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Carcinogens

Carcinogens

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Carcinogens

  1. 1. Faculty of Medicine NEOPLSIA 2021 Carcinogens King Abdulaziz University Rabigh Branch
  2. 2. Carcinogenic agents (carcinogens) Three Major types of Carcinogens – Chemical – Radiation – Viral and Microbial
  3. 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. 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. 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. 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. 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. 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. 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
  10. 10. VIRAL & MICROBIAL CARCINOGENESIS • Emerging Field – DNA viruses – RNA viruses – other organisms
  11. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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