Angiogenesis 2 Flashcards
1
Q
anti-angiogenic therapy
A
“does not aim to destroy tumours, but instead by limiting their blood supply it attempts to shrink tumours and prevent them from growing”
2
Q
5 classes of angiogenic antagonists
A
- inhibitors of proteases
- inhibitors of endothelial cell migration and proliferation
- inhibitors of angiogenic growth factor
- inhibitors of matrix proteins on endothelial cell surface, such as integrins and copper
- inhibitors with unique mechanisms
3
Q
anti-VEGF therapies
A
- monoclonal antibodies directed against specific proangiogenic growth factors or their receptors
- small molecule tyrosine kinase inhibitors of multiple proangiogenic growth factor receptors
4
Q
bevacizumab
A
monoclonal antibody against VEGF-A
5
Q
ramucirumab
A
monoclonal antibody to VEGFR-2
6
Q
monoclonal antibody to VEGFR-2
A
tyrosine kinase inhibitors that target VEGF receptors
7
Q
process of VEGF binding
A
VEGF binds to receptor -> receptor dimerisation and autophosphorylation -> production of various proangiogenic factors
8
Q
ANTI-VEGF
A
- bevacizumab
- recombinant anti-VEGF MAb
- T 1/2 = 14-21 days
- neutralises all forms of VEGF
9
Q
Side effects of bevacizumab
A
- hypertension
- proteinuria
- gi perforations
- bleeding
10
Q
alfibercept
A
- protein comprised of segments of the extracellular domains of VEGFR1 and VEGFR2
- fused to constant region (Fc) of human IgG1
- functions as soluble decoy receptor, binds VEGF and prevents it binding to actual VEGF receptor
11
Q
protein kinases
A
- catalyse transfer of gamma phosphate from ATP to one of more amino acid residues in a protein substrate side chain
- results in conformational change, affecting protein function
12
Q
tyrosine kinase inhibitors structure
A
- ligand binding extracellular domain
- single transmembrane domain
- cytosolic tyrosine kinase domain
- flexible C-terminal tail
13
Q
how RTK inhibitors work
A
- phosphorylation sites that promote TKD activation present in juxtamembrane domain, activation loop and C-terminal tail
- activation loop resides within active site of TKD thus sterically hindering access by ATP to nucleotide-binding pocket
- phosphorylation of activation loop promotes conformational changes, inducing swinging out of activation loop which releases auto-inhibition effects as well as stabilising activated TKD
14
Q
NRTKs (non-receptor tyrosine kinases)
A
- subgroup of tyrosine kinases, intracellular cytoplasmic proteins or anchored to membrane of cell
- 9 subfamilies according to sequence similarities
- each NRTK family defined according to sequence homology of kinase domain
15
Q
how sorafanib works
A
- inserts into hydrophobic pocket within catalytic loop of RAF-1
- prevents receptor kinase from binding ATP and phosphorylating their respective tyrosine target residues
- targets ATP binding domain and competes with ATP
