Mechanisms of Action of Chemotherapy

Question 1

List 3 cellular responses to DNA damage.

Answer 1

1 - Entry into G0 and repair of the DNA.

2 - Continuation of proliferation.

3 - Apoptosis.

Question 2

How do cancer cells respond differently from normal cells to DNA damage?

Answer 2

• Normal cells enter G0 when DNA damage is detected.
• The nature of cancer cells means that they are unable to enter G0 as they are innately unresponsive to DNA damage due to loss of function of the necessary signalling pathways.
• Therefore a greater-than-normal amount of DNA damage is required for the cell to elicit a response. This amount of DNA damage must be achieved by chemotherapy to cause apoptosis.

Question 3

Describe the mechanism by which the extrinsic signalling pathways lead to apoptosis.

Answer 3

• Apoptotic pathways can be triggered by external signalling molecules that bind to cells via:

1 - Fas receptor.

2 - Tumour necrosis factor receptor (TNFR).

• FADD is involved in mediating the extrinsic response when triggered by a fas receptor.
• TRADD is involved in mediating the extrinsic response when triggered by a TNFR.
• These pathways trigger a final common pathway between intrinsic and extrinsic signalling pathways that is mediated by caspases to cause apoptosis.

Question 4

Describe the mechanism of action of antimetabolites such as 5-fluorouracil.

Answer 4

• It is phosphorylated and methylated in the body to become a pyrimidine mimic.
• This process relies on folate, which is often coadministered with 5-FU.
• It is then incorporated into DNA.
• The fluorine bound to the carbon ring causes DNA damage.

Question 5

List 4 anthracyclines.

What is their mechanism of action?

Answer 5

1 - Doxorubicin.

2 - Daunorubicin.

3 - Idarubicin.

4 - Epirubicin.

• They are topoisomerase II inhibitors.

Question 6

What is the function of topoisomerase II?

Answer 6

To cut both strands of the DNA helix simultaneously in order to manage DNA tangles.

Question 7

List 2 ways by which anthracyclines are eliminated from the body.

Answer 7

1 - They are metabolised by aldoreductases.

2 - They are excreted by the biliary system.

Question 8

List 5 risks of anthracycline use.

Answer 8

1 - Heart failure.

2 - Myelosuppression.

3 - Gastrointestinal disturbances.

4 - Alopecia.

5 - Local tissue damage.

Question 9

Give an example of a drug class other than anthracyclines that act as topoisomerase inhibitors.

Answer 9

Epipodophyllotoxins.

Question 10

List 5 functions of microtubules.

List 2 microtubule inhibitors.

Answer 10

Microtubule functions:

1 - Formation of the mitotic spindle.

2 - Chemotaxis.

3 - Cytoskeleton.

4 - Secretion.

5 - Signalling.

Microtubule inhibitors:

1 - Vinca alkaloids.

2 - Taxanes.

Question 11

Describe the mechanism of action of vinca alkaloids.

Answer 11

They stop assembly and promote disassembly of microtubules by binding with high affinity to the ends and low affinity to the sides of the microtubules.

Question 12

Describe the mechanism of action of taxanes.

Answer 12

They stabilise microtubules, inhibiting dynamic reorganisation.

Question 13

What effect do vinca alkaloids and taxanes have on the cell cycle?

Answer 13

They sustain metaphase / block anaphase.

Question 14

List the tissues that are particularly susceptible to damage by microtubule inhibitors.

Answer 14

1 - Nervous tissue.

2 - Bone marrow.

Question 15

Describe the mechanism of action of alkylating agents.

Answer 15

• The drugs have an R group and a leaving group.
• The leaving group, containing a cytotoxic molecule such as chlorine, is released when the drug absorbs in tissues.
• The leaving group then binds and crosslinks macromolecules to produce cytotoxic effects.
• The R group confers other functions to the drug such as:

1 - Selectivity of DNA binding.

2 - Tissue specificity.

3 - Lipid solubility.

4 - Metabolism.

Question 16

Describe the mechanism of platinum analogues.

Answer 16

The mechanism is the same as alkylating groups, where there is a leaving group and an R group bound centrally by a platinum molecule.

Question 17

List 2 platinum analogues.

Answer 17

1 - Cisplatin.

2 - Carboplatin.

Question 18

List 2 adverse effects of cisplatin.

Answer 18

1 - Hearing loss.

2 - Renal toxicity.

Question 19

What is the purpose of the delay between chemotherapy treatments?

Answer 19

• Damage to non-cancerous tissues by chemotherapy is reversible, as DNA damage will cause non-cancerous tissues to enter G0.
• Time is required for the DNA damage to be repaired and for the non-cancerous tissues to re-enter the cell cycle.

Question 20

List 4 irreversible toxicities that cannot be remediated by delays between chemotherapy treatments.

Answer 20

Damage to slow-growing cells:

1 - Kidney.

2 - Nerves.

3 - Heart.

4 - Lungs.

Question 21

List 5 reversible toxicities that can be remediated by delays between chemotherapy treatments.

Answer 21

Damage to fast-growing cells:

1 - Bone marrow.

2 - GIT.

3 - Germinal epithelium.

4 - Lymphoid tissue.

5 - Hair follicles.

Question 22

List 4 assumptions made in the use of cytotoxic chemotherapy.

List any potential flaws in these assumptions.

Answer 22

1 - Tumour growth proceeds exponentially, independent of growth homeostasis.

• Problem: A proportion of all tumours are non-dividing cells, and the growth fraction may vary as a function of tumour size.

2 - Each dose results in the same proportional log death as log growth.

• Problem: Tumours are heterogeneous, and large tumours are more likely to contain drug resistant cells.
• Problem: The proportional death relates to growth fraction.

3 - The intensity of the dose influences outcome.

4 - Different drugs have different cytotoxic properties.

Question 23

What is the assumption of Gompertzian growth kinetics?

Answer 23

Smaller tumours have a greater proportion of cells that are proliferating.

*This can be seen on a timeline of tumour growth - the rate of growth as a proportion of the total number of cells is greatest at the early stages of growth (growth is logarithmic).

Question 24

What must be true of the population of cells within a tumour to allow the tumour to be completely removed by chemotherapy alone?

How does this affect clinical outcome?

Answer 24

• There cannot be one cell in the population that is resistant to the treatment, as treatment will give it a selective advantage.
• This means that relatively large tumours are much more likely to be uncurable by chemotherapy.

Question 25

List 2 genetic factors that affect sensitivity to 5-fluorouracil.

Answer 25

1 - A promotor polymorphism for the thymidylate synthetase gene.

2 - Level of expression of dihydropyrimidine dehydrogenase.

Question 26

List 3 mechanisms of action of oxaliplatin that relate to immune clearance of cancer cells.

Answer 26

1 - Therapy-induced endoplasmic reticulum stress leads to exposure of calreticulin to the plasma membrane, which acts as an ‘eat me’ signal to dendritic cells.

2 - Induction of apoptosis leads to release of ATP, which acts as a chemoattractant for dendritic cells.

3 - During secondary necrosis (which occurs when apoptotic cells are not cleared by the immune system), the cell membrane becomes permeabilised, leading to the release of HMGB-1. This is recognised by dendritic cells, leading to enhanced dendritic cell activation and antigen presentation.