L08 - Chemotherapy Mechanisms of Action

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

What is the mechanism of action of anti-metabolites?

Give an example.

Answer 3

• e.g. 5-fluorouracil (5-FU)
• 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 4

List 4 anthracyclines.

What is their mechanism of action?

Answer 4

1 - Doxorubicin

2 - Daunorubicin

3 - Idarubicin

4 - Epirubicin

• They are topoisomerase II inhibitors

Question 5

What is the function of topoisomerase II?

Answer 5

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

Question 6

How are anthracyclines eliminated from the body?

Answer 6

1 - They are metabolised by aldoreductases

2 - They are excreted by the biliary system

Question 7

What are the risks of anthracycline use?

Answer 7

1 - Cardiotoxicity

2 - Myelosuppression

3 - GI disturbances

4 - Alopecia

5 - Local tissue damage

Question 8

What drug classes act as topoisomerase II inhibitors?

Answer 8

• Anthracyclines

- Epipodophyllotoxins

Question 9

What are the functions of microtubules?

Answer 9

1 - Formation of the mitotic spindle

2 - Chemotaxis

3 - Cytoskeleton

4 - Secretion

5 - Signalling

Question 10

List 2 microtubule inhibitors.

Answer 10

1 - Vinca alkaloids

2 - Taxanes

Question 11

What is 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

What is 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

What tissues are particularly susceptible to damage by microtubule inhibitors?

Answer 14

1 - Nervous tissue

2 - Bone marrow

Question 15

What is the mechanism of action of alkylating agents?

Answer 15

• Act by covalently binding to charged nucleophiles in DNA & RNA, affecting DNA replication, repair & transcription
• Selectivity determined by alkyl carbonium ion & pharmacokinetic properties by R group

Question 16

What is the mechanism of action 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

What is the purpose of the delay between chemotherapy cycles?

Answer 17

To allow repopulation of compartments of rapidly dividing cells by stem cells

Question 18

Which irreversible toxicities cannot be remediated by delays between chemotherapy treatments?

Answer 18

• Kidneys
• Nerves
• Heart
• Lungs

Question 19

Which reversible toxicities can be remediated by delays between chemotherapy treatments?

Answer 19

• Bone marrow
• GI
• Lymphoid tissue
• Hair follicles

Question 20

What assumptions are made about a tumour in cytotoxic chemotherapy?

Answer 20

• Tumour growth proceeds exponentially, independent of growth homeostasis, but a proportion of cells are non-dividing and the proportion of these non-dividing cells may vary
• The size of the growth fraction decreases exponentially with tumour growth, therefore as the size of the tumour increases, the numbers of actively dividing cells decreases (smaller growth fraction). Therefore the larger the tumour, the more resistant it is to chemotherapy as it will have smaller numbers of susceptible cells within it
• The growth fraction is maximal at 37% of maximum tumour size, this is why chemotherapy is given to treat all potential micro-metastasis, as when they are clinically detectable they are more difficult to treat

Question 21

What is the assumption of Gompertzian growth kinetics?

Answer 21

• Clinically undetectable tumours have the highest growth fraction
• A large tumour mass has a small number of cells susceptible to cytotoxic therapy

Question 22

Why are multiple cycles of chemotherapy needed?

Answer 22

• Each dose of chemotherapy will result in the same proportional log kill, meaning that multiple cycles of chemotherapy will be needed. However, this proportional kill may also relate to growth fraction
• As tumours are heterogenous, some cells within the tumour will be resistant to the chemotherapy agent. The larger the tumour, the more likely that it will contain resistant cells
• This can be expressed in terms of the finite probability that a tumour will contain no resistant cells, and therefore be totally eradicated by the drug. This probability will decrease as the tumour grows

Question 23

Why are cytotoxic drugs given close to the maximum tolerated dose?

Answer 23

Dose reduction due to toxicity can reduce chances of cure

Question 24

What is the aim of combination chemotherapy?

Answer 24

• Achieve the maximum cell killing with minimum toxicity
• Given to increase kill fraction of resistant cells in heterogeneous tumour & prevent/slow outgrowth of resistant malignant clones