ANTI ANGIOGENESIS: A NEW FRONTIER IN CANCER THERAPY, BETTER HOPE FOR THE PEOPLE WITH CANCER.

Authors: Tisa Cherian, Bijina Hameed, Teenu Anne Tony,                                  Pushpagiri College of Pharmacy, Thiruvalla. INDIA

 

 

ABSTRACT:

Cancer cells are having the ability to colonize and invade new areas in the body. In order to grow and metastasis, a tumor cell must have adequate blood supply. They achieve this by stimulating angiogenesis which supply nutrition to the tumor. Tumor angiogenesis is a complicated process that begins when the cancer cells release substances called growth factors such as VEGF (vascular endothelial growth factor). Anti-angiogenesis is based on the shutdown of ability of tumor cells to form new blood vessels, thereby cutting its source of food. One of the foremost benefits of targeted therapies is reduced toxicity and improved quality of life. Several anti-angiogenic drugs are undergoing the clinical trials for the treatment of cancer. Anti-angiogenesis therapy has proven to be more effective when compared to radiational therapy as radiational therapy results in damage of subsidiary cells which in turn lead to prevalence on necrosis.

INTRODUCTION:

Cancer is a large, heterogeneous class of diseases in which a group of cells display uncontrolled growth, invasion that intrudes upon and destroys adjacent tissues, and often metastasize, wherein tumor cells spread to other locations in the body through the lymphatic system and or through the blood stream. Angiogenesis is a natural process through which the body develops new blood vessels, and is thought to play a central role in the growth factors, VEGF (vascular endothelial growth factor).After the release of VEGF it attaches to nearby cells which triggers new blood vessels to sprout towards the tumor. These blood vessels provide the tumor with a steady blood supply and nutrients. By means of anti-angiogenic therapy, it provides the action by inhibiting the supply of blood vessels to the tumor prone areas.

ANGIOGENESIS AND CANCER:

 Angiogenesis is a physiological process involved in the growth of new blood vessels from pre-existing vessels. Different forms include, sprouting and intussusceptive angiogenesis.

By creating their own network of blood vessels, tumors develop an independent and reliable source of nutrients and oxygen which feeds the tumor.

To spread they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes.

ANGIOGENIC SEQUENCE:

The angiogenic process takes place by the following sequences;

A cell activated by lack of oxygen release angiogenic molecules that attract inflammatory and endothelial cells and promote their proliferation.

 

During their migration, inflammatory cells also secrete molecules that intensify the angiogenic stimuli.

The endothelial cells that form the blood vessels respond to the angiogenic call by differentiating and by secreting matrix metalloproteases (MMP), which digest the blood-vessel walls to enable them to escape and migrate toward the site of the angiogenic stimuli.

Several protein fragments produced by the digestion of the blood-vessel walls intensify the proliferative and migratory activity of endothelial cells, which then form a capillary tube by altering the arrangement of their adherence-membrane proteins.

Finally, through the process of anastomosis, the capillaries emanating from the arterioles and the venules will join, thus resulting in a continuous blood flow.

ANTI ANGIOGENESIS THERAPY:

History:

Anti-angiogenic treatment is designed to prevent the growth of new blood vessels. Without these blood vessels, the tumor no longer has a way to get the oxygen and nutrients needed to survive and grow. The history has evolved in 1970 Dr. Judah Folkman introduced the idea of anti-angiogenic agent as possible tool in the fight against cancer. In 1980 researches were able to identify VEGF growth factor which starts the growth of blood vessels; this in turn leads to the discovery of new anti-angiogenic agents.

Therapy:

Ø Anti-angiogenic drugs work by stopping the growth of new blood vessels – starving tumors of the blood and nutrients essential for growth.

Ø Inhibitors may be natural or synthetic include protese inhibitors (tissue inhibitors of matrix metalloproteinases), tyrosine kinase inhibitors, interleukins and proteolytic fragment of diverse molecules (endostatin, vasostatin, arrestin,..)

Ø Anti-angiogenic drugs prevent the vascular endothelial growth factor from binding with the receptors on the surface of the endothelial cells.

Ø Act by impeding the growth of endothelial cells inside the tumor, which in turn prevent the proliferation of tumor. So these target the blood vessels which in turn impede the development of epithelial cells in tumor.

Ø Also act in multiple ways, inhibition of endothelial cell proliferation, migration, by protease activity, tubule formation and induction of apoptosis.

Ø Angiogenic inhibitors can act synergistically with conventional treatments and tends to have non overlapping toxicities.

Ø Different anti-angiogenic drugs act by different mechanism.

Ø

INHIBITORS	USES	MECHANISMS
Bevacizumab	Cancer	Binds VEGF
VEGFR antagonist	Prostate cancer	Inhibit binding of angiogenic stimulators
Matrix metalloproteinase inhibitors		Inhibit basement membrane degradation
Tetrathiomolybdate	Cancer	Copper chelation which inhibit blood vessel growth

Ø Avastin is the first Anti-angiogenic drug developed for cancer therapy. It’s an antibody that targets the VEGF that is released by growing tumor cells, inhibiting it. Avastin in combination with intravenous 5-flurouracil-based chemotherapy is indicated for first or second line treatment of patients with metastatic carcinoma of the colon and rectum.

Ø Human diets can also act as mild angiogenesis inhibitors such as soy products, (which contain the inhibitor genistein), black raspberry extract, green tea (catechins), liquorice (glycyrrhizic acid), red wine (resveratrol).

MECHANISM OF ACTION:

Anti-angiogenic agent binds directly to the VEGF ligand to prevent its interaction with receptors on the surface of endothelial cells thereby inhibiting the biological activity of VEGF.

CONCLUSION:

Although the use of anti-angiogenesis drugs in cancer treatment strategy is still in its infancy, they have a great potential. The anti-angiogenesis approach bears fewer side effects and is generally a less risky mode of treatment. Anti-angiogenesis drugs pose no risk of a chemo brain and subsequent brain damage or of the Alzheimer’s disease for some genetically predisposed patients. As research goes on, we can today hope with greater trust that our loved ones will be saved from the throes of cancerous pain.

BIBLIOGRAPHY:

· Journal of the National Cancer Institute (JNCI).

· Journal of Young Investigators.

· American Journal of Human Genetics.

· www.newfrontierin cancer.org

COURTESY: Tisa Cherian