ETIOLOGY OF

CANCER:
CARCINOGENIC
AGENTS

[Link]. Nasuhi Engin AYDIN

Carcinogenic agents (carcinogens)

 Agents causing genetic damage and

neoplastic transformation of cells
Carcinogenic agents (carcinogens)
 (1) chemical carcinogens,
 (2) radiant energy, and

 (3) microbial agents

(oncogenic viruses and

some other organisms)
 Chemical Carcinogens
 More than 200 years ago, Percival Pott
attributed scrotal skin cancer in chimney
sweeps to chronic exposure to soot.
Subsequently, hundreds of chemicals
have been shown to be carcinogenic in
animals and humans
 First documented scientific experiment
 Yamagiwa,K., and Ichikawa, K.J.:
Experimental study of the pathogenesis of
carcinoma. Cancer Research, 3: 1-29,1918
“by the repeated application of coal tar, in rabbit
skin 8 cases of carcinoma in its earliest stage,
16 in an early stage, and 7 complete carcinoma
were produced”
 Robbins and Cotran Pathologic Basis of
Disease, 8th ed., 2009

Approximately 72 million pounds of

recognized carcinogens, are released per
year in the United States.
Of about 100,000 chemicals in
commercial
use in the United States, only a very
small
proportion has been tested
experimentally
for health effects.
Basic mechanisms of chemical carcinogens
 Chemicals are tested for their
carcinogenic effects by long term
(1 or 2 years or even more) tests
mainly in rodents
This is a tremendous task which
is almost impossible to conclude
in every chemical that enter our
life
 There are some short-term tests
such as Ames mutagenicity test
in bacteria (Salmonella spc.)
 Even small aquarium fish has
been used for this purpose
yielding liver cancers in a few
weeks, e.g. Medaka and Zebra
fish species
 Chemical Carcinogens
 Chemical carcinogens have highly
reactive electrophile groups that directly
damage DNA, leading to mutations and
eventually cancer

 There are two main classes of chemical

carcinogens
 Classes of chemical carcinogens
 Direct-acting agents (these do not
require metabolic conversion to be
carcinogenic)
 They are weak carcinogens but are

important because some of them are

anticancer drugs (e.g., alkylating agents)
 Pro-carcinogens
(indirect-acting chemicals),
are metabolically converted to
molecules with potent activity
Direct-acting chemical carcinogens
( I ) ALKYLATING AGENTS
β-Propiolactone
Dimethyl sulfate
Diepoxybutane
Anticancer drugs:
(cyclophosphamide, chlorambucil,
nitrosoureas, and others)
Direct-acting chemical carcinogens

( II ) ACYLATING AGENTS
1-Acetyl-imidazole
Dimethylcarbamyl chloride
 Procarcinogens
(indirect-acting agents )

 Polycyclic and heterocyclic aromatic

hydrocarbons
 Aromatic amines, amides, azo dyes
 Natural plant and microbial products
 Others ………………………
Polycyclic And Heterocyclic
Aromatic Hydrocarbons

Benz(a)anthracene
Benzo(a)pyrene
Dibenz(a, h)anthracene
3-Methylcholanthrene
7,12-Dimethylbenz(a)anthracene
 These compounds are formed in the
high-temperature combustion of
tobacco in cigarette smoking.
 These products are implicated in the
causation of lung cancer in cigarette
smokers
 These may also be produced from
animal fats during the process of
broiling meats and are present in
smoked meats and fish
 The principal active products in many
hydrocarbons are epoxides which form
covalent adducts (addition products)
with molecules in the cell, principally
DNA, but also with RNA and proteins
Aromatic amines, amides, azo dyes

2-Naphthylamine (B-naphthylamine)
Benzidine
2-Acetylaminofluorene (2-AAF)
Dimethylaminoazobenzene (butter yellow)
 β-naphthylamine was responsible for a
50-fold increased incidence of bladder
cancers in heavily exposed workers in
the aniline dye and rubber industries
Natural plant and microbial products

Aflatoxin B1
Griseofulvin
Cycasin
Safrole
Betel nuts
 Aflatoxin B1 is of interest because it is
a naturally occurring agent produced
by some strains of Aspergillus, a
fungus that grows on improperly stored
grains and nuts.
 There is a strong correlation between
the dietary level of Aflatoxin B1 and the
incidence of liver cell cancer in Africa
and the Far East.
 Many others……
 vinyl chloride,
 arsenic,
 nickel,
 chromium,
 insecticides, fungicides,
 polychlorinated biphenyls
 Potential carcinogens in the workplace
and about the house.
 Nitrites used as food preservatives cause
nitrosylation of amines contained in the
food.
 The nitroso compounds (amines and
amides) so formed are carcinogenic to
upper gastrointestinal tract
 Radiation Carcinogenesis
 UV rays of sunlight,
 x-rays, (Roentgen rays)
 nuclear fission,
 radionuclides
 Radiation Carcinogenesis

 Ionizing radiation causes

chromosome breakage,
translocations, and, less frequently,
point mutations, leading to genetic
damage and cancer
 Survivors of the atomic bombs dropped on
Hiroshima and Nagasaki disclosed a
markedly increased incidence of leukemia
after an average latent period of about 7
years, as well as an increased mortality
rate from thyroid, breast, colon, and lung
carcinomas.
 The nuclear accident at Chernobyl
continues to yield a high cancer
incidence in the nearby areas

 Therapeutic irradiation of the head and

neck can give rise to thyroid cancer
years later
UV rays induce the formation of
pyrimidine dimers within DNA, leading to
mutations and cause carcinomas and
melanomas of the skin
Viral and Microbial Oncogenesis

Oncogenic RNA Viruses

Oncogenic DNA Viruses
Hepatitis B and Hepatitis C Viruses
Helicobacter pylori
 Oncogenic RNA
Viruses
HTLV-1 causes a T-cell leukemia that is endemic in
Japan and the Caribbean

HTLV-1 encodes a viral protein, which stimulate T

cell proliferation. Although this proliferation is initially
polyclonal, the proliferating T cells are at increased risk
of secondary mutations that lead to the outgrowth of a
monoclonal leukemia.
 Oncogenic DNA
Viruses
 HPV has been associated with
papillomas (warts), as well as
uterine cervical cancer.
 The oncogenic ability of HPV is
related to the expression of two
viral oncoproteins, E6 and E7
EBV has been implicated in the
pathogenesis of lymphomas, and
nasopharyngeal carcinoma

(Burkitt lymphomas, lymphomas in immunosuppressed

individuals with HIV infection or organ transplantation,
some forms of Hodgkin lymphoma)
Hepatitis B and Hepatitis
C Viruses
 The oncogenic effects of HBV and
HCV are multifactorial, but mainly by
immunologically mediated chronic
inflammation, hepatocellular injury,
stimulation of hepatocyte
proliferation, and production of
reactive oxygen species that can
damage DNA.
 Between 70% and 85% of liver cell carcinomas (hepatocellular
carcinomas) worldwide are due to infection with
HBV or HCV

The HBx protein of HBV and the HCV core

protein can activate a variety of pathways
that may also contribute to carcinogenesis.
 Helicobacter pylori
 By far the most important etiology of
chronic gastritis world wide is
infection
caused by Helicobacter pylori
 Though it probably had been
suspected long ago, it was first
scientifically documented in
Australia in 1983, when the
bacterium was called initially as
Campylobacter pyloridis
 Helicobacter pylori
1) Gastric intestinal type adenocarcinoma
2) Low grade B-cell lymphoma
(MALT lymphoma or MALToma)
• This may proceed to a fatal high grade

lymphoma in time such as “large cell”

Helicobacter pylori, kronik gastrit;
intestinal metaplazi..displazi…karsinoma
 A simple stain (Giemsa or
toluidine blue) for demonstration
for Helicobacter pylori
Genta stain using silver salts
 Helicobacter pylori

 The mechanism of H. pylori-

induced gastric cancers includes
immunologically mediated
chronic inflammation,
stimulation of gastric cell
proliferation, and production of
reactive oxygen species that
damage DNA
 Helicobacter pylori
 H. pylori infection leads to B-cell
proliferations and to finally monoclonal
B-cell neoplasia (MALT lymphoma) as a
result of mutations
 Schistosoma
haematobium
 In endemic areas like Egypt and Sudan
(Nile
river valley) schistosoma parazite is an
established
risk of bladder cancer
 Larvae released from freshwater snails
penetrate swimmers' skin by releasing
collagenase, elastase, and other enzymes
that dissolve the extracellular matrix, and
finally reach to the urinary bladder and
cause chronic cystitis
 The ova are deposited in the
bladder wall and incite a brisk
chronic inflammatory response
that induces progressive mucosal
squamous metaplasia and
dysplasia and, finally cancer