Wk 13: Mitotic inhibitors Flashcards
What is the mechanism of action of mitotic inhibitors?
Suppress cell division by inhibiting mitosis - disrupt balance between polymerised + depolymerised microtubules
What is the composition of microtubules?
- Tubulin form dimers
- Consists of a + b units
- Dimer stack into protofilaments
- Protofilaments bind laterally forming microtubules
What is the equilibrium process of microtubules?
- Assembly: binding a/b tubulin to GTP
- Disassembly: binding B tubulin to GDP
What are examples of taxanes?
- Paclitaxel
- Docetaxel
- Cabazitaxel
What is the mode of action of taxanes?
Microtubule antagonist:
- Bind tubulin dimer + microtubule filaments reversibly
- Induces assembly of tubulin into microtubules, inhibiting depolymerisation
- Stabilises mitotic spindles
- Equilibrium shifts to form microtubules
- Dysfunctional = stopped in metaphase
- Cell death
How do taxanes bind to tubulin dimer + microtubule filaments?
- Taxol binds near M loop of B tubulin, makes lateral contact btw adjacent protofilaments
- Stabilises microtubules by strengthening lateral interactions
- Counteracts destabilising effects of GTP induced hydrolysis
What is the mechanism of action of vinca alkaloids?
- Binds to tubulin
- Inhibits polymerisation of microtubules
- Shifts equilibrium towards disassembly
- Prevents mitotic spindle formation
- Metaphase arrest
- Cell division inhibited
What is the difference in binding sites of vinca alkaloids + taxols?
- VA: bind to high affinity sites of b tubulin at (+)end to suppress assembly
- Taxol: bind in interior surface, suppression disassembly
What is the use of eribulin?
Metastatic breast cancer + liposarcoma
What is the mechanism of action of eribulin?
- Binds to high affinity sites at plus ends of existing microtubules
- Creates non-functional aggregation of tubulin blocking microtubule polymerisation
- Apoptosis induced after mitotic blockade
What is the mechanism of action of mandrake plant extracts?
Teniposide + etoposide:
- Breakdown microtubules + prevent polymerisation
- Generates irreversible DNA strand breaks
What is the mechanism of action of camptotheca tree extracts?
Topotecan - inhibit topoisomerase I
