Chemotherapy Flashcards
What are the different possible treatments available for cancer?
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.
Explain the transformation of a cell into a malignant cells and some of the anti-cancer defences
- 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.
What is the main target of chemotherapy?
- 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
What are the general side effects of chemotherapy?
- 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
What are the phases of the cell cycle?
- S-phase (DNA replication)
- G2 phase
- Mitosis,
- G0 phase (quiesent)
- G1 phase (biosynthesis)
What are the different cell populations within a tumour
- 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
What are the main classes of cancer chemotherapy drugs?
- Alkylating agents,
- Antimetabolites.
- Cytotoxic antibodies,
- Microtubule inhibitors,
- Steroid hormones and antagonists
Explain the mechanism of action of alkylating agents
- 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
Name the different types of drugs within the alkylating agent group
- 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
Describe features of cyclophosphamide
- 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.
Describe features of cisplatin
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.
Name different classes and examples of antimetabolites
- Folate antagonists, eg, Methotrexate.
- Pyrimidine analogues eg, fluoro-uracil (prevents thymidine formation and stops DNA synthesis)
- Purine analogues, eg, Mercaptopurine, fludarabine,
Explain the mechanism of action of methotrexate
- 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.
Explain the mechanism of action of merccaptopurine
- Converted into false nucleotides which then disrupts purine nucleotide synthesis. May be incorporated into DNA which disrupts the helix.
What class of drug is cytarabine and what is its mechanism of action?
- Nucleotide analogue.
- It is specific to S-phase cell cycle
- Inhibits DNA polymerase and is incorporated into the DNA causing chain termination
