Dr.

Emanuel Cummings
Senior lecturer in Biochemistry
School of Medicine
Faculty of Health
Sciences
University of Guyana
Biochemistry of Cancer

Carcinogenesis
Definition

Malignant neoplasm – new type of cell growth

that usually invades and take over normal
cellular tissue.
Cell birth > Cell death
Carcinoma- Neoplasm epithelial tissue
Sarcoma- Neoplasm connective tissue –
Mesodermal cells
2nd most common cause of death in the USA
Cancer
 Is a disease on uncontrolled growth .
 That results from a series of acquired defects in the
DNA
 That causes dereugulation of the cell growth
processes
 Damaged cell transform from benign to malignant
 Malignant tumor infiltrates adjacent tissues and
metastasizes
Properties of cancer cells
 Diminished or Unrestrained control of growth
 Invasion of local tissue
 Spread or Metastasis to other parts of the body
 Benign tumors do not invade other tissues –fibrous
capsule.
 Cancer is a multi-step disease results from several
mutations.
 Risk increases with age
 Multi-step hypothesis of cancer
Gene Type- Tumor suppre-. Oncogene Tumor suppre - Tumor suppre

Gene Change- Loss Activation Loss Loss

Gene name APC k-ras DCC p53

Norm. Hyperprolif. Early Intermed. Late Carci

Epithl. Epithelium Adenom Adenoma Adenoma noma

METASTASIS
Transformation of normal cells to
cancer cells

Lack of balance between

Proliferative Quiescent

Dying
The total number of cells in a tissue depends
upon the proportion of cells in these 3 states.
Genomic changes

1- That converts Pro-Oncogene to oncogene

a) Acquisition of viral oncogene
b) Mutations by chemicals and radiation
c) Gene amplification
d) Gene translocation
2-Loss of Function of Suppressor genes
a) Mutations by chemicals and ionizing radiation
b) inactivation of tumor-suppressor gene products
Causes

 Physical
 Chemical
 Biological.
 1920 x rays and Radioactive substances
workers developed cancer on their fingers and
hands
Causes

1. Radiation or Radiant energy.

-UV light cause the formation of pyrimidine dimers,
Apurinic or Apyrimidimic sites form through elimation
of bases. Single or double strand breaks.
-X rays and  rays cause formation of free radicals
superoxide interact with DNA – molecular damage.
Both are mutagenic and carcinogenic
Causes (Viruses)
 RNA virus-HTLV1- retrovirus,- adult T cell leukemia South Japan
 Hepatitis C- Togavirus- Liver- Tropical Africa ( aflatoxin& alcohol)
 DNA virus(Human papilomaviruses)-Papovirus- carcinoma of the
of the cervix (HPV-16), juvinile papillomas, Squamous cell
carcinoma eg HPV-5 ( Smoking activation of ras oncogene, x-rays
and strong sunlight). Immunocompromised.
 Epstein-Barr- Herpesvirus- Burkitt’s lymphoma-Africa
Nasopharyngeal carcinoma.- China, Alaska, East Africa,
Singapore, Papua New Guinea ( salted fish ( Nitrosamines) salted
nuts.
Hepatitis B-Hepadnavirus – Primary liver cell cancer. Taiwan,
Tropical Africa ( Smoking, alcohol,aflatoxin, genetic).
Cause

2. Chemicals
1775 Percival Pott in London found a high
incidence of cancer of the scrotum among
chimney sweeps.
1920 Japanese workers painted extract of soot
on mice resulted in skin cancer.
1929. Kennaway isolated from soot the first pure
chemical carcinogen- Dibenzanthracene
Other Chemicals (Polycylic
aromatic hydrocarbons / Aromatic
amines
 Benzopyrene
 3 Methylcholanthrene
 7,12 Dimethylbenzanthracene
 2,3 Dimethyl-4 amino azobenzene
 N,N Dimethyl-4amino azobenzene
 2 Naphthylamine.
 Cigarette smoking was noted as a prime cause of lung cancer .
 Analysis of the smoke and tar demonstrated benzopyrene.
Aromatic amines-Bladder (Manufactures of dyes and rubber)
2 Acetylaminofluorene and N- methyl 4 aminobenzene
Nitrosamines Several sites including liver- (Workers of Salted food and
leather workers, manufacturers of herbicides
Dimethylnirosamine and diethylnitrosamine.
Various Drugs
Diethylstlbestrol and Fulcin (Griseofulcin
Naturally. Occurring compounds
Dactinomycin Aflotoxin B1 from Aspergillus flavus (Diet)
Inorganic compounds
Arsenic, asbestos, cadium, chromium, berylium
Incomplete Combustions of fossils fuels- Polycyclic hydrocarbons
How do chemical carcinogens enter
the body

1). Skin application- soot on chimney workers-

Reduce with the use of protective clothing for
workers.
2). Inhalation-
Soot, polycyclic hydrocarbons, asbestos, vinyl
chloride, napthylamine.
Smoke from fire extinguishers, vehicles exhaust
Inhalation of smoke from others
Through the digestive tract.
1) Natural constituents of food ( fungal contam.)
2) Formed by the interaction of foodstuffs ( in acidic conditions 2nd
amines would react with nitrites to from nitrosamines (smoked
fish- stomach cancer)
3) Formed during cooking ( Imidazoquinoline may be generated by
heating of a mix of glycine and glucose and Nitropyrenes formed
when meat is cooked over a smoky flame ( barbecued meat)-
cancer of liver, intestines , fibrosarcomas.
4) Bacterial action on partially digested food.or on bile acids. – high
fat diets
Formation of carcinogens in gut
Food 1 1o Amines Food 2
Fish (R-NH) Protein
Wine Tobaco A.A Bac. decarbox
2ndo Amines Food 3
G.Vegetab.
Nitrates Cooking
Bac. Red.

Nitrites Food Preser.

Phenols
Nitrosophenols (Catalyst)
Nitrosamines ( Carcinogenic)
eg. CH3
N-N=O
CH3
Factors affecting Carcinogenicity of
Chemicals

 Incidence- total dose of application and

frequency of application
 Synergism- The effect of 2 carcinigens applied
together is greater than 1.
 Promoters- 2 chemicals may exhibit synergistic
effects. Greater effect when applied together.
Initiation and Promotion
 Primary carcinogen- initiator
 Addition of promoter afterwards produce a tumor
 Sequence of treatment is important.
 When promoter follows initiator tumors always develop
 When promoter precedes initiator tumors do not develop.
 Some initiators can act as promoters (complete carcinogens
 Multiple applications of complete carcinogens or a single application
followed by promoter hastens the dev. of cancer.
 Initiators-Polycyclic hydrocarbons, N-methyl-N-nitrosourea( Saccharin)
 Promoters-cyclamates, saccharin, trytophan,-tumors of the bladder.,
Metab. Of tyrosine-phenol, p-cresol and of tryptophan indole act as
promoters of GI tract. Asbestos (ini-smokers)
Antipromoters
 Act to prevent the progression from initiation to
malignancy.
 Vitamin A
 Vitamin C
 Vitamin E
 Selenium
 Lycopene
 Cruciferous vegetables.
Metabolism of Carcinogens
 Carcinogens do not cause cancer themselves but their
metabolites.
 Lipophilic carcinogens are metabolized on the ER by means
of an Electron transport chain using Cytochrome P450.
 Eg. Polycyclic hydrocarbons are oxidized to Epoxide.
 Epoxides are very reactive and can attack DNA.
 Carcinogens are metabolized to electrophiles with a strong
affinity for the nucleophilic sites of Nucleic acids
 O

CH2 =CH-Cl
+O CH2-CH-Cl
Vinyl chloride Epoxide

CH
N-N=O +O H2O + CH 3 + + N2
CH3 Dimethylnitrosamine
Several steps
 Vinyl chloride- epoxide
 Dimethylnitrosamine- very reactive free methyl radical
 Nitrosamines- methyl radical
 Polycyclic hydrocarbons-epoxide

 All bind on nucleophilic sites of DNA and RNA

Site of DNA attack

Methyl radical- O-6 atom of guanine and N-7 of

guanine as well as N-3 of adenine
Epoxide of benzopyrene –2 amino group of
Guanine. More mutagenic than above
Binding on the base cause anomalous base
pairing and thus mutations.
Chemotherapy
 Drugs that act on the cell cycle
 M phase- Colchicine, Vincristine,Taxol.
 G Phase- Etoposide
 S Phase- 5- Fluorouracil, 6-mercaptopurine
 G1 phase- Methotrexate.
 Cell Cycle non specific-Nitrogen mustard, Dactinomycin- bind to
DNA.Cisplatin- cross linking.
 Drugs tha interfere with chromatin function-Colchicine.
 Topoisomerase inhibitors-Etooposide.