Metals in Medicines: Cisplatin

Question 1

What is cisplatin?

Answer 1

platinum based drug

50% of all chemotherapeutic regimes used a platinum based drug

PtCl₂(NH₃)₂

Question 2

Why is cisplatin used instead of transplatin?

Answer 2

transplatin is not cytotoxic

cisplatin (both Cl on same side) and binds to DNA

Nitrogen from DNA can bind to the same side

Question 3

Why does hydrolysis of cisplatin occur?

Answer 3

required for it to bind to DNA in nucleus

occurs in cytoplasm as less Cl in cytoplasm

if it happens earlier, its too reactive and will bind to proteins in cell

Question 4

What co transporter allows cisplatin into DNA cells?

Answer 4

CTR1

Question 5

What does cisplatin bind to to leave cell?

Answer 5

binds to MRP2 by glutathione

or leaves via ATP7A/ ATP7B

Question 6

What is cisplatin administered with and why?

Answer 6

NaCl to keep the Cl bound

if not administered with this, cisplatin hydrolyses and will bind to proteins in cytosol leading to deactivation

Question 7

What are the two resistance mechanisms of cisplatin?

Answer 7

inherent: lack of sensitivity - tumour doesnt respond

acquired: development of cellular detoxification mechanisms

• increased efflux - more glutathione, more cisplatin binding to MRP2, less cisplatin binding to DNA
• decreased efflux - downregulation of CTR1, less cisplatin in cell
• enhanced DNA repair - repair DNA damage

Question 8

What are other platinum drugs for cancer and what do they all contain?

Answer 8

carboplatin, oxaliplatin, nedaplatin

• 2 nitrogen ligands
• 2 oxygen ligands, can be removed by hydrolysis
  
  • oxygens are linked so less hydrolysis so more time for drug to reach nuclei and exert activity

Question 9

What are unwanted side effects of cisplatin?

Answer 9

• nephrotoxicity
• hepatic malfunction
• ototoxicity