CE L5 Angiogenisis - angio continued Flashcards
Angiogenic process:
- Surrounding cells release angiogentic factors which bind to nearby epithelial cells
- Endothelial cells activated and produce enzymes which digest the basement membrane
- Endothelial cells proliferate and migrate out of vessel
- Adhesion molecules and MMPs aid formation of new blood vessel
- Vessel is stabilised by smooth muscle and pericytes
What cells take part in angio
epithilial cells
what 2 things aid formation of new blood vessel
Adhesion molecules and MMPs
What stabilises the new blood vessel
smooth muscle
direction of new blood vessel is
towards the source of the stimulus (VEGF producing tumour)
Why are new blood vessels required in cancer
to bring oxygen and nutrients to the centre
enables growth, invasion and metastasis
What does VEGF stand for
how many forms are there
vascular endothelial factor
5 - VEGF-A is best characterised
What triggers VEGF
oncogenes and hypoxia mediated stabilisation if TF - drives VEGF transcription
4 current approaches to VEGF targeting
Antisense RNA
2 other signals that antisense RNA could target to stop angiogenisis
bFGF
PDGF
4 current approaches to VEGF targeting
Antisense RNA
Soluble receptors/mab - Avastin
Enzyme inhibitors
Activation of tumour supressors (p53)
2 other signals that antisense RNA could target to stop angiogenisis
bFGF
PDGF
Why does activation of tumour supressors help target angiogenisis
p53 unpregulates antiangiogeic factors (e.g. thrombospondin, downregulations of bFGF)
e.g. of enzyme inhibitors targeting angio
VEGFR inhibitors:
sunitinib
sorafenib
What is Avasin
humanised mab. anti VEGFA
used to treat breast/colon/renal cancer in combo
Avastin is also called
Bevacizumab
How does avastin work
mops up he VEGF-A (the ligand that stimulates angiogenisis).
Why must avastin be used early
doesnt affect already formed blood vessels
Disadvantage of avastin
if you get damage to another part of the body you cant have angiogenisis
Disadvantage of avastin and other antiangiogenisis therapies
if you get damage to another part of the body you cant have angiogenisis
Advantages of antiangiogenic drugs?:
May be useful in preventing metastasis
Use in combo for lower doses with cytotoxics or other anti angio drugs that target a different stage
What is the aim of new anti angio therapies
to target newly formed blood vessels - these are leaky and poorly made setting the neovasculare and established vessels appart
2e.g of novel anti angi therapies
Vitaxin - antiangiogenic mab against abv3
ANET - antineovascular therapy
how does ANET work?
it directs cytotoxic drugs
how does ANET work?
it directs cytotoxic drugs
eg adriamycinor dominant molecules
eg mutant Raf to endothelelial cells
what is required by antineogenisis therapies
drug delivery systems e.g. liposomes targetted to integrins
only endothelial cells have the right TF to express
e-selectin - adhesion molecule
concept of gene therapy:
reqiures ……………….. and …………………..
to correct or alleviate disease by delivery of genes
identification of appropriate gene, specific delivery of gene to required area
avastin oonly works in what tumours?
those driven by veg f
avastin oonly works in what tumours?
those driven by veg f
How can we target using E-selectin?
Retroviruses specifically target rapidly proliferating cells
- link this to an endothillial cell specific promoter such as E-selectin or VEG F
