To understand the mechanism of action and the therapeutic indications of angiogenesis inhibitors (also called anti-angiogenic drugs) it is necessary, first of all, to understand what is meant by this term.
The word angiogenesis indicates the process of formation of new blood vessels, starting from the already existing ones. Angiogenesis is a natural (physiological) process, necessary for many functions of the organism such as normal tissue growth, embryonic development, wound healing. In some cases, however, the angiogenesis mechanism can lose normal regulation and contribute to the development of certain diseases.
Angiogenesis is based on the growth, differentiation and migration of the cells that line the inner wall of blood vessels (endothelial cells). This process is controlled by specific growth factors, called angiogenic factors. Some of them, like the vascular endothelial growth factor (identified with the acronym VEGF, from the English Vascular Endothelial Growth Factor), they bind to receptors normally present on the surface of endothelial cells. The link between the growth factor and the corresponding receptor stimulates cell growth favoring the formation and survival of new blood vessels.
The factors angiogenesis inhibitors (for example, angiostatin), on the other hand, counteract the formation of new blood vessels.
Under normal (physiological) conditions, the production of stimulating (pro-angiogenic) and inhibitory (anti-angiogenic) factors is finely regulated and blood vessels are formed when and where it is needed. Sometimes, for reasons not yet fully understood, normal regulation fails, causing uncontrolled growth (proliferation) of blood vessels in abnormal positions (pathological neovascularization). For example, angiogenesis is the cause of age-related macular degeneration, a disease of the retina that can lead to decreased vision (low vision) or blindness.
Angiogenesis and tumors
Angiogenesis plays an important role in the growth of a tumor mass. In fact, solid tumors need the supply of nutrients and oxygen through the blood to grow. The tumor, therefore, must create a network of blood vessels that provide it with the necessary nourishment, and it does so by producing factors proangiogenetics and inducing its production by the surrounding normal cells.
The new blood vessels feed the tumor favoring its growth and invasion of the surrounding tissue and, through its spread to distant tissues and organs, the formation of metastases.
Mechanism of action of angiogenesis inhibitor drugs
Solid tumors cannot grow beyond a certain size, nor spread throughout the body without blood supply: scientific research has produced drugs called angiogenesis inhibitors which, in fact, block the growth of the tumor by preventing it from forming an abnormal network of blood vessels. The purpose of anti-angiogenic drugs is to prevent and / or slow down the growth of the tumor by preventing the supply of substances necessary for its growth (pathological neovascularization).
Angiogenesis inhibitors therefore, they represent a particular type of therapy because they do not act directly on tumor cells but on the network of blood vessels necessary for tumor development.
There are currently many angiogenesis inhibitors approved for the clinical phase, used as anticancer and for various eye diseases. Most anti-angiogenesis drugs target vascular endothelial growth factor (VEGF), its receptor, or other molecules involved in the process of angiogenesis. In general, drugs are represented by monoclonal antibodies that bind to the receptor and block its function, or by the growth factor itself modified in order to still be able to bind the receptor without activating its function.
Among the anticancer therapies, angiogenesis inhibitors are, in general, less toxic than traditional drugs, but less effective if not used in combination with other drugs. In fact, considering the existence of numerous growth factors, the block of a single factor seems not to be enough. Furthermore, since angiogenesis inhibitors fight the tumor by slowing or stopping its growth, but do not kill cancer cells, they must be taken for long periods of time. However, it must be said that angiogenesis inhibitors, used in combination with traditional therapies, they increase its effectiveness without increasing the risk of toxic side effects.
The use of these drugs in eye therapies is also important, in particular for the treatment of the retina. The drug is injected into the eye after administration of anesthetic eye drops. The treatment is outpatient but, as it requires a sterile environment, it takes place in the operating room. The administration is quick and practically painless.The blocking of the growth of new vessels has given good results in the treatment of various diseases such as exudative age-related macular degeneration, macular edema secondary to diabetic retinopathy and venous thrombosis.
Angiogenesis inhibitor drugs can cause various unwanted side effects, such as, for example, bleeding, blood clots in the arteries (resulting in stroke or myocardial infarction), high blood pressure, difficulty in healing wounds, protein in the urine (proteinuria ) and a reversible brain disorder, called posterior leukoencephalopathy syndrome.
Rarer side effects are gastrointestinal fistulas or perforation.
Angiogenesis inhibitors that target the del vascular endothelial growth factor (identified with the abbreviation VEGF, from the English Vascular Endothelial Growth Factor), can cause additional undesirable effects, such as tiredness, diarrhea, hypothyroidism, hand-foot syndrome (painful redness of the skin of the hands and feet), heart failure, changes in the hair .
National Cancer Institute. Angiogenesis inhibitors (English)
Italian Association of Cancer Patients, Relatives and Friends (AIMaC). Thalidomide
Italian Medicines Agency (AIFA). Medicines database