Key words tumor angiogenesis; tumor angiogenesis inhibitors; radiotherapy; chemotherapy

A large number of studies have shown that traditional cancer treatment and more directed against the tumor cells and there are a lot of defects, such as prone to tumor resistance within the tumor cells and other drugs is not easy to enter. Folkman Professor at Harvard University in 1971 [1], the point of view of the growth and metastasis of solid tumors is dependent on angiogenesis, domestic and foreign researchers have done a lot of in-depth study, and made substantial progress in the suppression or destruction of tumor angiogenesis. cut off a the cancer source of nutrition and “starve" the tumor become a new effective therapy. This article on the anti-angiogenic mechanism, treatment progress, and combined with radiotherapy, chemotherapy effect are reviewed.

    An anti-angiogenic principle

    1.1 tumor angiogenesis

    Angiogenesis (angiogenesis) is on the basis of existing vascular bed, an endothelial cell differentiation to generate new blood vessels in tissue, so as to provide blood supply away from the existing vascular system neogenetic tissue. Oxygen and nutrients required for tumor growth when the neovascular not generate, through the organization of the dispersion effect. When the tumor volume more than 2mm3 or the number of tumor cells reached 107, the dispersion effect can not meet the needs of tumor growth [1]. Tumor center area of ​​hypoxia-induced hypoxia-inducible factor 1 (HIF1) raised, the start transcription vascular endothelial growth factor (vascular endothelial growth factor, VEGF) and other growth factor synergy to promote new blood vessel formation. The process is a critical step in tumor progression, known as the “angiogenic switch," [2].

    1.2 the regulatory mechanism of tumor angiogenesis

    Angiogenesis promoting factors including VEGF, basic fibroblast growth factor (bFGF), insulin-like growth factor  I (IGF I), tumor necrosis factor α (TNFα), transforming growth factor-β (TGF  β) and platelet derived endothelial cell growth factor (PD  ECGF). The first three factor receptor distribution in endothelial cells, vascular endothelial cell division, chemotaxis and migration, increase vascular permeability and promote neovascularization. TNFα degradation of extracellular matrix, to raise the local content of VEGF and bFGF [1]. TGF  β induction of TNF and plasminogen activator inhibitor produces. PD  ECGF promote vascular endothelial cell mitosis, promoting the formation of the vessel lumen.

    The inhibition of angiogenesis factors mainly include angiostatin (angiostatin), endostatin (of endostatin in), cell resting associated protein (restin). Angiostatin plasminogen fragment inhibit vascular endothelial cell migration, and induction of apoptosis in endothelial cells. Endostatin for the Ⅹ Ⅷ collagen carboxy-terminal fragment selectively induce apoptosis, inhibit vascular endothelial cell proliferation [3]. The cell resting related protein Ⅹ Ⅴ type I collagen α1 chain carboxy-terminal fragment, can inhibit the migration of vascular endothelial cells, but no effect on cell proliferation.

    The more tumor angiogenesis gene regulation p53 gene. The p53 protein can stimulate the expression of the gene Smad4 inhibiting angiogenesis, thereby inhibiting angiogenesis. p53 mutation causes angiogenesis, tumor growth to accelerate into the performance of advanced tumors [4].

    2 anti-angiogenic Research Survey

    Angiogenesis is a complex multi-step process, blocking of which any step can inhibit angiogenesis, the main therapeutic strategies are the following:

    2.1 Direct inhibition of endothelial cell proliferation and (or) promote apoptosis

    Angiostatin (angiostatin) and endostatin (endostatin) were digested fragments of plasminogen and collagen X, the most ever found a direct anti-angiogenic agents, they specifically act on endothelial cells, inhibition endothelial cell proliferation and migration, induction of apoptosis, significant inhibition of tumor growth and metastasis [5], tumor dormancy therapy drugs, and the study confirmed that the combination of endostatin and angiostatin has a multiplier effect [6], but the precise mechanism is not fully understood. In addition, as CombrestastatinA  4prodrug (CA4p) induced proliferation of endothelial cell apoptosis, mainly for treatment of breast cancer cell sarcoma, obvious effect, has entered a Phase I clinical study stage [7].

    2.2 inhibit the degradation of the extracellular matrix

    Matrix metalloproteinases (matrix metalloproteinases, MMPs) that can degrade the extracellular matrix and basement membrane, caused by the migration of endothelial cells, release or activation angiogenic factors, tumor growth, angiogenesis, invasion and metastasis has important significance. The tissue inhibitor of metalloproteinase (tissue inhibitor of metallo proteinases, TIMPs) can be combined with the zinc ions active groups of MMPs and inhibiting its activity, thereby inhibiting the degradation of the extracellular matrix and basement membrane destruction, and ultimately to inhibit tumor angiogenesis [8] . At present, the known natural TIMP, Neovastat (Phase III clinical trials), the synthetic AG  3340 and CGS  27023A, are in clinical trials.

    2.3 blocking endothelial cell-specific integrin

    Some of the endothelial cell surface integrins, such as ανβ3 and ανβ5 combined with the extracellular matrix, promoting the migration of endothelial cells and the formation of new blood capillaries lumen. Therefore, the role of anti-angiogenic factors can also be reached by blocking endothelial cell-specific integration. Belong to this class of drugs such as arresten, canstatin, and tumstatin.

    2.4 closed angiogenic factors and their receptors

    Angiogenic factors such as VEGF, bFGF, and PDGF can promote tumor angiogenesis and the biological effects of its corresponding receptor-mediated achieved through the closure of these vascular endothelial growth factor and its receptor can reach the anti-angiogenic purposes. Such as anti-angiogenic agents of ZD1839, ZD6474, OSI774 CI1033 PKI1666 and IMC225 inhibited promote angiogenic factors VEGF, bFGF and TGF  α activity and tumor cells, EGF receptor tyrosine kinase activity [9]; PTK787, SU6668 the role and SU11248 on VEGF receptor, PTK787 and SU11248 also the role of the PDGF receptor; the Herceptin can inhibit VEGF, raised thrombospondin  1 expression and inhibits the activity of receptor tyrosine kinase HER  2/neu; Avastin recombinant humanized VEGF antibody, has now been approved by the FDA for a clinical drug inhibits angiogenesis therapy, its mechanism of action is through inhibition of VEGF, thereby inhibiting the proliferation of endothelial cells.

    2.5 anti-angiogenic gene therapy

    The so-called anti-angiogenesis gene therapy is introduced to the tumor or the surrounding tissue of the target cells, angiogenesis regulating factor gene, to achieve the purpose of the treatment of tumors by changes in tumor vascular inducing factor and the suppression of the balance between factors. Currently, the anti-angiogenic gene therapy primarily through three ways: (1) down pro-angiogenic factor expression; (2) induction of angiogenesis inhibitors generated; (3) interfere with signaling between cells.

    2.6 RNA interference

    RNA interference (RNAinterference, RNAi) is a new method of inhibiting angiogenesis, it is to design targeting VEGF RNAi sequence into the DNA plasmid will be transfected into vascular endothelial cells, and ultimately through the lower endothelial cells The expression of VEGF and to achieve the purpose of anti-angiogenesis.

    2.7 Other anti-angiogenesis therapy

    IL  12 in addition to direct anti-tumor effect, but also by the anti-angiogenic and anti tumor effects. The platelet factor  4 can inhibit the proliferation and migration of vascular endothelial cells, and intratumoral injection of platelet factor  4 on murine tumors and human transplantation tumor was inhibited.

    3 anti-angiogenic therapy clinical efficacy

    To date, more than 30 kinds of anti-vascular generation drug achieved good results in the the antitumor experimental studies, and has started to move towards clinical its preliminary results for sure, but the effect is not so good like animal experiments. Currently, researchers be combined with conventional therapy has shown good treatment [10]. The past three years, the FDA has approved three tumor angiogenesis inhibitor class of drugs (Avastin, Sunitinib malate, Sorafenib) listed.

    The results confirmed colorectal cancer in combination with Avastin (bevacizumab) can improve the first-line, second-line chemotherapy regimens, at the same time with different mechanism of action other molecular targeted preparation associated, can further improve efficacy. Hurwitz et al [11] conducted a randomized Phase III clinical study: 900 patients were randomly divided into two groups, IFL + bevacizumab group IFL + placebo group, the two groups have 45% and 35%, respectively, effective and continuous 10.4 months and 7.1 months, progression-free survival were 10.6 months and 6.2 months, the median survival time was 20.3 months and 15.6 months. Ⅲ ~ Ⅳ degree bleeding adverse reactions were 3.1% and 2.5%, thromboembolism was 19.3% and 16.1%, respectively, III proteinuria were 0.8%, Ⅲ degree of hypertension of 10.9% and 2.3%, respectively. Bevacizumab in combination with IFL chemotherapy regimen for first-line treatment of advanced colorectal cancer can extend overall survival and tumor-free survival rate, improve objective response rate and duration of remission. As a result of this study, February 26, 2004, the FDA formally approved bevacizumab listed for the first-line treatment of advanced colorectal cancer.

    Sorafenib (Nexavar) is approved by the U.S. Food and Drug Administration (FDA) in December, 2005 first-line drugs for the treatment of advanced kidney cancer. Escudier et al [12] reported The Sorafenib second-line treatment of metastatic renal cell carcinoma stage Ⅲ randomized, multi-center, double-blind, placebo-controlled study that TARGET study, 903 patients were included, Sorafenib therapy group (2 times a day, every time 400mg) 451 cases , placebo-controlled group of 452 cases. The results of the treatment group, median disease progression-free survival of 24 weeks on average, significantly higher than the placebo group, 12 weeks (P <0.00001, relative risk 0.44, 95% confidence interval 0.35 to 0.55). The middle of the 216 patients in the placebo group, a result of tumor progression unblinded into the treatment group, the average treatment group had a median survival of 19.3 months in the placebo group was 14.3 months into the treatment group, about 50% of patients transferred into the treatment group, the median survival time of the group average of 15.9 months, the overall survival of an extension of 1.6 months. At the same time, 76% were taking Sorafenib in patients with tumor volume has narrowed, while only 25% of the placebo-control group. Phase III clinical studies, sorafenib could significantly prolong the survival of patients with metastatic renal cell carcinoma disease progression-free period.

    SU011248 (Sunitinib) was first introduced in January 2006 by the U.S. FDA approval in the United States. Development of the Phase III clinical trial results confirmed gastrointestinal stromal tumors [13], Sunitinib can delay has generated imatinib (Imatinib, Gleevec) in the treatment of drug-resistant (or can not tolerate), to significantly reduce the mortality rate of patients . For generating the resistance of renal cell carcinoma patients, but also has a high response rate, can be effective in delaying the development of tumors. Compared with the use of interferon 2α treatment to patients with advanced or metastatic renal cell carcinoma (MRCC) Sunitinib, the condition does not worsen the patient’s survival time from May to November. Oral Sunitinib may be fatigue, weakness, nausea, indigestion, diarrhea or oral mucositis, neutropenia, thrombocytopenia and dermatitis, skin discoloration or hair fade with mild to moderate adverse reactions, patients can be well tolerated .

    As against the in-depth study of tumor angiogenesis, generally considered the neovascularization of anti-tumor drugs with traditional anti-cancer drugs have the advantage of the following aspects: (1) endothelial cells Biogen shape is relatively stable, low mutation rate, easy to produce drug ; (2) vascular endothelial cells can be used directly in contact with the drug in the blood, the drug reaching the tumor cells is required through the tissue membrane, which is made more demands on the physicochemical properties of the drug; (3) Since a large number of tumors cell nutrition is provided by a small number of capillaries, so the drug is simply acting in such a small amount of vascular endothelial cells can cause tumor tissue necrosis due to ischemia; (4) tumor vascular endothelial cells is different from the normal shape of the cell biology of vascular endothelial , which we study the selective effect of drugs in tumor vascular endothelial cells possible. In addition, due to the different mechanisms of wound healing mechanism and tumor angiogenesis, the present experiment found no anti-angiogenic drugs have an adverse effect on wound healing [14].

    4 anti-angiogenic therapy with radiotherapy and chemotherapy combined with

    4.1 antiangiogenic therapy in combination with chemotherapy

    4.1.1 associated with the principle of

    Associated with one hand after the use of chemotherapy drugs kill tumor cells; the other hand, the use of anti-angiogenic drugs inhibit tumor angiogenesis. In addition, tumor cells easily develop resistance to chemotherapy drugs, but the endothelial cells against no-angiogenic drugs to produce resistance, so even if the resistance of tumors to chemotherapeutic drugs, anti-angiogenic drugs are still effective, since remedial treatment.

    4.1.2 associated with clinical trials

    As mentioned earlier, Hurwitz et al [11] published IFL + bevacizumab first rule of 813 cases in Phase III clinical trials of patients with colorectal cancer, the combination therapy can significantly prolong the survival time of the patients, median survival of their patients was 20.3 months, and the only chemotherapy, the median survival time was 15.6 months, and disease-related symptoms in patients with recent disappearance, the toxicity of combination chemotherapy drug CPT  11 mild reaction [15]. Another advanced metastatic non-small cell lung cancer patients II clinical trial results show that, on the basis of the standard carboplatin / paclitaxel chemotherapy plus Avastin, time to disease progression was significantly longer than with chemotherapy patients, both were 32.1 weeks and 18.4 weeks [15]. In January 2005 to the 29th meeting of the American Second Gastrointestinal Cancers Symposium, researchers announced Avastin and oxaliplatin combined with the treatment of colorectal cancer Phase III clinical trial, preliminary results also associated with tumor response rate can be increased significantly prolong the median survival period. It was also reported in the literature, Herceptin and cytotoxic chemotherapy drugs, such as vinorelbine, gemcitabine, Xeloda, Taxol and other treatment of breast cancer, have clear efficacy, and more effective than with Herceptin or single chemotherapy [16].

    4.2 anti-angiogenic therapy with radiotherapy combined with

    4.2.1 associated with the principle of

    The synergistic effect of angiogenesis inhibitors and radiotherapy: (1) enhancing tumor radiosensitivity. The important factor is the presence of hypoxic cells in tumor radiosensitivity. Jain [17] proposed anti-angiogenic role of vascular network with alterations of tumor disorders, while inhibiting angiogenesis and thereby improve local blood circulation, reduce tumor interstitial pressure, increase of local oxygen partial pressure, enhance the radiosensitivity of tumor; ( 2) enhance the destruction of endothelial cells. Can weaken the protection mechanisms of endothelial cells through inhibition of endothelial cell proliferation and radiotherapy play the synergistic effect of the anti-vascular endothelial cells, causing tumor cell apoptosis [18].

    4.2.2 associated with the test

    Antiangiogenic and cytotoxic therapies, including radiation therapy, including the thinking associated with the earliest by Teicher et al [19] test confirmed. The TNP  470 is a synthetic fumagillin-like substance with a strong anti-angiogenic activity Teicher study found, improve oxygen supply TNP  470 with radiation therapy associated with better enhance the anti tumor effect, but also reduce the desired radiation treatment dose to achieve the same anti-tumor effect. Gorski et al [20] combined with VEGF antibody and radiotherapy-treated mice allograft Lewis lung carcinoma and three xenograft human tumors. The VEGF antibody dose used alone does not cause tumor growth hysteresis, in the treatment of four tumor radiotherapy associated with markedly enhanced the efficacy of radiation therapy. Lewis tumor doubling time extended from 310 to 510 days of radiotherapy alone to combined with the 718 to 1016 days after 18 days; U87 glioblastoma radiotherapy, tumor volume was reduced by 68.8% compared with the control group, the combined group 83.4% reduction. Geng et al [21] to soluble VEGFR  2 gene therapy and radiotherapy associated with, originally 2Gy dose does not make tumor neovascularization degradation, but even if the same dose and single with no therapeutic effect of small doses of VEGFR  2 associated with , which inhibit the angiogenic effect also approximates irradiation dose 6Gy. Mauceri et al [22] angiostatin and radiation therapy for the treatment SQ of  20B tumors found that tumor volume was reduced by 64% compared with the control group, single angiostatin only reduced by 10%, reduced by 18% in the radiotherapy group. Griscelli et al [23] and Hanna [24] A similar test has also made anti-tumor effect than each alone.

    5 Conclusion

    The tumor can be seen as a two-bedroom model by tumor cells and endothelial cells, and they interact. In the same time, the anti-angiogenic treatment with radiotherapy or chemotherapy joint targeting tumor cells and tumor endothelial cells has a synergistic anti-tumor effect, should be the future direction of development of the cancer treatment. Associated with the evaluation of adverse reactions associated with program design, combined with the detailed mechanism but we need further study.