Metals in Medicines Flashcards
Metal-based anti-cancer drugs
- Platinum drugs are highly successful
- 50-70% of cancer cases involve treatment with a platinum drug at some point
The platinums
- Cis-platin
- Carboplatin
- Oxaliplatin
- Nedaplatin
- Satraplatin
Cis-platin
One of the most prolific anti-cancer drugs
Effective therapeutic agent in cancers:
○ Ovarian
○ Testicular
○ Uterus
○ Bladder and head and neck
- Administration route: I/v injection
Cis-platin MoA
1) Cisplatin is inactive and enters the body
2) In the extracellular environment, Cl conc is high and in the intracellular environment Cl conc is low
3) Cl diffuses into the cell from high to low conc
4) Hydrolysis - one Cl is lost and replaced with H2O
5) Compound is now active and can react with DNA
6) Forms two types of cross links with DNA and prevents transcription
- within the same DNA strand (intra)
- between two different strands of DNA helix (inter)
7) DNA damage occurs
Want to form as many cross-links as possible to cause cell death.
Cis-platin target
- N7 atom in purine (A,G) bases
- Primarily G
- For both of these bases it binds at the same position
- N atom contains lone pair which reacts with Pt and displace a water molecule from the Pt
- Both water molecules will be be displaced and Pt will bind to two bases within DNA, cross linking it, inhibiting transcription
Cis-platin toxicity
Cis-platinum is highly toxic:
○ Hematologic toxicity
○ Ototoxicity
○ Nephrotoxicity
○ Neurotoxicity
Once administered it binds to a wide variety of groups within protein and DNA (off-target binding).
Causes severe toxicity.
Off-target binding of Cisplatin
- Once administered
- Undergoes hydrolysis immediately
- Activated
- Combines to wide range of chemicals in both protein and DNA
- Off-target binding leads to serious toxicity
Carboplatin
- Second generation Pt anti-cancer drug
- Wide activity profile.
- Effective against many solid tumours.
- Administration route: i/v injection
- Carboplatin activation is much slower that cis-platin
Carboplatin MoA
Carboplatin + water and chloride ions –> chelate ring opening and activation of carboplatin.
- cross links with DNA, preventing transcription.
- Killing cancer cells
Carboplatin toxicity
- Reduced exchange rate, thus reduced frequency of toxic side-effects.
- Less toxic than cis-platin.
Why is carboplayin less toxic than cisplatin? Relate to structure
- Main difference = organic group that replaces chlorides
- Organic group is removed far less quickly in carboplatin by hydrolysis
- Exchange rate is reduced = less off-target binding = less toxic SFx
Nedaplatin
- Registered for head and neck, testicular, ovarian, lung and cervical cancer.
- Cross-resistant with cis-platin
- Exchnage rate slower = activation slower = less off-target binding
- Administration route: i/v injection
Nedaplatin toxicity
- Slightly reduced nephrotoxicity, but has no marked advantage.
Oxaliplatin
- Third generation
- Usually administered as a combination infusion with 5-fluorouracil and leucovorin (5-FU/LV).
- Initially approved for use in the treatment of metastatic carcinoma of the colon or rectum
Oxaliplatin toxicity
- Lower activity spectrum –> lower toxicity
Satraplatin
- Only platinum drug to be active by oral administration
- Has successfully finished Phase 3 clinical trials against hormone-refractory prostate cancer.
- Cisplatin and carboplatin have Pt (II) at their core whilst Satra has Pt (IV)
- Pt(IV) complexes can be readily reduced in vivo to Pt(II) by reductants such as ascorbate or thiols (e.g. cysteine, glutathione).
- Pro-drug (removal of acetate groups in vivo to give active form)
Summary of Platins
Toxicity Side Effects of Platins
- Increased infection risk
- Breathlessness, pale
- Bruising, bleeding gums or nosebleeds
- Tiredness and weakness during and after treatment
- Kidney damage
- Hearing changes
Platin drug expectations
- Soluble in blood
- Interact with its target in a therapeutically useful way
- Low (or tolerable) toxicity (low off-target binding)
- Accumulates in affected cells (either specifically or with selectivity)
- Controllable through external influence: control activation with light
Photodynamic Therapy
1) Drug is administered (either topically, intravenously or orally)
2) Wait time usually 2-3 days: allow compound to distribute to tissues within the body
3) Drug is activated in specific cancerous area using intense laser light
4) Cells are damaged/destroyed in area exposed to light
5) Other cells aren’t affected, reducing toxicity making it somewhat selective
6) Remaining drug is excreted
Phototherapy MoA
- Compound needs to strongly absorb light e.g. tetrapyrrole
- Compound needs to strongly absorb deep-red to NIR light
- Electronics of compound need to either cause damage OR generate something else which can cause damage, when light is absorbed e.g. reactive oxygen species
How is a reactive O2 species generated
- Current PDT agents generate singlet oxygen from cellular oxygen:
1. The energy from the light that has been absorbed is transferred to an oxygen in the surrounding tissue
2. Transfer of energy causes the oxygen to become excited
3. Forms reactive oxygen species (singlet oxygen)
4. Can cause damage to cancer cells and lead to their death
Tetrapyrrole
The basic building block of the porphyrin-class of compounds
Drawbacks of PDT agents in large tumour masses
- Need O2 within cells to work
- large tumour masses contain very low concentrations of oxygen at their core
- Agents far less effective in large tumour masses than in surface cancers
