| Angiogenesis, or new blood growth, is defined as a process in which a network of new blood vessels are formed from pre-existing vessels. Highly regulated and transient angiogenesis plays an important vole in embryogesis, wound healing and corpus luteum formation. By contrast, uncontrolled and persistent angiogenesis is associated with diseases such as solid tumors, diabetes, rheumatoid arthritis, and atherosclerosis. In particular, the growth, intrasavation and metastase of tumors are found to depend on tumor angiogenesis. It is therefore expected that angiogenesis inhibitors may be clinically useful for the treatment of these diseases related to angiognesis, including tumors.Angiogenesis can be divided into a series of temporally regulated responses, including protease induction, endothelial migration, proliferation and differentiation. This is a highly complex process, in which a number of cytokines and growth factors released by endothelial cells (ECS), tumor cells and matrix cells are involved. Vascular endothelial growth factor (VEGF) has been shown to be one of the most potent angiogenic factors. It binds to endothelial cell surface receptors and activates various functions of the cell including angiogenesis. The major VEGF receptors expressed, preferentially on ECS are Flt-1 (fms-like tyrosine kinase) and KDR (kinase- insert- domain containing receptor)/Flk-1.Therefore, it is suggested that inhibition of VEGF secretion or Flt-1 and KDR/Flk-1 expressions can interrupt the VEGF-induced angiogenesis. VEGF can be secretion by many human tumors and yet it is a growth factor specific for vascular endothelial cells. The secretion of VEGF in a variety of tumors suggests that the angiogenesis in tumor is VEGF-induced. This has been demonstrated in several recent studies supporting the idea that inhibition of VEGF-induced angiogenesis suppresses tumor growth.Artemisinin, the active principle of the Chinese herb Artemisia annua and its derivatives form a promising class of antimalarial drugs, which are now commonly used in the treatment of drug-resistant falciparum malaria. Dihydroartemisinin is a more water-soluble and effective antimalarial analog of artemisinin. Recently, it was reported that artemisinin analogs also showed antitumor activity both in vitro and in vivo. However, to our knowledge, anti-angiogenic activity of dihydroartemisinin has not yet been demonstrated.In the present investigation, we developed and investigated the inhibitory effect of ART on angiogenesis in vitro and in vivo. The anti-angiogenic activity was tested on in vitro models of angiogesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial (HUVE) cells and in vivo model of the xenotransplanted ovarian carcinoma as well as immunohistochemical stainings of VEGF and its receptors Flt-l,KDR/Flk-l.Results1. Tumour Volume and Animal WeightAll nude mice developed tumor after implantation of HO-8910 cells. Tumors in mouse flank skin became palpable after 2 days of inoculation. When drug administration was started, there was no significant difference in the tumor volume of the four treatment groups. The increase in tumor size in the four groups from day 0 to day 15 is shown in Figl. There was no statistical difference in the tumor volume in animal group that received low dose (l0mg/kg body weight) of artesunate and control. On the other hand, The groups that received 50 and l00mg/kg were significantly different from control group regarding the tumor volume. Tumor growth of 50mg/(kg.d) or 100 mg/(kg.d) treatment group was reduced by 41% or 62%. After 15-day administration of ART. No significant difference was foundbetween the body weights of the four treatment groups when compared with each other in pairs. (P>0.05)2.H&E Staining and Microvessel DensityA pathologist supervised the delineation of the tumor area using H&E staining. In the control specimens, only a few necrotic areas were shown in the tumors. But in the three experimental groups, the necrotic areas expended in different levels a... |
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