Chemotherapy (anti-cancer)

Question 1

What are the general mechanisms by which anti-cancer drugs function?

Answer 1

1. Preventing DNA replication
2. Damaging mechanisms of cell division (e.g. spindle assembly)
3. Blocking pathways that support cell division (e.g. growth factors)

Question 2

What are the mechanism by which selective toxicity can be achieved in anti-cancer drugs?

Answer 2

1. Differential accumulation: Cancer cells have increased rate of glycolysis, and increased rate of anaerobic respiration, leading to lactic acid production and reduced intracellular pH. Drugs that are trapped inside cells by protonation (e.g. anthracyclines) selectively accumulate in cancer cells.
2. Differential activation: Cancer cells are generally hypoxic, so promote activation of pro-drugs that require reduction (e.g. mitomycin C).
3. Differential importance: Cancer cells are fast-replicating, and so have greater dependence on mechanisms mediating DNA replication and cell division.

Question 3

What is the mechanism by which nitrogen mustards are activated?

Answer 3

1. Nitrogen mustards contain 2 2-chloroethyl chains
2. Each 2-chloroethyl group undergoes cyclisation reaction that releases a Cl to form an imonium ion
3. Imonium ion becomes carbonium ion that is highly reactive and alkylates guanine

Question 4

What is the process of activation of cyclophosphamide?

Answer 4

It is a pro-drug that is converted by liver Cytochrome P450 enzymes to active phosphoramide mustard

Question 5

How is selectivity achieved by melphalan?

Answer 5

Melphalan selectively accumulates in skin as it is a phenylanaline derivative (used to make melanin), so is used to treat melanomas.

Question 6

What are the side effects of vinca alkaloids?

Answer 6

Inhibits other processes involving microtubules that may relate to side effects:

1. Leukopaenia (decrease in white blood cell count)
2. Neurotoxicity (inc. paraesthesia) – Inhibition of neuronal axon transport

Question 7

What types of cancers can be treated using hormone anti-cancer drugs?

Answer 7

1. Breast cancers:
   - Anti-oestrogens
   - Aromatase inhibitors
   - GnRH analogues
2. Prostate cancers:
   - GnRH inhibitors
   - Anti-androgens

Question 8

What types of cancers can be treated with prednisone (glucocorticoid)?

Answer 8

Leukemias (e.g. acute lymphoblastic leukemia)