Triazene compounds

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  • Mechanism of action based on methylation of O6 guanine
    • Mediated by methyldiazonium ion
    • Triazene Compounds
      • Includes dacarbazine and temozolomide
      • Pharmacokinetics: How the organism affects a drug
        • Dacarbazine requires hepatic activation
        • Temozolomid is  converted into active metabolite at physiological pH
          • 100% bioavailability with oral administration
      • DNA Repair Systems
        • MGMT - Promotes resistance
          • Methyl-guanine methyl-transferase - s a small protein that removes alkyl adducts from O6 of DNA guanine
            • Also called O6-alkylguanine-DNA-alkyltransferase
          • Mechanism of removal is a stoichiometric and auto-inactivating reaction
            • Consists in a covalent transfer of the alkyl group from the site in DNA to an internal cysteine residue of MGMT protein
          • High levels responsible for normal and tumour cell resistance to triazenes
            • MGMT inhibitors can be used and greatly increase activity of triazenes against MGMT expressing target cells
        • Mismatch repair (MMR) - Promotes effect of triazenes
          • A protein complex dedicated to the repair of biosynthetic errors generated during DNA replication
    • DNA O6-methylguanine adducts generate base/base mismatches
      • with cytosine and with thymine
      • Leads to cell death, or mutations represented by C:G - T:A transition in DNA helix
  • Such as lomeguatrib - O6-(4-bromotenyl) guanine
  • Recognises base mismatches and insertion-deletion loops, cuts the sequence and restores the correct base sequence
  • BUT unable to repair incorrect base pairing cuased by triazenes, futile attempts lead to cell apoptosis

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