AT L1 DNA alkylation Flashcards
Why use compounds in combination
- less side-effects than one compound at a higher dose
- cause many types of damage so that cell cannot increase all these damage repair mechanisms
Explain neuclotide excision repair
- Damage recognised by XPC-R23
- Several other proteins bind - forms a complex that unwinds DNA
- XPG cuts 3’ and XPF cuts 5’ side of the damaged in the damaged strand of DNA. Removes 27-30 neucloitides.
- Repair synthesis using DNA polymerase and other proteins (uses undamaged strand as a template)
what sort of damage does parp repair
single strand break
What does PARP repair and NER have in common?
both have one strand still in tact to use as a tempate (therefore relatively easy for cell)
What sort of damage does parp recognise?
Alkylation of N in a ring creates a prositive charge and therefore instability.
Strand breaks and base pulls away from sugar, folds up, creates hole.
Hole recognized by PARP
Name theraputic mustards
chlorambucil
estramustine
cyclophosphamide
melphalan
What was chlorambucil designed for/
to be administered orally - aromatic ring softens the electrophile so reacts with DNA more slowly
What was estramustine designed for
attempt to tarfet oestrogen dependent tumour cells
what was cyclophosphamide designed for?
target to release agent through enzymatic degredation
what was melphalan designed for?
enhance cellular uptake through phenylalanine transpor mechanism
know mechanism of action of temozolomide?
…
What happens if G-CH3 is not repaired?
results in G to A transversion or strand break
How can the damage of telozolomide be repaired?
AGT scans DNA for alkylation of O6 of guanine. AGT is inactivated and guanine returns to normal through covalent transfer
How does telzolamide cause damage?
methylates DNA
