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Carcinogenic Agents

  1. Chemicals            
  2. Radiation             
  3. Microbes
  1. Chemical carcinogens
    1. Carcinogenesis is a multi step process involving a sequence of initiation (mutation) followed by promotion (proliferation)
    2. Initiators
      1. Direct- Acting chemical carcinogens.
        These are mutagens that cause cancer directly by modifying DNA.
      2. Indirect – Acting chemical carcinogens (procarcinogens).
        These require metabolic conversion to form active   carcinogens.
    3. Promotors e.g. Phorbo1 esters, phenols, hormones like DES, drugs, saccharin etc.
      1. Cause cellular proliferation of mutated (initiated) cells
      2. Proliferation of a mutated cell may lead to accumulation of additional mutations
    4. Clinically important chemical carcinogens
      1. Nitrosamines; gastric cancer
      2. Cigarette smoke; multiple malignancies
      3. Polycyclic aromatic hydrocarbons; bronchogenic carcinoma
      4. Asbestos; bronchogenic carcinoma, mesothelioma
      5. Chromium and nickel; bronchogenic carcinoma
      6. Arsenic; squamous cell carcinomas of skin and lung, angiosarcoma of liver
      7. Vinyl chloride; angiosarcoma of liver
      8. Aromatic amines and azo dyes; hepatocellular carcinoma
      9. Alkylating agents; leukemia, lymphoma, other cancers
      10. Benzene; leukemia
      11. Naphthylamine: bladder cancer
    5. Potential carcinogens are screened by the Ames test
      1. Detects any mutagenic effects on bacterial cell in culture e.g. In S. typhi murium
      2. Mutagenicity in vitro correlates well with carcinogenicity in vivo. 
  2. Radiation
    1. Non-Ionizing radiation:
      Long λ low frequency e.g. electric power, microwaves, radio waves, infra­red, UV
    2. Ionizing radiation:
      Short α, high frequency,
      1. ionize targets, eject electrons
      2. X rays, γ rays, cosmic rays
    3. Particulate radiation: classify by type of particles emitted: α, β, e, protons
    4. Biological effects
      1. Dose rate: single dose> divided
      2. Target: DNA: => Rapidly dividing cells - Most sensitive (Hematopoietic, Germ cells, GI epithelium; squamous epithelium; endothelial cells, lymphocytes)
      3. Single dose to whole body> regional doses
      4. G2 & M: most sensitive to ionizing radiation.
        Ionizing radiation - produce oxygen derived free radicals
    5. UV rays:
      1. UV Rays:- Seen as etiology factor for sq cell ca, Basalcell ca, multiple mycloma
      2. UVA (320-400 mm)
      3. UVB (280-320 mm) → Induction of Cutaneous Carcinoma
      4. UVC (200-280mm) → filtered by ozone
      5. UVB => formation of Pyrimidine dimmers (normally removed by NER pathway)
        • e.g. Xeroderma pigmentosum: AR
        • ↑ photosensitivity
        • 200 X - risk of skin Ca
        • Neurologic abnormalities
        • Mutation in oncogenes & tumor suppressor genes
    6. Ionizing radiation:
      Cancers: Most frequent: Leukemias (except CLL); thyroid Ca Intermediate: Breast, lung, salivary gland
      Least: Skin, bone, GIT
  3. Viruses
    1. DNA
      1. Adeno virus - in animals            
      2. HPV             
      3. EBV             
      4. HBV & KSHV
    2. HPV:
      1. 70 types      
      2. Warts of Cx, anogenital, oral & larynx
      3. Risk
        a. Low' risk - 6,11
        b. Intermediate risk - 31, 33    
        c. High risk - 16, 18
      4. Benign warts & Preneoplastic, lesions - Nonintegrated, episomal
      5. In Ca → integrated - Site of integration: Random but clonal
      6. Virus: E1/E2 ORF - Interruption
      7. E2 inhibits E6 E7
      8. E7 - binds to under phosphorylated pRb and displaces E2F which in turn is
      9. transcriptional  activator
      10. E6 - binds to and degrades p53 (high risk E6, E7 - high affinity)
      11. HPV infection → initiation (co-mutations required)
    3. E.B. virus:  
      1. Disease caused by E.B virus
  • Burkitt's lymphoma B- cell lymphoma in immunosuppressed. (in HIV infection)
  • Nasopharyngeal carcinoma
  • Hodgkin's disease
  • Infections mononucleosis
  1. CD21  EBV receptor
  2. Virus: Latent Inf., episomal form immortalized
  3. No direct tumor effect
  4. EBV encodes Ebren codes - 2 gene: transactivates cyclin D & src genes and promotes cellular proliferation Q
  5. Ebren codes ↑ LMP - 1 (Latent membrane. Protein) → ↑ bel2, promotes cell growth (↑ bel - 2, promotes. Cell growth)
  6. HBV: Viral DNA integrated & clonal insertion Q
  7. No onco proteins encoded by HBV genome
  8. No consistent pattern of integration
  9. Injury & regeneration
  10. HBV encodes HBX protein - disrupts normal growth control of Hepatocytes.
  11. HBx binds to & interferes with p53
  1. RNA oncogenic viruses: Q
    1. HCV: Chronic liver Cell injury & regeneration
    2. HTLV-1: T cell leukemia/ lymphoma, Tropical spastic para paresis, uveitis, arthritis
    3. Tropism for CD4 + T cell.
    4. Path
      tax gene (-essential for viral replication)↑ transc. of host genes e.g. C-fox, C-sis
      Inhibits complex formation between CDK4 & p16 (INK)
  2. H. pylori: Gastric Carcinoma, lymphomas (B cells) Q
Oncogenic microbes and parasites  
Organism Neoplasm
Human papilloma virus (Papovaviridae) Cervical, vulvar, penile cancers, squamous cell carcinoma, oropharyngeal carcinoma
HSV type 2 Cervical carcinoma
Hepatitis B virus (Hepadnaviridae) Hepatocellular carcinoma
Hepatitis C virus (Flaviviridae) Hepatocellular carcinoma, lymphoplasmacytic lymphoma
HTLV – I (Retroviridae) Adult T cell leukemia / lymphoma
HTLV – II (Retroviridae) T cell variant of hairy cell leukemia
HTLV – III (Retroviridae) AIDS related malignancies, NHL, Kaposi sarcoma, SCC (esp of UG tract). Diffuse large B cell lymphoma
Burkitt’s lymphoma
Epstein barr virus (Herpesviridae) Mixed cellularity Hodgkin’s, Nasopharyngeal carcinoma (anaplastic), African Burkitt’s lymphoma, post organ transplant lymphoma, primary CNS diffuse large B cell lymphoma, extranodal
NK/T cell lymphoma (nasal type)
H. pylori Gastric malt lymphoma, Gastric cancer
Human Herpes virus 8 Primary effusion lymphoma, multicentric Castleman’s disease
Schistosoma hematobium Bladder cancer (squamous cells)
Clonorchis Cholongio carcinoma
Opisthorchis Cholangiocarcinoma

Tumor Immunity Q
  1. Immune surveillance (Thomas & Burnet) - destroys neoplastic cells via recognition of l0 non-self" antigens
  2. Tumor antigens
    i. TSA positive in tumor cells, negative in normal cells
    ii. TAA positive in tumor cells & normal cells
    iii. TSAs which evoke Cytotoxic T cell response - derived from peptides uniquely present in tumor cells presented by MHC1 molecule.     
  3. T-S shared Ag: Genes are silent in normal tissue e.g. MAGE (except Testis)
  4. (12 genes GAGE, RAGE- Mucins)
  5. Tissue specific antigens.: e.g. Tyrosinase
  6. Ag resulting from mutations: p53, CDK4 Q
  7. Over expressed Ag: C-erb B2
  8. Viral Antigens: E7protein of HPV
  1. Oncofetal Ag: CEA, αFP
  2. Differentiation Ag e.g. CALLA
  3. Anti tumor Effector Mechanism: - cells that seem to destroy the tumor cells
    1. Cytotoxic T lymphocytes   
    2. NK cells       
    3. Macrophages
  4. Humoral mechanism; antibodies against tumor antigens destroy the tumor cells by complement activation and ADCC Q
Effects of tumor: Q
  1. Location & physical effect e.g. Pituitary adenoma
  2. Functional Effect e.g. hormone synthesis
  3. Bleeding & secondary infection
  4. Acute symptoms.: e.g. Pituitary adenoma
  5. Cachexia: - by CKs (TNF−α, IL-1, IFN-gamma)
    ↓ food intake, ↑ BMR, ↑ calorie expenditure

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