Metallotherapeutics Flashcards
How does cisplatin enter the cell?
(1) Prodrug, converted in vivo
(2) Encounters much lower chloride concentration inside the cell
(3) Removes chloride groups from cisplatin molecule + replaces with water
(4) Reacts with DNA each time it loses a chlorine
What is the target of cisplatin?
DNA
Nitrogen-7 on the adenine/ guanine
How does cisplatin affect the DNA?
Binds to nitrogen-7 on adenine/ guanine
Forms a covalent bond + displaces the water on the cisplatin
Intrastrand cross-links
- either on same strand/ opposite strands
Why is nitrogen-7 in adenine and guanine able to react so easily?
Lone pair of electrons
What is intrastrand linking?
Bridging 2 bases within the same strand
What is interstrand linking?
Bridging 2 bases on multiple DNA strands
More damaging to DNA
What types of toxicity is cisplatin associated with?
- haemotologic toxicity
- ototoxicity
- nephrotoxicity
- neurotoxicity
What is an example of off-target binding of cisplatin?
Ribonuclease A
Causes many side effects
Why is there a need for new platinum drugs?
(1) Cisplatin can have severe side effects
(2) Activity is required against a wider range of cancer types
(3) Cancer cells become resistant to cisplatin after repeated treatment
What is carboplatin?
2nd generation platinum anticancer drug
Less toxic than cisplatin
Chelate rings opens when reacting with water/ chloride ions
Reduced rate of reaction
What is nedaplatin?
New generation platinum anticancer drugs
How are nedaplatin, carboplatin, and cisplatin administered?
IV injection
What is oxaliplatin?
3rd generation platinum anticancer drug
Usually an IV infusion
Less toxicity
How is oxaliplatin usually administered?
IV infusion
with 5-fluorouracil and leucovorin (5-FU/LV)
What is satraplatin?
Can be given orally, only platinum anticancer drug currently able to do this
Prodrug
- removal of acetate groups in vivo give active form
What is the mechanism of action of platinum anticancer drugs?
Crosslinks DNA
What are some benefits of oxaliplatin use, over cisplatin?
Reduced ototoxicity + nephrotoxicity
What is the basis of photodynamic therapy?
Control of activation of the drug using light
To only activate drug in cells/ tissues of a very specific area
Can be used to localise treatment to reduce side-effects
How can photodynamic therapy drugs be administered?
- Topically
- IV
- PO
How long after drug administration is light used to activate the drug, in photodynamic therapy?
2-3 days later
What is a side effect of photodynamic therapy?
Damages the cells exposed to the laser light
What is important when designing a drug that can be used in photodynamic therapy?
(1) Compounds needs to strongly absorb light
- e.g. tetrapyrrole (porphyrins)
(2) Needs to absorb deep-red to near infrared (NIR) light
(3) Needs to cause damage/ generate something that can cause damage when light is absorbed
What is tetrapyrrole?
Basic building block of porphyrins?
Compound that strongly absorbs light
- often used in photodynamic therapy
Why is deep-red to near-infrared (NIR) light useful in photodynamic therapy?
Penetrates furthest through tissue
What is the significance of alternating single and double bonds in photodynamic therapy?
Very good for absorbing light
What is current photodynamic therapy used to convert in cells?
Oxygen to singlet oxygen, from cellular oxygen
Singlet oxygen is an ultra-reactive species
What is Photofrin?
Branded porfimer sodium
Used for palliative treatment of oesophageal cancers
Selectively accumulates in cancerous tissue
Describe the structure of Photofrin.
Polymer chain of porphyrin units (up to 6)
What is a benefit of Photofrin over anticancer platinum-containing compounds?
Does not cause kidney damage
nephrotoxicity
What is Purlytin?
2nd generation photodynamic therapy compound
Tin atom at centre of porphyrin
Monomer
What is a PDT compound?
Photodynamic Therapy drug
Used 2-3 days before being activated by light
