Page 233 - Textbook of Pathology, 6th Edition

217 Neoplasia

CHAPTER 8

Figure 8.22 Sequential stages in chemical carcinogenesis (left) in evolution of cancer (right).

I. Direct-acting carcinogens. These are a few chemical Besides these two, additional factors such as age, sex and
substances (e.g. alkylating agents, acylating agents) which nutritional status of the host also play some role in
can induce cellular transformation without undergoing any determining response of the individual to chemical
prior metabolic activation. carcinogen.
II. Indirect-acting carcinogens or procarcinogens. These require b) Reactive electrophiles. While direct-acting carcinogens
metabolic conversion within the body so as to become are intrinsically electrophilic, indirect-acting substances
‘ultimate’ carcinogens having carcinogenicity e.g. polycyclic become electron-deficient after metabolic activation i.e. they
aromatic hydrocarbons, aromatic amines, azo dyes, become reactive electrophiles. Following this step, both types
naturally-occurring products and others. of chemical carcinogens behave alike and their reactive
In either case, the following steps are involved in electrophiles bind to electron-rich portions of other molecules
transforming ‘the target cell’ into ‘the initiated cell’: of the cell such as DNA, RNA and other proteins.
a) Metabolic activation. Vast majority of chemical carcino- c) Target molecules. The primary target of electrophiles is
gens are indirect-acting or procarcinogens requiring DNA, producing mutagenesis. The change in DNA may lead
metabolic activation, while direct-acting carcinogens do not to ‘the initiated cell’ or some form of cellular enzymes may
require this activation. The indirect-acting carcinogens are be able to repair the damage in DNA. The classic example of
activated in the liver by the mono-oxygenases of the such a situation occurs in xeroderma pigmentosum, a
cytochrome P-450 system in the endoplasmic reticulum. In precancerous condition, in which there is hereditary defect
some circumstances, the procarcinogen may be detoxified in DNA repair mechanism of the cell and thus such patients
and rendered inactive metabolically. are prone to develop skin cancer. The carcinogenic potential
In fact, following 2 requirements determine the of a chemical can be tested in vitro by Ames’ test for
carcinogenic potency of a chemical: mutagenesis (described later).
i) Balance between activation and inactivation reaction of Any gene may be the target molecule in the DNA for the
the carcinogenic chemical. chemical carcinogen. However, on the basis of chemically
ii) Genes that code for cytochrome P450-dependent enzymes induced cancers in experimental animals and epidemiologic
involved in metabolic activation e.g a genotype carrying studies in human beings, it has been observed that most
susceptibility gene CYP1A1 for the enzyme system has far frequently affected growth promoter oncogene is RAS gene
higher incidence of lung cancer in light smokers as compared mutation and anti-oncogene (tumour suppressor) is p53 gene
to those not having this permissive gene. mutation.