Mutagen, Karsinogen Dan Karsinogenesis: DR. Muhammad Da'i, M.Si., Apt
Mutagen, Karsinogen Dan Karsinogenesis: DR. Muhammad Da'i, M.Si., Apt
Mutagen, Karsinogen Dan Karsinogenesis: DR. Muhammad Da'i, M.Si., Apt
Karsinogenesis
DR. Muhammad Dai, M.Si., Apt.
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.
Carcinogen:
An agent that contributes to the formation
of a tumor, such as (1) chemicals (2)
radiation (3) viruses
Genotoxic
Non-Genotoxic
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.
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.
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.