Thursday, March 15, 2012



Development of new blood vessels from the older ones or angiogenesis is a very crucial process required for the normal functioning of the body including growth and development. In fact in adults many vital processes like healing of wounds and reproduction essentially require angiogenesis for their completetion. However this process is also associated with some diseases like cancer. Number of factors has been identified as angiogenesis promoters like VEGF family members – VEGF- A, B, C and D. They are the components of the VEGF pathway, which plays a dominant role in tumor angiogenesis. Regorafenib acts on VEGF family members.


Due to an uncontrolled cell division during the tumor growth, the oxygen diffusion is limited. A condition of hypoxia is created which activates transcription factors like HIF (hypoxia-inducible factor). This in-turn activates VEGF family members and when they combine with proteolytic factors, they stimulate the development of new vasculature within the tumor area. If this angiogenesis process is arrested the oxygen supply to the tumor will be cut and as a result the growth of tumor will be controlled. Various tyrosine kinase inhibitors are being designed which act as second generation inhibitors of VEGFR. Tivozanib is a tyrosine kinase inhibitor which inhibits three VEGFRs at concentration ranging between 0.16 nM to 0.24 nM. It is being tested under phase I clinical trails. Axitinib inhibits all the members of VEGFR family at a lower concentration and is considered to be very efficient [1]. Regorafenib was also discovered for the same purpose and in the same lines [1].


Various angiogenesis inhibitors are being tested for their potential to control melanoma and spread or metastasis of cancers. According the present research the effective mechanism to control the process of angiogenesis, is through the use of monoclonal antibodies like bevacizumab or by developing receptor traps which bind to the VEGF ligands. Another mechanism is the use of tyrosine kinase inhibitors with targets the members of VEGF family. Use of monoclonal antibodies offers a cytotoxic chemotherapeutic measure to control angiogenesis. The tyrosine kinase inhibitors do not allow the tumor to grow beyond the size of 1-2 mm as they cutl the supply of oxygen [2].


Tyrosine kinase and VEGFR -2 both contain a homology domain 2 and they are very essential for the growth and development of tumors. Regorafenib inhibits the kinases within the endothelial regions and angiogenesis kinases like VEGFR1 and VEGFR3, PDGFR – β and FGFR1. The kinases which are oncogenic in nature are B-RAF, KIT and RET. Regorafenib controls the levels of these kinases. MRI imaging studies were used to study the antiangiogenic effects. Within rats the process of extravasation was controlled. This inhibitor controlled the growth of tumor in a dose dependent manner. Regorafenib is well tolerated and does not cause adverse toxic side effects [3]. After undergoing clinical testing under phase I, it was found that Regorafenib is well tolerated at a concentration of 60 mg under physiological conditions. It was safe and inhibited all the angiogenic kinases.


Regorafenib is a second generation angiogenesis inhibitor which targets multiple kinases. It controls the growth of tumors by cutting the supply of oxygen.


1. Bhargava P and Robinson MO. Development of Second-Generation VEGFR Tyrosine Kinase Inhibitors: Current Status. Curr Oncol Rep 2011 April; 13(2): 103–111.
2. Corrie PG. Targeting angiogenesis in melanoma: prospects for the future. Ther Adv Med Oncol 2010 November; 2(6): 367–380.
3. Wilhelm SM, Dumas J, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer 2011 Jul 1; 129(1):245-55
4. Hedbom S, Steinbild S, et al. Phase I study of BAY 73-4506, a multikinase inhibitor, administered for 21 days on/7 days off in patients with advanced solid tumors. Journal of Clinical Oncology, ASCO Annual Meeting Proceedings Part I 2007; 25(18S); 3593.

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