PARP inhibitors and Intercalating Agents Flashcards
What are BRCA1 and BRCA2? What is their purpose?
are human genes that produce human tumour suppressor proteins
- help repair damaged DNA and play a role in ensuring the stability of genetic material
What do mutations in BRCA1 and BRCA2 result in?
damaged DNA cannot be repaired
women
- breast and ovarian cancers
men
- breast and prostate cancers
What drugs are BRCA1 cancers hypersensitive to?
mitomycin C
- bioreductive agent
cisplatin
- alkylating agents
What do poly (adenosine diphosphate ribose) polymerase (PARP) do? What does PARP inhibition result in?
PARP
- are involved in mediating single strand breaks in DNA
inhibition results in
- inhibition of DNA repair and replication in cancer cells
= increase in the frequency of DNA double strand breaks
What are types of PARP inhibitors? What are they used to treat?
olaparib
treat
- BRCA mutated advanced cervical cancer
- metastatic pancreatic cancer
- castration resistant prostate cancer
What mutations are associated with hereditary cancers? How are they detected?
BRCA1
BRCA2
FANC
- mutations in these genes are associated with hereditary cancers
DNA cross-linkers are used to detect BRCA/FANC mutated cancers.
What are the types of DNA intercalators? What are their structural features?
berberine
proflavine
topoisomerase inhibitors
- camptothecin = only clinically approved Top1 inhibitor
- topotecan, irinotecan
- doxorubicin = Top2
tend to be
- aromatic, planar and cationic (+)
How do DNA intercalators work?
intercalation is the insertion of a molecule between base pairs of the DNA duplex, perpendicularly to the double helix
- intercalators are electrostatically attracted to the backbone of DNA due to the negative charge pf phosphate ions
= associate with the anionic sugar phosphate backbone then diffuse along the backbone until thermal motion opens up a cavity suitable for intercalation - intercalating ions forms pi-stacking interactions with the bases above and below the intercalation site
What is the function of topoisomerase?
topoisomerase enzymes prevent DNA supercoiling
- reduce local DNA twisting
topoisomerase 1 - causes a single strand break
topoisomerase 2 - causes a double strand break
levels are elevated in cancer cells
How do topoisomerase 1 enzymes work?
a tyrosine residue of topoisomerase enzyme 1 attacks the 3 position anionic phosphorus in DNA
- breaks the phosphorus-oxygen bond
causes 5 hydroxyl strand break with the topoisomerase enzyme bound to the remainder
Top1 enzymes allow DNA relaxation, allowing the 3 hydroxyl to swivel around the intact DNA
ligation occurs rejoining the DNA strand alongside Top1 enzyme disassociation
What is the structure activity relationship topoisomerase 1 inhibitor, camptothecin and synthetic derivatives?
camptothecin
- active form is the S-enantiomer which has a lactone ring
= is poorly soluble/hydrophobic
- E ring must be intact during the chemotherapeutic process
= basic pyridine ring can be reacted with acid to stabilise it, making it water soluble
polar derivatives are to increase solubility under physiological conditions
Why can camptothecin be inactivated?
in basic conditions, the lactone ring can be cleaved
= hydrolysis occurs to the hydroxyl and carboxylate group
the carboxylate structure is inactive
How do Top1 inhibitors work?
inhibits the re-association of DNA after cleavage by Top1 and traps the enzyme in a covalent linkage with DNA
the enzyme complex is then ubiquitinated and destroyed by the proteasome
- thus depleting cellular topoisomerase 1
What is the structure relationship activity of doxorubicin?
is an anthracycline
- has 3 benzene rings with a central quinone ring
How does doxorubicin work?
has 2 mechanisms of action
- intercalation
= intercalates with DNA inhibiting Top2. it stabilises Top2 after it has broken the DNA chain for replication
= prevents DNA from being resealed as it blocks ligation and enzyme dissociation - bio reduction
= has a quinone moiety which generates radicals for oxidative stress processes
= donates previously accepted electron to form superoxide from oxygen, SO can create ROS and oxidative stress.
= can also extract a proton from DNA and damage DNA strand cleavage
