Page 234 - Textbook of Pathology, 6th Edition

218 d) The initiated cell. The unrepaired damage produced in 1. INITIATOR CARCINOGENS
the DNA of the cell becomes permanent and fixed only if the Chemical carcinogens which can initiate the process of
altered cell undergoes at least one cycle of proliferation. This neoplastic transformation are further categorised into 2
results in transferring the change to the next progeny of cells subgroups—direct-acting and indirect-acting carcinogens or
so that the DNA damage becomes permanent and irreversible, procarcinogens.
which are the characteristics of the initiated cell, vulnerable I. DIRECT-ACTING CARCINOGENS. These chemical
to the action of promoters of carcinogenesis. carcinogens do not require metabolic activation and fall into
The stimulus for proliferation may come from 2 classes:
regeneration of surviving cells, dietary factors, hormone-
SECTION I
induced hyperplasia, viruses etc. A few examples are the a) Alkylating agents. This group includes mainly various
occurrence of hepatocellular carcinoma in cases of viral anti-cancer drugs (e.g. cyclophosphamide, chlorambucil,
hepatitis, association of endometrial hyperplasia with busulfan, melphalan, nitrosourea etc), β-propiolactone and
endometrial carcinoma, effect of oestrogen in breast cancer. epoxides. They are weakly carcinogenic and are implicated
in the etiology of the lymphomas and leukaemias in human
2. PROMOTION OF CARCINOGENESIS beings.
Promotion is the next sequential stage in the chemical carcino- b) Acylating agents. The examples are acetyl imidazole and
genesis. Promoters of carcinogenesis are substances such as dimethyl carbamyl chloride.
phorbol esters, phenols, hormones, artificial sweeteners and II. INDIRECT-ACTING CARCINOGENS (PRO-
drugs like phenobarbital. They differ from initiators in the CARCINOGENS). These are chemical substances which
following respects: require prior metabolic activation before becoming potent
i) They do not produce sudden change. ‘ultimate’ carcinogens. This group includes vast majority of
ii) They require application or administration, as the case carcinogenic chemicals. It includes the following 4 categories:
may be, following initiator exposure, for sufficient time and a) Polycyclic aromatic hydrocarbons. They comprise the
in sufficient dose. largest group of common procarcinogens which, after
iii) The change induced may be reversible. metabolic activation, can induce neoplasia in many tissues
iv) They do not damage the DNA per se and are thus not in experimental animals and are also implicated in a number
mutagenic but instead enhance the effect of direct-acting of human neoplasms. They cause different effects by various
carcinogens or procarcinogens. modes of administration e.g. by topical application may
v) Tumour promoters act by further clonal proliferation and induce skin cancer, by subcutaneous injection may cause
expansion of initiated (mutated) cells, and have reduced sarcomas, inhalation produces lung cancer, when introduced
General Pathology and Basic Techniques
requirement of growth factor, especially after RAS gene in different organs by parenteral/metabolising routes may
mutation. cause cancer of that organ.
It may be mentioned here that persistent and sustained Main sources of polycyclic aromatic hydrocarbons are:
application/exposure of the cell to initiator alone combustion and chewing of tobacco, smoke, fossil fuel (e.g.
unassociated with subsequent application of promoter may coal), soot, tar, mineral oil, smoked animal foods, industrial
also result in cancer. But the vice versa does not hold true and atmospheric pollutants. Important chemical compounds
since neither application of promoter alone, nor its included in this group are: anthracenes (benza-, dibenza-,
application prior to exposure to initiator carcinogen, would dimethyl benza-), benzapyrene and methylcholanthrene. The
result in transformation of target cell.
following examples have evidence to support the etiologic
3. PROGRESSION OF CARCINOGENESIS role of these substances:
Smoking and lung cancer: There is 20 times higher incidence
Progression of cancer is the stage when mutated proliferated of lung cancer in smokers of 2 packs (40 cigarettes) per day
cell shows phenotypic features of malignancy. These features for 20 years.
pertain to morphology, biochemical composition and Skin cancer: Direct contact of polycyclic aromatic hydro-
molecular features of malignancy. Such phenotypic features carbon compounds with skin is associated with higher
appear only when the initiated cell starts to proliferate rapidly incidence of skin cancer. For example, the natives of Kashmir
and in the process acquires more and more mutations. The carry an earthen pot containing embers, the kangri, under
new progeny of cells that develops after such repetitive their clothes close to abdomen to keep themselves warm, and
proliferation inherits genetic and biochemical characteristics skin cancer of the abdominal wall termed kangri cancer is
of malignancy. common among them.
Tobacco and betel nut chewing and cancer oral cavity: Cancer
Carcinogenic Chemicals in Humans of the oral cavity is more common in people chewing tobacco
The list of diverse chemical compounds which can produce and betel nuts. The chutta is a cigar that is smoked in South
cancer in experimental animals is a long one but only some India (in Andhra Pradesh) with the lighted end in the mouth
of them have sufficient epidemiological evidence in human (i.e. reversed smoking) and such individuals have higher
neoplasia. incidence of cancer of the mouth.
Depending upon the mode of action of carcinogenic b) Aromatic amines and azo-dyes. This category includes
chemicals, they are divided into 2 broad groups: initiators the following substances implicated in chemical
and promoters (Table 8.7). carcinogenesis: