Chemotherapy

Question 1

What are the different possible treatments available for cancer?

Answer 1

Surgical removal - Only for solid tumours, depends on locations and only if non-metastasised
Irradiation - Only if localised and depends on location.
Chemotherapy - often only treatment possible, selective toxicity is required.

Question 2

Explain the transformation of a cell into a malignant cells and some of the anti-cancer defences

Answer 2

• Multi-step process with genetic change either: Inactivation of TSGs or activation of proto-oncogenes into oncogenes. Results in a cell with uncontrolled growth.
• ## Innate defences include immune system or apoptosis of cancer cells which occurs if they fail check points of cell division.

Question 3

What is the main target of chemotherapy?

Answer 3

• Attack cell division (explains why side effects occur in systems with dividing cells, eg, hair, GI, immune system)
• They do no reverse differentiation, invasion or metastasis

Question 4

What are the general side effects of chemotherapy?

Answer 4

• Bone marrow suppression (anaemia, immune depression and impaired wound healing)
• Hair loss,
• Damage to GI epithelium,
• Damage to liver, heart and kidneys,
• Depression of growth in children,
• Sterility
• Teratogenic

Question 5

What are the phases of the cell cycle?

Answer 5

• S-phase (DNA replication)
• G2 phase
• Mitosis,
• G0 phase (quiesent)
• G1 phase (biosynthesis)

Question 6

What are the different cell populations within a tumour

Answer 6

• Dividing cells (sensitive to chemotherapy)
• Resting cells (Not sensitive to chemotherapy, can divide later on so are the reasons for relapses - hense the need for TOTAL kill of all cancer cells)
• Cells which can no longer divide but contribute to tumour size

Question 7

What are the main classes of cancer chemotherapy drugs?

Answer 7

• Alkylating agents,
• Antimetabolites.
• Cytotoxic antibodies,
• Microtubule inhibitors,
• Steroid hormones and antagonists

Question 8

Explain the mechanism of action of alkylating agents

Answer 8

• Forms covalent bond with DNA, interfering with transcription and replication.
• Most agents have two reactive groups which allows them to cross link within one strand of DNA and across two strands of DNA

Question 9

Name the different types of drugs within the alkylating agent group

Answer 9

• Nitrogen mustards: Cyclophosphamide,
• Platinum based compounds: Cisplatin
• Nitrosoureas: Lomustine (active in CNS because it is Lipid soluble)
• Alkylsulphonates: Busulphan (Selective for bone marrow)
• Other example is temozolomide

Question 10

Describe features of cyclophosphamide

Answer 10

• It is a prodrug that requires activation by phosphoramidase. In some tumours there is high activity of phosphoramidase.
• Aldehyde dehydrogenase protects against toxicity of the drug. There is high concs of aldehyde dehydrogenase in bone marrow cells, hepatocytes and intestinal epithelial cells so these are less affected.

Question 11

Describe features of cisplatin

Answer 11

Stops DNA replication by targeting the 7th nitrogen of purine nucleotides and prevents cross linking. However resistance can occur due to nucleotide excision repair mechanisms and efflux transporters for copper. So some patients do not respond well to cisplatin.

Question 12

Name different classes and examples of antimetabolites

Answer 12

• Folate antagonists, eg, Methotrexate.
• Pyrimidine analogues eg, fluoro-uracil (prevents thymidine formation and stops DNA synthesis)
• Purine analogues, eg, Mercaptopurine, fludarabine,

Question 13

Explain the mechanism of action of methotrexate

Answer 13

• High affinity for dihydrofolate reductase which prevents the formation of dihydrofolate.
• This results in the inhibition of purine/pyrimidine nucleotide synthesis (especially thymidine) so halts DNA and RNA synthesis.

Question 14

Explain the mechanism of action of merccaptopurine

Answer 14

• Converted into false nucleotides which then disrupts purine nucleotide synthesis. May be incorporated into DNA which disrupts the helix.

Question 15

What class of drug is cytarabine and what is its mechanism of action?

Answer 15

• Nucleotide analogue.
• It is specific to S-phase cell cycle
• Inhibits DNA polymerase and is incorporated into the DNA causing chain termination

Question 16

Name some examples of cytotoxic antibiotics and their mechanism of action

Answer 16

• Dactinomycin: Isolated from Streptomyces. Inserts itself into minor grove at DNA helix, disrupting RNA polymerase function.
• Doxorubicin: Also isolated from Streptomyces. It causes local uncoiling and impairs DNA and RNA synthesis. Very effective

Question 17

Name an example of a plant derivative (microtubule inhibitor) and its mechanism of action

Answer 17

• Vinca alkaloids eg, vincristine.
• It binds to microtubular proteins, blocking tubulin polymerisation and blocks normal spindle formation. Thus disrupting cell division.

Question 18

Name the different steroid hormone used in cancer treatment and how it works?

Answer 18

Predisone which is converted into prednisolone in the body and supresses lymphocyte growth.

Question 19

Name some examples of hormone antagonists and their mechanism of action

Answer 19

• Tamoxifen: Antagonist of oestrogen so used in oestrogen sensitive cancers.
• Bicalutamide: Testosterone antagonists so used in prostate cancer
• Prostap: LHRH agonists which inhibit the release of LH. LH normally stimulates testies to produce testosterone.

Question 20

What is tumour lysis syndrome?

Answer 20

• Acute side effect and metabolic emergency of chemotherapy
• Rapid cell lysis causes large amounts of metabolites in the blood, resulting in hyperuricaemia, hyperphosphatemia, hyperkalaemia and hypocalcaemia.
• Can result in AKF, cardiac arrest and death