Antimitotics Flashcards
What is the process of mitosis
- Dynamic microtubules bind to chromosomes (metaphase plate)
- Chromosomes move towards spindle poles
——-> cells divide
Explain tubulin assembly
a- and b- tubulin (dimeric subunits)
-> heterodimers form a protofilaments which then forms microtubules
Its a dynamic process
List microtubular function
- Generate the mitotic spindle = (Essential for separation of chromosomes during mitosis)
- Provide cell microstructure
- Neurochemical signalling
- Angiogenesis
How are antimitotic drugs classified
Traditional broad classifications:
○ Microtubule destabilising agents
○ Microtubule stabilising agents
How do microtubule destabilising agents work
Drugs that inhibit microtubule polymerisation by binding to tubulin - either by binding at vinca site of tubulin or the colchicine site
How do microtubule stabilising agents work
inhibit depolymerisation
by binding at the taxane site of tubulin
(Taxanes)
What are vinca alkaloids and how do they work
- binds to tubulin so prevents mitosis
- naturally derived
They have multiple versions separated by R group chain
What are the clinical uses of vinca alkaloids (name all 5)
Vincristine = many paediatric and all adult cancers
Vinblastine = lymphomas + solid AD tumours
Vinorelbine = recurrent Non small cell lung cancer
Vindesine = AD solid tumours
Vinflurine = advanced bladder cancer
List vinca alkaloids mechanism of action
○ Binding to microtubule ends
○ Disruption of dynamic instability
○ Disruption of mitotic spindle
Disruption of mitosis causes =
the incomplete separation of duplicate chromosomes = apoptosis
Explain the pharmacokinetics of vinca alkaloids
IV administration
large volume distribution
long terminal half-life (dont cross BBB)
Hepatic metabolism
Faecal elimination
Ouline the toxicities of vinca alkaloids
Neurotoxicity (Vincristine)
Myelosupression (Main toxicity of others)
What are the mechanism of resistance associated with vinca alkaloid
Multidrug resistance
Reversing agents
Give an example of taxanes
Paclitaxel (Taxol)
Docetaxel (Taxotere)
Cabazitaxel
What is the history behind paclitaxel and what are the uses
Widely used in treatment of breast, ovarian and lung cancer
10-Deacetybaccatin III = Isolated from a tree thus supply issues
How was the supply issue of natural taxanes
semisynthesic versions developed
palcitaxel and docetaxel
What is the mechanism of action for palcitaxel
Binding and stabilisation of microtubules = promotes tubulin polymerisation
= Inappropriate structures
= Failure of chromosomes to reach metaphase plate
= G2M blockade
——-> apoptosis
Cells in G2/M may _ when treated with Paclitaxel
may escape and reenter S phase but no mitosis
How does Paclitaxel effect p53/Bcl-2
Independent of p53
May involve inactivation of Bcl-2
Outline the clinical pharmacology of Paclitaxel and its uses
Main uses in ovarians as well as Breast and lung
Formulated in cremophor/ethanol
1-96hr infusion, 3 weekly schedule (175mg/m2) or weekly schedule of (80-100mg/m2)
Metabolised and excreted in bile
How are Paclitaxel metabolised
CYP2C8 and CYP3A4
As Paclitaxel doses increases =
Non-linear increase in plasma concentration
Decreased clearance
Saturable elimination
What is cremophor
a formulation vehicle used to improve solubility of various poorly-water soluble drugs
how does cremophor effect taxanes use
- Concentration rises during infusion
- Critical micellar concentration (Sequesters paclitaxel, Plasma paclitaxel concentration elevated)
What are the toxicity associated with taxanes
Haematotoxicity (dose limiting)
Peripheral neuropathy (numbness in hands/feet)
Hypersensitivity (needs pre-administration corticosteroids + antihistamines)
Alopecia
How do tumour cells become resistant to antimitotics
Multidrug resistance
Tubulin modification
Bcl-2
