Cispaltin And Analogues

Question 1

What is the mechanism of action for cisplatin and its analogues

Answer 1

Formation of platinum-DNA adducts
Activate various signal transactions pathways

Involve cross-linking of 2 nucleotides

Question 2

What 2 nucleotides are usually affected by cisplatin and its analogues

Answer 2

Guanine and adenine

Question 3

What is the mechanism of action for cisplatin

Answer 3

Kill tumour cells as a direct consequence of the damage caused by their reaction w DNA
Correlated closely with covalent binding to nuclear DNA

Question 4

What do the most active platinum compounds have in common

Answer 4

2 labels bonds to platinum atom
= can from 2 bonds w cellular target molecules

Question 5

What is the metabolism of cisplatin

Answer 5

Cisplatin -> squealed platinum complex -> DNA cross links

Question 6

What is the rate limiting step in the reaction of platinum

Answer 6

Intracellular hydrolysis

Question 7

Describe the metabolism of carboplatin

Answer 7

Carboplatin -> monofunctional adduct -> bifunctional adduct

Question 8

Why does carboplatin have a lower interaction with DNA compared to cisplatin

Answer 8

Due to the slow loss of the second arm of the bidentate ligand

Question 9

What is the major difference bwteeen cisplatin and carboplatin

Answer 9

Kinetics of adduct formation not the nature of the reaction with DNA

Question 10

What is the most common type of cisplatin adduct formation

Answer 10

Intrastrand cross links
Less than 10% interstrand and DNA-protein cross-links

Question 11

Why are testicular cancer cells limes hypersensitive to cisplatin

Answer 11

Reduced DNA-repair activity in response to adducts
Low constitutive nucleotide excision repair pathway
Low DNA repair capability = cisplatin induced apoptosis

Question 12

What are the two classes of resistance to platinum agents

Answer 12

Reduced access of drug to target DNA i.e decreased uptake into cells, changes in tumour vasculature
Increased repair or tolerance of DNA damage

Question 13

What is the mechanism of resistance to cisplatin when there is insufficient DNA binding

Answer 13

Related to decreased drug uptake by CTR1
Increased levels of cytoplasmic thiol-containing species

Question 14

What is the mechanism of resistance to cisplatin when there is resistance mediated after DNA binding

Answer 14

Increased DNA-repair capacity
Increased tolerance to platinum-induced DNA damage through loss of MMR pathway = decreased apoptosis
Decreased expression of apoptotic signalling pathway

Question 15

What is the DNA-repair pathways that is known to remove cisplatin lesions from DNA

Answer 15

Nucleotide - excision repair (NER)

Question 16

How can the influx and efflux of cisplatin in tumour cells be affected

Answer 16

Influx: CTR1
Efflux: ATP7a/b

Question 17

What are the different strategies used to circumvent cisplatin resistance

Answer 17

Increased delivery of platinum to the tumour
Platinum resistance modulators
Combination of platinum drugs with molecularly targeted agents
Novel platinum drugs targeting resistance mechanism

Question 18

What have in vitro studies shown to be the major cause of cisplatin resistance

Answer 18

Reduced drug uptake

Question 19

What malignancies can cisplatin be used to treat

Answer 19

Germ cell tumours
Ovarian cancers
Head and neck cancers
Bladder cancers
Childhood cancers

Question 20

What are some severe acute and long-term toxicities of cisplatin

Answer 20

Nephrotoxicity
Neurotoxicity
Ototoxicity
Nausea and vomiting

Question 21

What malignancies can carboplatin be used to treat

Answer 21

Germ cell tumours
Ovarian cancers
Childhood cancers
High dose chemotherapy regimes

Question 22

What are some of the severe acute and long-term toxicities of carboplatin

Answer 22

Haematological toxicities e.g thrombocytopenia and neutropenia
Nausea and vomiting

Question 23

What does measuring ultrafilterable platinum show

Answer 23

Non-protein bound platinum species with anti tumour and toxic properties

Question 24

What does measuring the total platinum show

Answer 24

Protein bound and ultrafilterable platinum species

Question 25

How are platinum compounds usually administered

Answer 25

IV infusion with variable infusion times

Question 26

Describe the current approaches to carboplatin dosing

Answer 26

Renal function based carboplatin dosing
Almost all drug elimination via kidenys
Rest remains protein bound

Question 27

What is the formula used to calculate dose of carboplatin to achieve a particular exposure

Answer 27

Total dose = target AUC x (GFR + 25)

Target AUC values commonly 5-7mg/ml.min

Question 28

Name 4 alternative platinum complexes

Answer 28

Oxaliplatin
Satraplatin
Picoplatin
BBR3464

Question 29

Describe oxaliplatin

Answer 29

Superior anti-tumour effect and reduced toxicity vs cisplatin
Lack of cross-resistance w other Pt agents

Neurotoxicity and nausea/vomiting

Question 30

Describe satraplatin

Answer 30

Oral administration
Comparable activity w carboplatin/cisplatin
Lack off cross resistance w cisplatin
Reduced inactivation by thiol containing species

No nephro/neurotoxicity

Question 31

Describe picoplatin

Answer 31

First oral and IV drug
Activity in carboplatin/cisplatin resistant tumours
Steric hindrance to inactivation by thiol-containing species

Myelosuppresion

Question 32

Describe BBR3436

Answer 32

Adducts formed may be less susceptible to repair i.e persist longer than those formed by cisplatin
Activity in tumours resistant to cisplatin