Triazene compounds
- Created by: lucy-cello
- Created on: 24-10-19 14:03
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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
- Methyl-guanine methyl-transferase - s a small protein that removes alkyl adducts from O6 of DNA guanine
- Mismatch repair (MMR) - Promotes effect of triazenes
- A protein complex dedicated to the repair of biosynthetic errors generated during DNA replication
- MGMT - Promotes resistance
- 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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