VASCULAR ENDOTHELIAL GROWTH FACTOR-
HISTORY-
In 1948, Issac Michaelson was the first
to postulate that a diffusible factor produced by the retina (“factor X”) was
responsible for retinal and iris neovascularization associated with conditions
such as proliferative diabetic retinopathy and central retinal vein occlusion. In
1983, Senger et al. identified a protein that could induce
vascular leakage in skin. They named this protein “tumor vascular permeability
factor” or VPF. In 1989, Ferrara and Henzel isolated a
diffusible protein from bovine pituitary follicular cells that showed cell specific
mitogenic activity for vascular endothelium. They named this protein vascular endothelial
growth factor (VEGF). They were the same molecule.
VEGF is produced by the pigment epithelial cells, all
types of neurons, glia, pericytes and endothelial cells of the retina in
response to hypoxia through hypoxia-inducible factor 1 (HIF-1), a basic
helix-loop-helix transcription factor. The VPF / VEGF [now called VEGF-A, to
differentiate from other related genes: VEGF-B, VEGF-C, VEGF-D, and PIGF
(placental growth factor))] gene is at 6p21.3. Alternative splicing gives rise
to at least 6 different protein isoforms - 121, 145, 165, 183, 189, and 206
amino acids in length. VEGF-165
is the predominant isoform and the primary mediator of neovascularization in
the eye.[12] VEGF has 3 receptor tyrosine kinases, VEGFR-1, VEGFR-2,
and VEGF-3.
VEGF is pro-angiogenic- stimulates endothelial cell proliferation
(mitogenic), invasion, migration, and enhancement of cell survival.
It also increases vascular permeability (50000 times
more potent than histamine in producing vascular leakage) by both vasodilation
and uncoupling of endothelial tight junctions. Vascular leakage is thought to
facilitate angiogenesis because the leakage of plasma proteins and fibrin
creates a gel-like environment conducive to endothelial cell growth and
migration. Increased vascular permeability may be mediated via the nitrous
oxide synthase (NOS) pathway which may explain why hypertension
has been observed in some patients treated with VEGF inhibitors.
Studies have confirmed that VEGF levels are increased
in the retina and vitreous in patients with diabetic retinopathy. Furthermore,
as expected, VEGF levels are higher in patients with PDR than with NPDR.Laser photocoagulation has been associated with a 75% decrease in VEGF
levels in s with PDR, suggesting that the formation and regression of new
vessels are correlated with VEGF levels. Elevated VEGF levels
have been confirmed in animal models of diabetic retinopathy as well. All these
point out that VEGF is the ‘factor X’ Dr Michaelson thought of 60 years ago.
Progression of diabetic retinopathy begins with
alterations in the retinal vasculature characterized by the degeneration of
retinal capillary pericytes, thickening of the basement membrane, and adhesion
of leukocytes to the endothelium. These changes are accompanied by blockages of
retinal capillaries, loss of endothelial cells, and the formation of acellular
vessels, resulting in areas of local nonperfusion. The resultant hypoxia leads
to local upregulation of factors such as VEGF.
BEVACIZUMAB –
The only two anti-VEGF agents currently approved by
the FDA for use in eye are pegaptanib (Macugen) (2004) and ranibizumab (Lucentis)
(2006) for choroidal neovascularisation (CNV). Pegaptanib is an aptamer (short single
stranded oligonucleotide) that specifically binds and inhibits the action of
the VEGF-165 isoform. Ranibizumab is a fragment of a humanized monoclonal
antibody directed against all VEGF-A isoforms, including active breakdown
products, and is a potent inhibitor of CNV.
Bevacizumab is a highly specific, recombinant,
humanized monoclonal (IgG1) antibody that selectively binds to and neutralizes
the biologic activity of human vascular endothelial growth factor (VEGF). It is
approved by FDA (label approved on 07/31/2009 for AVASTIN, BLA no. 125085) for -
- Metastatic
Colorectal Cancer
- Non-Squamous
Non−Small Cell Lung Cancer
- Metastatic
Breast Cancer
- Glioblastoma
- Metastatic
Renal Cell Carcinoma.
Intravitreal
bevacizumab has been used (off label indications) in -
MACULAR EDEMA due to –
- Central
retinal vein occlusion,
- Branch
retinal vein occlusion
- Diabetic
retinopathy,
- Uveitis
- Pseudophakic
cystoid macular edema
NEOVASCULARISATION from–
- Neovascular
glaucoma
- Proliferative
diabetic retinopathy (preoperative, intraoperative and postoperative use
has also been described)
- Wet
Age related macular degeneration
- Retinopathy
of prematurity
BEVACIZUMAB IN PDR-
PREOPERATIVE – The intravitreal injection of anti-VEGF
drugs leads to a significant reduction of neovascularization, with decreased adherence of the
fibrovascular membrane to the retina. This helps delamination and reduces intraoperative
bleeding during delamination and segmentation as the membrane
becomes fibrous with less vascularity. Mean time from intravitreal bevacizumab injection
to increase in tractional retinal detachment due to contraction of
fibrovascular tissue was 13 days in study by Arevalo et al. So
VR surgery is preferably done within 7 days of injection. Increased subretinal
bleeding are potential complications of preoperative bevacizumab.
INTRAOPERATIVE- The injection of anti-VEGF drugs at the
end of vitrectomy has been shown to prevent postoperative recurrent bleeding.However study by Romano MR et al did not find significant decrease
in rebleed.
POSTOPERATIVE- The intravitreal injection of anti-VEGF
drugs in patients with postoperative bleeding leads to resolution of the
hemorrhage. A single dose of intravitreal bevacizumab is likely to provide complete
intravitreal VEGF blockage for 4 weeks.
IN RUBEOSIS IRIDIS- In eyes with complete panretinal
photocoagulation, the combination of cryotherapy and intravitreal anti-VEGF
injection in the same surgical procedure produces a disappearance of iris
neovascularization together with a long term effect with no recurrences. In
neovascular glaucoma, preoperative anti-VEGF drugs can also facilitate
filtrating surgery.
DIABETIC MACULAR EDEMA- Anti-VEGF therapies may
be effective in reducing retinal thickness, achieving an improvement in visual
acuity.
