Carcinogenity

• Carcinogenesis


  Carcinogenic effect

  
• Cancer is a group of diseases
• Neoplasia


  • New growth or autonomous growth of tissue
• Neoplasm


  The lesion resulting from the neoplasia
• Types of neoplasms


  • Benign: Lesions characterized by expansive growth, frequently exhibiting slow rates of proliferation that do not invade surrounding tissues
  • Malignant: Lesions demonstrating invasive growth, capable of metastases to other tissues and organs
• Metastases


  Secondary growths derived from a primary malignant neoplasm
• Tumor


  Lesion characterized by swelling or increase in size, may or may not be neoplastic
• Cancer


  Malignant neoplasm
• Carcinogen


  A physical or chemical agent that causes or induces neoplasia
• Types of carcinogens


  • Genotoxic: Carcinogens that interact with DNA resulting in mutation
  • Nongenotoxic: Carcinogens that modify gene expression but do not damage DNA

  
• Hallmarks of neoplastic cells

  • Sustaining cell proliferation
  • Resisting cell death (apoptosis)
  • Inducing angiogenesis
  • Enabling replicative immortality
  • Activating invasion and metastasis
  • Evading growth suppressors
  • Reprogramming of energy metabolism
  • Evading immune destruction
• In normal condition, there is an equilibrium between cell proliferation and cell death to maintain cell number within a tissue
• An imbalance between cell growth and death within a tissue can cause cancer process

  
• Factors that contribute to carcinogenesis

  • Endogenous factors that influence DNA damage
  • Endogenous factors that influence cell growth
  • Endogenous factors that influence cell death
  • Exogenous factors that influence DNA damage
  • Exogenous factors that influence cell growth
  • Exogenous factors that influence cell death
• The causes of most human cancers remain unidentified
• Environmental and life style factors, especially chemical agents, are important contributors to carcinogenesis

  
• Endogenous (i.e. estrogen) and exogenous substances (PAH) can cause carcinogenesis

  
• Carcinogen


  An agent whose administration to previously untreated animals leads to a statistically significant increased incidence of malignant neoplasms as compared with that in appropriate untreated control animals

  
• Types of carcinogens


  • Chemicals
  • Physical agents (UV light and gamma radiation)
  • Biological agents (Viruses)

  
• Chemical carcinogens are the most commonly investigated carcinogenic agents
• To define molecular and cellular mechanisms of chemical carcinogenesis have critical importance for carcinogenic risk assessment and for chemopreventive and therapeutic strategies for the management of human cancers

  
• Linkage between increased occurrence of scrotal and nasal cancer among chimney sweepers and their profession was described

  1775
• Relationship between sunlight exposure and skin cancer in humans was described

  1875

  
• Relationship between lung cancer and uranium mining was noted

  1879

  
• Linkage between the aniline dyes and bladder cancer in dye workers was reported


  1895
• 1. napthylamine and benzidine in dye were determined the cause of skin and bladder cancer
• 1. naphthylamine is not used in chemical industry and exposure to a variety of other aromatic amines is regulated by law
• Polycyclic aromatic hydrocarbon (PAH), benzo(a)pyrene, from the coal tar is determined as a carcinogen in rodents
• Exposure of workers to chromium, nickel, asbestos was shown to be associated with an increased incidence of lung cancers in workers
• Multistage nature of chemical carcinogenesis

  Involves three stages: Initiation, Promotion, and Progression

  
• Clinical stages of cancer

  • Stage 0 (carcinoma in situ)
  • Stage I
  • Stage II
  • Stage III (IIIA and IIIB)
  • Stage IV

  
• Initiation


  • DNA modification
  • Mutation
  • Genotoxic
  • One cell division necessary to lock-in mutation
  • Modification is not enough to produce cancer
  • Nonreversible
  • Single treatment can induce mutation

  
• Promotion


  • No direct DNA modification
  • Nongenotoxic
  • No direct mutation
  • Multiple cell divisions necessary
  • Clonal expansion of the initiated cell population
  • Increase in cell proliferation or decrease in cell death (apoptosis)
  • Reversible
  • Multiple treatments (prolonged treatment) necessary
  • Threshold

  
• Progression


  • DNA modification
  • Genotoxic event
  • Mutation, chromosome disarrangement
  • Changes from preneoplasia to neoplasia benign/malignant
  • Irreversible
  • Number of treatments needed with compound unknown (may require only single treatment)

  
• Initiation


  The first stage of the cancer process, defined as a stable, heritable change resulting from a carcinogen-induced mutational event

  
• Examples of initiators


  • Polycyclic hydrocarbons
  • Nitrosamines
  • Biological agents (such as viruses)
  • Physical agents (X-rays and UV light)
• Critical steps in the initiation process by carcinogenic chemicals

  1. Conversion of a chemical to a DNA-reactive metabolite (an ultimate carcinogen)

  2. Interaction of the ultimate carcinogen with DNA, leading to DNA structural alteration

  3. DNA repair that may reverse the structural damage

  4. Cell proliferation leading to the fixation of the DNA damage

  5. Mutations of protooncogenes/ oncogenes, such as the ras genes may result in their activation, leading to neoplastic transformation

  
• The metabolic pathway of benzo(a)pyrene leading to carcinogens

  
• Promotion


  The second stage of the carcinogenesis process, involving the selective clonal expansion of initiated cells to produce a preneoplastic lesion

  
• Tumor promoters


  Agents capable of inducing tumor promotion