Anti-angiogenesis strategies

Question 1

What do most anti-angiogenic therapies target?

Answer 1

VEGF

Question 2

What causes VEGF transcription?

Answer 2

hypoxia generating HIF1a

Question 3

First VEGF antibody?

Answer 3

Bevacizumab (Avastin)

Question 4

Antibody inhibiting VEGF receptor activation

Answer 4

Ramucirumab

Question 5

Drugs that inhibit VEGF receptor

Answer 5

pazopanib, axitinib, regorafenib and sunitinib

Question 6

Development of avastin/bevacizumab

Answer 6

1. Mince immunised with VEGF peptide
2. B lymphocytes isolated from spleen
3. fusion of lymphocytes with myeloma cells
4. selection of clones that generate single antibody
5. purify antibody from media
6. reverse transcribe to cDNA
7. PCR using heavy and light chain N terminal primers
8. clone variable region into human fixed chain
9. humanise

Question 7

Is anti-angiogenic therapy very effective for metastatic cancer?

Answer 7

No, it only has a very modest increase in survival and depends greatly on the chemotherapy used alongside

Question 8

Where has anti-VEGF been effective?

Answer 8

restoring vision temporarily in human neovascular AMD

Question 9

Other angiogenesis potential targets

Answer 9

VEGF production and secretion
endothelial activation (VEGFR2, Ca, NO, MAPK)
increased permeability
matrix metalloproteinase production
pericyte withdrawal and basement membrane degradation
endothelial migration
cell division behind migrating sprout
lumen formation
sprout connection and blood flow