3. Chemical Carcinogens
• Direct Carcinogens :Directly produce damage
without prior metabolic conversion
• Indirect Carcinogens (Procarcinogen): Metabolic
conversion in liver by microsomal cytochrome P-
450 dependent mono-oxygenases (found in the
smooth endoplasmic reticulum of hepatocytes)
ultimate carcinogen
4. Action of chemical carcinogens
• Initiator - Chemical inducing irreversible DNA
damage
• Promoter -Augment effect of initiator by
promoting cell growth, e.g. phorbol ester (PTA)
activate signal transduction or GF secretion,
hormones, saccharine …..etc
• No tumor develops unless the promoter is
applied AFTER the initiator.
5. Mode of action in chemical Carcinogens
• Chemical carcinogens contain highly reactive
electrophil groups that combine to DNA, RNA, or
proteins producing mutations
• Genes commonly affected are RAS & P53
• May be very specific‘ Signature Mutation’
• Some strong chemicals act as Initiator &
Promoter e.g. polycyclic hydrocarbon
6. CHEMICAL CARCINOGENS
• Alkylating Agents: Direct, used in chemotherapy
of cancer
– Cyclophosphamide: can cause leukemia,
lymphoma
• Polycyclic aromatic hydrocarbons: Indirect &
very strong, can cause cancer in the region of
contact (lung and bladder cancer), it is found in
tobacco smoke, smoked meats and fish.
• Aflatoxin B1: Naturally occurring carcinogen
present in fungus (Aspergillus flavus
Hepatocellular CA)
7. CHEMICAL CARCINOGENS
• Nitrosamines: Endogenous or food preservatives,
it is converted to nitrites in the GI tract, which
may cause gastric cancer and other GI cancers.
• Aromatic Amines & Azo dyes: Rubber & Food
Industry e.g. naphthylamine Bladder CA
• Asbestos (ships insulation): lung Ca,
mesotheliomas, GI Ca
• Vinyl chloride - rare type of liver Ca
• Chromium, nickel - lung Ca
• Arsenic - skin cancer
8. PHYSICAL CARCINOGENS
• U-V light:
– Effect depends on intensity of exposure &
quantity of melanin
– Production of pyrimidine dimers in DNA
MUTATION in RAS, P 53
– Failed repair Skin CA
• Skin cancer includes: Squamous Cell CA,
Basal Cell CA, Melanoma
9. PHYSICAL CARCINOGENS
• Ionizing Radiation
– Explosions Leukemia after 7 yrs, Latent
period Breast, colon, thyroid, lung CA
• Leukemias (for example Chronic lymphocytic
leukemia) represent the most common radiation-
induced cancer in humans
– Therapeutic exposure Thyroid CA,
Leukemia
– Mechanism: Free radical injury Mutations
in RAS, RB. P53
11. Viral & Microbial Carcinogenesis
Viruses
RNA Oncogenic viruses
Human T-Cell Leukemia Virus type 1 (HTLV-1)
• RNA retrovirus targets / transforms T-cells
causing T-Cell leukemia/Lymphoma
• Transmitted like HIV but only 1% of infected
develop T-Cell leukemia/Lymphoma
• No cure or vaccine exists for HTLV-I, treatable
with chemotherapy, but relapse is common
12. Viral & Microbial Carcinogenesis
Viruses
DNA Oncogenic Viruses such as:
• Human Papilloma Viruses (HPV).
– sexually transmitted
– Two types: Benign HPV and Malignant HPV
• Low risk groups (6, 11) Genital
Squamous Cell Papilloma
• High risk group ( 16, 18 ) Squamous
Cell CA in cervix, vulva, perianal &
oropharyngeal regions
13. Viral & Microbial Carcinogenesis
Viruses
• Epstein-Barr (EBV) infects B lymphocytes and
epithelial cells of oropharynx and may result in
malignancy
• Burkitt’s Lymphoma
• B cell lymphoma in immunosuppressed
• Nasopharyngeal carcinoma
• Hepatitis B virus (HBV) has strong association
with Liver Cancer.
• Herpes virus 8 causes Kaposi sarcoma
14. Viral & Microbial Carcinogenesis
Helicobacter Pylori
• Bacteria infecting stomach implicated in:
– peptic ulcers
– gastric carcinoma
– marginal zone lymphomas (mucosa-
associated B-cell lymphomas (MALTomas) )
• The best and strongest evidence links
Helicobacter pylori infection with the onset of
mucosa-associated B-cell lymphomas
(MALTomas) of the stomach, which are also
known as marginal zone lymphomas.
15. Viral & Microbial Carcinogenesis
Helicobacter Pylori
• It is thought that H. pylori activates T cells, which
in turn promote polyclonal proliferation of B cells
in the gastric mucosa. In this process, some
cells obviously become malignant and give rise
to T-cell independent low-grade monoclonal
lymphomas
16. Tumor’s Effects on host
Tumours cause problems because of:
• Location and effects on adjacent structures:
– 1cm pituitary adenoma can compress and
destroy the surrounding and cause
hypopituitarism).
– 0.5 cm leiomyoma in the wall of the renal
artery may lead to renal ischemia and serious
hypertension).
• Tumors may cause bleeding and secondary
infections
(lesion ulcerates adjacent natural surfaces)
17. Tumor’s Effects on host
• Effects on functional activity such as Hormone
synthesis
– adenomas and carcinomas of B cells of the
islets of the pancreas produce hyperinsulinism.
• Cancer cachexia (wasting due to cancer):
manifests with weakness, weight loss, anorexia,
anemia and infection.
– The principal cytokine responsible for such
changes is Tumor necrosis factor-a.
18. Tumor’s Effects on host
Paraneoplastic syndromes
• They are diverse symptoms associated with many
different tumors that occur in patients and cannot
be explained.
– Could be earliest manifestation of hidden cancer
in some cases
• Bronchogenic and breast cancers and hematologic
malignancies are the most often neoplasms
associated with these syndromes.
19. Examples of Paraneoplastic
Syndromes
• Small Cell CA lung increased ACTH (Cushing
syndrome), increased ADH, Bone changes,
nervous system disorders
• Squamous Cell CA lung & Breast CA
Parathormone related & others Hypercalcemia
• Hepatic & Renal CA Polycythemia
• Pancreatic, Gastric CA Carcinoid S.
20. Examples of Paraneoplastic
Syndromes
• Advanced Cancers Nonbacterial thrombotic
endocarditis.
• Colonic Adenocarcinoma Acanthosis
nigricans
• Pancreatic & lung CA clotting factors Deep
vein thrombosis
– N.B. Hypercalcemia is commonly produced by
lytic bone metastases
