Formation of new blood vessels from pre-existing vessels is called angiogenesis and is purely a physiological process normal and vital in growth development, in wound healing and in granulation tissue. The process of angiogenesis regularly occurs during growth and development in children and less often in adults except during the healing of a deep cut or after menstruation.
Angiogenesis is a fundamental step involved in the transition of tumour from its early state to a malignant one. The growing tumour requires nutrients and oxygen to help them grow and invade tissues in close vicinity and metastasize. Further the cancer cells recruit new blood vessels for helping the cancer cells grow and spread. The drugs which can interrupt this process can be used in treating cancer.
Angiogenesis inhibitors are substances that are used for inhibiting the growth of new blood vessels. Some inhibitors act by the normal part of the body’s control, some administered as drug and some come from the diet consumed. Though angiogenesis inhibitors were once considered as potential for the treatment of many types cancer, but were not seen in practice.
Blood supplies are essential for cancerous cells to grow beyond a few millimetres in size. The cancerous cells stimulate nearby normal cells to produce angiogenesis signalling molecules. The new blood vessels provide growing tumours with oxygen and nutrients to invade nearby tissue to spread throughout the body to form new colonies of cancer cells called metastases. This has paved for the use of angiogenesis inhibitors in the treatment of cancer.
Angiogenesis are of two types, sprouting which occur in well-characterized stages. The rate at which the sprouting occurs requires several millimetres per day, and allows new vessels to grow across the gaps in the vasculature. The second type of angiogenesis is called intussusceptions also called splitting angiogenesis, was first identified in neonatal rats and has for phases.
Intussusceptions are important since it is reorganization of existing cells. The process allows for an increase in the number of capillaries without any corresponding increase in the number of endothelial cells.
Angiogenesis can be stimulated by several means, which is not well characterized. The current knowledge suggests that an increase in muscle contraction can increase angiogenesis which is due to an increase in the production of nitric oxide during exercise. The stimulation by means of chemical is performed by various angiogenic proteins, which include several growth factors.
The sequence of events in the angiogenic process is when a cell is activated by angiogenic molecules, attracts inflammatory and endothelial cells and promotes their proliferation. Inflammatory cells also secrete molecules increasing the angiogenic stimuli. During their migration endothelial cells which form the blood vessels respond to the angiogenic stimuli by differentiating and by secreting matrix metalloproteases(MMP), which digest the blood-vessel walls enable them to escape and migrate toward the site of the angiogenic stimuli.
The digestion of the blood-vessel walls produce several protein fragments which will intensify the proliferative and migratory activity of endothelial cells forming a capillary tube by altering the arrangement of their adherence-membrane proteins. The capillaries emanating from the arterioles and the venules will join finally by a process of anastomosis and result in a continuous blood flow.
The anti-angiogenesis drugs will not act directly on cancer cells instead target blood vessels that are required by the cancer cells to survive and grow. The process may help to prevent growth of new tumours.
Angiogenesis will bind signalling molecules, similar to vascular endothelial growth factor (VEGF) creating signals within these cells and initiate the growth and survival of new blood vessels.
Angiogenesis inhibitors interfere with various steps and serve as a potential in cancer therapy. Angiogenesis can be considered as a target to fight against disease characterized by either poor vascularisation or abnormal vasculature. The modern clinical application of principles of angiogenesis can be divided into two main broad classes anti-angiogenic therapies to fight against cancer and malignancies and second class pro-angiogenic therapies to treat cardiovascular diseases.
The drugs used as antiangiogenic inhibitors include bevacizumab for glioblastoma and are approved by FDA. Bevacizumab used in combination with other drugs are used to treat metastatic colorectal cancer, non-small cell lung cancers and metastatic renal cell cancer and showed significant improvement in patients. Other drugs approved by FDA having antiangiogenic activity include everolimus, sorafenib, sunitinib and pazopanib. The angiogenesis inhibitors are also tried in treating disease condition involving development of abnormal blood vessel growth in non cancer conditions such as macular degeneration.
Botanist has identified many herbs as potential for the treatment of cancer. The herbs used naturally as anti- cancer treatment and as anti-angiogenic through multiple interdependent processes include Artemisia annua, Viscum album, Scutellaria baicalensis, Curcuma longa, Magnolia officinalis, Camellia sinensis, Ginkgo biliba, Quercetin, Poria cocos, Zingiber officinalis, Panax ginseng, Rabdosia rubescens and Chinese destagnation herbs. Natural health products target the molecular pathways other than the angiogenesis, including epidermal growth factor receptor, nuclear factor kappa-B transcription factor, protein kinases, Bcl-2 protein, HER2/neu gene, cyclo-oxygenase-2 enzyme and coagulation pathways. Quality assurance of extracts of natural product, dose repose, appropriate combinations and potential toxicities are essential prior to clinical trials.
The chemotherapeutic agents work by attacking cells in the body that grow and divide quickly. They can also harm other cells that divide quickly such as cells present in bone marrow, skin, mouth and intestine. The net result lead to serious side effects like low blood cell count, hair loss, nausea, diarrhoea and mouth sores.
The anti-angiogenesis drugs will not harm these normal cells. The angiogenic inhibitors act on parts of the blood and blood vessels and can likely cause side effects such as rise in blood pressure; though the side effects is serious can be cured by proper medication. The side effects such as serious bleeding, blood clots, heart failure, heart attacks are rarely reported. The patients at higher risk for these conditions are advised to discuss the risk and benefits of these treatment and the remedial measures to monitor the risks with medical practitioner.
The researchers are working to find a new class of drugs that can target VEGF or other angiogenesis pathway and are in clinical trial stage. Phase I and phase II clinical trials are on to see the possibilities of combination of angiogenesis inhibitor therapy with other treatments that targets blood vessels like tumor-vascular disrupting agents which can damage the existing tumour blood vessels.
(The author is Associate Professor & HOD, Department of Pharmaceutics,National College of Pharmacy, Calicut, Kerala).