Cancer Chemotherapy

Question 1

Describe the targets of chemotherapy

Answer 1

• Chemotherapy targets DNA replication in cells
• Some cancer cells are in the G0 phase, whereby the cell cannot be targeted by chemotherapy
• Can use drugs that induce the cell cycle in the cells, therefore being able to be targeted

Question 2

Be able to describe the factors contributing to tumour growth and metastasis and the challenge this presents to successful chemotherapy

Answer 2

• Tumour growth factors include
  
  • Growth fraction
  • Duration of cell cycle
  • Rate of cell loss
• Tumour growth is only detected at 10^9 cancer cells - limit of clinical detection
• At 10^12 cancer cells, the patient is dead so chemotherapy has a small window in which it can be used effectively
  - Ideally, it should be used before the limit of clinical detection

Question 3

Define fractional kill ratio in chemotherapy

Answer 3

• Fractional kill hypothesis states that a defined chemotherapy concentration will kill a constant fraction of the cells population
• Repeated doses needed to continue the reduction in tumour size

Question 4

Describe the effect of chemotherapy on bone marrow cells

Answer 4

• Chemotherapy given in pulses rather than 1 large dose
• When chemotherapy given, there is a reduction of bone marrow cells as well as tumour cells
  
  • Bone marrow cells recover quicker than tumour cells
  • Chemotherapy needs to be administered when the bone marrow cells have recovered
  • Overall, there is a depletion in bone marrow cells - patient with long term cancer have low blood counts

Question 5

State the main chemotherapeutic groups

Answer 5

• Antimetabolites
• Alkylating/intercalating agents
• Mitotic inhibitors

Question 6

Describe the mechanism of action of antimetabolites

Answer 6

• 5- Fluorouracil broken down and inhibits enzyme Thymidylate synthase (TS)
  
  • TS responsible for converting pyrimidines into DNA - problem of DNA synthesis
  • Commonly used to treat GI cancers
• Methotrexate targets enzyme dihydrofolate reductase, inhibiting the folate cycle and preventing purine formation

Question 7

Describe the mechanism of action of alkylating agents and its specific ADRs

Answer 7

• Eg. Cyclophosphamide, chlorambucil, cis-platin
• Platinated bond formed between two strands of DNA
  
  • Prevents formation of replication fork, leading to cell death
• Form both interstrand and intrastrand adducts leading to inhibition of DNA synthesis
• However, there are repair mechanisms in the body which remove the bond preventing DNA replication
• Specific ADRs - peripheral, sensory and motor neuropathy, ototoxicity

Question 8

Explain the mechanism of action of mitotic inhibitors and its specific ADR

Answer 8

• Taxoids promote assembly of microtubules (polymerisation) and prevents disassembly (depolymerisation)
  
  • Prevents cell from continuing growth by maintaining microtubules
    
    • Eg. Paclitaxel
• Vinca alkaloids prevent spindle formation
  - Prevent anaphase from completing
  - Eg. Vincristine, vinblastine
• Specific ADRs - neurotoxicity - glove and stocking peripheral neuropathy

Question 9

Describe locations where drug resistance to chemotherapy may occur

Answer 9

• Pump on the surface of the cell which may be pumping out the chemotherapy being given
• Proteins within cytoplasm which bind to chemotherapy agent and nullify its action
• DNA repair mechanisms in the nucleus

Question 10

List the routes of delivery of chemotherapy

Answer 10

• IV pumps - bolus, infusion bag, continuous pump infusion
  
  • Peripherally inserted central catheter (PICC) line
  • Hickman line - tunneled under skin and enters subclavian vein
• Oral
• Subcutaneous
• Into a body cavity - bladder, pleural effusion
• Intralesionally - directly into a cancerous area
• Intrathecal - into the CSF through lumbar puncture
• Topical

Question 11

Describe the main ADRs of chemotherapy

Answer 11

• Side effects mainly occur in areas where there is constant DNA replication and division
• Alopecia - hair loss due to prevention of hair follicle division
  
  • Head cooling therapy given to reduce alopecia
• GI symptoms as mucosa differentiation and replacement reduced
  
  • Diarrhoea, vomiting, nausea
  • Vomiting main ADR
  • Mucositis - most common in oropharynx (white spots around oropharynx)
• Cardiotoxicity - affecting muscle function and arrhythmias
• Lung toxicity - bleomycin lung toxicity gets worse if given oxygen, causing pulmonary fibrosis
• Cystitis - mucosa in the bladder
• Myelosuppression - reduced division of blood cells
  
  • Reduced platelets leading to increased bleeding
  • Anaemia
• Skin toxicity - drug kills skin around IV entry point

Question 12

Understand the clinical monitoring required to minimise ADR risk of chemotherapy

Answer 12

• Response of the cancer
  
  • CT scans
  • Tumour markers in blood
  • Bone marrow samples - leukemia
• Drug levels
• Check for organ damage
  
  • Creatinine clearance (kidney)
  • Echocardiogram (heart)
    
    • Liver function

Question 13

Define neo-adjuvant and adjuvant

Answer 13

• Neo-adjuvant - given before surgery or radiotherapy for primary cancer
• Adjuvant - given after surgery to excise the primary cancer, aiming to reduce relapse risk

Question 14

Define palliative, primary and salvage treatment

Answer 14

• Palliative - to treat current or anticipated symptoms without curative intent
• Primary - 1st line treatment of cancer
• Salvage - chemotherapy for relapsed disease

Question 15

Describe the mechanism of intercalating agents / free radical generators and its specific ADRs

Answer 15

• Doxorubicin
  
  • Targets DNA synthesis in S phase by inserting between base pairs of DNA and interfering with transcription/replication
  • Generate free radicals - damages DNA
  • Specific ADR - cardiotoxic
• Bleomycin
  
  • Most effective in G2 stage
  • Forms free radicals when chelated with Fe2+ ions which attack phosphodiester bonds in DNA, causing DNA strands to be cut
    
    • Specific ADR - pulmonary fibrosis