IndividualPredisposition* Host factors*

Environmental factors:( Carcinogens )

1. Physical 2. Chemical3. Biological

TUMOUR

INDIVIDUAL

Molecular Basis of Neoplasia:

Proto-oncogene

Oncogene

Latent period of about 7 years,

Acute and chronic myeloid leukemias,

Solid tumors – thyroid gland,

- breast,

-lung;

Radiation carcinogenesis

Sir Percival Pott (1775) …..Chimney sweeps

Carcinoma Scrotum

2. Chemical Carcinogens:

Soot

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

1911 - Peyton Rous,Cell Culture

Sarcoma in chicken;[ virus ]

Nobel prize in 1968;

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;

RNA viruses activate oncogenes

DNA viruses counteract tumor suppressors

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:

t( 8; 14 )

C - myc

( 8 )

Juxtaposed to

Immunoglobulin

Heavy chain gene

( 14 )

C - myc

activation

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;