L5.1 Anti-cancer drugs - exploit other biology

Question 1

What is selective toxicity

Answer 1

• Selective toxicity based on rapid dividing cells are limited
  
  • Leads to dose-limiting SE profile (dose given limited by SE)

Question 2

What does exploiting other biological aspect allow?

Answer 2

• ↑selectivity
• Less SE
• ↑Desired dose

Question 3

Hormone

Answer 3

• Some tumour growth dependent on hormonal signalling
• Oestrogen
  
  • Androgen-dependent prostatic tumours
  • Given for functional antagonism
• Anti-oestrogen
  
  • Tamoxifen - personalised medicine → only given if breast cancer found to be oestrogen depedent
  • Oestrogens-dependent breast cancer → compete with oestrogen for R

Question 4

Angiogenesis

Answer 4

• Growth of new vessels from pre-existing vessels
• Normally tightly controlled, occurring only during:
  
  • Late embryonic development
  • Menstrual cycle
  • Wound healing

Question 5

What effect does the presence of a tumour have on angiogenesis

Answer 5

• Angiogenesis is necessary for the growth & spread of solid tumour
  
  • Infiltrate into tumour → provide BS for tumour
• “angiogenic switch” → tumour turning on angiogensis to create own BS

Question 6

Multistep process of angiogenesis

Answer 6

1. Degradation of basement membrane by matrix metalloproteinases
   
   • Breakdown matrix to make space
2. Endothelial cells → migrate & proliferate
3. Formation of new matrix
4. Stabilisation by pericytes

Question 7

Process of endothelial cell proliferation

Answer 7

• Under control of variety of growth factors
• Vascular endothelial GF (VEGF) → Control growth of vascular EC
  
  • Produced by tumour as part of angiogenic switch
  • Drives endothelial cell proliferation → angiogensis

Question 8

What are VEGFs?

Answer 8

Vascular endothelial growth factor

• VEGF A → binds to VEGFR 2 → mainly for blood vessels angiogenesis
• VEGF C/D → binds to VEGFR 3 → mainly for lymphatic vessels
• All VEGF R are tyrosine kinase receptors

Question 9

VEGF inhibitor mechanism

Answer 9

• Binds to ligand:
• Inhibits receptor via:
  
  • Using anti VEGF monoclonal AB
  • Inhibiting TK
  • Competitive inhibition
• Works on endothelial cells - which are genetically stable - not cancer cells

Question 10

Using VEGF monoclonal AB

Answer 10

• Bevacizumab
  
  • Prevents binding of VEGF-A to R
  • Best clinical effect seen in combination with cytotoxic drugs

Question 11

Mechanism of bevacizumab

Answer 11

• Binds to VEGF-A
• Induction of tumour hypoxia
• ↓VEGF mediated ↑in vascular permiability
  
  • ↓Interstitial pressure → ↑Drug delivery

Question 12

SE of bevacizumab

Answer 12

• Proteinuria (abnormal [protein] in urine)
• Hypertension
• Risk of thrombosis/bleeding
• Impaired wound healing (can’t be given during surgery/recovery)

Question 13

VEGF receptor TK inhibition

Answer 13

• Small molecules bind to active site of TK
• Sunitinib - inhibits VEGFR 1&2, PDGFR
• Sorafenib - inhibits all of the above + B-RAF
  
  • These don’t just inhibit 1 TK (NOT selective) → ↑spectrum of TK inhibited → important for treating cancer

Question 14

Inhibition of VEGF based on competitive inibition

Answer 14

• Structure of VEGF:
  
  • Disulphide linked dimer
  • Solvent exposed loops → forms 2 bind poles which help dimerisation
    
    • Mimicking structure → able to act as antagonist

Question 15

Features of Chronic myeloid leukemia

Answer 15

• Accounts for 15% of adult leukemia
• From 1 genetic fault → creates “philedelphia chrm” → express constituively active kinase → Fuses BCR & ABL kinase → constant cell proliferation
• Poor prognosis (Median survival ~ 6years)

Question 16

Features of Imantinib mesylate

Answer 16

• Small molecule inhibiting BCR-ABL kinase:
  
  • Binds to kinase domain
  • Stabilises protein in closed inactive conformation

Question 17

Progress of imantinib development

Answer 17

• Inhibits growth of BCR-ABL in vitro & in vivo (in animals)
• Phase I trials: Normalisation of blood counts in 95% of patients(Haemotologic)
• Phase III trials → Showsx better response than standard cytotoxic treatment

Question 18

Clinical use of imantinib

Answer 18

• Slows progression of CML, but NOT a cure
• SE not significant
  
  • Nausea/vomiting
  • Liver toxicity & severe fluid retention
• Resistance is common
  
  • From mutation of BCR-ABL
  • Prevents adaption of closed conformation → imatinib unable to bind

Question 19

Features of drug resistance

Answer 19

• Primary: when drug first given
• Secondary: Develop during treatment
• Consequences:
  
  • Need to ↑ dose for same killing effect
  • ∴↑SE → limits effectiveness of treatment

Question 20

Resistance of tumour cells

Answer 20

• Tumour cells primed to develop resistance
  
  • ↑cell #
  • Rapid growth rates
  • ↑mutation rates → a result from loss of function from tumour suppressor cells

Question 21

What are P-glycoproteins

Answer 21

• Used for protection against env toxin → clears out cells by pumping toxins out of cells

Question 22

5 mechanism of drug resistance

Answer 22

1. ↓Intracellular accumulation
   
   • Mutation causes ↑expression of P-glycoprotein
   • Able to pump out more than 1 type of toxin (non-selective) → Develop multiple resistance
2. ↓Uptake by cell
   
   • Methotrexate & ↓expression of folate carrier
3. ↓activation
   
   • 5-flurouracil & deactivation by phosphorylation
4. ↑inactivation
   
   • Inactivation of antimetabolites from deanimation
5. Insensitivity to apoptosis
   
   • Loss of p53 tumour suppressor function
   • Leukaemia, lymphomas, testicular cancer → from wild type p53 → highly responsive to chemotherapy
   • Pancreas, lung, colon → loss of p53 mutations → poorly responsive to chemotherapy