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Saaliha Part 4 – PM4B > Metals in Medicines > Flashcards

Metals in Medicines Flashcards

1
Q

Metal-based anti-cancer drugs

A
  • Platinum drugs are highly successful
  • 50-70% of cancer cases involve treatment with a platinum drug at some point
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2
Q

The platinums

A
  • Cis-platin
  • Carboplatin
  • Oxaliplatin
  • Nedaplatin
  • Satraplatin
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3
Q

Cis-platin

A

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
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4
Q

Cis-platin MoA

A

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.

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5
Q

Cis-platin target

A
  • 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
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6
Q

Cis-platin toxicity

A

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.

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7
Q

Off-target binding of Cisplatin

A
  • Once administered
  • Undergoes hydrolysis immediately
  • Activated
  • Combines to wide range of chemicals in both protein and DNA
  • Off-target binding leads to serious toxicity
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8
Q

Carboplatin

A
  • 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
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9
Q

Carboplatin MoA

A

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

  • cross links with DNA, preventing transcription.
  • Killing cancer cells
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10
Q

Carboplatin toxicity

A
  • Reduced exchange rate, thus reduced frequency of toxic side-effects.
  • Less toxic than cis-platin.
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11
Q

Why is carboplayin less toxic than cisplatin? Relate to structure

A
  • 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
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12
Q

Nedaplatin

A
  • 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
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13
Q

Nedaplatin toxicity

A
  • Slightly reduced nephrotoxicity, but has no marked advantage.
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14
Q

Oxaliplatin

A
  • 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
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15
Q

Oxaliplatin toxicity

A
  • Lower activity spectrum –> lower toxicity
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16
Q

Satraplatin

A
  • 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)
17
Q

Summary of Platins

A
18
Q

Toxicity Side Effects of Platins

A
  • Increased infection risk
  • Breathlessness, pale
  • Bruising, bleeding gums or nosebleeds
  • Tiredness and weakness during and after treatment
  • Kidney damage
  • Hearing changes
19
Q

Platin drug expectations

A
  • 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
20
Q

Photodynamic Therapy

A

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

21
Q

Phototherapy MoA

A
  1. Compound needs to strongly absorb light e.g. tetrapyrrole
  2. Compound needs to strongly absorb deep-red to NIR light
  3. 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
22
Q

How is a reactive O2 species generated

A
  • 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
23
Q

Tetrapyrrole

A

The basic building block of the porphyrin-class of compounds

24
Q

Drawbacks of PDT agents in large tumour masses

A
  • 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
25
Q

Porphyrin

A

Porphyrin is used in photodynamic therapy to treat cancer and other diseases. It works by using a photosensitizer to create reactive oxygen species that can damage cancer cells.

26
Q

Deep-red to NIR light

A
  • Type of light that can penetrate most strongly in human tissues
  • We want to activate the light in a given area with as little fibre optic introduction as possible
27
Q

How do we stop UV light from being damaging

A
  • Deep-red to NIR light less damaging
  • Decrease intensity/ time of exposure
  • We can radiate for longer but at a lower intensity to activate more of the compound but without damaging tissue
28
Q

Photofrin

A
  • Generic name: porfimer sodium (First generation)
  • UK approval in 1998 for palliative treatment of obstructing oesophageal cancers
  • Administered intravenously
29
Q

Purlytin (Rostaporfin)

A
  • 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

Saaliha Part 4 – PM4B (73 decks)

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