Chemical Carcinogenesis

Dr. Kevin Manuel

Assistant Professor
Department of Pathology
18.09.18
 Introduction and History
• 17th century - London surgeon Sir Percival Pott
- Scrotal skin cancer in chimney sweeps to
chronic exposure to soot.

• Danish Chimney Sweeps Guild ruled that its

members must bathe daily

• Hundreds of chemicals have been shown to be

carcinogenic in animals
Characteristics of Cancer
Asbestos and Mesothelioma
 Major Chemical Carcinogens

• Direct acting carcinogens

• Indirect acting carcinogens – Procarcinogens

that require metabolic activation
Direct acting carcinogens
Indirect acting carcinogens
Categories of Chemical Carcinogens
 Steps in Chemical carcinogenesis

• Multistep process

• Classic experiments that allowed the

distinction between initiation and promotion
were performed on mouse skin
 Steps in Chemical carcinogenesis
• Initiation results from exposure of cells to a sufficient dose of a
carcinogenic agent (initiator); an initiated cell is altered, making it
potentially capable of giving rise to a tumor. Initiation alone, however, is
not sufficient for tumor formation.
• Initiation causes permanent DNA damage (mutations). It is therefore
rapid and irreversible and has “memory.”

• Promoters can induce tumors in initiated cells, but they are

nontumorigenic by themselves. Cellular changes resulting from the
application of promoters do not affect DNA directly and are reversible.
 Experiments demonstrating the initiation
and promotion phases of carcinogenesis in
mice

Group 2: application of promoter repeated at twice-weekly intervals for several months. Group 3:
application of promoter delayed for several months and then applied twice weekly. Group 6:
promoter applied at monthly intervals
Chemical Carcinogens
Electrophilic Carcinogens

• Benzo[a]pyrene is activated to
have an epoxide group.
• DNA-carcinogen complexes are
called DNA adducts.
Carcinogens and DNA Damage
 Direct-Acting Agents
• Direct-acting agents require no metabolic
conversion to become carcinogenic.

• Most of them are weak carcinogens

 Indirect-Acting Agents
• Chemicals that require metabolic conversion to an
ultimate carcinogen before they become active.

• Polycyclic hydrocarbons - are present in fossil

fuels
• Benzo[a]pyrene and other carcinogens - Formed
in the high-temperature combustion of tobacco in
cigarette smoking. These products are implicated
in the causation of lung cancer in cigarette
smokers.
 Molecular Targets of Chemical
Carcinogens
• DNA is the primary target for chemical carcinogens
• RAS and p53

• Strong correlation between the dietary level of food

contaminant aflatoxin B1, a naturally occurring
agent produced by some strains of Aspergillus [mold
that grows on improperly stored grains and nuts] and
the incidence of hepatocellular carcinoma in parts
of Africa and the Far East
 Radiation carcinogenesis
• Radiant energy, whether in the form of the UV rays of
sunlight or as ionizing electromagnetic and particulate
radiation, is a well-established carcinogen

• UV light is clearly implicated in the causation of skin

cancers

• Increased incidence of breast cancer has become

apparent decades later among women exposed during
childhood to atomic bomb tests. The incidence peaked
during 1988–1992 and then declined
 Ultraviolet Rays
• UV rays derived from the sun cause an increased
incidence of squamous cell carcinoma, basal cell
carcinoma, and melanoma of the skin
• The UV portion of the solar spectrum can be divided
into three wavelength ranges: UVA (320–400 nm),
UVB (280–320 nm), and UVC (200–280 nm).
• UVB - Responsible for the induction of cutaneous
cancers
• The carcinogenicity of UVB light is attributed to its
formation of pyrimidine dimers in DNA
 Ionizing Radiation
• Electromagnetic (x-rays, γ rays) and
particulate (α particles, β particles, protons,
neutrons) radiations are all carcinogenic

• Survivors of the atomic bombs – Leukemias,

solid tumors with longer latent periods (e.g.,
breast, colon, thyroid, and lung)
Thank You…