New targets

PAR

3rd nucelic acid in mammalian cells

poly(ADP-ribose)

made from ADP-ribose and NAD+

PARP

PAR polymerase

uses NAD+ as a substrate and makes PAR chains

PARP-1

allows for the repair of damaged DNA

builds PAR chains onto the histone

since it is anionic, it disintangled the DNA cause like charges repel so other things can do the fixing easier

good target for cancer therapy → stop = stopping dna replication

Main feature of PARP-1 inhibitors

• EWG is disfavoured - R is not EWG

• mimics nicotinamide

• size, polarity and h-bonding is not important

radiotherapy examples and their effect on DNA

radiation, bleomycin

ss breaks/ds breaks/damage to bases

mono-alkylators examples and their effect on DNA

TMZ

damage to bases

cross linkers examples and their effect on DNA

mitomycin C, platinum drugs, N-Mustards

ds breaks, damage to bases

TOP inhibitors examples and their effect on DNA

etoposide

ss breaks and ds breaks

antimetabolites examples and their effect on DNA

5FU, thiopurines

damage to bases

PARG

enzyme breaks the PARP off the histone to finish the repair

Main role of PARP inhibitors

to potentiate DNA damage via other products such as TMZ

never really used as a single agent

BRCA 1/2 mutations in the context of PARP

Patients with this mutation are sensitive to PARP inhibitors

BRCA 1/2 fix the ds breaks in DNA

if BRCA isnt working well then the ds break wont be fixed so DNA is already damaged and PARP inhibitors can work as a single agent to enhance the effect of existing DNA damage by fixing the PARP to it

Tumour Hypoxia

Condition in which tumor cells are deprived of adequate oxygen supply, making them more resistant to treatment.

this means while the low O2 means less proliferation, it is insensitive to radio and chemo therapy cause the free radicals need O2 for stability and oxidative damageand can lead to treatment failure due to reduced effectiveness of therapies that rely on oxygen.

How to we fix hypoxia?

radio-sensitizing drugs

• parp1 inhibitors/electron-affinic radiosensitisers

• persist even if no o2

hypoxia-selective drugs

• selectivity for hypoxic conditions relies on re-oxidation by o2

• designed to specifically target hypoxic tumor cells, which are often more resistant to standard therapies → are inactive (or less active) in normal oxygen conditions and become toxic only in low-oxygen (hypoxic) environments

Radiosensitizing drugs

drugs that enhance the effectiveness of radiation therapy by making tumor cells more sensitive to radiation, particularly under hypoxic conditions.

e.g. nitroimindazoles → etanidazole OR PARP inhibitors OR Mitomycin C

Etandazole MOA

reduces glutathione conc and inhibits the glutathione S-transferase making the tissues more sensitive to the radiation

too much glutathione can neutralise free radicals generated during radiation therapy, reducing its efficacy.