Platinum Compound Chemotherapy Flashcards
How is cisplatin activated?
Intracellularly by displacement of the 2 Cl- by water molecules (aquation)
How does aquation activate cisplatin?
Makes it a potent electrophile
What does the activated cisplatin then do?
Covalently binds to DNA to form DNA adducts
What do DNA adducts cause?
Distortion of the DNA
What does DNA distortion cause?
Impaired replication and transcription
In which 2 cancers is cisplatin especially effective?
Ovarian and testicular
Where is cisplatin especially toxic to?
- Kidneys
- GI tract
How is the nephrotoxicity combatted in cisplatin use?
With aggressive pre-hydration techniques
How does carboplatin compare to cisplatin?
Carboplatin is less toxic with similar ant-cancer activity
What is a dose-limiting side effect for carboplatin?
Thrombocytopenia
Can tumour cells be intrinsicly resistant to cisplatin?
Yes
Which cancer can be hypersensitive to cisplatin?
Testicular cancer
What 2 problems lead to intrisic resistance to cisplatin?
- Failure of enough platinum to reach the DNA
2. Failure to achieve cell death after adduct formation
What 3 resistance phenotypes can tumour cells have?
- Altered drug uptake
- DNA damage recognition and repair upregulated
- Altered apoptosis pathways
What can influence the uptake of cisplatin into a cell?
- [K+]
- [Na+]
- pH
- Presence of reducing agents
Which plasma membrane transporter has an important role in cisplatin influx?
CTR1 (Copper transporter - copper and platinum make similar complexes as they are both d block metals)
What can loss of the CTR1 lead to?
2-3 fold increase in resistance
Which mechanism of resistance predominates in platinum drug resistance?
Decreased uptake i.e. CTR1 gets downregulated, especially in ovarian cancers
What species presence in the cytoplasm has been suggested as a cause of resistance?
Thiol-containing species
How do thiol-containing species cause cisplatin/carboplatin resistance?
Detoxification occurs as the sulphur residues bind to the Platinum
What is the major pathway by which cisplatin lesions are removed from DNA?
Nucleotide excision repair
Loss of which DNA repair pathway can lead to increased platinum-damage tolerance?
Mismatch repair
What 4 methods have been suggested to avoid platinum drug resistance in cancer patients?
- Improved platinum drugs
- Improved platinum drug delivery
- Co-administration with modulators of resistance mechanisms
- Combination therapy with new molecularly targeted drugs
Which platinum compound seems less dependant on CTR1?
Oxaliplatin
What is another benefit of oxaliplatin?
Mismatch repair proteins don’t recognise oxaliplatin-induced adducts resistance less likely
What is oxaliplatin used in combination with to achieve a good level of activity?
5-FU (antimetabolite)
What is the dose limiting toxicity with oxaliplatin and 5-FU?
Cumulative sensory neuropathy
Which drug was developed to be an orally active version of carboplatin?
Satraplatin
Which 2 drugs are currently active against cisplatin-resistant cells?
Satraplatin and Picoplatin
How is Picoplatin able to be more resistant to resistance?
Bulkier around the central platinum so less likely to be deactivated by thiol-containing species
Has delivery of a platinum drug in a vehicle selectively to a cancer cell been trialled clinically?
Yes
Why didn’t it have quite so high anti-tumour activity (suggested)?
Platinum has to be delivered in its inactive form so release and activation has to be achieved inside the cell - not optimum
