Cancer 111

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NeoplasiaAetiology

Aetiology

Introduction Development and progression of

malignancies is a multi-step process involving number of genetic changes over a period of time as a result of continuous exposure to chemical physical viral or any other carcinogenic agent.

Risk factors for a cancer

• Age

• Genetic factors.

• Geographical

• Racial factors

• Environmental factors.

The possible causative agents of carcinogenesis

Chemical carcinogens

Physical carcinogens

Viruses

Hereditary factors

Hormones

Cancers associated with chronic diseases

Physical agents

Ionizing radiation:

UV radiation

What happens when exposed

• Radiation causes its effect by transferring energy to the substance through which it passes

Result may be:• Ionization

• Change in the energy state of the electrons or charged molecules.

Physical agents

Ionizing radiation:• X rays , , and rays

• These agents injure the cells through which it pass by dislodging ions from water and other molecules– Formation of free radicals.

• React with DNA nucleic acids, proteins,and other molecules.

• DNA damages may be;

Point mutation (Changes in single bases) Breaks in the DNA double strand (wrong reunion)

• Lethal doses - Immediate cell death

• Sub lethal doses - Permanent damage in DNA. Malignant transformation.

• Effect of the radiation on different tissues depends on the

Nature of the tissues (Bone)

Type of radiation (Determined the depth of penetration)

Evidence to show effects of ionized radiation

• Nuclear weapons testing; Radio strontium • Hiroshima and Nagasaki (1945) - leukaemias &

other cancers • Dial painters (Osteosarcomas).

• Radiologists

UV light:• Farmers with fair skin who have no melanin protection.

(Solar keratosis) lip cancers, Squamous cell carcinomas Basel cell carcinomas Malignant melanomas Mechanism; Dimmer formation between bases

E.g.:Thymidine bases in the DNA.

(Dimer causes mutation in DNA replication)

Xeroderma Pigmentosum: Lack of enzyme involved in the repair mechanism of

damaged DNA.

Hormones

• Relationship between neoplasia and hormones is complex.

• Animal experiments to show hormonal involvement in carcinogenesis:

• Mice: High cancer strains oestregen Breast cancers

Low cancer strains oestregen Hyperplasia

• Mice or rats. Two ovaries were removed and one implanted in the

spleen to stop the feed back inhibition of pituitary. (result is occasional ovarian tumours)

• Mice or rats Low I, diet and thiouracil Reduce thyroxin formation (no feed back effect) Result is thyroid hyperplasia/ademoma/carcinomas

• However evidence of hormonal involvement in human tumours are rare. But association of hormones in tumours in man have been shown

Granular cell OESTROGEN

tumour of the ovary Endometrial Endometrial

hyperplasia Carcinoma Artificial sex Oestrogen Enlargement of

change Breast Carcinoma Hyperplasia

• Hormone dependency ;

Even though the role of hormones in the aetiology of tumours is not clear, it is clear that hormones are important in maintaining of some tumours. Administration Progress the growth Deprival Regress the tumour eg; prostate

• 30% Breast tumours, are hormone dependent

• Later hormonal dependent Independent.

Hereditary predisposition ;• Cancer of the breast

• Cancer families

• Hereditary diseases;

Polyposis coli: Autosomal dominant

Retinoblastoma

Xeroderma pigmentation

Virus and cancer

Ellerman and Band (1908)

• Chicken Cell free extract Erythroid leukaemia

Rous (1911)• Chicken Cell free extract Sarcoma

of sarcoma

Bittner(1936):

• Foster mothers from cancer free strains New bone mice with cancer susceptible strains

New bone mice from cancer free strains

• Foster mothers from cancer strains

• Both RNA and DNA viruses have been shown to be capable of causing cancers in various vertebrate species including man.

• Integrate there genetic material into the DNA of the host cell.

• EBV: Africans

• Burkitt’s lymphomas

• Nasopharyngeal carcinomas.

• 98% of the tumour cells show EBV genom

• High antibody levels in the serum.

• Human papilloma virus.

• Type 5.6,11 papillomas

• Type 16 & 18 involved in cervical carcinomas.

• Hepatitis B: Hepatocellular carcinoma.

CHEMICAL CARCINOGENESIS• Epidemiological evidence shows that there is a

large number of chemicals with carcinogenic properties

• Eg Industrial cancers (Occupational cancers); Result of prolong exposure to chemical

carcinogens.• Scrotal cancers - Chimney sweepers

(Percival Pott in 1775)• Skin cancers - Tar workers • Bladder cancers - Aniline die workers (1895)• Liver angiosarcomas - PVC factory workers• Lung cancers - Asbestos workers

Experimental evidence for chemical carcinogens

• 1917 (Yamagiwa and Itchikawa)

• Coal tar application in rabbit skins Polycyclic hydrocarbons ; Dibenzanthracene

Methyl cholanthrene

Benzpyrene (carcinogens)

• It has been shown that most of the Poly cyclic hydrocarbons, Aromatic amines Nitrosamines, aflatoxins are carcinogenic.

• mineral oils/fuels, atmosphere of industrialized cities

Action of chemical carcinogensDirect acting carcinogens:

Need no activation

Electrophilic form

Weak carcinogens

Procarcinogens: Poly cyclic hydrocarbons, Aromatic amines

Nitrosamines,

Aflatoxins

How do chemical carcinogens including poly cyclic hydocarbons act.

Procarcinogens Ultimate carcinogens (Carcinogen compo) (Ultimate carcinogens) Positively charged Negatively charged

electrophilic reactants proteins & N acids ++++ - - - - (Elec dense)

Insertion of a reactant between bases of the DNA leads to alter the base pair (mutations).

Hydroxylation

• Benzidine and derivatives ;

Used in Laboratories (Occult blood) /Industries Induce bladder cancers

• Dimethylaminoazobenzene (Butter yellow); Induced liver cancers (Hepatomas)

• Asbestos (silicates);

Malignant Mesotheliomas of the pleura Bronchial carcinomas

• PVC (v c monomer); Haemangiosarcoma in the liver

• Habits; Betel/smoking(Oral/Lung)

Preservatives;

• Nitrites in meat Nitrites + HCl= Nitrous sausages acid

Nitrosamines secondary +

(Carcinogenic) amines

• Aflatoxine;

(Metabolites of Aspergillus flavus)

liver cancer

Bladder cancer in rubber industry workers

Liver -naphtylamine 1 hydroxy 2 naphtylamine

Conjugate with

Glucuronic Acid Doges/ humans secretion of Glucuronidase in the bladder Glucuronide Excrete in urine

The example of remote carcinogenesis

Features of chemical carcinogens• Induction of cancer:

Dose dependent

Duration of exposure

Dosage- Light smoking -- cancers

Heavy smoking -- no

Individual susceptibility

Genetic predisposition

• Chemical carcinogenesis involves two distinct but sequential effects on cells.

• Initiation

• Promotion

Initiation and promotion;

Skin of mice: (Compete Carcinogen)

Methylcholanthrene long time Cancer

Croton oil

(Promoter/co-carcinogens)

• Initiation • Chemical carcinogens are initiating agents,

Two steps:

Alteration in DNA

Mitosis

Initiation is an irreversible process.

Initiated cells can be silent for long time. Carcinomas develop ones a promoter is

available.

Promotion:

The steps involved in this is not known.

Selective proliferation of initiated cells.

Nonspecific

Slow acting.

Reversible at least at the beginning .