3. carcinogenesis dr. sinhasan, mdzah
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Transcript of 3. carcinogenesis dr. sinhasan, mdzah
IndividualPredisposition* Host factors*
Environmental factors:( Carcinogens )
1. Physical 2. Chemical3. Biological
TUMOUR
INDIVIDUAL
Latent period of about 7 years,
Acute and chronic myeloid leukemias,
Solid tumors – thyroid gland,
- breast,
-lung;
Radiation carcinogenesis
STEPS:
… 1. Initiation,
… 2. Promotion;
1915 -- Yamagiwa and Ichikawa
Carcinoma of skin
Painting with Coal tar products
Rabbit ears
- Initiator ( Polycyclic hydrocarbon )Group-1 No Tumour
Group-2 Tumour
Group-3 Tumour
Group-4 No Tumour
Group-5 No Tumour
Group-6 No Tumour
- Promoter ( Croton oil ).
A. Direct acting carcinogens1. Alkylating agents
a) Beta - propiolactone
b) Dimethyl sulphate
c) Diepoxybutane
d) Anticancer drugs - Cyclophosphamide
- Chlorambucil,
2. Acylating agents
a) 1 - acetyl - imidazole
b) Dimethyl carbamyl chloride
Major Chemical Carcinogens:
2. Aromatic Amines, Amides, Azo dyesa) 2 - Naphthylamine ( B - Naphthylamine )
b) Benzidine
c) Acetylaminofluorene
d) Dimethylaminoazobenzene (Butter yellow)
3. Natural plant & microbial products
a) Aflatoxin B1 – Aspergillus flavus
b) Griseofulvin
c) Cycasin
d) Safrole
e) Betel nuts & leaves
4. Others
* Nitrosamines & amides
* Vinyl chloride
* Asbestos
* Nickel & chromium
* Polychlorinated biphenyls;
Occupational CarcinogensCarcinogen Occupational Exposure Cancer Risk
4-aminobiphenyl Chemical & dye workers Bladder
Arsenic Mining, pesticides lung, skin, liver
Asbestos Construction Lung
Auramine Dye workers Bladder
Benzene Leather, petroleum Leukemia
Benzidine Chemical, dye & rubber Bladder
Ether Chemical workers Lung
Chromium metal workers, Lung
electroplaters
Isopropyl alcohol manufacturing by Nasal
strong acid process
Leather dust boot & shoe making Nasal, bladder
3, 4 Benzpyrene
Affects about 10% Smokers
( Aryl hydrocarbon hydroxylase )
Other tumours associated with smoking
Carcinoma of Esophagus,
Carcinoma of Pancreas,
Tumours of kidney,
Urinary bladder tumours;
Cigarette Smoking & Lung Cancer
ELECTROPHILIC
INTERMEDIATES
CHEMICAL
CARCINOGEN
BIND TO DNA:
ADDUCT FORMATION
PERMANENT DNA LESION:
(mutation)INITIATED CELL
CELL PROLIFERATION:
ALTERED DIFFERENTIATION
PRENEOPLASTIC CLONE
MALIGNANT NEOPLASM
EXCRETION
DETOXIFICATION
METABOLIC
ACTIVATION
DETOXIFICATION
NORMAL
CELL
CELL
DEATH
PROLIFERATION -
MORE MUTATIONS
DNA repair
Viruses: Oncogenic in wide variety of animals;
In humans:
Viruses:
- DNA viruses,
- RNA viruses;
Bacteria:
- Helicobacter pylori
Microbial carcinogenesis
DNA viruses:
- Human papilloma virus (HPV),
- Epstein-Barr virus (EBV),
- Hepatitis B virus (HBV),
- Kaposi sarcoma herpes virus (KSHV),
Microbial carcinogenesis
• RNA VIRUS:
… HTLV – 1,
… Hepatitis C virus;
1. Human Papilloma virus ( HPV )
High risk types --
-- 16, 18, 31, 33, 35 & 51,
* Squamous cell carcinoma, cervix,
* Carcinoma anal region,
* Carcinoma larynx,
* Carcinoma oral cavity,
Low risk types - 1, 2, 4, 7 etc.
* Genital warts;
Papilloma Viruses
Urogenital cancer
wart malignant squamous cell ca.Papilloma viruses are found in 91% of women with cervical cancer
Squamous cell carcinoma:
Larynx
Esophagus All histologically similar
Lung
10% of human cancers may be HPV-linked
Burkitt’s Lymphoma ( African form ),
Nasopharyngeal Carcinoma,
B - Cell Lymphomas in
Immunosuppressed patients
… HIV Infection,
… Organ transplantation,
Hodgkin Disease;
DNA Tumor Viruses In Human Cancer
Considerable evidence for role in human cancer
• Some very tumorigenic in animals
• Viral DNA found in small proportion of tumor cells: “hit and run”
Epstein-Barr Virus
• Burkitt’s Lymphoma
• Nasopharyngeal cancer
• Infectious mononucleosis
• Transforms human B-lymphocytes in vivo
Enters B-cells - CD21 molecule
Common in African countries,
EBV infection worldwide,
100% Show levels of antibodies
t (8 : 14) > activation of C - myc,
Causes infectious mononucleosis,
( self limiting condition )
Burkitt’s Lymphoma:
3. Hepatitis - B virus:
* Hepatocellular Carcinoma;
* Endemic in far east and Africa,
* 200 fold increases risk,
* Viral DNA integrated form,
* Cofactor - Aflatoxins,
* HBx protein > growth-promoting genes
* " -- binds to p53;
DNA Virus: ( contd …)
Human T-cell Leukemia virus -
Type 1 - ( HTLV - I )
--- Adult T - cell leukemia / lymphoma
* Endemic -- parts of Japan,
-- Caribbean,
* Tropism for CD4+ T - Cells,
* Transmission: .. Sexual intercourse
.. Blood products,
.. Breast feeding;
Helicobacter pylori:
- Stomach ---
... Lymphomas,
… Carcinoma,
Chronic infection > H. Pylori
reactive T - cells
B - lymphocyte proliferation;