2.1 Mode of action of cytotoxic drugs

Question 1

What are the mechanisms of drug resistance?

Answer 1

• Avoidan
• Multidrug efflux pumps
• Reduced drug uptake
• Reduced drug activation
• Increased drug inactivation
• Increased DNA repair
• Change in drug target

Question 2

How do efflux pumps cause drug resistance?

Answer 2

Pumps e.g. P-gp or MRPs recognise and bind to drugs and pump them out of the cell

e.g. vinca alakloids, antrhacyclines

Question 3

What is an example of reduced drug uptake?

Answer 3

Point mutation in RFC-1 reduces methotrexate uptake into cell

Question 4

What is an example of reduced drug activation?

Answer 4

reduced uridine kinase leads to 5-FU resistance

Question 5

What is an example of increased drug activation?

Answer 5

Increased DPD expression causing 5-FU degredation (inactivation)

Question 6

What strategies can optimise efficacy of cytotoxic chemotherapy?

Answer 6

1. Radiosensitisation
2. Drugs with different parts of cell cycle (R-CHOP)
3. Reduce toxicity of individual drugs e.g. bolus and infusional 5-FU prevents mucositis and neutropenia
4. Use multiple drugs with different side effects to avoid cumulative tox
5. Prophylaxis for infections
6. Scheduling
   - refular intervals to ensure BM recovery
   - use supportive medications to avoid dose reductions - especially if curable