Mutagen, Karsinogen dan

Karsinogenesis
DR. Muhammad Dai, M.Si., Apt.

What cause cancer?

 Hyperplasia (or "hypergenesis") is a

general term referring to the
proliferation of cells within an organ or
tissue beyond that which is ordinarily
seen. Hyperplasia may result in the gross
enlargement of an organ and the term is
sometimes mixed with benign neoplasia/
benign tumor.

 Dysplasia is a term used in pathology to

refer to an abnormality of development.
Dysplasia is characterised by four major
pathological microscopic changes:
Anisocytosis (cells of unequal size)
Poikilocytosis (abnormally shaped cells)
Hyperchromatism
Presence of mitotic figures (an unusual number
of cells which are currently dividing).

MUTATION/EPIGENETIC
THEORIES of CARCINOGENESIS
A. Definitions of Mutagenesis: The Qualitative (Gene)
and Quantitative (Chromosomal) Alteration of
Genetic Information in the GENOME of a Cell.
B. Mechanism of Mutagenesis.
1. Errors of Replication
2. Errors of DNA Repair
C. Mutagens
1. Physical Agents ( X Rays; UV Light).
2. Electrophilic Chemicals ( Nitrosamines, Benzo
(a)pyrenes)

Lanjutan
D. Definition of Epigenesis: Alteration of Gene
Expression at the Transcriptional,
Translational, or Posttranslational Levels.
1. Translational Level- Altered Methylation of
DNA or Acetylation of Nuclear Proteins.
2. Translational Level- Alternative Splicing of
mRNA.
3. Posttranslational Level: Modification of
Proteins by Phosphorylation or Nitrosylation.

F. Epigenetic Carcinogens or Tumor

Promoters.
1. Non-Mutagenic chemicals( e.g., DDT,
Phenobarbital).
2. They Act as Either Mitogens and / or
Inhibitors of Apoptosis.

Carcinogen:
An agent that contributes to the formation
of a tumor, such as (1) chemicals (2)
radiation (3) viruses
Genotoxic
Non-Genotoxic

Three Stages in Carcinogenic

Process
Initiation
Promotion
Progression

Initiation
An initiated cell is one in which a chemical
carcinogen has interacted with DNA to produce
a mutation, often a single base alteration, in the
genome.
An initiated cell is not a tumor cell because it has
not yet acquired autonomy of growth.
The DNA alteration may remain undetected
throughout the life of the organism unless further
events stimulate development of a tumor.

Three Cellular Events Are Important

in Initiation
Metabolism: may activate of inactivate the
chemical carcinogens.
DNA repair: may either correct or introduce an
altered base into the genome.
Proliferation: is necessary to permanently
embed the change in the genome.
Initiation is irreversible, but not all initiated cells
will go on to establish a tumor, because many
will die by apoptosis.

Tumor Promotion
In general, tumor promotion can be viewed as
the clonal expansion of an initiated cell via
altered gene expression that gives the cell a
selective growth advantage.
Tumor promoters cause cells to proliferate but
not to terminally differentiate, resulting in
proliferation of preneoplastic cells (benign
lesions).
Unlike initiators, most promoters do not bind
covalently to DNA and usually do not cause
mutations.

Tumor Progression
Tumor progression describes the process whereby
tumors acquire the ability to grow, invade local
tissue and establish distant metastases.
Increased genetic instability and karyotypic
alterations are hallmarks of progression.
Inherited or acquired mutations in genes such as
p53 or DNA mismatch repair can increase the rate
of mutation in other genes (mutator phenotype) and,
therefore, promote the tumor progression.

Two classes of chemical

carcinogens
Activation-independent: these compounds
bind directly to DNA without being
metabolized, such as alkylating agents
used in chemotherapy.
Activation-dependent (procarcinogens):
these compounds require cellular
enzymatic metabolism into ultimate
carcinogen in order to exert their
carcinogenic action.

Two classes of drug-metabolizing

enzymes
Phase I enzymes: mono-oxygenases,
oxidases, reductases, dehydrogenase and
esterases.
Phase II enzymes: UDPglucuronosyltransferases,sulfotransferase
s, methyltransferases, glutathione Stransferases and acetyltransferases.

Targets of Chemical Carcinogens

Protooncogenes: when protooncogenes
are activated by a mutational event,
signals for cell growth are increased (e.g.,
ras).
Tumor suppressor genes: tumor
suppressor genes regulate cell growth
negatively; relevant mutations result in a
loss of function (e.g., p53).

Ras
In papillomas and carcinomas induced in
mouse skin by 7,12dimethylbenz[a]anthracene, there is an
activating mutation in codon 61 (A to-T
transversion) of the H-ras gene.

p53
In humans, mutations in p53 are present
in more than 50% of tumors. The sites of
mutations are not random but occur at hot
spots: (1) the high efficiency of adduct
formation or low efficiency of DNA repair
at the site (2) specific mutations that
predispose to oncogenesis are selectively
retained in tumor cells during promotion
and progression.

p53
Lung tumors and the nontumorous lung tissues
from smokers with lung cancer carry a high
mutational load at hotspots 157, 248, and 273 in
the p53 gene.
Lung tumors that develop in nonsmokers contain
a different spectrum of p53 mutation than the
tumors from smokers.
Lung cancers from ex-smokers contain a p53
mutational spectrum similar to that in active
smokers.

Chemoprevention of Cancer
Agents that decrease bioactivation or
increase detoxification of carcinogens
Agents that alter promotion and
progression (e.g., synthetic retinoids,
nonsteroidal antiinflammatory agents).
Agents inhibits DNA adduct formation
(e.g., antioxidant compounds).
Agents that enhance DNA repair capacity.