CHAPTER 5
CHEMICALS AND
CANCER
This chapter will cover:
Identifying chemicals that cause cancer
Mechanisms of chemical carcinogens
This chapter will cover:
Identifying chemicals that cause cancer
Mechanisms of chemical carcinogens
Chemical carcinogens were first
discovered more than 200 years ago
In 1761, John Hill reported that people who routinely
use tobacco snuff suffered an abnormally high incidence of
nasal cancer
Percival Pott reported an unusual prevalence of oozing
sores on the scrotums of men who all served as chimney
sweepers in their youth
- chimney soot chemicals had become dissolved in the
natural oils of the scrotum, irritating the skin and eventually
triggering the development of cancer
In the early 1900s elevated rates of skin cancer were
noted among workers in the coal tar industry
An increased incidence of bladder cancer was
seen in factories that produced aniline dyes
Workers in the aniline dye industry
developed the first cancers known to
be caused by specific chemicals
William Perkin discovered aniline purple, the first
synthetic dye (1856)
A compound related to aniline called 2-
naphthylamine is an ideal starting material for the synthesis of
many dyes
Bladder cancer triggered by
occupational exposure to 2-
naphtylaamine
- a long delay is typical of chemical
carcinogenesis
- dose dependence
- organ specificity (bladder is the prime
target)
Asbestos is the second most lethal
commercial product (after tobacco) in
causing cancer deaths
The natural mineral asbestos is a particularly striking
example of an organ-specific carcinogen
Insulation Roof Wall
Asbestos
mineral
Asbestos is the second most lethal
commercial product (after tobacco) in
causing cancer deaths
The widespread use of asbestos has had severe
health consequences
- it readily breaks down into a fine dust containing numerous
sharp, needle-like fibers
- These “needles of death” are easily inhaled and become
lodged in the lung, where they cause scarring that kills
people through suffocation: asbestosis
- workers began to develop lung cancer
- asbestos and cigarette smoke interact synergistically in
causing lung cancer: 50 times higher than is observed in
non-smokers or people who do not have significant
exposure to asbestos
Asbestos is the second most lethal
commercial product (after tobacco) in
causing cancer deaths
An unusual property of asbestos is its ability to
cause mesothelioma (a cancer found in the lining surrounding
the lungs, the stomach, or the heart, i.e., mesothelium)
- pleura: the lining around the lungs (pleural mesothelium)
- pericardium: the lining around the heart (pericardinal ~)
- peritoneum: the lining around the abdominal cavity (peritoneal ~)
Asbestos fibers
trigger chronic
inflammation that
promotes the development of
cancer in the mesothelial cells
Asbestos is the second most lethal
commercial product (after tobacco) in
causing cancer deaths
Governmental actions to regulate the
production and use of asbestos began in the
1960s
Nonetheless, mesothelioma deaths are still
rising
- a lag period of 30 or more years can intervene between
asbestos exposure and developing cancer
- countries that formerly used asbestos still contain vast
reservoirs of the carcinogen in existing buildings
Death rate trends
for mesothelioma
Workplace exposure to chemical carcinogens
occurs in numerous industries
Occupational Safety and Health Administration
(OHSA):
- formulate regulations designed to protect the safety and health of
workers
- worked to eliminate the most dangerous chemicals from the workplace
and to limit worker exposure to other chemicals
- workplace exposure to carcinogens now accounts for less than 5% of
all cancer deaths
In general, exposure to industrial carcinogens is a
greater problem in developing countries, where less
progress has been made in regulating the workplace use of toxic
chemicals
Environmental pollution is not
a major source of cancer risk
Cancer risk is related to carcinogen dose
- ethylene dibromide (EDB): banned in 1984; 150 mg/d vs 0.00042 mg
Misconception
- when cancer rate is adjusted for the increasing average age of the
population, it is clear that a significant growth in age-adjusted cancer
rates has not occurred
- most of the cancers that are common
today were also common one hundred
years ago, and the main exception, lung
cancer, is triggered by cigarette smoke
and has little to do with industrial pollution
Risks from low-dose exposures to chemical
carcinogens are difficult to assess
Dioxins, a family of chlorinated chemicals produced as a by-product
during the burning of municipal wastes, the bleaching of paper, and the
production of herbicides
- high doses of dioxin cause cancer but low doses can sometimes
decrease cancer rates in rats (human vs rodents)
Dichlorodiphennlytrichloroehtnae (DDT)
- mimic the action of estrogen, which is known to promote the
development of breast cancer
- measurements of the concentration of organochlorines in the blood
failed to reveal any relationship between exposure to organochlorine
compounds and the development of breast cancer
Pollution of outdoor and indoor
air creates small cancer risks
People located in cities with the largest amounts of
this fine particle soot have lung cancer death rates roughly
10% higher than in cities with minimal pollution
- cigarette smoking increases by 2500%!
For the average citizen, the
greatest exposure to toxic airborne
chemicals turned out to occur inside
their homes
- cleaning compounds, paints,
carpeting, gasoline, air fresheners, dry
cleaning, and disinfectants
Comparison of indoor
and outdoor air pollution
Thresholds can cause animal studies
to overestimate human cancer risks
Epidemiological testing is not sensitive enough to
reliably detect small increases in cancer incidence
- scientists often turn to animal testing: animals are often exposed to the
maximum tolerated dose (MTD) of a suspected carcinogen
- at these high doses, many chemicals cause tissue destruction and cell
death. The remaining cells proliferate to replace those cells that have
been destroyed
- this enhanced cell proliferation creates
conditions that are favorable for the
development of cancer
Threshold: a dose that must be
exceeded before cancer rates begin to
rise Possibility of overestimating cancer risk when
extrapolating from high-dose data
Thresholds can cause animal studies
to overestimate human cancer risks
Why threshold?
- tissue destruction and cell death
- DNA damage
Scientists use three models to
view the relationship b/t carcinogen dose
and cancer risk
- Linear model: assumes a linear dose-
response relationship, no threshold
- threshold model: no cancer risk at lower
doses
- hormetic model: cancer rates decline at
very low doses of carcinogen
Humans and animals differ in their
susceptibilities to some carcinogens
Animals often differ from humans in their
susceptibility to different carcinogens
- 2-acetylaminofluorene (AAF): a potent carcinogen in rats but not in
guinea pigs
- saccharin (artificial sweetener): causes bladder cancer in rats but not
in guinea pigs and mice
Caution is needed in labeling substances as human
carcinogens when the information has been derived largely from animal
studies
- known to be human carcinogens: animal studies + enough human data
- reasonably anticipated to be human carcinogens: animal studies only
guinea pigs
Some medications and
hormone can cause cancer
High dose exposures
- occupational exposure to industrial chemicals, tobacco
smoke
- prescription drugs for treating certain illnesses
:diethylsilbestrol (DES): a synthetic estrogen that was
prescribed to pregnant women starting in 1940s as a way
of preventing miscarriages
:immunosuppressive drugs, azathioprine and cyclosporin:
given to organ transplant patients to prevent rejection of
transplanted organs
(cyclosporin vs rapamycin)
This chapter will cover:
Identifying chemicals that cause cancer
Mechanisms of chemical carcinogens
Many carcinogens are electrophilic
molecules that react directly with DNA
When metabolized in Relationship between carcinogenic
potency and DNA-binding ability
the liver, carcinogens are
converted into highly
unstable compounds with
electron-deficient atoms
(electrophilic)
- DNA, RNA, and proteins all
have electron-rich atoms
- a direct relationship exists
between potency of
carcinogens and their ability
to become covalently linked
to DNA
Many carcinogens are electrophilic
molecules that react directly with DNA
Before a polycyclic
hydrocarbon can
interact with DNA, it must
be activated
- metabolic reactions catalyzed by
cytochrome P450 in the liver
convert benzo[a]pyrene into
activated derivatives containing
an epoxide group
- reaction of the epoxide group
with guanine DNA adduct
Metabolic activation of
bezo[a]pyrene
Many carcinogens are electrophilic
molecules that react directly with DNA
Other types of electrophilic
groups
- nitrenium ions and carbonium
ions: positively charged nitrogen
and carbon atoms
- free radicals: compounds
containing an unpaired electron
Depending on the carcinogen
involved, almost every electron-
rich site in the various DNA bases
can serve as a target for carcinogen
attachment Sites of carcinogen
attack in DNA bases
Many carcinogens are electrophilic
molecules that react directly with DNA
Carcinogens can inflict DNA
damage in several other ways
- crosslinks between the two strands of
the double helix
- chemical linkage between adjacent
bases
- hydroxylation (Incorrect pairing, epigenetic
- removal of individual
changes)DNA bases
- breaks in one or both DNA strands
Summary of DNA
damage caused by
chemical carcinogens
The initiation stage of carcinogenesis
is based on DNA mutation
Carcinogens that act by
causing mutations are said
to be genotoxic because they
cause gene damage
- the carcinogen methylnitrosourea
attacks the base guanine (G) in DNA
An important principle that
applies to many mutations
- it is crucial that mutations be
repaired swiftly, before subsequent
rounds of DNA replication create a
permanent mutation
Process by which a DNA mutation
becomes permanent
Tumor promotion involves a prolonged
period of cell proliferation
- the time required for promotion contributes to the long
delay that often transpires b/t exposure to an initiating
carcinogen and the development of cancer
- phorbol esters, the class f tumor promoters found in croton oil
: tetradecanoyl phorbol acetate (TPA) Structures of three
phorbol esters with
binds to and activates protein kinase C differing tumor
promoting activity
- other promoting agents stimulate cell
proliferation indirectly, causing tissue
damage and cell destruction
- not all tumor promoters are foreign
substances (e.g., estrogen and
testosterone (prostate cancer)
- certain components of diet (e.g., alcohol)
Cancer is a genetic disease
Most carcinogens are mutagens
- A substantial number of skin cancer of the scrotum patients
were used to be chimney sweepers
Katsusaburo Yamagiwa
Treatment of coal tar (1863- 1930):
A pathologist who, along with Koichi Ichikawa, achieved
(initiator) followed by the world's first artificial
generation of cancer in experimental animals in 1915 by
Structures of carcinogenic hydrocarbons The first induction of tumors by chemical carcinogens
Tumor progression involves repeated cycles of
selection for rapid growth and other advantageous
properties
Main stages of chemical
carcinogenesis:
initiation, promotion, and
tumor progression
- tumor progression: the
gradual changes in the
properties of proliferating
tumor cell populations that
occur over time as cells
acquire more aberrant traits
and become increasingly Clonal selection
aggressive
Main stages of
carcinogenesis
Tumor progression involves repeated
cycles of selection for rapid growth and
other advantageous properties
How tumor progresses?
- additional mutations (clonal selection)
- epigenetic changes
Transplanting a cancer cell
nucleus into an egg cell
Tumor progression involves repeated
cycles of selection for rapid growth and
other advantageous properties
To sum up, tumor progression is a phase of
carcinogenesis that involves the gradual acquisition of
DNA mutations and epigenetic changes in gene expression,
accompanied by natural selection of cells that have
acquired advantageous properties generated by these
mechanisms
- the net result is a population of cells whose properties,
including growth rate and the ability to invade and
metastasize, slowly change over time
- the time required for tumor progression contributes to the
lengthy delay commonly observed between exposure to
carcinogenic chemicals and the development of cancer
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.