Angiogenesis InhibitorsAntiangiogenic drugs or neovascularization inhibitors are a new group of drugs which fall under the category of antivascular agents mostly used in antineoplastic therapy. This is a very fast growing branch in clinical pharmacology with great relevance to oncology patients, where most of the drugs are in various stages of development and clinical trial. So far, only a few drugs are FDA-approved and included in regular cancer therapy regimens. The first angiogenic inhibitor was discovered in 1975 by Dr. Judah Folkman and Dr. Henry Brem in cartilage tissue. Folkman postulated the hypothesis of angiogenesis as the process behind tumor growth and in an article in the New England Journal of Medicine in 1971. The drugs work by acting against the process of angiogenesis, hence they are termed antiangiogenic drugs or angiogenic inhibitors. Angiogenesis refers to the formation of new blood vessels. It is also known as neovascularization. Angiogenesis is an important biological process in the developmental stage of humans as before birth, where numerous blood vessels are formed in an organized network connecting all the organs of the body. This process also takes place in the uterine lining or endothelium of healthy females during each menstrual cycle, and during wound healing. When there is a trauma, proangiogenic molecules called endothelial growth factors are released. These molecules activate the endothelial cells of the blood vessels triggering angiogenesis. Like other complex biological processes angiogenesis is controlled by a dynamic equilibrium between promoters and retarders. The prominent proangiogenic factors identified in most of the tumors are vascular endothelial growth factors (VEGF). These growth factors spread to nearby tissues and attach to receptors on the endothelial lining of blood vessels. Endothelial cells, which are otherwise quiescent, respond by active proliferation and formation of new blood vessels. In case of tumor cells, somehow or other, this angiogenic switch is kept on and there is no control over the process by endogenous inhibitors leading to uncontrolled and unorganized angiogenesis, which is considered as the cause of rapid growth of tumor cells. Compared to normal cells, tumor cells are in a state of continuous mitosis or rapid growth and proliferation and therefore require much energy, nutrients, and oxygen for their development. Newly developed network of blood vessels helps to cater to this increased requirement, thus marking the significance of antiangiogenic therapy. As every tissue need oxygen and nutrients irrespective of their nature whether tumor or normal, once denied of these essentials, would not be able to grow or enlarge in size. Hence, the hypothesis is that, if the tumor cells are cut off from their blood supply would be subjected to starvation and that in turn would gradually reduce the rate of proliferation of the cells. Once mitosis comes under control, rapid growth gets arrested and the tumor stabilizes or becomes quiescent. In few cases, even reduction in size of the tumor occurs. Even though it is not evident that antiangiogenic drugs can cure a cancerous condition, it is certain that they can help in controlling the metastasis and further progression of the disease. When given in combination with standard antineoplastic regimen, antiangiogenic inhibitors have demonstrated much better response with increase in lifespan than treatment with standard chemotherapeutic or radiation therapy drugs alone. Some antiangiogenic drugs work by blocking the signaling process by acting on the receptor or factor while others work by inhibiting the process itself and some by blocking the enzymatic action of MMP. There are some other drugs which act on the oncogene, which is responsible for keeping the angiogenic switch to be on. Different types of tumor cells produce different angiogenesis growth factors and some produce more than one factor. Rational drug design seeks to block all factors. The most common angiogenic factor is VEGFand most drugs target it. Drugs which act on these factors either block the factor from gaining attachment to the blood vessel or block the specific receptor by small molecules leaving the factors with no receptors to attach. Some drugs block the MMP from clearing the intercellular matrix, which is essential for directional growth of the blood vessels to the tumor cells. Antiangiogenic drugs work by any one or more of these methods. The first drug to be approved by FDA as first-line treatment for a cancerous condition was bevacizumab under the trade name Avastin for metastatic colorectal carcinoma (mCRC) in February 2004. This is a monoclonal antibody, genetically engineered from mouse and human cells. It is used in combination with Saltz regimen or 5-FU based chemotherapy for colorectal carcinoma. In locally advanced recurrent metastatic non-small cell lung carcinoma, it is used in combination with carboplatin and paclitaxel (Taxol). Avastin in combination with paclitaxel (Taxol) is approved as first line antineoplastic therapy for locally advanced recurrent metastatic breast carcinoma. It has also been used in some mesothelioma cases. Other monoclonal antibodies include Erbitux (generic name cetuximab), Vectibix (panitumumab), and Herceptin (trastuzumab). Erbitux is used as a single line treatment and also in combination
with radiation therapy for metastatic squamous cell carcinoma of head
and neck. In colorectal carcinoma, it is used as a single agent or
in combination with irinotecan. Herceptin (trastuzumab), another FDA approved monoclonal antibody is a very commonly used and effective drug in HER2/neu positive breast carcinoma. This drug is used either as a single-agent or in combination with paclitaxel or with doxorubicin, cyclophosphamide, and paclitaxel. Some angiogenic inhibitors are classified as small molecule tyrosine kinase inhibitors or TK inhibitors. These drugs include Tarceva (erlotinib), Nexavar (sorafenib), Sutent (sunitinib), Tykerb (lapatinib), Iressa (gefetinib), and Gleevec (imatinib). Macugen (pregaptanib) is also an approved antiangiogenic drug, which is useful in age-related macular degeneration. Revlimid (lenalidomed) is an angiogenesis inhibitor used in treating multiple myeloma or myelodysplastic syndrome. Erlotinib (Tarceva) is used in non-small cell lung carcinoma as a monotherapeutic agent and in combination with gemcitabine in treating metastatic pancreatic tumor. Sorafenib (Nexavar) is useful in treating cases of advanced renal cell carcinoma (kidney cancer) and hepatocellular carcinoma (cancer of the liver). Sunitinib (Sutent) is also very useful drug in treating advanced renal cell carcinoma and gastrointestinal stromal tumor. Gefetinib (Iressa) is a tyrosine kinase inhibitor used for treating non-small cell lung carcinoma, which has some action on the oncogene also. Imatinib or Glivec (Gleevec) is used in treating Ph+ve CML (chronic myeloid leukemia) and Kit-positive (CD117) malignant GIST (gastrointestinal stromal tumor). Lapatinib (Tykerb or Tyverb in EU) is another tyrosine kinase inhibitor useful in treating HER2/neu over expressed patients of breast carcinoma, which is the latest in this category. Another subcategory coming under angiogenic inhibitors is mTOR inhibitors (mammalian target of tapamycin) which consists of temsirolimus (Torisel) used in the treatment of advanced RCC. Other FDA medications showing antiangiogenic activity are bortezomib (Velcade), thalidomide (thalomid), Captopril, Celebrex, Vioxx, etc. Bortezomib (Velcade) is used in treating mantle cell lymphoma and multiple myeloma. Thalidomide (Thalomid) is also used in treating multiple myeloma in combination with dexamethasone. Captopril, Celebrex, and Vioxx are some of the drugs showing antiangiogenic activity, but are approved for some other medical condition. And ranibizumab (Lucentis) is another antiangiogenic drug which is used for age-related macular degeneration. Therapy using angiogenesis inhibitors is sometimes called targeted therapy. This mode of treatment is considered to be superior to traditional chemotherapy as regards to their PFS (progression-free survival) rate. Chemotherapeutic drugs work on the principle of destruction of the tumor cells. As most of the chemo drugs are administered systemically (to the whole body), they destroy normal healthy tissue along with the tumor cells. Antiangiogenic drugs, on the contrary, do not directly attack the tumor cells; instead they are directed to the tumor vasculature. They inhibit the process of formation of new blood vessels, which is very crucial in the multiplication and metastasis of cancer cells and are considered to have less chances of acquiring resistance as against chemotherapeutic drugs during long-term use. Though considered to be better armed against cancer, angiogenic inhibitors too have side effects, but not as serious as chemotherapy regimen and have lesser toxicity and intolerance history. The major side effects of antiangiogenic drugs are increased susceptibility
to infection, poor wound healing, bleeding and clotting problems,
cardiac problems, disturbances in reproductive system, hypertension,
and fetal abnormalities when used during pregnancy. As active clinical
trials continue, observers expect an array of new antineoplastic agents
under the category of angiogenesis inhibitors in the coming years.
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