Cancer Therapy and Standard Modes of Treatment - Research Paper Example

The potential of angiostatic approaches to cancer therapy Angiogenesis is defined as the generation of new blood vessels from an existing vessel (Folkman, 2001).it is also defined as "Angiogenesis is a prominent feature of many physiological and pathological processes, including wound healing, luteinization, and tumor growth" (Folkman, 1987., Folkman, 1992). Sustained Angiogenesis is one of the six Hallmarks of Cancer determined by Hanahan and Weinberg in 2000 proposed six characteristic capabilities by which normal cells become cancer cells (Sato 2002. The study of microvascular changes induced by tumors has prognostic value (Bosari, 1992., Weidner, 1993) and permits design of new approaches to cancer therapy (Jam, 1988., Kerbe, 1997).Whenever any injury occurs to any body part it is taken care of good blood supply and good supply is maintained by new blood vessel formation or in other words angiogenesis. Areas of the body that have a poor blood supply show delayed repair and as we know repair is the formation of new tissue. In cancers growth or new tissue formation occurs without any stop signals. It goes out of control and that is what is called cancer. Whenever growth occurs whether under control or goes out control as in cancers the physiological process is that new vessels keep forming with that process. Vessel formation is the key component for the growth of the tumour. Once tumour size increases and blood supply to the deeper tissue of it ceases that causes necrosis or death of the deeper tissue which signifies how important angiogenesis is for tumours to grow and if this can be controlled by anti angiogenic interventions that will be adding a great deal to the treatment of cancer therapy. However, in the reality Judah Folkman determines the discovery of the role of angiogenesis in the development of cancer in 1971 he had hypothesised that the growth of the tumour is dependent on angiogenesis. Moreover, there are many experimental evidences that can confirm the relation between the development of cancer and the angiogenesis. In the mid 1980s this hypothesis was supported by pharmacologic, biologic evidences but in the mid 1990s was confirmed by the genetic evidences. Genetic and functional experiments indicate that neutrophils, mast cells, eosinophils and activated T lymphocytes also contribute to malignancies by releasing extracellularproteases, pro-angiogenic factors and chemokines(Kuper, 2000., Pharmacologically the proof was such that it was based on the inhibition of the angiogenesis using molecular and biochemical methods like targeting bFGF using an anti bFGF antibody was synthesized in the laboratory and then introduced to mice bearing the tumour, resulted in dramatic reduction in neovascularisation as well as the tumour volume. Showed that if neovascularization is not there then tumour growth can be stopped. This showed that if neovascularization is not there then tumour growth can be stopped. Biological evidence was also generated and that evidence based on the condition of the cell culture like Human retinoblastoma that has metastasized to the vitreous are viable and a vascular and tumour spread is restricted. (Folkman, 2001) means that since it is an avasculr treatment and it does not have it's own blood supply it can only maintain it's life if it is getting blood from the nearby vessels which will not give it enough capability to increase in size and gets metastasized. Genetic evidence is the most convincing and direct one. Genetically the evidence was based on the transfection of genes for antiangiogenic proteins into cancer cells such as the down regulation of the ras oncogene in a melanoma, resulted to huge cell death of microvascular endothelium in the tumour mass starting within 6 hours. Tumour cells commence to die days later and the tumour mass had totally disappeared by 12 days. (Folkman, 1973) The tumour angiogenesis or Neovascularisation of tumour tissue is considered as the fundamental mechanism for the tumour growth, proliferation not only the growth of the tumour but also the tumour invasion and metastasis become angiogenesis dependent, and this appears to be an essential process at the beginning as well as at the end of the metastatic cascade (Folkman, 1973). That was proved using different activator of the angiogenesis like VEGF, bFGF that can increase the production of plasminogen activator and c, 5ollagenases in the proliferation of the endothelial cells in animal models that were used(Folkman 2002) A family of chemotactic cytokines, named chemokines, which possess a relatively high degree of specificity for chemo attraction of specific leukocyte populations(Natur, 2001., Rossi, 2000., Homey, 2002 agents for the immunotherapy of cancer In addition, there are many clinical signs and symptoms in cancer patients that may be in relation with the angiogenesis for example in metastatic prostate cancer clinicians rely on between the bone pain and the formation of neovascularisation (Folkman, 1995). This is not proved until yet because of the multiple symptoms that can be due to the inflammation. The angiogenic switch mechanism is a discrete incident, which takes place during the development of tumorigenesis, starts with the premalignant stage in the mouse models. By the time, most human tumours are detected using the different imaging like CT scan, MRI scan and ultrasound scan those methods can allow the staging of the tumour as well using the biopsy which can allow the grading of the cancer. However most tumours can exist without neo vascularization for many years, and then developed to the angiogenesis phenotype. Until this day, the researchers determine four principal mechanisms of angiogenic switch, which can allow the tumour to proliferate and spread: 1. Prevascular tumours recruit their own blood supply: The implanting embryo and the newly arrived tumour nodule require a blood supply in order to grow. The study of angiogenesis has occupied numerous investigators for more than a century.(Sabin 1917, Hertig, 1935) Tumour cells must initiate angiogenesis to fuel their progression and continued growth.[129] Most of studies of the regulation and cellular biology of angiogenesis have focused on solid tumours and their need to establish a blood supply. As postulated nearly three decades ago,[137] pharmacological therapy utilizing antiangiogenic agents is showing promise as a treatment modality for a variety of cancers.( Aviezer, 1994., Coller 1997) 2. Circulating endothelial stem cells in tumour angiogenesis: During angiogenesis, endothelial cells also exhibit invasive and migratory behaviour and utilize cell processes similar to those of both invading cytotrophoblast and spreading tumour cells. The process of angiogenesis has three phases: initiation, proliferation-invasion, and maturation-differentiation.[145] Normally, the more than 1 trillion vascular endothelial cells in the adult remain in a quiescent state with a turnover time exceeding 1000 days( For stationary functional vascular endothelial cells to form new vessels requires a shift in the equilibrium between the positive and negative regulators of angiogenesis, analogous to the coagulation cascade.[148] 3. Nonendothelial host cells may amplify tumour angiogenesis: During angiogenesis, endothelial cells also exhibit invasive and migratory behavior and utilize cell processes similar to those of both invading cytotrophoblast and spreading tumor cells. The process of angiogenesis has three phases: initiation, proliferation-invasion, and maturation-differentiation.[145] Normally, the more than 1 trillion vascular endothelial cells in the adult remain in a quiescent state with a turnover time exceeding 1000 days(Jaffe, 1973., Denekemp, 1993) For stationary functional vascular endothelial cells to form new vessels requires a shift in the equilibrium between the positive and negative regulators of angiogenesis, analogous to the coagulation cascade. (Dameron, 1994) some type of cancer can attract other mast cells, macrophages and some inflammatory cells those cells play the key role in the tumour angiogenesis by liberating proangiogenic molecules such as bFGF or by releasing metalloproteinase which can stimulate VEGF and some other angiogenic activators.( Ware , 2001) Vessel cooption: In certain type of metastatic tumour (example of brain tumour in the mice), cancer cells already exist from micro vessels in the organ and when the tumour start to grow that cause the endothelial cells goes apoptosis, and in the mean time induce neo vascularization from neighbouring vessels.( Veikkola, 2000) "In contrast with the prevailing view that most tumours and metastases begin as avascular masses, evidence is presented here that a subset of tumours instead initially grows by coopting existing host vessels. This coopted host vasculature does not immediately undergo angiogenesis to support the tumour but instead regresses, leading to a secondarily avascular tumor and massive tumour cell loss. Ultimately, however, the remaining tumor is rescued by robust angiogenesis at the tumor margin. The expression patterns of the angiogenic antagonist angiopoietin-2 and of pro-angiogenic vascular endothelial growth factor (VEGF) suggest that these proteins may be critical regulators of this balance between vascular regression and growth". (Holash J, 1999) 4. ANGIOGENESIS AND REGULATORY PROTEINS: Physiologically there is a set of activators which includes both inducers and promoters and another set of angiogenesis inhibitors that play a balanced role through feedback mechanism and it lead to a normal formation of new vessels. Any injury occurs the formation of new tissue starts as a part of repairing and for the new tissue loaded new blood vessels form under the stimulative affect of angiogenesis stimulators and once it is complete it switches off due to the presence and action of inhibitors. Activation of angiogenic programmes represents a shift in the balance between pro- and antiangiogenic factors (Hanahan, 2000). By contrast, in the cancer cells there is no check and balance things go out of control and inhibitors play no role in there, the activators of the angiogenesis are the key step in the growth and the spread of the cancer, which are over expressed in 95% of cancer. (Veikkola 2000) Promoters of angiogenesis are the mediators that lead to the production of different growth promoters further and as a consequence angiogenesis or vessel proliferation and the metastatic phenotype of the tumour. Angiogenesis promoters are the main markers that if not inhibited leads to sustained cell proliferation which is called cancer and its and metastasis. Three of these promoters like basic Fibroblast Growth Factor (bFGF), Vascular Endothelial Growth Factor (VEGF), and Angiopoietins have a very prominent role in the uncontrolled angiogenesis. Apart form these promoters there are a lot more in this category that can induce and maintain angiogenesis like the proteases specially the Matrix Metalloproteinase (MMP2- MMP9) as well as the integrins specially- v3. Fig 1: Angiogenesis activators (Patrick, et al. 2007) www.cmjournal.org/.../1749-8546-2-6-3-l.jpg 1. Basic Fibroblast growth factors: Basic fibroblast growth factor (bFGF) is known to be important in the regeneration of granulation tissue. This growth factor stimulates proliferation and differentiation of mesodermal tissues, such as fibroblasts and endothelial cells, as well as neuroectodermal cells (Bennett, 1994., Bennett, 1993., Bhora, 1995., Baird, 1989) Not only is bFGF chemotactic for vascular endothelial cells it also functions to stimulate mRNA, DNA, and protein synthesis in fibroblasts and epithelial cells.( Bennett. 1993., Lindner, 1991., Wang, 1997).In-vitro studies have demonstrated stimulation of fibroblast, vascular endothelial cell, and keratinocyte division, while in-vivo studies have demonstrated granulation tissue formation and epidermal regeneration.( Roesel, 1995 Uhl, 1993) bFGF (also known as FGF-2) was the first activator of angiogenesis to be isolated from an existing cancer.( Lopez 1998),this growth factor has the potential to provoke the angiogenesis by inducing endothelial cell mitosis and migration in vitro and is the most potent of the angiogenic proteins in vivo, in addition those pro-angiogenic molecules have high affinity for heparin and heparan sulphate(Folkman2001), which are found in extracellular matrix or in the surface of the cells this way of storage of bFGF allow the regulation of the secretion of the FGF. The bFGF signals determined by four receptor tyrosine kinases.[ FGFR-1, FGFR-2, FGFR-3 and FGFR-4 ] but the most notable in the activity is the FGFR-1 (Henry,2001).that can create a specific pathway by phosphorylate a specific tyrosine kinases residue in the intracellular domain of the receptor, this activation can stimulate direct signalling via receptors like Crk and PLC- ,or indirect mechanism such us Shc and FRS-2.( Lopez 1998) [fig 1 ]. . Fig. 2. Overview of FGFR-1 signalling. (Dailey, 2007) www.reactome.org/figures/fgfr_signaling.png 1. VEGF ligands and receptors: VEGF is a homodemeric protein with a molecular weight of 40-45 kDa (Folkman, 2001), and it is up regulated in a wide array of human tumour classes. The main activity of the VEGF is to promote the proliferation and the migration of the vascular endothelial cells. Nevertheless, this function is determined by a number of factors that can regulate the expression of the VEGF and that includes the hypoxia that mediates hypoxia-inducible factor (HIF)-1 as well as the tumour suppressor gene von-Hippel-Lindau (VHL) which plays a crucial role in providing negative control of the VEGF and other hypoxia-inducible genes. The second factor that can up-regulate the secretion of the VEGF is the growth factors like the EGF, TGF-, TGF-, FGF, and PDGF(Henry, 1999). The vascular endothelial growth factor (VEGF) or vascular permeability factor (VPF) plays a critical role in both physiological angiogenesis in the embryogenesis stages or in the repair of any injury and pathological angiogenesis in particular in the proliferation and metastasis of the cancer cells (Lopez 1998). the third factor is the oncogenes like the ras ocogene that can overexpress the VEGF through activation of its pathway including Raf-Mek-Erk-Ap1.( Folkman, 2001),( Sato2000) "There are many members of the VEGF, that comprise VEGFA, B, C, and D as well PLGF (placental growth factor) but the main sub class is the VEGFA, which is considered as a mitogenics for the endothelial cells and function as a survival element for them in both in vivo and in vitro. The biological effect of the VEGFA mediated by two receptor tyrosine kinases [VEFGR-1 and VEFGR-2], VEGFR-1 is unregulated by the hypoxia and its mediators" (Sato2000) by contrast the VEGFR-2 activated by the v3. The figure two summarizes the interaction between the different VEGF family and its receptors. . Figure2.Role of the VEGF receptor tyrosine kinases in different cell types journals.prous.com/.../df320757/images/fig01.jpg (Sorbera, 2007.757) After the activation of the specific tyrosine kinases residue in the intracellular domain of each receptor, the VEGFR-1 leads several signalling pathway that can bind with its SH2 domain like Grb2, PLC. However, VEGFR-2 can create a direct signalling pathway that can activate a several proteins that can play a major role in the cancer like PI3K, P38 and RAF (Lopez 1998). Many studies show that the VEGF mRNA is over expressed in a wide range of human cancer and that can be the key of targeting VEGF using VEGF antibody or other antibody that can target its receptors(Henry, 1999). "A family of chemo tactic cytokines, named chemokines, which possess a relatively high degree of specificity for Chemo attraction of specific leukocyte populations recruits downstream effector cells and dictates the natural" (Balkwill,2001., Rossi, 2000., Homey,2002). Fig.4: Overview of VEGFR-1 and VEGFR-2 signalling www.clinsci.org/cs/109/0227/cs1090227f02.gif (Hiroyuki, 2005. 227-241) 3: Angiopoietins: Angiopoietin-1, a factor previously considered to be proangiogenic, can offset VEGF-induced angiogenesis in vivo. Direct evidence from in vivo studies have also shown the synergistic effect of angiopoietin-2 and VEGF on the induction of angiogenesis. Furthermore, we show that these two classes of factors control the ratio of arterial and venous blood vessel types during angiogenesis. Angiopoietin-1 (Ang1) in postnatal mouse skin has a synergistic effect on the induction of angiogenesis (Thurston, 1999). Furthermore, it has been shown that Ang1 can rescue the vessel leakiness caused by VEGF-A without interfering with induction of angiogenesis (Thurston 1999). On the basis of this study, it has been suggested that VEGF-A and Ang1 collaborate to induce angiogenesis and make nonleaky mature vessels. 4: The Matrix Metalloproteinase's (MMPs): "MMP can stimulate cancer development by inducing cancer cell proliferation, migration, metastasis and angiogenesis. Not all the MMPs are a positive control for the tumour angiogenesis but only few in particular MMP-2 and MMP-9, which are degraded in the extra-cellular matrix [ECM] and allow vascular invasion and angiogenesis. The MMP-2 acts by cleavage of collagen IV. However, MMP-9 increases the bioavailability of the VEGF. In general, the growth factors, cytokines, oncogenes and other molecules control the expression of MMPs"(Criqui, 1985) (Sato, 2000). This factor sounds kind of more active a more dangerous for the reason that along with a promoter of the endothelial cell formation and reorganization it is also working like an inducer for different processes in the tumour mass growth and neo vessel formation. 5: Integrins: The different member of the integrin family are a cell adhesion molecules that can allow the formation of the vascular tubes after the interaction between the extracellular matrix and the endothelial cells; v3 is an example of an adhesion molecule involved in this interaction because it was highly expressed in many cancer types.( Simons, 2002) (Sato, 2000), and that can be the principal element for bFGF to induce the tumour angiogenesis (Bosch1999). This is also primarily an inducer but can work as a promoter as well. B) Inhibitors of angiogenesis: There are many negative controls of the physiologic angiogenesis that can block the blood vessel growth and migration. These have a major role in the cancerous growth but its not their presence it is their absence that makes things happen in an unfavourable way. The table below showed the different proteins, which play this role. Lung colonization. By melanoma cells that express sialyl-Lewis X is significantly reduced in E/P-selectin-deficient mice (Kim, 1998) These results indicate that receptors expressed in the vasculature are crucial in targeting sialyl-Lewis X-dependent cancer cells(Zhang ,2002) P-selectin facilitates human carcinoma metastasis in immunodeficient mice by mediating early interactions of platelets with blood borne tumor cells via their cell-surface mucins, a process that can be blocked by heparin (Borsig, 2001). L-selectin on neutrophils, monocytes and/or NK cells also may facilitate metastasis. (Borsig, 2002). Metastasis could involve the formation of tumor-platelet-leukocyte emboli that interact with the vasculature of distant organs. In addition, expression of L-selectin on tumor cells can foster metastasis to lymph nodes (Qian, 2001) those negative controls of the angiogenesis raise the possibility to restrain the proliferation of the tumour. because it came as a reality that the tumour cannot proliferate beyond a limited size unless it develops a neovascularisation from the host that can provide the oxygen and nutrients that is why many researchers prefer to target the tumour angiogenesis rather than other pathways. The second reason that there are many advantages of using angiogenesis inhibitors as drugs: Firstly, these inhibitors are not limited to the histological type of the cancer, secondly, the cancer microvasculature are handy and accessible, thirdly is the physiological condition that can induce the angiogenesis and finally that the endothelial cell are genetically stable. Worth mentioning that those angiogenesis inhibitors act within under mechanisms direct and indirect in the Direct angiogenesis inhibitors the main difference lies in their inhibition of the endothelial cells in the stable situation as well as in the mutated one (Olsen, 1988), that is these are unlikely to be used as anti-angeogenic drugs. It will have a huge side effect of influencing the normal physiology very badly and Indirect angiogenesis inhibitors: indirect angiogenesis inhibitors act in general by three ways, 1. blocks the secretion of the promoters of the angiogenesis, 2. block its receptors in the endothelial cells, and 3. Neutralise the activators of the angiogenesis in the blood. (Judah Folkman. 2007. 273-286) www.nature.com/.../v6/n4/images/nrd2115-f7.jpg (Judah Folkman. 2007. 273-286) Fig 4: type of angiogenesis inhibitors http://www.ncbi.nlm.nih.gov/books/bv.fcgirid=cmed6.figgrp Since the role of angiogenesis and tumour occurrence and it metastasis is a great one the scientists now days are concentrate more on how to targeting the different pathways of the tumour angiogenesis. That is giving them new directions and new strategies to go on. DRUGS, WHICH CAUSE DIRECT INHIBITION OF THE ENDOTHELIAL CELL: Called as well vascular-targeting strategies that can cause the tumour cell death by damaging the microvascular and it also promotes blood vessel occlusion (Lazarous, 2000). Angiostatin: is an internal fragment of plasminogen protein with a molecular weight of 38kDa isolated from the serum and the urine of mice with Lewis lung tumour acts by the direct inhibition of the endothelial cells growth (Folkman 2001) and is at the present time undergoing clinical trial as an anticancer drug. The mechanism of action of the angiostatin is not limited in the induction of the apoptosis of the endothelial cell but can also inhibit other tumour type by decreasing the oncogene protein kinase ERK-1 and ERK-2 in endothelial cells. Angiostatin act by binding to tree kind of proteins ATP synthase, aVb3, and angiomotin and those can mediate a cascade of signalling that can lead to the inhibition of the angiogenesis. A recent study in the clinical trial of this drug shown there is no dose-limiting toxicity of using angiostatin but there is only a transient rash seen in some patient and this was a decrease in bFGF in the 7 patients urine by 15%-92%(n=15) as well as the urine VEGF by 30%-60%(Sato2000). The use of the angiostatin gene therapy in different type of cancer in mice like breast cancer, melanoma, renal cell cancer, and Kaposi's sarcoma cells (Lederman2001) shows an important result of using this gene therapy and it is under clinical trial. "The angiostatin protein therapy occupied the first interest in targeting tumour angiogenesis because was Shawn a significant effective especially when it used with a combination with the endostatin. As well there is another approaches in the lung cancer therapy is the replacement of angiostatin after the tumour regression using the radiotherapy". (Lederman, 2002) 1. Endostatin: "Endostatin is a 20 kDa C-terminal fragment of collagen XVIII. Endostatin specifically inhibits endothelial proliferation and potently inhibits angiogenesis and tumor growth. By a novel method of sustained release, E. coli-derived endostatin was administered as a nonrefolded suspension. Primary tumors were regressed to dormant microscopic lesions. Immunohistochemistry revealed blocked angiogenesis accompanied by high proliferation balanced by apoptosis in tumor cells. There was no toxicity. Together with angiostatin data, these findings validate a strategy for identifying endogenous angiogenesis inhibitors, suggest a theme of fragments of proteins as angiogenesis inhibitors, and demonstrate dormancy therapy" (O'Reilly, 1997). The mechanism of action of the endostatin is well know in many published paper, endostatin can inhibit the VEGF receptors especially VEGFR-1 and VEGFR-2 by blocking its tyrosine kinases phosphorylation and the intracellular cascade signalling (fig3). Endostatin can also downregulate the VEGF secretion by acting as a direct inhibitor of the angiogenesis (fig 4) as well preventing the bFGF and VEGF to adhere to the basement membrane in the endothelium and the inhibition of the MMPs and the integrins that can promote the tumour neovascularisation. The endostatin is as well under clinical trial phase in patients with prostate cancer and it shows an increase in its efficacy in either sole drug or combined with angiostatin, chemotherapy, immunotherapy or the radiotherapy. 2. Thalidomide: the exact mode of action of thalidomide is not known but it works as an anti-angiogenic drug. This drug used to be used for morning sickness during pregnancy but then it was found to be teratogenic and that quality of it was used as an anti cancerous activity.(Lopez, 1998) (18 page 214). In1999 32% of patients with multiple melanoma treated with thalidomide had a positive response(Byrne, 2001) DRUGS WHICH BLOCK THE ACTIVATORS OF ANGIOGENESIS: 1. Antivascular: The use of Avastin as single drug shows an increase effect in the renal cell cancer, ovarian cancer and breast cancer, the main side effects of using this drug is the hypertension(Furchgot, 1990).this drug is still under clinical phase three. Endothelial growth factor antibody: Avastin or Bevacizumab is the first anti VEGF monoclonal antibody available for clinical use as an anticancer drug combined with the chemotherapy in the USA, used in the treatment of many advanced cancer including the metastasis form like colon cancer and small lung carcinoma (Furchgot1990). 2. 2. SU5416 OR Semaxanib: this agent is still under clinical trial and is targeting specifically VEGF receptors 1 and 2 and the rest of the intracellular pathway (Fournier, 1987) although its an anti-angiogenic potential and its ending of the phase three clinical trial but is still intended for use as anticancer drug especially in colorectal cancer. (Luscher, 1995) DRUGS THAT BLOCK THE BREAKDOWN OF THE ECM [THE EXTRACELULAR MATRIX]: 1. Marimastrat: The result of phase three clinical trial is encourage a lot to use this drug because it shows a significant reduction of the size in many number of tumour as well the metastasis like colorectal cancer, ovarian cancer, pancreatic cancer because it acts as an angiogenesis inhibitor by limiting the growth of the blood vessels and also as metastasis inhibitor by preventing the malignant cells from breaching the basement membranes. (Azadzoi, 1991) The main side effect of this drug is the musculoskeletal toxicity (Sato, 2000). It is considered to be the first oral drug that can inhibit the MMP-2 and MMP-9, because the inhibition of MMPs can prevent the migration of the endothelial cells as well preventing the entry and the exit of malignant cells into existing blood vessels. 2. BAY12-9566: This drug has also shown a drastic improvement as an anti-angiostatic agent acts by inhibiting the formation of the tubule in human endothelial cell in vitro but did not inhibit the growth of the endothelial cells. The efficacity of this drug occurs in the reduction of the number of lung metastasis by 57% and the volume of lung metastasis by 88 %.(Kim, 1994) DRUGS WITH NO SPECIFIC MECHANISM OF ACTION AFFECTING ANGIOGENESIS: Carboxyamido-trizole (CAI): it acts as a calcium-mediated signal transduction inhibitor and through that it causes the antiangiogenesis affect of it; in vitro CAI can down regulate the MMP-2 and reduce the tumour spread. It still under the clinical trial phase three and four; but it shows a relevant result in the treatment of the no small cell lung cancer [NSCLC] the main side effect of this drug in the dose-limiting toxicity is the ataxia.(seto, 2001) DRUGS THAT INHIBIT ENDOTHELIAL- SPECIFIC INTEGRIN: VITAXIN: This is a monoclonal antibody v3 integrin it can induce cell death for the newly formed endothelial cells. And as we know endothelial cells have a major role in the formation and reorganization of new blood vessels it starts working like an angiostatic drug. Is under clinical trial phase one for melanoma and prostate cancer and in phase two for metastatic bone tumour in which shows a safe and potentially active anti-angiogenic drug. (Henry, 2000) ANTIANGIOGENIC CHEMOTHERAPY: Several published studies have shown the effectiveness of the anti-VEGF drugs combined with chemotherapy or radiotherapy than either drug alone. Chemotherapy has always been the main stay of cancer treatment so combining it with any other mode of therapy causes promising results. (Henry, 1999) VEGF (also known as VEGFA) is a prototypic, angiogenic agent that causes endothelial proliferation in vitro and angiogenesis in vivo. VEGF-A exists in at least four isoforms (121, 165, 189, or 206 amino acids) that are produced by alternative splicing of a single mRNA transcript. Most of the successful clinical trials used the inhibitors of the angiogenesis required some of the conventional chemotherapy drugs like Paclitaxel, which can inhibit endothelial cell growth and migration in vitro and the tumour angiogenesis in vivo. (Folkman, 2001) Pharmacological inhibitors of angiogenesis:. Class of inhibitors Active principle Drugs VEGF antagonists AntiVEGF-mAb Avastin (Bevacizumab); HuMV833 VEGF trap s-Flt-1, s-Flk-1; s-Flt-1/Flk-1 Other VEGF-inhibitors NM-3; GFB 116 Broad GF inhibitors Inhibitors of heparin-GF binding Suraimn, LMW Heparin (Fragmin); Tecogalan Receptor antagonists AntiVEGF-R2 mAbs IMC-1C11 VEGF-R2 (kinase )inhibitor SU5416 (Semaxanib); SU6668; CGP41251;; ZD6474; CEP5214; BIBF1000; VGA1102 VEGF-R mRNA ribozyme Angiozyme PDGF-R inhibitors Gleevec (STI574) Endothelin R (AT4) inhibitor GBC-590; ABT-627 Anti-Endoglin mAbs (TGF-R) SN6f; SN6j; SN6k Signalling inhibitors PKC inhibitors PKC-412; CGP 41251; Bryostatin-1, Ro 31-8220; Ro 32-0432 PKA inhibitors 8-CI-cAMP; AS PKAI MAPK inhibitors PD 98039 mTOR inhibitors Rapamycin, RAD001 Farnesyltransferase inhibitor R115777; L-778123; Sch-66336; L-744832; BMS-214662 Anti Inflammatory drugs NSAIDs Indomethacin; Aspirin; Sulindac COXIBs (COX-2 inhibitors) Celecoxib; Rofecoxib; NS398 PLA-A2/COX-2 suppressor Cortisol Inhibitor of M activation Thalidomide Proteinase inhibitors MMP inhibtors 'Classical': Batimastat; Marimastat (BB2516); AG3340; BAY-12-9566; BMS-275291;CGS-27023A; COL-3, Doxyclicline; Neovastat; Ro-28-2653; ABT-518, N-acetyl-Cysteine 'New generation':TSR-1265; SI 27; MMI-166 PA-inhibitors PAI-1 Heparinase PI-88 Cytotoxic drugs Pro-apoptotic factors Tumor Necrosis Factor Tubulin-binding agents Combretastatin A4; BMS 186527 CD36-ligand Thrombospondin/ Thrombospondin peptides> Mixed mechanisms ATP synthase inhibitors Angiostatin Inhibitors of EC proliferation TNP-470; CAI; Interleukin-12; IFN-; Thrombospondin HSP90 inhibitor Geldanamycin derivatives CONCLUSION Most of anti-angiostatic drugs are still under the clinical trials and that is because of the condition of trial itself and that include the safety, side effects, proper dosage and the best way to give the drug pill or injection. Apart from this a lot of ethical issues are also involved in it. Since for cancer therapy standard modes of treatment which are already FDA approved are in place so getting new modes of therapy launched is not an easy task and has to be covered properly from every aspect. On the other hand, because of the problems that can be found during the trial such as difficulties with the production of the drugs or even the reproduction or the death of some patients under the trial. However, the result of the anti-angiogenenic clinical trial is not always the desired result such as the treatment with endostatin did not promote a significant tumour regression in neuroendocrine tumours (Lederman, 2001) and there is no survival advantages were demonstrated after treatment with Marimastrat. In January 2007 researchers reported that there is no improvement in the survival rate of patients under trial with advanced pancreatic tumour treated with Avastin(Furchgott,1990) as well a very new study In the 5th of December 2007 shows that the risks of using Avastin is more than its benefits in the treatment of the breast cancer. A number of experimental models are available for the study of angiogenesis in normal (Funk, 1986., Passaniti 992)and tumor tissues (Ausprunk, 1975., Leunig 1992),but no model allows detailed assessment of the early phases of tumor induced angiogenesis with simultaneous visualization of growth of micro tumors in vivo. In a recent study, however, we used fluorescent intravital microscopy to develop a technique that allows noninvasive, in vivo and in situ monitoring of tumor angiogenesis and tumor growth in conscious mice (Tones, 1995). But this did not prevent the fact that anti-angiogenic can be an effective alternative drugs to treat some kind of cancer better than the other established modalities with also with an acceptable set of side effects. With this knowledge, the approach to cancer therapy has rapidly shifted from an empirical process of anti-cancer drug discovery, radiation planning and studying safe margins surgically to a more tumor specific and less toxic strategies which include protocols based upon immunotherapeutic use of effector cells, antibodies, cytokines, anti-angiogenic drugs, low molecular weight receptor antagonists, enzyme inhibitors and antisense oligonucleotides (Gibbs, 2000) Several orthotopic human tumor xenograft models have been established and successfully exploited to evaluate different therapies (Cuenca, 1996., Boehle, 2000). 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