Platinum Anticancer drugs Flashcards
How is cisplatin synthesised?
PtCl4 –> PtI4 –> PtI3NH3 –> PtI2(NH3)2 –> Pt(H2O)2(NH3)2 –> PtCl2(NH3)2
How is the trans effect involved in the synthesis of cisplatin?
Second addition of NH3 adds cis to the initial one. This is because iodine is more trans directing than ammonia.
How is cisplatin activated?
Hydrolysis of Pt-Cl bond is key - this gives Pt- hydroxide ligands which easily fall off to allow it to bind to DNA.
What are the methods of cellular uptake?
Two main methods to know: passive uptake via diffusion and active uptake (requires energy) by membrane changes
What does cisplatin target and what is its mode of action?
Cisplatin targets DNA by binding to N7 on guanine forming 1,2-intrastrand crosslinks. This disables DNA replication, leading to cell apoptosis.
How can cells develop resistance to cisplatin?
Cells have developed repair enzymes which can remove cisplatin from DNA or techniques to remove cisplatin from cells before binding occurs.
How can we overcome cellular resistance to cisplatin?
By using other drugs or tweaking the drug to overcome resistance by being less recognisable to cells.
What are the advantages of other similar Pt drugs like carboplatin and oxaliplatin?
Use of chelating and bulk ligands reduces rate of ligand exchange and can block paths for incoming nucleophiles (potentially reduces off-target activity). Oxaliplatin, in addition, forms inter-strand crosslinks and creates a smaller kink in DNA that is less detectable to cellular systems. Oxaliplatin may overcome resistance to cisplatin.
How can we measure DNA binding?
Usage of electrophoresis gels. sc-DNA added to varying amounts of drug. Drug changes mobility of sc-DNA and so moves different amounts up gel. NB. drug likely to break DNA up a bit so expected to move further.
Where do side effects arise from in the case of cisplatin?
Only a small amount of cisplatin makes it to the DNA. Side effects occur from the binding of cisplatin in other places in the body, generally related to hydrolysis of cisplatin in bloodstream. Dosage needs to be kept relatively small.
