Antimitotics

Question 1

What is the process of mitosis

Answer 1

• Dynamic microtubules bind to chromosomes (metaphase plate)
• Chromosomes move towards spindle poles
  ——-> cells divide

Question 2

Explain tubulin assembly

Answer 2

a- and b- tubulin (dimeric subunits)
-> heterodimers form a protofilaments which then forms microtubules
Its a dynamic process

Question 3

List microtubular function

Answer 3

• Generate the mitotic spindle = (Essential for separation of chromosomes during mitosis)
• Provide cell microstructure
• Neurochemical signalling
• Angiogenesis

Question 4

How are antimitotic drugs classified

Answer 4

Traditional broad classifications:
○ Microtubule destabilising agents
○ Microtubule stabilising agents

Question 5

How do microtubule destabilising agents work

Answer 5

Drugs that inhibit microtubule polymerisation by binding to tubulin - either by binding at vinca site of tubulin or the colchicine site

Question 6

How do microtubule stabilising agents work

Answer 6

inhibit depolymerisation
by binding at the taxane site of tubulin
(Taxanes)

Question 7

What are vinca alkaloids and how do they work

Answer 7

• binds to tubulin so prevents mitosis
• naturally derived
  They have multiple versions separated by R group chain

Question 8

What are the clinical uses of vinca alkaloids (name all 5)

Answer 8

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

Question 9

List vinca alkaloids mechanism of action

Answer 9

○ Binding to microtubule ends
○ Disruption of dynamic instability
○ Disruption of mitotic spindle

Question 10

Disruption of mitosis causes =

Answer 10

the incomplete separation of duplicate chromosomes = apoptosis

Question 11

Explain the pharmacokinetics of vinca alkaloids

Answer 11

IV administration
large volume distribution
long terminal half-life (dont cross BBB)
Hepatic metabolism
Faecal elimination

Question 12

Ouline the toxicities of vinca alkaloids

Answer 12

Neurotoxicity (Vincristine)
Myelosupression (Main toxicity of others)

Question 13

What are the mechanism of resistance associated with vinca alkaloid

Answer 13

Multidrug resistance
Reversing agents

Question 14

Give an example of taxanes

Answer 14

Paclitaxel (Taxol)
Docetaxel (Taxotere)
Cabazitaxel

Question 15

What is the history behind paclitaxel and what are the uses

Answer 15

Widely used in treatment of breast, ovarian and lung cancer
10-Deacetybaccatin III = Isolated from a tree thus supply issues

Question 16

How was the supply issue of natural taxanes

Answer 16

semisynthesic versions developed
palcitaxel and docetaxel

Question 17

What is the mechanism of action for palcitaxel

Answer 17

Binding and stabilisation of microtubules = promotes tubulin polymerisation
= Inappropriate structures
= Failure of chromosomes to reach metaphase plate
= G2M blockade
——-> apoptosis

Question 18

Cells in G2/M may _ when treated with Paclitaxel

Answer 18

may escape and reenter S phase but no mitosis

Question 19

How does Paclitaxel effect p53/Bcl-2

Answer 19

Independent of p53
May involve inactivation of Bcl-2

Question 20

Outline the clinical pharmacology of Paclitaxel and its uses

Answer 20

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

Question 21

How are Paclitaxel metabolised

Answer 21

CYP2C8 and CYP3A4

Question 22

As Paclitaxel doses increases =

Answer 22

Non-linear increase in plasma concentration
Decreased clearance
Saturable elimination

Question 23

What is cremophor

Answer 23

a formulation vehicle used to improve solubility of various poorly-water soluble drugs

Question 24

how does cremophor effect taxanes use

Answer 24

• Concentration rises during infusion
• Critical micellar concentration (Sequesters paclitaxel, Plasma paclitaxel concentration elevated)

Question 25

What are the toxicity associated with taxanes

Answer 25

Haematotoxicity (dose limiting)
Peripheral neuropathy (numbness in hands/feet)
Hypersensitivity (needs pre-administration corticosteroids + antihistamines)
Alopecia

Question 26

How do tumour cells become resistant to antimitotics

Answer 26

Multidrug resistance
Tubulin modification
Bcl-2