Angiogenesis Flashcards
What is angiogenesis?
Formation of new blood vessels from existing blood vessels.
In a healthy adult where/when can angiogenesis be seen?
Wound repair and the female reproductive cycle.
Describe an avascular tumour.
This is a tumour before angiogenesis has begun. Avascular tumours are slow growing and exist as a bundle of cells 10^5 to 10^6 cells.They can not grow further until they become vascularised.
Neovascularised tumours (after angiogenesis) show what kind of growth?
Expedential growth which can be 1cm^3 plus.
How can tumours be graded with respect to angiogenesis?
By their microvessel count (MVC).
What are direct angiogenic factors?
Factors what stimulate endothelial cell proliferation in vitro.
Give some examples of direct angiogenic factors.
VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), PD-EGF (platelet-derived endothelial growth factor).
What is VEGF (vascular endothelial growth factor)?
A direct angiogenic factor which stimulates endothelial cell growth and increases permeability.
What is fibroblast growth factor (FGF)?
A direct angiogenic factor which stimulates endothelial cell proliferation and differentiation.
What is platelet-derived endothelial growth factor (PD-EGF)?
A direct angiogenic factor which stimulates endothelial cell proliferation and the recruitment of smooth muscle.
What are indirect angiogenic factors?
Other cofactors to stimulate endothelial cell proliferation.
Give some indirect angiogenic factors.
Epidermal growth factor, transforming growth factor (extracellular matrix) (TGF-alpha and -beta), tumour necrosis factor (TNF-alpha), prostaglandins, HETE.
What are inhibitors of angiogenesis?
Factors that stop endothelial cell division.
Give come inhibitors of angiogenesis.
Angiostatin, endostatin, retinoic acid, tissue inhibitors of metalloproteinases (TIMP-1 & -2).
Describe the angiogenic process.
An avascular tumour needs angiogenesis to grow further.
The tumour produces angiogenic factors such as VEGF and bFGF.
Host capillaries prodice matrix metalloproteinases (MMPs).
ENdothelial cells grow towards the tumour.
Oxygen and nutrients can then reach the tumour and the tumour begins to grow rapidly.
This can then lead to metastasis.
What are matrix metalloproteinases?
Zinc containing enzymes which break down the extracellular matrix and tissues, allowing the endothelial cells to grow towards the tumour.
Outline the process of metastasis.
Tumour cells leave the primary tumour site and invade local host tissue. Tumour cells then enter circulation and eventually arrest at a distant vascular bed. They then extravate into the target organ tissue and proliferate as a secondary colony.
How many anti-angiogenic drugs are in developmenr, in clinical trials, or have FDA approval?
> 300.
What are the three main classes of anti-angiogenic drugs?
Blocking growth factors, blocking intracellular signalling, blocking intercellular signalling.
Give an example of anti-angiogenic drugs which block growth factors.
Bevacizumab (avastin), itraconazole.
Give an example of anti-angiogenic drugs which block intracellular signalling.
Tyrosine kinase inhibitors e.g. sunitinib (Sutent) and IFN-alpha.
Give an example of anti-angiogenic drugs which block intercellular signalling.
Thalidomide.
What are some other targets for anti-angiogenic drugs?
Other targets include basement membrane degradation (MMP inhibitors), migration inhibitors (endostatin) and immune stimulators (CM101).
How does SU11248 (Sunitinib) work?
It is a VEGF-R2 receptor antagonist which prevents the autophosphorylation of the receptor.
Sunitinib is well tolerated however it does have some side effects, give some of the side effects.
side effects include hypertension, fatigue, asthenia, diarrhea, and chemotherapy-induced acral erythema.
Are the side effects of sunitinib reversible?
reversible within 24 – 48h drug holiday
With the use of sunitinib, what is observed with lung, colorectal, and renal cancers?
Stable disease.
For what cancer is sunitinib aproved?
Renal cell carcinoma.
Describe angiostatin.
internal fragment of plasminogen approximately 38kDa inhibits endothelial cell proliferation well tolerated high efficacy In phase III clinical trial
Describe endostatin.
20kDa fragment of c-terminus of collagen XVII
blocks mitogen activated protein kinase (MAPK) in endothelial cell proliferation
30 times more potent than angiostatin
phase I clinical trial few side effect and tolerated well, now in phase III
patients with sarcoma, melanoma and neuroendocrine tumours
Biologically, what is avastin?
Bevacizumab – anti-VEGF monoclonal antibody
How does avastin work?
Sequesters VEGF preventing receptor activation
What is avastin approved for use in?
colorectal, lung, breast (outside the USA), glioblastoma (USA only), kidney and ovarian
What side effects may be seen with avastin?
Side effects may include heightened risk bleeding, hypertension, exacerbation CAD and other artery diseases.
What are the advantages of using inhibitors of angiogenesis?
Low toxicity and high efficacy Ideal for combination therapy Prevent micrometastasis
What are the disadvantages of using inhibitors of angiogenesis?
Angiogenic inhibitors are cytostatic rather than cytotoxic Tumour stops growing but does not disappear
Need a biological marker to measure effectiveness of the inhibitors
What is the main potential for angiogenic inhibitors?
The potential for angiogenic inhibitors seems to be in combination therapy or as a preventive of tumour metastasis
