Cispaltin And Analogues Flashcards
What is the mechanism of action for cisplatin and its analogues
Formation of platinum-DNA adducts
Activate various signal transactions pathways
Involve cross-linking of 2 nucleotides
What 2 nucleotides are usually affected by cisplatin and its analogues
Guanine and adenine
What is the mechanism of action for cisplatin
Kill tumour cells as a direct consequence of the damage caused by their reaction w DNA
Correlated closely with covalent binding to nuclear DNA
What do the most active platinum compounds have in common
2 labels bonds to platinum atom
= can from 2 bonds w cellular target molecules
What is the metabolism of cisplatin
Cisplatin -> squealed platinum complex -> DNA cross links
What is the rate limiting step in the reaction of platinum
Intracellular hydrolysis
Describe the metabolism of carboplatin
Carboplatin -> monofunctional adduct -> bifunctional adduct
Why does carboplatin have a lower interaction with DNA compared to cisplatin
Due to the slow loss of the second arm of the bidentate ligand
What is the major difference bwteeen cisplatin and carboplatin
Kinetics of adduct formation not the nature of the reaction with DNA
What is the most common type of cisplatin adduct formation
Intrastrand cross links
Less than 10% interstrand and DNA-protein cross-links
Why are testicular cancer cells limes hypersensitive to cisplatin
Reduced DNA-repair activity in response to adducts
Low constitutive nucleotide excision repair pathway
Low DNA repair capability = cisplatin induced apoptosis
What are the two classes of resistance to platinum agents
Reduced access of drug to target DNA i.e decreased uptake into cells, changes in tumour vasculature
Increased repair or tolerance of DNA damage
What is the mechanism of resistance to cisplatin when there is insufficient DNA binding
Related to decreased drug uptake by CTR1
Increased levels of cytoplasmic thiol-containing species
What is the mechanism of resistance to cisplatin when there is resistance mediated after DNA binding
Increased DNA-repair capacity
Increased tolerance to platinum-induced DNA damage through loss of MMR pathway = decreased apoptosis
Decreased expression of apoptotic signalling pathway
What is the DNA-repair pathways that is known to remove cisplatin lesions from DNA
Nucleotide - excision repair (NER)
How can the influx and efflux of cisplatin in tumour cells be affected
Influx: CTR1
Efflux: ATP7a/b
What are the different strategies used to circumvent cisplatin resistance
Increased delivery of platinum to the tumour
Platinum resistance modulators
Combination of platinum drugs with molecularly targeted agents
Novel platinum drugs targeting resistance mechanism
What have in vitro studies shown to be the major cause of cisplatin resistance
Reduced drug uptake
What malignancies can cisplatin be used to treat
Germ cell tumours
Ovarian cancers
Head and neck cancers
Bladder cancers
Childhood cancers
What are some severe acute and long-term toxicities of cisplatin
Nephrotoxicity
Neurotoxicity
Ototoxicity
Nausea and vomiting
What malignancies can carboplatin be used to treat
Germ cell tumours
Ovarian cancers
Childhood cancers
High dose chemotherapy regimes
What are some of the severe acute and long-term toxicities of carboplatin
Haematological toxicities e.g thrombocytopenia and neutropenia
Nausea and vomiting
What does measuring ultrafilterable platinum show
Non-protein bound platinum species with anti tumour and toxic properties
What does measuring the total platinum show
Protein bound and ultrafilterable platinum species
