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Biology of Cancer SSC > Platinum Compound Chemotherapy > Flashcards

Platinum Compound Chemotherapy Flashcards

1
Q

How is cisplatin activated?

A

Intracellularly by displacement of the 2 Cl- by water molecules (aquation)

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2
Q

How does aquation activate cisplatin?

A

Makes it a potent electrophile

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3
Q

What does the activated cisplatin then do?

A

Covalently binds to DNA to form DNA adducts

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4
Q

What do DNA adducts cause?

A

Distortion of the DNA

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5
Q

What does DNA distortion cause?

A

Impaired replication and transcription

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6
Q

In which 2 cancers is cisplatin especially effective?

A

Ovarian and testicular

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7
Q

Where is cisplatin especially toxic to?

A
  • Kidneys

- GI tract

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8
Q

How is the nephrotoxicity combatted in cisplatin use?

A

With aggressive pre-hydration techniques

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9
Q

How does carboplatin compare to cisplatin?

A

Carboplatin is less toxic with similar ant-cancer activity

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10
Q

What is a dose-limiting side effect for carboplatin?

A

Thrombocytopenia

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11
Q

Can tumour cells be intrinsicly resistant to cisplatin?

A

Yes

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12
Q

Which cancer can be hypersensitive to cisplatin?

A

Testicular cancer

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13
Q

What 2 problems lead to intrisic resistance to cisplatin?

A
  1. Failure of enough platinum to reach the DNA

2. Failure to achieve cell death after adduct formation

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14
Q

What 3 resistance phenotypes can tumour cells have?

A
  1. Altered drug uptake
  2. DNA damage recognition and repair upregulated
  3. Altered apoptosis pathways
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15
Q

What can influence the uptake of cisplatin into a cell?

A
  • [K+]
  • [Na+]
  • pH
  • Presence of reducing agents
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16
Q

Which plasma membrane transporter has an important role in cisplatin influx?

A

CTR1 (Copper transporter - copper and platinum make similar complexes as they are both d block metals)

17
Q

What can loss of the CTR1 lead to?

A

2-3 fold increase in resistance

18
Q

Which mechanism of resistance predominates in platinum drug resistance?

A

Decreased uptake i.e. CTR1 gets downregulated, especially in ovarian cancers

19
Q

What species presence in the cytoplasm has been suggested as a cause of resistance?

A

Thiol-containing species

20
Q

How do thiol-containing species cause cisplatin/carboplatin resistance?

A

Detoxification occurs as the sulphur residues bind to the Platinum

21
Q

What is the major pathway by which cisplatin lesions are removed from DNA?

A

Nucleotide excision repair

22
Q

Loss of which DNA repair pathway can lead to increased platinum-damage tolerance?

A

Mismatch repair

23
Q

What 4 methods have been suggested to avoid platinum drug resistance in cancer patients?

A
  1. Improved platinum drugs
  2. Improved platinum drug delivery
  3. Co-administration with modulators of resistance mechanisms
  4. Combination therapy with new molecularly targeted drugs
24
Q

Which platinum compound seems less dependant on CTR1?

A

Oxaliplatin

25
Q

What is another benefit of oxaliplatin?

A

Mismatch repair proteins don’t recognise oxaliplatin-induced adducts resistance less likely

26
Q

What is oxaliplatin used in combination with to achieve a good level of activity?

A

5-FU (antimetabolite)

27
Q

What is the dose limiting toxicity with oxaliplatin and 5-FU?

A

Cumulative sensory neuropathy

28
Q

Which drug was developed to be an orally active version of carboplatin?

A

Satraplatin

29
Q

Which 2 drugs are currently active against cisplatin-resistant cells?

A

Satraplatin and Picoplatin

30
Q

How is Picoplatin able to be more resistant to resistance?

A

Bulkier around the central platinum so less likely to be deactivated by thiol-containing species

31
Q

Has delivery of a platinum drug in a vehicle selectively to a cancer cell been trialled clinically?

A

Yes

32
Q

Why didn’t it have quite so high anti-tumour activity (suggested)?

A

Platinum has to be delivered in its inactive form so release and activation has to be achieved inside the cell - not optimum

Biology of Cancer SSC (16 decks)

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