Modern Chemotherapy Ribs And Nibs W8 Flashcards
What are BRCA genes responsible for?
Double DNA strand repair
What is BRCA1 and BRAC2?
They are genes that code for the enzyme also called BRCA1/2
What do BRCA1/2 recognise?
Double stranded brakes and with another protein called RAD51, bind and carry out homo ologist recombination
They find another sequence and start pacing it back together
There is a healthy strand and a non-Health one and by crossing them over and putting them back together
Is double stranded brake repair error free
Yes, because you are copying from a healthy template
What is single strand repair carried out by?
PARP enzyme
BRCA mutations
When there is no BRCA1/2 available and so won’t bind to 51 and won’t recognise DNA and so homologous recombination doesn’t work making the double stranded brake persist
What happens if double strand break persists?
Sell death or miss reading of DNA and translocations and this leads to mutations
Inhibitors of DNA repair proteins
If there is an inhibitor of PARP, then there is no DNA repair to the single strand
Proliferation occurs and this leads to a double strand break from the single strand break
It is either repaired by a homologous combination or cell death
Olaparib
Used in ovarian cancer
1st inhibitor licences in Europe
Why do people with a BRCA mutation more likely to get cancer?
because these genes are crucial for DNA repair. When they’re mutated, cells accumulate DNA damage over time, which increases the risk of uncontrolled cell growth
BRCA Genes Are Tumor Suppressors
Mutation = DNA Repair Fails
Tyrosine kinase inhibitors
Tyrosine is a protein phosphorus things - adds a phosphate group
- It is an amino acid with a phenol
Imatinib Mesylate
The first selective kinase inhibitor
Comes as assault
- Kinases need ATP
- It will bind and sit in every single kinase
This drug was able to block only one kinase that binds ATP and not the rest of them that do
Imatinib is a kinase inhibitor
blocks the activity of specific tyrosine kinases
binds to the ATP-binding site of BCR-ABL:
Prevents it from phosphorylating proteins.
Stops the cancer cells from growing and dividing.
Phosphorylation
acts like a switch to turn proteins on or off
Why were kinases a poor target?
Too Many Kinases (Lack of Specificity)
High ATP Concentrations in Cells - Inhibitors had to compete with ATP
Fear of Disrupting Essential Cell Functions
BCR-ABL fusion protein
Also called the Philadelphia chromosome
Chromosome 9 (ABL) and 22 (BCR) break and then put together to form BCR – ABL
This mutation resulted in a kinase that is always turned on
Development of Imatinib
Took 2 phenol and started to add to it to make it more selective
A methyl group was added which showed selectivity for ABL
Piperizine was also added to the end
BRAF mutations in melanoma
In about 40–60% of melanomas, there is a mutation in the BRAF gene.
This mutation makes BRAF Permanently active:
- Sends continuous “grow and divide” signals to the cell — even when it shouldn’t.
- Leads to uncontrolled growth of melanoma cells.
What is BRAF
gene that makes a protein called B-Raf, a type of serine/threonine kinase.
BRAF Inhibitors
block the activity of mutant BRAF proteins by binding
This slows all stops tumour cell growth
Resistance to Tyrosine Kinase Inhibitors
is a major challenge in cancer treatment
Secondary mutations in the kinase domain:
- The cancer cell mutates again — this time in a way that prevents the drug from binding.
Activation of bypass signaling pathways:
- Cancer cells find alternative growth pathways to survive.
