further subdivided into subgroup A (carcinogens of high probability), represented by hundreds of substances carcinogenic to animals of two or more species (aflatoxin, benz (a) pyrene, beryllium, etc.) and subgroup B (low-probability carcinogens ), characterized by carcinogenic properties for animals of the same species (adriamycin, chlorophenols, cadmium, etc.). The third category is carcinogens, substances or groups of compounds that can not be classified because of a lack of data.

This list of substances is currently the most convincing international document containing data on carcinogenic agents and the degree of evidence of their carcinogenic risk to humans.

Regardless of the structure and physico-chemical properties, all chemical carcinogens have a number of common features of action. First of all, all carcinogens are characterized by a long latent period of action. It is necessary to distinguish between a true, or a biological, and a clinical latent period. Malignancy of cells does not begin with the moment of their contact with the carcinogen. Chemical carcinogens are exposed to the processes of biotransformation in the body, resulting in the formation of carcinogenic metabolites, which, penetrating into the cell, cause deep disorders, fixed in its genetic apparatus, causing malignancy of the cell.

The true, or biological, latent period is a period of time from the formation of carcinogenic metabolites in the body before the uncontrolled multiplication of malignant cells begins. Usually the concept of a clinical latent period is used, which is considerably longer than the biological one. It is calculated by the time from the beginning of contact with the carcinogenic agent before the clinical detection of the tumor.

The second significant regularity of the action of carcinogens is the dose-time-effect relationship: the higher the single dose of the substance, the shorter the latent period and the higher the incidence of tumors.

Another regularity characteristic of the action of carcinogens is the staged morphological changes preceding the development of cancer. These stages include diffuse non-uniform hyperplasia, focal proliferates, benign and malignant tumors.

Chemical carcinogens are divided into two groups, depending on their nature. The vast majority of carcinogenic chemical compounds have anthropogenic origin, their appearance in the environment is associated with human activities. At present, many technological operations are known in which, for example, the most common carcinogens, polycyclic aromatic hydrocarbons, can be formed. This is primarily the processes associated with the combustion and thermal processing of fuel and other organic materials.

The second group - natural carcinogens, not related to production or other human activities. These include the products of vital activity of some plants (alkaloids) or molds (mycotoxins). Thus, aflatoxins are metabolites of corresponding microscopic molds parasitizing on various food products and feeds.

It was previously assumed that fungi that produce aflatoxins are common only in tropical and subtropical countries. According to modern ideas, the potential danger of the appearance of these fungi, and consequently, of food contamination with aflatoxins, is almost universal, except for countries with a cold climate, such as the North of Europe and Canada.

[6], [7], [8], [9], [10], [11], [12], [13],

Physical carcinogens

These include the following carcinogens:

• various types of ionizing radiation (X-ray, gamma rays, atomic atomic particles - protons, neutrons, alpha, beta particles, etc.);
• ultraviolet radiation;
• mechanical injury of tissues.

It should be noted that even before the discovery of chemical carcinogens, in 1902 E. Frieben described human skin cancer caused by X-rays, and in 1910 J. Clunet first received tumors in animals with the help of X-ray irradiation. In subsequent years, efforts of many radiobiologists and oncologists, including domestic ones, found that not only different types of artificially induced ionizing radiation, but also natural sources, including ultraviolet radiation of the sun, have tumorigenic effects.

In modern literature, it is customary to refer to physical carcinogenic agents of the environment only radiation factors - ionizing radiation of all kinds and types and ultraviolet radiation of the sun.

Considering carcinogenesis as a multi-stage process consisting of initiation, promotion and progression, it is established that ionizing radiation is a weak mutagen in the activation of proto-oncogenes, this can make a difference in the early stages of carcinogenesis. At the same time, ionizing radiation is highly effective in deactivation of tumor suppressor genes, which is important for the progression of tumors.

Biological carcinogens

The role of viruses in the etiology of tumors arose at the beginning of the 20th century. In 1910, P. Rous, for the first time, transformed a cell-free filtrate into a tumor in birds and explained this by the presence of a tumor virus, which confirmed the position of A. Borrel and even earlier authors about viruses as a cause of cancer.

It is now known that 30% of all cancers cause viruses, including human papillomaviruses. Human papillomavirus is defined in 75 to 95% of cases of squamous cell carcinoma of the cervix. Several types of human papillomavirus are found in tumors with invasive cancer of the oral cavity, oropharynx, larynx and nasal cavity. Human papillomaviruses of the 16th and 18th types play an important role in the carcinogenesis of head and neck cancer, especially in oropharyngeal cancer (54%) and larynx (38%). Scientists are studying the relationship of the herpes virus with lymphomas, Kaposi's sarcoma, hepatitis B and C virus with liver cancer.

However, the incidence of cancer is an order of magnitude lower than the frequency of viral infections. This suggests that for the development of the tumor process a single presence of viruses is not enough. It is also necessary to have some kind of cellular changes or changes in the host's immune system. Therefore, at the present stage of oncology and oncovirus development, one should think that from the clinical point of view, oncogenic viruses are not infectious. Viruses, as well as chemical and physical carcinogens, serve only as exogenous signals that affect endogenous oncogenes-genes that control cell division and differentiation. Molecular analysis of viruses associated with the development of cancer has shown that their function is, at least in part, associated with a change in the coding of suppressor proteins that regulate cell growth and apoptosis.

From the point of view of oncogeneity, viruses can be conditionally divided into "truly oncogenic" and "potentially oncogenic". The first, regardless of the conditions of interaction with the cell, cause the transformation of normal cells into tumor cells, i.e. Are natural, natural pathogens of malignant neoplasms. These include RNA-containing oncogenic viruses. The second group, which includes DNA-containing viruses, is capable of causing cell transformation and the formation of malignant tumors only in laboratory conditions and in animals that are not natural, natural carriers ("hosts") of these viruses.

By the early 1960's. LA Zilber in the final form formulated the virusogenetic hypothesis, the main postulate of which is the idea of physical integration of the genomes of the virus and the normal cell, i.e. When an oncogenic virus enters an infected cell, the first introduces its genetic material into the chromosome of the host cell, becoming its integral part - the "gene" or "battery of genes", thereby inducing the transformation of a normal cell into a tumor cell.

The current scheme of viral carcinogenesis is as follows:

1. the virus enters the cell; its genetic material is fixed in the cell by physical integration with cellular DNA;
2. in the viral genome there are specific genes - oncogenes, whose products are directly responsible for the transformation of a normal cell into a tumor cell; such genes in the integrated viral genome should begin to function with the formation of specific RNA and oncoproteins;
3. oncoproteins - products of oncogenes - act on the cell in such a way that it loses sensitivity to the influences that regulate its division, and becomes tumorous according to other phenotypic signs (morphological, biochemical, etc.).

[14], [15], [16], [17], [18]