PARP inhibition Flashcards
how were the toxicities associated with cisplatin improved through drug design?
A more stable leaving group was used instead of the two chlorine ions. This did however remove some potency from the drug
What is responsible for the variety in toxicity seen using carboplatin
It is excreted through the kidneys. People have different glomerular filtration rates so this was responsible for the differences.
What is methotrexate?
A folic acid competitive inhibitor
What is the mechanism of methotrexate?
It depletes the cell of tetrahydrofolate (FH4). FH4 is used to produce purines and thymidine. Methotrexate inhibits the production of FH4 from FH2 by inhibiting the enzyme DHFR. In doing so no FH4 is produced, so no purine or thymidine synthesis can occur.
What substance can be used to alleviate the effect of methotrexate and why is this the case?
Folinic acid reproduces cellular FH4 independently of FH2 and DHFR.
Why are children with leukaemia treated with lethal doses of methotrexate
Because only high doses are capable of crossing the BBB. To prevent the toxities the child is given folinic acid a few hours later.
What is Pemetrexate?
An analogue of 5, 10-methylenetetrahydrofolate which binds and inhibits the TS enzyme, preventing the production of FH2 which prevents the synthesis of thymidine in cells
What cancer has pemetrexate had large success in treating
Mesothelioma
What was the problem with pemetrexate?
Unpredictable toxicity - 4% GI toxicity and bone marrow suppression.
Who is likely to get toxicity from pemetrexate? How is this prevented?
People with high homocysteine levels in the plasma. Prevented by giving the patient folic acid.
What is Imatinib?
Small molecule that inhibits the tyrosine kinase activity of the BCR-ABL fusion protein.
What is the activity of PARP
PARP is activated by a DNA strand break. It forms ADP-ribose polymers which attach to histone proteins and to itself, using NAD as a substrate. The polymers are negatively charged so repel the histone proteins away from DNA causing their dissociation. This allows enzymes to come in and repair the SSB.
What genetic mutation sensitizes cells to PARP inhibition
BRCA1/2
How do PARP inhibitors in BRCA1/2 deficient cells induce synthetic lethality
If there is a single strand break, PARP inhibition will lead to its persistence. These become double strand breaks during replication. In normal cells these can be repaired as there is a functional copy of BRCA1/2 but in BRCA1/2 deficient cancer cells this is not the case. HR cannot be performed which leads to a collapsed replication fork and cell death.
Are tumours which lack RAD51 sensitive to PARP inhibitors
Yes, HR will not function properly so SSB becomes a DSB which will cause cell death.
