PHARMACOLOGICAL BASIS OF ANGIOGENESIS AND ANTIANGIOGENIC THEREPY

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ABOUT AUTHOR:
Hargobind Rajput
Punjab Technical University,
Jalandhar
hargobind.rajput@gmail.com

ABSTRCT:
The use of antiangiogenic drug is an advantage as a novel treatment for a number of conditions, ranging from cancer to psoriasis. Antiangiogenic therapy becomes a new course of treatment for cancer. This has led to the reassessment of antiangiogenic therapy for cancer, and new strategies have been proposed to increase the efficacy of these agents in this setting. Angiogenesis has also been implicated in other conditions that are notoriously difficult to treat, such as arteriosclerosis, arthritis, psoriasis and diabetic retinopathy.Increased understanding of the angiogenic process, the diversity of its inducers and mediators, appropriate drug schedules and the use of these agents with other modalities may lead to radically new treatment regimens for many of these conditions. The role of angiogenesis in different pathological settings and emerging antiangiogenic agents currently in preclinical and clinical studies are discussed in this review. However, while potential benefits are profound, limitations of antiangiogenic therapy have also been identified, suggesting that there is also a need for caution in applying these compounds to the clinical setting.


REFERENCE ID: PHARMATUTOR-ART-1835

1.1 INTRODUCTION

ANGIOGENESIS
The term “angiogenesis” was first coined by Dr. Arthur Tremain Hertig in 1935 in order to describe the formation of new blood vessels in placenta in monkeysand is defined as the formation of new blood vessels from preexisting vessels, capillaries and post capillary venules. Angiogenesis is important for the survival and growth of all cells and tissues, because the transportation of gases and nutrients in the blood through the vascular network is highly dependent on angiogenesis. [3] Angiogenesis is therefore, an incredibly beneficial phenomenon for many normal physiological processes such as normal tissue growth, embryonic development, wound healing and menstruation. [4]The improper angiogenesis in the body can lead to many severe disease states, e.g., inadequate angiogenesis can lead to ischemic tissues (tissues with restricted blood flow) and cardiac failure, while abnormally high levels of angiogenesis can result in pathological processes such as: cancer, age-related macular degeneration, atherosclerosis, rheumatoid arthritis, Crohn’s disease, diabetic retinopathy, psoriasis, endometriosis and adiposity [5].

1.2 MECHANISM OF ANGIOGENSIS
Blood vessels are joined with endothelial cells which are in direct contact with blood. Below theendothelial cells, blood vessels are surrounded by pericytes.Endothelial cells are active and selectively permeable to small peptides and proteins[6]. Angiogenesis is initiated by the release of pro-angiogenic factors which activate signaling cascades. The increased release of pro-angiogenic factors is normally in response to the release of cytokines by cells in a hypoxic or ischemic environment. Endothelial cell firstly initiate angiogenesis in all situations. The vascular endothelial growth factor (VEGF) is the most important molecule involved in the initiation of angiogenesis and cause vasodilation by releasingNitrous Oxide [7]. Increased endothelial cell permeability allows plasma proteins to enter the tissue and form a fibrin-rich provisional network to support the growth of new blood vessels [8].VEGF?s importance in initiating the angiogenic cascade is supported by the fact that its production is controlled by hypoxia inducible factor [9]. Even though VEGF is arguably the most important factor involved in angiogenesis, evidence has shown that angiogenesis in not entirely VEGF dependent [10]. In the process of angiogenesis, activated endothelial cells migrate to the desired location of the body. The endothelial cells elongate and align to create a solid sprout, while the lumen of the vessel is formed by a curvature in each endothelial cell [11]. The endothelial cells continue to proliferate, increasing the length of the sprout, until finally two hollow sprouts will join at their tips to create a loop and allow blood to flow. Pericytes then line the base of the loop and new sprouts can grow from its apex [12]. The exact process of these last steps of angiogenesis is not entirely understood, but the process is believed to be guided by specialized cells at the front of the sprout called “tip cell”.



Figure 1: Mechanism of angiogenesis[13]

1.3 BODY CONTROL MECHANISM OF ANGIOGENESIS
Angiogenesis is an important natural process occurring in both the body of healthy and diseased individuals. Angiogenesis occurs in the healthy body for healing wounds and for restoring blood flow to tissues after injury. In females angiogenesis also occurs during the monthly reproductive cycle and during pregnancy. The healthy body controls angiogenesis through a series of "on" and "off" switches: The main "on" switches are known as angiogenesis stimulating growth factors and the "off switches" are known as angiogenesis inhibitors.When angiogenic growth factors are produced in excess of angiogenesis inhibitors the balance is tipped in favours of blood vesselgrowth. When inhibitors are present in excess of stimulators angiogenesis is stopped. The normal healthy body maintains a perfect balance of angiogenesis modulators. In general angiogenesis is "turned off" by the production of more inhibitors than stimulators. [14]

1.4  Table 1: HISTORICAL HIGHLIGHTS IN THE FIELD OF ANGIOGENESIS

Sr.No.

       Year

Description

1

1787

British surgeon Dr. John Hunter first called the term "angiogenesis" to describe blood vessels growing in the (Deer) Reindeer antler.

2

1935

Boston pathologist Dr. Arthur Tremain Hertig describes angiogenesis in the placenta of pregnant monkeys.

3

1971

Surgeon Judah Folkman supposes that tumour growth is dependent upon angiogenesis.

4

1975

The first angiogenesis inhibitor is discovered in cartilage by Dr. Henry Brem and Dr. Judah Folkman

5

1989

Vascular endothelial growth factor is discovered Dr. Napoleone Ferrara.

6

1992

The first clinical trial of an anti angiogenic drug (TNP-470) begins in cancer patients.

7

1997

The first angiogenesis-stimulating drug (Becaplermin, Regranex) is FDA-approved for treatment of diabetic foot ulcers.

8

1998

The first angiogenesis-stimulating laser is FDA-approved for the treatment of severe, end stage coronary disease.

9

1999

The first vascular targeting therapy is FDA-approved for treatment of age-related macular degeneration.

10

2004

Pegaptanib  becomes the first anti-VEGF drug to be FDA approved for the treatment of age-related macular degeneration.

11

2005

Sorafenib (Nexavar) is a multi-tyrosine kinase inhibitor that demonstrates significantly longer progression-free survival vs. placebo in patients with advanced renal cancer in a randomized phase 3 trial.

1.5 ANGIOGENESIS AND METASTASIS
Escape of the tumor cell from the confines of the primary tumor to distant body parts is the pre-requisite for hematogenous metastasis. This escape route is provided by the tumor vasculature. Thus, it was envisioned that inhibition of angiogenesis will also lead to inhibition of metastasis. This phenomenon was demonstrated by very elegant mouse model studies using angiostatin [20-21]. Angiostatin was also demonstrated to be secreted by some primary tumors leading to restricted growth of the metastasis leading to “dormancy” of the metastasis. Mice deficient in angiogenesis (Id1 & Id3 deficient) showed significantly less tumor take rates [22]. Independent studies showed absence of metastasis in angiogenesis deficient mice [23-24].Defective angiogenesis was attributed to impaired VEGF-dependent recruitment of precursor endothelial cells from the bone marrow to the newly developing tumor vasculature [25].

1.6  LYMPHANGIOGENESIS
Metastasis of malignant tumors to regional lymph nodes is one of the early signs of cancer spread in patients, and it occurs at least as frequently as hematogenous metastasis [26]Particularly, in cancers, such as breast cancer, lymphatic metastasis is a predominant route for tumor spread. The contribution of lymphatic system to the tumor growth is an area that is relatively less studied. However, lymphatic vessels are speculated to contribute to tumor growth and metastasis in a variety of ways. The VEGF, FGF2 and PDGF produced by vascular endothelial cells are proposed to be involved in the activation of lymphatic endothelial cells, which in turn produce matrix metalloproteases and urokinase plasminogen activator (uPA) that can promote malignant tumor growth. Thus, there exists a synergistic crosstalk between the tumor and the lymphatic vessels and blood vessels.

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