Cancer Chemotherapy Flashcards
What type of medication targets Proliferation Signalling
EGFR inhibitors
What type of medication targets Evading growth suppressors
Cyclin-Dependent kinase inhibitors
What type of medication targets Enabling Replicative immortality
Telomerase Inhibitors
What type of medication targets Inducing angiogenesis
Inhibitors of VEGF signalling
What type of medication targets Genome instability and Mutation
PARP inhibitors
What type of medication targets Resisting cell death
Proapoptotic BH3 mimetic
What do Anti-mitotics target?
Targets microtubules
What are microtubules formed of?
alpha and beta tubulin dimers
How do anti-mitotics target microtubules?
Disrupt assembly- Bind to free alpha-beta tubulin dimers
or
disrupt disassembly- stabilises microtubules and prevents cell division
Give an example of a disrupting assembly anti-mitotic
Vinblastine- amine protonated
vincristine- amide not protonated - slightly more potent
Give an example of a disrupting DISassembly anti-mitotic
Paclitaxel- most common
or
Docetaxel- more soluble
How can resistance be developed for anti-mitotics?
Overexpression of p-glycoproteins
Mutations in tubulin gene
What is an anti-metabolite?
An analogue of precursors for macromolecules
They inhibit essential enzymes
How does poisoning Thymidylate synthesis work?
5Fu -> FDUMP inhibits dUMP -> dTMP
Poisons enzyme
Michael addition
Causes DNA damage
What is an Alkylator?
Nitrogen mustards
How do alkylators work?
Crosslink DNA- Prevents DNA polymerase from separating strands.
Crosslink between N7 of Guanine (interstrand crosslink)
What chemical group is reactive on an alkylator?
The highly reactive aziridinium ion (N containing three membered ring)
Give an example of an Alkyl nitrogen mustard
melphalan (L-PAM)
Chlorambucil
cyclophosphamide (prodrug)
How are aniline mustards better?
Less side effects due to Lone pair on N delocalised into ring
Explain how cyclophosphamide is a good drug (nitrogen mustard)
Prodrug
Not active in body- has to be activated- less TOXICITY
Has to be activated by cytochrome P450
How can resistance be developed in relation to Nitrogen Mustards?
Increased expression of glutathione-S-transferase & levels of glutathione (thiol will substitute with triangle N group)
Can administer glutathione-S-transferase inhibitors^
Increased expression of excision repair enzymes
Changes in drug repair
What are DNA platinating agents?
Cisplatin anti-tumour drug
What chemical changes happen to cisplatin in the body?
the 2 chlorine groups are displaced with water (OH groups in turn)
How do platinating agents work? suspectedly….
Inhibit DNA Polymerase
Target N7 Guanine
How can resistance develop for DNA platinating agents?
Increase repair mechanism for intrastrand crosslinks (on same strand)
over expression of glutathione
How do Topoisomerase inhibitors work?
Intercalate into DNA, causes shape of helix to change- therefore enzymes cant process DNA well- Prevents cell replication and causes cell death
Prevents topoisomerase from fixing double strand break
examples of DNA intercalators (anthracyclines)
Doxorubicin
Daunorubicin
How do anthracyclines work
Amino sugar sits in minor groove of DNA
Planar aromatic structure fit into DNA
3 rings, 2 aromatic, middle has 2 c=o which are parallel
Whats the difference between DNA topoisomerase 1 and 2?
Topo 1 cuts 1 strand
Topo 2 cuts 2 strands- also fixes double strand break
What do anthracyclines do in relation to Topoisomerases?
Inhibits topo 2 by preventing the fix of a double strand break
What are the modern approaches to chemo
PARP inhibitors
Tyrosine Kinase Inhibitors
How do PARP inhibitors work
Inhibits PARP (Poly ADP ribose polymerase)
which fixes single strand breaks caused by topoisomerase 1
leads to cell death as fix is prevented and double strand break may occur instead.
What are the genes that are targeted by PARP inhibitors?
BRCA1 AND BRCA2 - Fix double strand break, if mutation than this cannot be fixed.
In healthy cells- can undergo normal homologous recombination.
What is Olaparib?
BRCA PARP Inhibitor
What are tyrosine Kinase Inhibitors?
NIBS- target proteins
What are BCR and ABL?
2 genes- chromosome 9 and chromosome 22
What forms the Philadelphia chromosome
translocation between bcr and abl (9 and 22)
What does the Philadelphia (BCR-ABL) chromosome do?
Protein is always on- proliferation
Acts as a tyrosine kinase
Found in CML
What was the first tyrosine kinase inhibitor? (BCR-ABL kinase inhibitor)
Imatinib
What about Imatinib makes it a tyrosine kinase inhibitor?
Methyl group caused selectivity for ABL kinase
Piperidine means water soluble
2-phenylaminopyrimidine initial structure
What does the BRAF pathway cause?
Cell proliferation
Gene expression
Mitosis
Differentiation
What does a mutation in BRAF protein cause?
Constant signalling and activation
Causes uncontrolled cell proliferation
What are vemurafenib , dabrafenib and sorafenib examples of?
BRAF inhibitors
what are erlotinib or gefitinib
EGFR for NSCLC inhibits ras
Cetuximab is for what
CRC blocks egfr (HER1)
What is the mutation for Braf inhibitors
single mutation of V600E
