Angiogenesis is an essential property of many solid tumors, and the target of se
ID: 3517774 • Letter: A
Question
Angiogenesis is an essential property of many solid tumors, and the target of several anticancer drugs. One clinically important angiogenic pathway involves vascular endothelial growth factor (VEGF) and its cognate receptors.
a) What is VEGF and how is it important in tumor growth and survival?h
b). What agents target the VEGF pathway and what are their mechanisms of action?(1/2 page)
c.) What kinds of tumors are effectively treated with agents that target the VEGF pathway?(1/2 Page)
d) What are the important toxicities of the agents that target the VEGF pathway?
Explanation / Answer
a) The full form of VEGF is the vascular endothelial growth factor which belongs to the family of growth factors which are the specific group of proteins. They are mainly involved in formation of blood vessels. The VEGF has specific receptors on the target cells and are released by a specific physiological stimulation. When they are released then they travel to their cell surface receptoron the target cells and their binding causes dimerization of the receptors. These are receptor tyrosine kinases and they autophosphorylate eachother upon binding of VEGF and creates phosphorylated tyrosine residues which are the docking sites for other proteins and when the target proteins bind to them they alsogets phosphorylated and froms dimer and this dimer then transferred to the nucleus to start cell division. VEGF are of several types and they perform different functions. VEGF-A causes angeogenesis, vasodialation and also causes chemotaxis of macrophages. VEGF-B works in the embrayonic stages of vasculature development. VEGF-C and D causes formation of lymphatic vesicles.
To understand its role in tumor development one needs to understand the difference between vasculogenesis and angeogenesis. The former terminology explains the formation of new vasculature in embrayonic development. The later term is used for the formation of new blood vessels from the preexisting one. When cancerous tumor developes then it cannot grow until and unless it receives food and oxygen after growing for a certain time period and when it feels hypoxic condition then it releases VEGF-A that causes formation of new blood vessels from the older one so that the malignant tumor can get food and oxygen to grow.
b) The anticancer drugs target the VEGF pathway to stop the formation of new blood vessels that will supply food and oxygen to the malignant tumor. A food and drug administration (FDA)approved agent that targets the VEGF pathway to theat gynecological malignancy is the humanized monoclonal IgG1 antibody known as Bevacizumab. Also there can be soluble VEGF receptors or anti VEGF receptor antibody. The mechanism of action of VEGF targeting agent is like this- the monoclonal antibodythat trgets the VEGF it binds to the VEGF out side the cell and so the VEGF-antibody complex cannot bind to the targer receptor. Again the soluble VEGF receptors will bind to the VEGF out side the cell and as the solublu receptors do not have the kinase domain so there will be no activation of the downstream pathway and there will be no gene activation. The VEGF receptor would form a complex with the specific antibody and there will be no space to interact to VEGF and hence there will be no gene activation.
c) Gynocological tcancer show good response when treated with targeted VEGF receptor along with the other chemotherapeutic agents and the type of cancers that are being treated with this type of therapy is the following form of cancers- ovarial cancer, endometrial cancer and cervical cancer. Though the response will vary depending on the type, severity of the cancer along with the age, sex and other physiological conditions of the subject. There are increased levels of VEGF in ovarian and endometrial cancer and there are limited data regarding cervicakl cancer, proven by histochemistry.
d) For the IgG1 humanized monoclonal antibody there is no data regarding bowel perforation but as these agents cause inhibition of blood vessel formation so there will be delay in wound healing, bleeding and if given to pregnant patieng ithen this will hamper the vasculogenesis in embrayo and may cause death of the embrayo as well. The oher side effects of IgG1 is on theheart and kidney and also the hormonal homeostasis of the body but the side effects are not severe and can be controlled.