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K1-Introduction to
Cancer Biologyby: Dr. Suyatno SpB(K)Onk
BERTHA NAPITUPULU
080100151
FK USU
A2
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PERSPECTIVE
Cancer is not modern disease
Hippocrates (± 4oo bc): Cancer as imbalance
between black humor (spleen) and threebodily humor (blood,phlegm, bile)
Sir Percival Pott (1775): one of the first
scientific inquiries in to the cause of the
cancer observed chimney soot as
carcinogen for prostate cancer
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Recenly, the most important in knowledgeabout the biology of cancer are
understanding of moleculer genetics
The current model for cancer development cells undergoing a series genetic
mutations and/or alteration, which result
inability to respon normally to intracellular
and/or extracellular signals
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Basic molecules of life
All life depends on three critical molecules: DNAs
± Hold information on how cell works RNAs
± Act to transfer short pieces of information todifferent parts of cell
± Provide templates to synthesize into protein Proteins
± Form enzymes that send signals to other cells
and regulate gene activity ± Form bodys major components (e.g. hair, skin,etc.)
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Mathematical Biosciences Institute (Ohio State Univ), 2 October 2003
RNA
Protein
DNADOGMA CENTRAL
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Central Dogma of Molecular Biology
DNA
RNA
Protein
Transcription
Translation
A gene is expressed in 3 steps:
1) Transcription: RNA synthesis
2) Splicing: removal of intron sequence from RNA
3) Translation: Protein synthesis
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Howmuch DNA do we
have?
Humans have 2 x 23 chromosomes EACH cells contains 6 billion bases DNA
That is 1 meter of DNA
A human being has
>100.000.000.000.000 cells That is 100 billion km of DNA
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Genetic alteration may arise direct orindirect from:
1. Inherited gen mutations
2. Chemical or radiation induced DNAdamage and genetic instability
3. Incorporation of virus into the cell
4. Random error during DNA synthesis
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Characteristic Cancer Growth
Disturbed Growth Control :
- Lose of ³contact inhibition´,
- Need of growth factor is decreased,
- Anchorage independent
Fail of maturationImmortal
Could to transplantation
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Cancer:
General
Etiologyand
Pathogen
esis
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Carcinogenesis is multi stage process:
± inisiation
± promotion
± progression (malignant tranformation).
Inisiation and promotion cause
acumulation DNA mutation reversibel
eg. displasia
PROGRESSION irreversibel
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Step 1: Initiation
Inisiation is exposed cell
by single carcinogenic
agent (inisiator)
Simple mutation in one
or more cellular genes
that control key
regulatory pathways of
the cell
From: Brooks, Chap. 7
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Step 2: Promotion
From: Brooks, Chap. 7
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Step 3: Progression
Karyotypicinstability
± Increased growthrates
± Increasedinvasiveness
± Increasedhormonalreponsse
± Anaplasia
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Interaction Inisiator and Promotor
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The Future of Oncology
Since increase understanding of cancer moleculer,
several therapy developed with better outcome
Eg ; patient with chronic myelogenous leukemia can
be treated with succesfully using imatinib (specificcompetitive inhibitor)
In the future, treatment strategies decide on
genetic footprint of the cancer rather than on
histopathological type.
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Key words
Oncogenesis: Pathogenesis of neoplasm (b/m)
Carcinogenesis: Pathogenesis of cancer (m)
Carcinogen - agent causing cancer.
Oncogen - agent causing neoplasm.
Mutagen - agent causing mutation.
Tumour Suppressor genes: are genes that act
to inhibit cell proliferation and tumourdevelopment.
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Impact on Technical
Operation of Breast Cancer
Ancient CRM/MRM BCT NSP+TRAM
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K2-Cancer EpidemiologyHematology Oncology Division
Child Health Departement ² Universtyof Sumatera Utara
20Basic science of Oncology 2011
BERTHA NAPITUPULU
080100151
FK USU
A2
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Epidemiology
The study of distribution and determinants of
disease inh
uman population ; wh
ydifferent population or group are at
different risks for diferrent disease
Patterns of incidence and death rates of
malignant disease :
sex,age,race,geography
21Basic science of Oncology 2011
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Childhood cancer
is rare less than 1 % of all cancer inindustrialized countries
Several types of cancer are virtually unique
to childhood, whereas the carcinomas mostfrequently seen in adults
Some of the most striking progress incancer treatment has been made in
paediatric oncology Investigation of childhood tumours has ledto major advances in the understanding of the genetic
22Basic science of Oncology 2011
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Concept epidemiology
1.Disease is not randomlydistributed
2.Disease causation is multifactorial
23Basic science of Oncology 2011
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The scope of Epidemiology
Concerned with population health
Concern to clinicians
Clinical researchers Laboratory scientiest
24Basic science of Oncology 2011
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General approach
What
Who
Where
When
Descriptive epidemiology
Analytic epidemiology Why
How
25Basic science of Oncology 2011
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Types of epidemilogical
Occupational e pidemiology :
effects of workplace exposures on workers
Clini c al e pidemiology : outcome the patients
Geneti c e pidemiology : focus on familes or high
risk individual, concerned with determinants of
disease in families and on inherited causes of
cancer in population Nutritional or environmental epidemiology
Molecular epidemiology
26Basic science of Oncology 2011
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Application epidemiology
Planning
Evaluation of cancer control
Primary prevention Early detection
Scope of cancer epidemiology: broad
concern causes of cancer identificationof population where risk reduced
³prevention´
27Basic science of Oncology 2011
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Cancer statistic
When a patient is diagnosed with cancer
one of the first questions an oncologist will
be asked: ³ how long do I have ³
Survival based statisti c s : observational
st udies : 1.relative 5-year survival rates
2.Overall survival
3.Median survival
28Basic science of Oncology 2011
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Cancer trends
- Relatifve 5-year survival rate for allcancer: 1975 - 1977 : 51%
- 1996 - 2002 : 66%
The reason: Multifactorial:
Increasing:1. diagnostic
test:mammogram,Pap smears,prostate
specific antigen
2.immunosupression
3.the aging of population29Basic science of Oncology 2011
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Leading cancer types in Indonesia
1.Cervix cancer
2.Breast cancer
3.Colorectal cancer 4.Lung cancer
5.Nasopharyng cancer
( POI=Perhimpunan Onkologi Indonesia)
30Basic science of Oncology 2011
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Leading cancer types among African
American
Male Prostate
Lung and bronchus
Colon and rectum NHL
Oral cavity
Kidney
Urinary bladder
Pancreas
Stomach
liver
Female Breast
Lung and bronchus
Colon and rectum Uterine corpus
Pancreas
Ovary
NHL
Kidney
Multiple Myeloma
31
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Leading cancer in children
± Leukemia
± Lymphoma and Reticuloendothelial
neoplasms
± CNS tumours
± Retinoblastoma
± Renal Tumours
± Hepatic Tumours
32Basic science of Oncology 2011
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«««.cancer in children
± Malignant Bone tumours
± Soft Tissue sarcomas
± Germ Cell, trophoblastic and other gonadal
neoplasms
± Carcinomas and other malignant epithelial
neoplasms
± Other and unspecified malignant neoplasms
33Basic science of Oncology 2011
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Etiology
Chemical carcinogens
Environmental and industrial carcinogens
Drug induced cancers Radiation carcinogenesis
Viral and immunologic mechanisms
34Basic science of Oncology 2011
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Etiology
A.Chemical carcinogens
1.Industrial exposure
2-Naphthylamine
Benzidine
Bis(chloromethyl)ether
Bis(2-chloroethyl)sulfide(mustard gas)
Vinyl chloride
Certain tars,soots,oils
Chromium compounds
Nickel compounds
Asbestos
Benzene
35
Basic science of Oncology 2011
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Chemicals
pesticides (CNS tumors)
solvents (eg, CNS tumors, leukemia,neuroblastoma, hepatoblastoma)
metals (hepatoblastoma)
petroleum products (eg, Wilms tumor,leukemia, hepatoblastoma)
lead (Wilms tumor)
boron (Wilms tumor)
furnaces (lymp
homa)
chemotherapy (leukemia)
36Basic science of Oncology 2011
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2.Medical exposure
N,N-bis(2-chloroethyl)-2-
naphthylamine
(Chlornaphazin)
Diethylstilbestrol
Inorganic arsenic comp.
Mephalan,cyclophosphamide
Azathioprine,Phenytoin
3.Societal exposure
Cigarette smoke
Betel nut and tobacco
quid
37
Basic science of Oncology 2011
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2.Radiation carcinogenesis:medical x-rays,atomic
weapon,radon in house
3.Viral and immunologic mechanisms-Epstein-Barr virus
-Hepatitis-B
-HIV4.Environmental: ultraviolet
38Basic science of Oncology 2011
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Environmental Factors
± Ionizing radiation
Data derived from the atomic bomb
exposures at Hiroshima and Nagasaki
Leukemia
± Electromagnetic fields
Published reports have suggested that
electromagnetic fields have some potential
effect on the promotion of leukemia
39Basic science of Oncology 2011
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Cancer¶s 7 warning signals
1.Change in bowel or bladder habits
2.A sore that does not heal
3.Unusual bleeding or discharge
4.Thickening or lump in breast or elsewhere5.Indigestionor difficulty in swallowing
6.Obvious change in wart or mole
7.Nagging cough or hoarseness
If you have a warning signal ,see your doctor
40Basic science of Oncology 2011
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Role of infection
Epstein-Barr virus (EBV)
Underdeveloped country rate infection in
infancy ,h
igh
the age of onset
HD
-EBV is present in 40 ± 60% of cases
-chronic viral infection activation of cellular
oncogenes, loss of tumour suppressor genes and deregulation of several cytin
41Basic science of Oncology 2011
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± Epstein-Barr viru s ( E BV)
African Burkitt lymphoma
Hodgkin lymp
h
oma Nasopharyngeal carcinoma
± HIV-induc ed immunosu ppr ession
CNS lymphoma
Leiomyosarcoma
42Basic science of Oncology 2011
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K2B-CAR
CINOGE
NE
SISHematology-Oncology Division
Child Health Dept.
University of Sumatera Utara
43
BERTHA NAPITUPULU
080100151
FK USU
A2
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Normal human cell populate specific
areas of the body:function,grow,divide in
response to signals (i.e,growth factors) die ( checkpoints cell growth death )
Malignancy : cell develop genetic defects
DN A change lose growth pattern
resistent to celullar mechanism , ability to
acoid programmed cell death , leave their usual sitetravel ± blood stream, lymphatic
system grow in new location
44
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Principal genes
Oncogenes
Tumor suppressor genes Apoptosis ( programmed cell death )
45
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Oncogenes :genes whose normal functioninvolves promoting the growth andreproduction of cells in regulated
When uncontrolled malignanttransformation of cell
Tumor suppressor genes :normal to ³stop´
cell proliferation
p53P53 lost DN A damage not repair mutation malignant transformation
46
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Genesis of malignant tumor : multistep
process , involves derangement of multiple
genes normal function of cells
Most malignancy do not have a clear
hereditary genetic basis
47
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Genetic cancer syndromes
Familial Retinoblastoma
Li-Fraumeni syndrome
Wilms¶ Tumor Neurofibromatosis Type I
Familial Adenomatous polyposis
Multiple endocrine neoplasia Hereditary nonpolyposis colon cancer
48
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Carcinogenesis :multistage process that leads to
uncontrolled clonal cell growth evolution of
normal cells into malignant cells
Stage carcinogenesis:
1.Transformation
2.Growth
3.Local invasion
4.Metastasis
49
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Carcinogen: any subtance when exposed
to living tissue potential to lead cancer
1.Radiation : ultraviolet, ionizing
2.Infection agents: virus,bacteria,flatworms
3.Chemical :
-direct acting initiators: vinyl chloride
-indirect initiators (³procarcinogen´ ) :
polycyclic aromatic hydrocarbon
4.Foreign body reaction :asbestos, silica
50
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What are intervals between exposure to a
carcinogen and the development of cancer?
from a few years to decade
Epidemiologic studies very complicated
Smoking related cancers : after 15 years of
exposure Asbestos related cancer : 25 ± 40 years
Ionizing radiation related skin cancer and
leukemia : few years Malignancies of connective tissue , and
adenocarcinoma : 15 ± 30 years
51
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Exposure in children
Appear more dangerous
Carcinogenic interval : shorter
Increased overall exposure concentration Increased level of replicating cells
52
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How can prevent or minimized
carcinogenesis
Minimize exposure to carcinogen
Don¶t smoke
Maintain healthy diet : adequate fiber , antioxidant
Use sunscreen and limit intense sun exposure Childhood Immunization: avoid viral infection
associated with cancer ( Hepatitis B)
Hereditary risk cancer : ³intensive screening´
Treatment pre-cancerous lesion (e.g.excision) Avoid excessive iatrogenic drug (antineoplastic,
estrogen,oral contraceptive,diethylstilbestrol )
53
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How can we prevent or minimize
carcinogenesis?
Choose cancer ± free abcestors
Minimize exposure to carcinogens
Don¶t smoke
Maintain a nutritious diet with antioxidant Use sunscreen and limit intense sun exposure
Immunization: avoid viral infection associated with cancer
Intensive screening: for hereditary risk Treatment of pre-cancerous lesions
Avoid excessive iatrogenic drugs andhormones
54
BERTHA NAPITUPULU
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K3-4
BLOK ONCOLOGY
Biochemistry Department
Medical Faculty USU
BERTHA NAPITUPULU
080100151
FK USU
A2
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TUMOR GENETICS
PROTOONCOGENES
ONCOGENES
TUMORSUPPRESSOR GENES
CARCINOGENESIS:
MOLECULAR MECHANISM OF TUMOR
CELLULAR TRANSFORMATION
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TUMOR MECHANISM
HOW TO DETECT A TUMOR
HOW TO DIAGNOSED
HOW TO UNDERSTAND THE MECHANISM
HOW ARE THE MOLECULAR PATHWAY
IN WHAT CONDITION COULD WE TREAT THE TUMOR
WHAT KIND OF TREATMENT
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THE NEW TUMOR DRUGS
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Proto Oncogen and Oncogen
Oncogen
± Genes that possess the ability to cause cellular
transformation.
± Act in a dominant fashion, either overexpression or
activating mutations.
Cellular transformation.morphologic changes, loss of contact inhibition,
anchorage independent growth, ability to form
tumors when transplanted into nude mice.
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Proto-oncogene.
± Potential to become activated into a cancer
causing oncogene.
± Have been found in all multicellular organisms.
± Would be involved : basic essential functions of the cell related to control of cell proliferation and
differentiation.
± In normal cell : expression is tightly controlled.
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Protooncogen productsProtooncogen products
Nucleus
FOS
MYC
JUN
Orga
nella
ERB-B1
FMS
SIS
MOS
ABL
FMSSRC
R AS
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Cell-cycle control system is based on cyclically
activated protein kinases :
-Cdks (cyclin dependent kinases)
-Cyclins (cdk regulator protein), without
cyclins cdk is inactive.
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Proto-oncogenes
1.Growth Factors
± Stimulate cells in stationary stage to enter the cell
cycle.
± Occurs in a two stage process :
Stimulation to proceed into G1 provided by
PDGF,EGF,followed by progression factors :IGF to
progress through the cell cycle.
± Action via autocrine and paracrine model.
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2.Growth factor receptors
± Link the information from extracellularenvironment (GF) to a number of different
intracellular signaling pathways.
± The most important : transmembrane receptor
tyrosine kinases.
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3. Signal transducers.
± Cytoplasmic nonreceptor tyrosine kinases.
± Proteins with enzyme activity such as
phospholipase C, PI3-K
± Adaptor proteins : Grb2 ± SH2 and SH3 domain.
± Three major pathways : PI3-kinase (PI3-K/AKT
pathway, RAS/mitogen-activated protein kinase
(MAPK) pathway, JAK/STAT pathway.
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4. Nuclear proto-oncogene and transcriptionfactors.
± Involved in the control of gene expression by their
action on DNA itself
± Final site of action for messages sent from GF.
± Level at which control of growth and proliferation.
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G-Protein and Signal transduction
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CARCINOGENESIS
MOLECULAR MECHANISM OF TUMOR
CELLULAR TRANSFORMATION
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Mechanisms of oncogene activation
1. Structural alteration.
± Point mutations
± Chromosomal translocation
± Truncated form of protein (transition mutation)
2. Amplification
3. Deregulated expression
± Insertional mutagenesis
± Translocation.
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Tumor suppressor genes
Play an important role in tumorigenesis.
Involved in the control of abnormal cell
proliferation.
Loss or inactivation : association with the
development of malignancy.
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Viral Oncogene
Three major mechanisms by which an
infectious agent can cause cancer
1. Persistent infection chronic inflammation
repeated cycles of cell damage and cellular
proliferation
accumulate genetic mutations initiation
and promotion of cancer .
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RB Pathway
ATM
p14ARF
Cell Survival
NFOB Pathway
ATM
Cytokines Free radicals
DNA Damage
ApoptosisDNARepair
Cellcyclearrest
p53 Pathway
Cytokines, e.g., TNF, IL-1, IL-6, IL-8
ATM
Chronic Inflammation
CHRONIC INFLAMMATION AFFECTSMULTIPLE PATHWAYS
MEK/ERK
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2.Direct participation of infectious agents in
the transformation of the cell throughactivation of cellular oncogene pathway.
3. Relevant to HIV : infection may result inimmunosuppression and decreased
recognition of infected or transformed cell by
host immune system.
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Gene
Primary
transcript
mRNA
mRNA
Protein
TRANSCRIPTION
Degradation
MODIFICATION / PROCESSING
Degradation
Degradation
Ac tive inac tive
degradation
Trans port
TRANSLATION
NUCLEUS
CYTOPLASM
Mechanisms of retroviral
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Mechanisms of retroviral
oncogenesis.
1. Slowly transforming viruses.
± Insertional mutagenesis
2. Acutely transforming viruses.
± Oncogene transduction
3. Trans-acting retroviruses.
± Affect expression or function of cellular growth
and differentiation genes.
HTLV1 ( the only human retrovirus known to directly
cause cancer).
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1760-CH
FREE RADICALS AND INFLAMMATION
ROSOH O2-
(Hydroxyl (Superoxide)
radical)
RNSNO ONOO- N2O3
(Nitric Oxide) (Peroxynitrite)
MDA(malondialdehyde)
4HNE(4-hydroxynonenal)
DNA Damageand Mutation
Nitrosamines/Deamination8--oxo-dG
8-nitroguanineEtheno AdductsM1G AdductS-nitrosothiolSSB·sDSB·s
LipidPeroxidation
Arachidonic Acid
Cascade
Eicosanoids
Cell
Proliferation
Protein Damage
(DNARepair Enzymes, Caspases)
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Apoptosis
Programmed cell death
Intracellular machinery responsible for
apoptosis is called caspases.
Caspases
Synthesized in the cell as inactive precursor
called procaspases
Usually activated by cleavage at aspartic acidsby other caspases.