This document discusses angiogenesis, the process by which new blood vessels form from pre-existing vessels. It covers the positive and negative regulators of angiogenesis, as well as conditions of excessive and insufficient angiogenesis. The document also reviews several drugs that target angiogenesis, including inhibitors of endothelial cell activation, intracellular signaling, and extracellular matrix remodeling. These drugs show promise in treating diseases driven by abnormal angiogenesis like cancer and retinal diseases.

2. • Introduction
• Process of Angiogenesis
• Positive and Negative
regulators of Angiogenesis
• Conditions of Excessive and
Insufficient Angiogenesis
• Drugs Targetting
Angiogenesis
• Antiangiogenic therapy in
various Diseases

3. Terminology

4. Introduction
• The growth of new capillaries from existing blood vessels, which
is called angiogenesis, is mediated by a complex multistep
process comprising a series of cellular events that lead to
neovascularization.
• It occurs throughout life in both health and disease, beginning in
utero and continuing on through old age.
• Capillaries are needed in all tissues for diffusion and exchange of
nutrients and metabolites.
• Changes in metabolic activity lead to proportional changes in
angiogenesis and, hence, proportional changes in capillarity.
• Oxygen plays a pivotal role in this regulation.

5. History
• The term angiogenesis was coined in 1787 by
Dr. John Hunter, a British surgeon.
• He tied the artery supplying one of the deer’s
antler . Hunter expected deprivation of blood
supply would lead to fall off. But after a week
or two he week or two he found that the
artery was still blocked and around the
blockage he observed a network of new
vessel growth.
• In 1971, Dr Judah Folkman laid the
foundation of angiogenesis, with the
hypothesis that solid tumors caused new
blood vessel growth (angiogenesis) in the
tumor microenvironment by secreting pro-
angiogenic factors.

6. Angiogenic Process
Types

7. Sprouting angiogenesis
• Sprouting angiogenesis is characterized by sprouts
composed of endothelial cells, which usually grow
toward an angiogenic stimulus such as VEGF-A.
• Sprouting angiogenesis can therefore add blood
vessels to portions of tissues previously devoid of
blood vessels.

11. Intussusceptive Angiogenesis
• Intussusceptive angiogenesis involves formation of blood
vessels by a splitting process in which elements of interstitial
tissues invade existing vessels, forming transvascular tissue
pillars that expand.
• Intussusceptive angiogenesis is also called splitting
angiogenesis because the vessel wall extends into the lumen
causing a single vessel to split in two.
• This type of angiogenesis is thought to be fast and efficient
compared with sprouting angiogenesis because, initially, it
only requires reorganization of existing endothelial cells and
does not rely on immediate endothelial proliferation or
migration.
• Intussusceptive angiogenesis occurs throughout life but plays
a prominent role in vascular development in embryos where
growth is fast and resources are limited

12. Scanning electron micrographs of Mercox casts
The small holes indicated by arrows have diameters of about 2 µM.
The holes correspond to tissue pillars that extend across the capillary lumina.
Scale bars: (a) 12 and (b) 20 µM.
a.Fetal chicken lung
microvasculature.
b.Rat lung microvasculature at postnatal
day 44.

13. The process begins with protrusion of opposing endothelial cells into the
capillary lumen. (c,c') An interendothelial contact is established and
endothelial junctions are reorganized. (d,d') The endothelial (EC) bilayer and
basement membranes (BM) are perforated centrally allowing growth factors
to enter. Fibroblasts (Fb) and pericytes (Pr) migrate into the site of
perforation where they produce collagen fibrils (Co) and other components
of ECM forming a tissue pillar.

14. Positive Regulators
 GROWTH PROMOTERS:
• VEGF
• PDGF
• TGF
• Insulin like GF
 CYTOKINES :
• IL- 1,6,8
• TNF
 PROTEASES:
• MMP
• CATHEPSIN
 ADHESION MOLECULES AND
RECEPTORS :
• ANG 1
• AT 1
• Selectin
• Integrins
 Enzymes:
• Cyclo-oxygenase
• Thymidine Phosphorylase
 OTHERS :
• Hypoxia
• Nitric oxide synthase
• Estrogen

15. Negative regulators
 Protein fragments
• Angiostatin
• Endostatin
 Antiangiogenic
• antithrombin III
• Prolactin
 Soluble mediators
• Thrombospondin-1
• Interferons
• Interleukins
 Tissue inhibitors of
metalloproteinaise Matrix
• Arrestin
• Canstatin
• Fibulin
 Other angiostatics
• 2-methoxyestradiol
• PEX
• Vasostatin

16. INSUFFICIENT ANGIOGENESIS
• Ischemic tissue injury e.g.
critical limb ischemia in
diabetes
• Cardiac failure
• Delayed healing of gastric
ulcers
• Recurrent aphthous
ulcerations
• Organ dysfunction occurring in
pre-eclampsia
• Age-related diseases e.g.
nephropathy and osteoporosis
• Purpura, Telangiectasia
• Pulmonary fibrosis &
Emphysema
• Amyotrophic Lateral Sclerosis
• Alzheimer's disease

17. EXCESS ANGIOGENESIS
• Cancer
• Arthritis
• Psoriasis
• Blinding retinopathy
• Atherosclerosis
• Restenosis
• Transplant arteriopathy
• Warts
• Scar keloids
• Synovitis
• Osteomyelitis
• Asthma
• Nasal polyps
• Choroideal and intraocular
disorders
• Retinopathy of prematurity
• Diabetic retinopathy
• AIDS
• Endometriosis

18. Clinical modulation of angiogenesis

19. The VEGF family of proteins
VEGF is a member of a family of 6 structurally related proteins that regulate the growth
and differentiation of multiple components of the vascular system, especially blood and
lymph vessels. The angiogenic effects of the VEGF family are thought to be primarily
mediated through the interaction of VEGF with VEGFR-2.
There are 4 major isoforms of VEGFA (VEGF), each coded for by a different
portion of the VEGF gene. These isoforms are VEGF121, VEGF165, VEGF189,
and VEGF206. Although these isoforms behave identically in solution, they differ in
their ability to bind heparin and the extracellular matrix .

20. Mechanism of Action
• VEGF plays a crucial
role in physiological
angiogenesis, as well
as, has a role in
several human
cancers, diabetic
retinopathy,
rheumatoid arthritis,
and atherosclerosis.

22. Functions
• ANGIOGENESIS:
 Migration of endothelial cells
 Mitosis of endothelial cells
 Matrix metalloproteinase activity
 Creation blood vessel lumen
• CHEMOTACTIC:
 Macrophages and granulocytes
• VASODILATION
 By NO release

23. PDGF
Induces fibroblast,
smooth cell and
endothelial cell
proliferation
PDGF A, B, C,D
PGDFR
Alpha and beta
Tyrosin kinase
receptors
Expressed in
macropaghes,
platelets and
endothlium
Stimulates angiogenesis
in vivo
Involved in
vessel
maturation
and
recruitment of
pericytes

24. FGF-2 are found in the brain and pituitary gland. FGF-2 shows angiogenic activity in vivo. The
effects of FGFs are mediated via high-affinity tyrosine kinase receptors, of which at least four
members have been described. FGF-2 is implicated in both physiological and pathological
angiogenesis.
FGF-2 is thought to play a role in the growth and neovascularization of solid tumors.
High levels of FGF-2 are present in the EC of Kaposi’s sarcoma and in the serum and urine of
patients with many types of advanced cancinomas

26. Transforming Growth Factor β
• Transforming growth factor-β (TGF-β) has three
isoforms of TGF-β (TGF-β1, -β2, -β3).
• TGF-β participates in angiogenesis, cell regulation
and differentiation, embryonic development, and
wound healing and also has potent growth
inhibition properties.
• The TGF-β receptors are classified as type I, II, or III.

27. • Type I and II receptors contain
serine/threonine kinase domains in
their intracellular protein regions,
while type III does not possess
kinase activity but thought to
participate in transferring TGF-β
ligands to type II receptors.
• TGF-β ligands bind to and stimulate
type II receptors that recruit, bind
and phosphorylate type I receptors,
activating downstream signaling
proteins known as SMADs, which
are believed to be specific to the
TGF-β family.
• Activated SMADs eventually move to
the nucleus where they can interact
with different transcription factors,
regulating gene expression in a cell-
specific manner.
• SMADs have been found to be
mutated at a high rate in pancreatic
and colorectal cancer, and are found
in other cancers as well, indicating
that SMAD mutations and aberrant
regulation likely contribute to the
development of cancers

28. • TGF-β is thought to have both pro- and anti-angiogenic
properties, depending on the levels present.
• Low levels of TGF-β contribute to angiogenesis by upregulating
angiogenic factors and proteases, while high doses of TGF-β
stimulate basement membrane reformation, recruit smooth
muscle cells, increase differentiation and inhibit endothelial cell
growth and proliferation.
• Overexpression of TGF-β1 has been seen in gastric, breast, colon,
hepatocellular, lung and pancreatic cancer and is correlated with
tumor angiogenesis in addition to metastasis, progression and
poor prognostic outcome.
• High levels of endoglin, part of the TGF-β receptor complex, have
also been detected in cancers and are associated with tumor
metastasis.

29. Adhesion Molecules

31. Integrins
• In contrast to normal endothelium, angiogenic endothelium
overexpresses specific members of integrin family of ECM-
binding proteins that mediate EC adhesion, migration and
survival
• αvβ3 , αvβ5 , α5β1 mediates spreading and migration of ECs
• In addition αvβ3 forms cell-surface complexes with matrix
metalloproteinases that cleave ECM proteins

32. Matrix metalloproteinases
• Matrix metalloproteinases (MMPs), also known as matrixins,
are calcium-dependent zinc-containing endopeptidases.
• The MMPs belong to a larger family of proteases known as
the metzincin superfamily.
• Collectively, these enzymes are capable of degrading all kinds
of extracellular matrix proteins, but also can process a number
of bioactive molecules.
• They are known to be involved in the cleavage of cell surface receptors,
the release of apoptotic ligands (such as the FAS ligand),
and chemokine/cytokine inactivation.
• MMPs are also thought to play a major role in cell behaviors such
as cellproliferation, migration(adhesion/dispersion), differentiation, ang
iogenesis, apoptosis, and host defense.

33. Drugs inhibiting angiogenesis

34. Inhibitors of Activated EC
• TSP-1 is constitutively produced by normal cells and is the
main physiological inhibitor of angiogenesis.
• TSP-1 is downregulated, while the angiogenic activity is
increased, during tumorigenesis.
• Accordingly, mutation of the tumor suppressor p53 gene
results in the loss of TSP1 production and a switch to the
angiogenic phenotype.
• Decrease in angiogenesis and inhibition of tumor growth
occurs with overexpression of TSP-1.

35. • Angiostatin and Endostatin, are derived from the tumor
cells themselves.
• Angiostatin suppresses the growth of a number of
human tumors and their metastases, in mice.
• Endostatin, a fragment of collagen, derived through
elastase-mediated cleavage, has been isolated from the
media of hemangioendothelioma (EOMA) cells.
• Endostatin specifically suppresses endothelial cell
proliferation and shows potent inhibitory activity against
many tumor cell lines.
• In recent times, a potent antiangiogenic agent aaAT
(antiangiogenic antithrombin) has been purified from
small cell lung cancer.

36. • The anti-angiogenic activity of fumagillin was discovered
when a dish of cultured endothelial cells was accidentally
contaminated with the fungus Aspergillus fumigatus
Fresenius, a fumagillin producing organism.
• The contaminated endothelial cells stopped proliferating but
showed no outward signs of toxicity.
• After isolating fumagillin as the source of the activity, a series
of synthetic analogues were produced that also inhibited
endothelial cell growth and proliferation without cytotoxic
effects in vitro, and limited tumor-induced angiogenesis in
xenograft models.
Fumagilin

37. • TNP-470 (AGM-1470), a synthetic derivative of the antibiotic
fumagillin, is the most studied angiogenic inhibitor.
• TNP-470 has been shown to inhibit type 2 methionine
aminopeptidase, resulting in the abrogation of the processing
of methionine, which may lead to the inactivation of
unidentified proteins essential for EC growth.
• TNP-470 also affects cell cycle through activation of p53,
leading to an increase in the G1 cyclin-dependent kinase
inhibitor p21CIP/WAF and subsequent growth arrest.
• TNP-470 is effective in the treatment of a wide variety of
tumors and has shown to regress the growth of squamous
cell cancer of the cervix.

38. Side Effects
• Toxicities seen were mainly neurological including problems
with motor coordination, short-term memory and
concentration, dizziness, confusion, anxiety, depression.
Disadvantages
• Short half life
• Poor oral bioavailability
Lodamin- improved micelle formulation of TNP-
470 with increased half life and better bioavailability.
• Under Clinical Trials.

39. Thalidomide
• Thalidomide (THALOMIDE) is best known for the severe, life-threatening
birth defects it caused when administered to pregnant women.
• Available only under a restricted distribution program and can be prescribed
only by specially registered physicians who understand the risk of
teratogenicity if thalidomide is used during pregnancy.
• It has orphan drug status for mycobacterial infections, Crohn's disease, HIV-
associated wasting, Kaposi sarcoma, lupus, myelofibrosis, brain
malignancies, leprosy, graft-versus-host disease, and aphthous ulcers.
• Thalidomide has been reported to decrease circulating TNF-α in patients
with erythema nodosum leprosum.
• The anti–TNF-α effect has led to its evaluation as a treatment for severe,
refractory rheumatoid arthritis.

40. • Lenalidomide (REVLIMID) and pomalidomide (CC-4047, Actimid®),
thalidomide analog with 50,000 fold more potent with
immunomodulatory and anti-angiogenic properties.
• Lenalidomide and pomalidomide also lack some of the side-effects
seen with thalidomide such as constipation, peripheral neuropathy
and the sedative effects.
• In 2006, lenalidomide was approved by the FDA for use in relapsed
multiple myeloma in combination with dexamethasone, while
pomalidomide is currently in clinical development.
• The tubulin-binding drug Combretastatin A-4, exhibits a selective
toxicity for proliferating EC by induction of apoptosis.

41. Inhibitors of EC intracellular signaling
• Genistein and Lavendustin A have the ability to
block the activity of the angiogenic factors by
inhibiting the protein tyrosine kinase, which is the
second messenger system of these factors.
• Ang-2 Inhibits Tie-2 leading to inhibition of
angiogenesis.

42. Inhibitors of ECM Remodeling
• Activated EC secrete proteases, which degrade the extracellular
tissue to facilitate endothelial penetration.
• The MMPs are capable of degrading different protein types. PAs
activate the plasminogen into plasmin, which degrades several
components of extracellular matrix (ECM).
• Metalloproteinase inhibitors (MMPI) are theoretically the most
promising antiangiogenic agents.
• Batimastat was the first MMPI to be evaluated in humans, but
the trials were suspended due to its low oral bioavailability.
• MMPIs that have entered clinical trials for an oncologic
indication include prinomastat, BAY 12-9566, BMS-275291,
marimastat, MMI270(B), and Metastat.

43. • Carboxyamidotriazole (CAI) is a calcium channel
inhibitor that blocks tumor cell migration and
proliferation and has antiangiogenic activity.
• CAI retards metastasis in experiment animals and has
completed phase I clinical trials in cancer patients.
• Published results from trials showed disease
stabilization in 49% of the patients who had disease
progression before starting CAI treatment.

44. Inhibition of Cell Adhesion Molecules
• αv β3 integrin, an adhesion receptor for ECM components is
present selectively on activated endothelial cells, and
therefore, is an attractive target for antiangiogenic therapy.
• Both the peptide antagonist of αv β3 and an anti-αv β3
monoclonal antibody, inhibit adhesion-dependent signal
transduction by angiogenic factors, leading to apoptosis of the
activated endothelium.
• These compounds have been found to inhibit angiogenesis.
• Currently the clinical potential of an anti-αv β3 antibody,
Etaracizumab, is being evaluated in various phases of
clinical trials, for many patients with late-stage cancer.

45. Inhibitors of Angiogenic Mediators or
Their Receptors
Monoclonal antibody therapies
• Bevacizumab- It is a humanized monoclonal antibody that binds
VEGF-A and hinders its access to the VEGF receptor, interrupting
angiogenic signalling.
• Combined with 5-FU, bevacizumab is used in metastatic colorectal
cancer.
• Added to conventional chemotherapy, it improves survival in
metastatic non-small cell lung cancer, breast cancer, clear cell
renal carcinoma and glioblastoma.
• Deafness due to neurofibromatosis can be reversed by growth
inhibitory effect of bevacizumab.
• Being an antibody, bevacizumab is administered by i.v. infusion
every 2–3 weeks.
• Adverse effects are—rise in BP, arterial thromboembolism leading
to heart attack and stroke, vessel injury and haemorrhages, heart
failure, proteinurea, gastrointestinal perforations, and healing
defects.

46. Cetuximab
• This inhibitor of EGF receptor is a chimeric monoclonal antibody
directed to the extracellular domain of the EGF receptor.
• Binding to the receptor, it prevents transmembrane signalling
resulting in blockade of cell growth, proliferation and metastasis.
Survival of tumour cells is jeopardised.
• Infused i.v. in a loading dose followed by weekly or fortnightly
maintenance doses, cetuximab is approved for
advanced/metastatic squamous carcinoma of head and neck in
combination with radiation and/or cisplatin based chemothrapy.
• EGF receptor positive metastatic colorectal cancer is another
indication, either in combination with irinotecan + cisplatin or as
monotherapy in resistant cases.
• Adverse effects are acneform skin rash, itching, headache and
diarrhoea.
• Anaphylactoid reactions may occur during infusion.
• Hypomagnesemia and interstitial lung disease are infrequent.

48. Rituximab
• It is a chimerized MAb that binds to the CD20 B-cell
antigen expressed on the surface of B-lymphocytes and
B-cell lymphomas.
• Rituximab binding to the antigen promotes apoptosis
through transmembrane signalling as well as by ADCC
and CDC mechanisms.
• It is indicated in B-cell lymphoma, non-Hodgkin
lymphoma and chronic lymphocytic leukaemia, both as
single agent as well as in combination with cytotoxic
chemotherapy.
• Adverse effects are infusion reactions consisting of chills,
fever, urticarial rashes, pruritus, dyspnoea and
hypotension.
• Late onset neutropenia and depletion of B-lympocytes
are the other problems.

49. Other MAbs

50. • Aflibercept (VEGF-trap)—Aflibercept (VEGF-trap, AVE0005) is a
soluble fusion protein of the human extracellular domains of
the VEGFR-1 and -2 receptors and the Fc portion of human IgG.
• Aflibercept binds to both VEGF-A and PlGF with a higher affinity
than monoclonal antibodies and essentially renders the VEGF-A
and PlGF ligands unable to bind and activate cell receptors.
• In vitro, aflibercept showed significant anti-proliferative activity
and completely blocked VEGF-induced VEGFR-2
phosphorylation when added in a 1.5 molar excess of VEGF.
• In Phase II trials as a single agent in ovarian cancer
• Phase II trial of aflibercept in NSCLC
• Phase II trial of aflibercept in metastatic breast cancer
• Additional clinical trials of aflibercept are ongoing in a variety
of cancers including prostate, colorectal, ovarian, thyroid, RCC,
and brain cancers.

51. Receptor Tyrosine Kinase Inhibitors
Sunitinib
• This is a small molecular synthetic VEGF receptor-2
inhibitor, which enters cells and competitively blocks ATP
binding to the tyrosine kinase domain, thereby preventing
phosphorylation of angiogenic regulatory proteins.
• Sunitinib inhibits multiple receptor tyrosine kinases like
platelet derived growth factor (PDGF) receptor α and β, c-
KIT, RET, etc.).
• It is used in metastatic renal cell carcinoma and resistant
g.i. stromal tumour (GIST).
• Sunitinib is administered orally daily in 4 week cycles.
• Adverse effects are hypertension, rashes, diarrhoea,
weakness, bleeding, proteinurea, hypothyroidism,
neutropenia, rarely CHF.

52. • Sorafenib (Nexavar®, BAY 43-9006) is an oral inhibitor of the
intracellular Raf kinase (BRaf, C-Raf), therefore targeting the
MAPK and Raf/MEK/ERK signaling pathways.
• Sorafenib also inhibits VEGFR (-2 and -3), PDGFR-β and c-kit
(for review see reference136).
• Used in colon, pancreatic and breast, by inhibiting Raf
kinase, and blocking phosphorylation of ERK 1/2, an
indicator of MAPK pathway blockade

53. Semaxanib
• Semaxanib (SU5416) was the first tyrosine kinase
inhibitor tested in humans and is an inhibitor of
VEGFR.
• Semaxanib was tested in combination with 5-
FU/leucovorin compared to 5-FU/leucovorin alone in
a Phase III trial against metastatic colorectal cancer.

54. Imatinib
• It is the first selectively targeted drug to be introduced for
treatment of a malignancy.
• It inhibits a specific tyrosine protein kinase labelled ‘Bcr-Abl’
tyrosine kinase expressed by chronic myeloid leukaemia (CML) cells
and related receptor tyrosine kinases including platelet derived
growth factor (PDGF) receptor that is constitutively active in
dermatofibrosarcoma protuberans, stem cell receptor and c-kit
receptor active in gastrointestinal stromal tumour (GIST) which is a
rare tumour.
• Imatinib is found to be strickingly successful in chronic phase of
CML (remission in >90% cases) and in metastatic c-kit-positive GIST,
in which it is the drug of choice.
• It is also indicated in dermatofibrosarcoma protuberans.
• Resistance to imatinib develops by point mutations in Bcr-Abl
tyrosine kinase affecting its affinity for imatinib.
• Adverse effects are abdominal pain, vomiting, fluid retention,
periorbital edema, pleural effusion, myalgia, liver damage and CHF.

55. Nilotinib
• It is a second generation Bcr-Abl, PDGF-receptor β and c-
kit receptor tyrosine kinase inhibitor with 20–50 fold
higher affinity for these kinases than imatinib.
• Thus, it can overcome resistance to imatinib due to Bcr-
Abl mutation and is effective in chronic CML
nonresponsive to imatinib.
• It is only 30% bioavailable orally, but absorption is
improved by food. It is also useful in accelerated phase of
CML.
• Thus, it is an alternative drug in imatinib nontolerant or
resistant cases of CML, and has now been used as a first
line drug as well.
• Adverse effects are similar to imatinib; Q-T prolongation
has also been noted.

56. • Geftinib – binds to
tyrosine kinase domain
of EGF receptor (Erbβ1,
or HER1)- prevents
phosphorylation of
regulatory proteins
• Indicated for Non-small
cell lung Ca.(EGFR
activating mutation)
• ADR: Skin rash, diarrhea,
liver dysfunction,
Interstitial lung disease
EGF receptor inhibitors

57. • Erlotinib (Tarceva®, OSI-774) is an oral inhibitor of the
EGFR/HER1 receptor tyrosine kinase.
• Erlotinib is believed to exert anti-cancer activity at least
partially through the inhibition of expression of pro-
angiogenic factors.
• Indicated in non-small cell lung cancer.
• It has been combined with gemcitabine for advanced/
metastatic pancreatic cancer as well.
• Adverse effects - hepatic dysfunction have occured in patients
with preexisting liver disease.

58. Proteasome inhibitor
• Proteasomes are packaged complexes of proteolytic enzymes
which degrade several intracellular signalling proteins that
control cell cycle, apoptosis and survival response.

59. ADR: Peripheral neuropathy
Diarrhea
BM depression
Thrombocytopenia.
Used in Multiple myeloma
Refractory mantle cell
lymphoma
BORTEZOMIB: Boron containing comp which covalently binds to
proteasome & inhibits its activity disrupting intracellular signalling
pathways (NF-ƙB pathway)
NF-κB is a transcription factor that
normally resides in the cytoplasm bound
to an inhibitory protein IκB.
Hypoxia, cytotoxic drugs, DNA breaks and
other stressful stimuli activate
proteasome which cleaves and degrades
IκB to release NF-κB which then
translocates to the nucleus and transcripts
certain genes to produce molecules that
oppose apoptosis and promote cell
proliferation.
By inhibiting proteasome, bortezomib
prevents the breakup and degradation of
IκB, so that NFκB is not released to
transcript survival molecules.
It also causes build up of ‘Bax’, an
apoptosis promoting protein, and affects
other regulators of cell cycle.

60. Other anticancer Angiogenic Agents
• Sirolimus, Temsirolimus and Everolimus for advanced renal
cell carcinoma

61. • Perifosine is a lipid-based phosphatidylinositol
analogue that inhibits AKT by preventing
translocation of AKT to the cell membrane.
• Perifosine is currently in clinical trials for several
different cancers.

62. MAPK- Farnesyltransferase Rho and Ras
Inhibitors
• During Ras activation, a farnesyl group is transferred onto a
cysteine residue in the C-terminal end of Ras, enabling Ras to
interact with intracellular membranes via the farnesyl group.
• Without farnesylation, Ras can no longer interact with regulatory
and effector molecules in the cell membrane and no MAPK
pathway activation occurs.
• Ras is also involved in stabilizing HIF-1α and targeting Ras has
been shown to destabilize HIF-1α and decrease HIF
transcriptional activity.
• Two farnesyltransferase inhibitors are tipifarnib (zarnestra®,
R115777) and lonafarnib (Sarasar®, SCH66336).
• Tipifarnib has been the most studied farnesyltransferase inhibitor
thus far, with anti-angiogenic, anti-proliferative and pro-apoptotic
activity in preclinical studies.

64. Interferon Alpha-2a to Treat Hemangiomas
Hemangiomas occur in 1 out of
100 neonates and in 1 out of 5
premature infants. About 10% of
them may have serious tissue
damage that includes interfering
with a vital organ, obstructive
airway, heart failure, or
Kasabach-Merritt syndrome.
Kasabach-Merritt syndrome, a
platelet-trapping
thrombocytopenic coagulopathy,
and hepatic hemangiomas have
a mortality rate of 30%- 50%.
Interferon alpha-2a (IFNα-2a) is an
angiogenic agent that could be
useful for treating these
hemangiomas. It was also found
that therapy with IFNα-2a
accelerated the tumor regression in
18 of 20 hemangioma patients.
IFNα-2a suppresses the production
of FGFs in human tumor cells, which
could work for hemangiomas
because bFGF is an angiogenic
factor that is overexpressed in
hemangiomas.

65. Ocular Neovascularization
• Ocular neovascularization, includes agerelated macular degeneration (AMD),
proliferative diabetic retinopathy (PDR), diabetic macular edema (DME),
neovascular glaucoma, corneal neovascularization (trachoma), and
pterygium.
• Inhibiting VEGF is presently an antiangiogenic therapy that is approved for
ophthalmic conditions.
• Two currently approved antiangiogenic therapies for ophthalmic diseases
are an anti-VEGF aptamer (pegaptanib, Macugen) and a Fab fragment of a
monoclonal antibody directed against VEGF (ranibizumab, Lucentis).
• A photodynamic therapy called Visudyne (QLT Therapeutics/CIBA Vision)
has shown effectiveness for treating macular degeneration and was the first
FDA-approved blood vessel therapy for eye disease in 2004.

66. Rheumatoid Arthritis
Clinical trials of angiogenic
inhibitors have not been
performed yet in patients
with arthritis; however,
minocycline and TNP-470
(also known as AGM-470)
have shown efficacy as
potent inhibitors of the
vascular pannus in
experimental arthritis.

67. Cancer
• Angiogenesis plays a critical
role in the growth and
spread of cancer because a
blood supply is necessary
for tumor growth and
metastases.
• Many natural or synthetic
angiogenesis inhibitors, also
called antiangiogenic
agents, have been studied
to prevent or slow the
growth of cancer.
• Bevacizumab (Avastin) is a
monoclonal antibody that
specifically recognizes and
binds to VEGF, which
prevents VEGF from
activating VEGFR.
The other FDA-approved
antiangiogenic drugs are
sorafenib (Nexavar) for
hepatocellular carcinoma
and kidney cancer, sunitinib
(sutent) for kidney cancer
and neuroendocrine
tumors, pazopanib
(votrient) for kidney cancer
and neuroendocrine
tumors, and everolimus
(Afinitor) for kidney cancer.

68. Selected angiogenesis inhibitors in clinical trials