Metals in Medicines

Question 1

Metal-based anti-cancer drugs

Answer 1

• Platinum drugs are highly successful
• 50-70% of cancer cases involve treatment with a platinum drug at some point

Question 2

The platinums

Answer 2

• Cis-platin
• Carboplatin
• Oxaliplatin

Question 3

Cis-platin

Answer 3

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

Question 4

Cis-platin MoA

Answer 4

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.

Question 5

Cis-platin target

Answer 5

• Targets primarily guanine but adenine aswell
• Can only bind to purine
• For both of these bases it binds at the same position

Question 6

Cis-platin toxicity

Answer 6

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.

Question 7

Carboplatin

Answer 7

• 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

Question 8

Carboplatin MoA

Answer 8

Carboplatin + water and chloride ions –> chelate ring opening and activation of carboplatin.

Question 9

Carboplatin toxicity

Answer 9

• Reduced exchange rate, thus reduced frequency of toxic side-effects.
• Less toxic than cis-platin.

Question 10

Nedaplatin

Answer 10

• Registered for head and neck, testicular, ovarian, lung and cervical cancer.
• Cross-resistant with cis-platin
• Administration route: i/v injection

Question 11

Nedaplatin toxicity

Answer 11

• Slightly reduced nephrotoxicity, but has no marked advantage.

Question 12

Oxaliplatin

Answer 12

• 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

Question 13

Oxaliplatin toxicity

Answer 13

• Lower activity spectrum –> lower toxicity

Question 14

Satraplatin

Answer 14

• Only platinum drug to be active by oral administration
• Has successfully finished Phase 3 clinical trials against hormone-refractory prostate cancer.
• 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)

Question 15

Summary of Platins

Answer 15

Question 16

Toxicity Side Effects of Platins

Answer 16

• Increased infection risk
• Breathlessness, pale
• Bruising, bleeding gums or nosebleeds
• Tiredness and weakness during and after treatment
• Kidney damage
• Hearing changes

Question 17

Platin drug expectations

Answer 17

• 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

Question 18

Photodynamic Therapy

Answer 18

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

Question 19

Phototherapy MoA

Answer 19

1. Compound needs to strongly absorb deep-red to NIR light
2. 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

Question 20

How is a reactive O2 species generated

Answer 20

• 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

Question 21

Tetrapyrrole

Answer 21

The basic building block of the porphyrin-class of compounds

Question 22

Porphyrin

Answer 22

• Used in photodynamic therapy to treat cancer and other diseases.
• Uses a photosensitizer to create reactive oxygen species that can damage cancer cells.

Question 23

Deep-red to NIR light

Answer 23

• Penetrates most strongly in human tissues
• We want to activate the light in a given area with as little fibre optic introduction as possible

Question 24

How do we stop UV light from being damage

Answer 24

• Deep-red to NIR light less damaging
• Decrease intensity/ time of exposure
• We can radiate for long but at a lower intensity to activate more of the compound but without damaging tissue

Question 25

Photofrin

Answer 25

• Generic name: porfimer sodium (First generation)
• UK approval in 1998 for palliative treatment of obstructing oesophageal cancers
• Administered intravenously

Question 26

Purlytin (Rostaporfin)

Answer 26

• Second generation compound
• Has reached phase III clinical trials for macular degeneration
• Phase II/III trials for cutaneous metastatic breast cancer, phase II for prostate cancer
• Administered i/v injection