week 4 lecture 2: neoplasia 2

• what does the term 'carcinogen' refer to?

  any agent that produces cancer
• give 3 examples of carcinogens

  1. tobacco smoke
  2. certain industrial chemicals
  3. ionising radiation (X-rays, UV rays)
• what are the types of carcinogens?

  1. genotoxic
  2. non-genotoxic
• what are genotoxic carcinogens?

  agents that directly interact with and/or damage DNA, or modify DNA's structure
• how many applications of genotoxic carcinogens is enough for tumour initiation?

  one
• what do genotoxic carcinogens produce?

  DNA adducts
• what is a DNA adduct?

  a piece of DNA covalently bound to a chemical
• what do non-genotoxic carcinogens do?

  damage DNA as a result of secondary interactions
• give 4 examples of ways non-genotoxic DNA damages DNA

  1. increasing oxidative stress
  2. inflammation
  3. apoptosis
  4. gene/protein alteration
• what is oxidative stress?

  an imbalance of free radicals and antioxidants in the body, leading to cell damage
• what conditions does oxidative stress play a role in?

  heart disease, Alzheimer's, cancer, etc
• what can reduce oxidative stress?

  antioxidants, which can be found in foods
• what is a (free) radical?

  any molecular species containing an unpaired electron in an atomic orbital
• both genotoxic and non-genotoxic carcinogens cause cancer by causing alterations in DNA repair, cell viability, and proliferation
• what are the two types of genotoxic carcinogens?

  1. direct carcinogens
  2. pro-carcinogens
• which type of carcinogen requires modification to become activated?

  pro-carcinogens
• give an example of a direct carcinogen

  beta-propiolactone
• what is used to treat cancers caused by direct carcinogens?

  anti-tumoral chemotherapeutic drugs
• give examples of anti-tumoral chemotherapeutic drugs

  1. cyclophosphamide
  2. busulfan
  3. chlorambucil
  4. acetylating and alkylating agents
• what do pro-carcinogens need to be modified by (to become carcinogenic)?

  intracellular enzymes
• what was the first pure (pro) carcinogen to be discovered, and when?

  benzanthracene, in 1952
• what does benzanthracene need to be (bio)activated by?

  phases 1 and 2 metabolism
• all aflatoxins are pro-carcinogens, name one

  Aflatoxin B1
• name 3 structures that are pro-carcinogens

  • aflatoxins (Aflatoxin B1)
  • aromatic amines
  • Azo dyes
• name a carcinogen isolated from pure tar

  3,4-benzo(a)pyrene
• what is the most potent carcinogen?

  7,12-dimethylbenzanthracene
• what does PAH stand for?

  polycyclic aromatic hydrocarbon
• what are PAHs?

  a class of organic compounds produced by incomplete combustion, or high-pressure processes
• give an example of a PAH

  benzo[a]pyrene
• benzo[a]pyrene is initially oxidised, primarily by the microsomal NADPH-dependent cytochrome P-450, to several arene oxides
• benzo[a]pyrene derivatives can bind to, and therefore damage, DNA
• benzo[a]pyrene itself can bind to AR and activate gene expression
• what is AR?

  an Aryl hydrocarbon receptor
• what produces Aflatoxin B1?

  certain strains of the Aspergillus flarus fungi and A. parasiticus
• what has aflatoxin ingestion (through contaminated food) been proven to cause in humans, and where?

  human hepatocellular carcinoma (HCC) in china and sub-saharan africa
• what are tumour promoters?

  substances that enhance tumorigenicity when administered after a carcinogen
• why are tumour promoters not carcinogenic?

  because they do not cause cancer on their own
• tumour promoters promote cancer if administered after very small doses of initiating (true carcinogenic) agents
• promoting agents can 'wake up' tumours a long time after administration of the carcinogenic initiating agent
• give 3 examples of tumour promoters?

  1. phorbol esters
  2. growth factors
  3. oestrogen (hormones)