L4.3 Anti-Cancer drugs - target rapidly dividing cells

Question 1

What is cancer characterised by

Answer 1

1. Uncontrolled proliferation (faster than parent cells)
2. Dedifferentiate state (lose characteristic of parent cell)
3. Invasiveness
   
   • Loss recognition of normal restraints
   • Express matrix-degrading enz (allows exit of cell matrix)
4. Ability to metastasise
   
   • Secondary tumours distant from primary
   • Often travel through lymphatics → lodges somewhere else & grow elsewhere

Question 2

Treatment approaches

Answer 2

• Surgery (requires early detection)
• Irradiation (good adjunct treatment)
• Chemotherapy

Question 3

Causes of cancer

Answer 3

• Mutation:
  
  • Inactivation of tumour suppression genes
  • Activation of proto-oncogenes to oncogenes

Question 4

Tumour suppressor genes

Answer 4

• Usually acts as sentinels to detect DNA changes
• P53: most commonly mutated in human cancer (>50%)

Question 5

Difference b/w normal and mutated function of p53

Answer 5

• Normal function:
  
  • Looks for damaged DNA → deactivation/loss of p53 → cell cycle arrest leads to:
    
    1. Reversible → DNA repair
    2. If damage irreversible → apoptose
• Mutated:
  
  • Loss of p53 function → DNA damage is unchecked
    
    • No repair & apoptosis → cell accumulate → ↑mutations → cancer

Question 6

Mutation of proto-oncogenes

Answer 6

• Genes normally responsible for cell growth & differentiation → mutated to become an oncogene
• Mutated:
  
  • Abnormal growth
  • GF/GF.R/members of GF signalling pathways/cell transducers

Question 7

Example of a proto-oncogene mutation - Ras gene

Answer 7

• Normal:
  
  • Responsible for (20-30% of tumours)
  • Ras-GTP = on
  • Ras-GDP = off
  • Ras gene is the converging point of many cell signalling pathways → ↑proliferation
• Mutation:
  
  • ↓inactivation of ras
  • Ras-GTP becomes predominant → cell divides in absence of GF binding → abnormal proliferation

Question 8

Principle of cancer chemotherapy

Answer 8

• Exploits differences b/w normal & tumour cells, i.e.:
  
  • Rate of growth (traditional methods)
  • Some other aspects of biology (contemporary)
• Tumour growth may be exponential
  
  • Need near total removal of tumour cells for effective treatment

Question 9

What is the log cell kill model

Answer 9

• Cell destruction is 1st order: i.e. constant fraction of cells killed
• Side effects require intermittent dosing
  
  • Allows tumour regrowth
  • Development of resistant cells
  • Resistant cells grow exponentially regardless of treatment
  • Drugs have to be given intermittently → drugs are too toxic

Question 10

Tumour growth limitation:

Answer 10

• BS to tumour
  
  • Require angiogenesis (current new target in therapy)

Question 11

Limitations of chemotherapy

Answer 11

1. “resting” cells may be resistant to treatment
   
   • Becomes tumour stem cells
2. Therapeutic window is often non-existent
   
   • Dose for treatment ≥ dose giving side effects
   • Limits dose & duration of therapy
3. Selective toxicity
   
   • Targets rapid cell division aspect of cancer cells
   • Affects other fast-diving cells
     
     • Bone marrow suppression
     • Impair wound healing
     • Hair loss
     • Gut epithelium damage (can’t absorb nutrients well)

Question 12

Classes of anticancer cytotoxic drugs

Answer 12

• Cytotoxic drugs
  
  • Causes DNA damage/interfering with DNA synthesis → rapidly dividing cells will be most affected
    
    • Alkylating agents
    • Antimetabolics
    • Anthracyclines
    • Microtubule inhibitors

Question 13

Alkylating agents

Answer 13

• Covalently binds with nucleophilic cell components (N7 & O6 of guanine)
• Bifunctional → cross linking of DNA → creates kinks (intrastrand)

Question 14

Cisplatin (example of alkylating agent)

Answer 14

• For testicular & ovarian cancer
• Causes intrastrand cross linking → denatures DNA
• Trans-isomer of cisplatin = inactive (still binds to DNA but can’t form cross-links)
• S.E of cisplatin:
  
  • Nephrotoxic & neurotoxic → causes sensory neuropathy
  • Severe nausea & vomiting
  • Can be controlled with Ondansetron (a 5HT antagonist)

Question 15

Antimetabolites

Answer 15

• Inhibits DNA synthesis pathways (inhibits synthesis of dTMP)
  
  • dTMP required to syn new DNA​

Question 16

Methotrexate

Answer 16

• Inhibits dihydrofolate reductase → stops new DNA syn → death
• Has low lipid solubility → ∴ does not cross blood brain barrier
• S.E of methotrexate
  
  • Bone marrow depression, gut epithelium damage
  • Resistance is common
  • “Folate rescue” → getting around resistance
  • Administer ↑ [methotrexate] + folate

Question 17

5-fluorouracil

Answer 17

• Converted into false nucleotide (FdUMP), the substrate for dTMP
  
  • Phosphorylation needed for activation
• Inhibits thymidylate synthetase
• S.E of 5-flurouracil
  
  • Bone marrow toxicity + gut damage
  • Toxicity when administered with folate (inhibited enz is a complex with FdUMP & cofactor is derived from folate)

Question 18

Function of topoisomerase

Answer 18

• Required for DNA unwinding & rewinding to relieve supercoiling

Question 19

Anthracyclines

Answer 19

• Doxorubicin
  
  • Binds to DNA by intercalation (slides b/w base pairs)
  • Stabilises DNA & topoisomerase II → DNA remains cut → sends cell into apoptosis
• S.E. Cardiotoxicity
  
  • Generates free radicals → damage cardiac tissues
    
    • Reduced by coadiminstration of dexrazoxane (an Fe chelator)
      
      • ↓Fe2+ mediated free radical production

Question 20

Microtubules

Answer 20

• Paclitaxel
  
  • Promotes polymerisation and inhibits depolymerisation
    
    • Prevents spindle formation
  • SE: Bone marrow suppression & Neurotoxicity