Targeting the vascular endothelial growth factor pathway in the treatment of human malignancy

Over 30 years ago, it was proposed that blocking new blood vessel formation would significantly inhibit solid tumor growth and hence, limit cancer progression. Efforts guided by this philosophy have resulted in a better understanding of the molecular basis of tumor angiogenesis. The first successful therapeutic to emerge from this work, an antibody (bevacizumab) targeting the vascular endothelial growth factor (VEGF), was recently approved for the treatment of colorectal cancer. Additional positive clinical data with bevacizumab in the treatment of breast and lung carcinoma have also been reported. These clinical achievements have validated the approach of anti-angiogenesis therapy for cancer and provided further confirmation for antibodies as a therapeutic class in this disease. Nevertheless, important unanswered questions with regard to preclinical and clinical results of VEGF pathway inhibitors remain. For example, preclinical models with a number of VEGF pathway inhibitors suggest that these agents would have significant clinical activity on their own; yet, clinical activity in patients with bevacizumab or other VEGF pathway inhibitors as monotherapy have been disappointing. Moreover, while bevacizumab is approved for the treatment of colorectal cancer in combination with cytotoxics, the mechanism for the benefits of this combination are still poorly understood, with a number of viable mechanisms under active experimental evaluation. The 3-8-month survival benefit in colorectal cancer patients treated with bevacizumab is a positive step forward. However, improving our understanding of the mechanism for these effects, as well as the mechanism underlying the inability as yet to achieve greater effects, is needed in order to follow up on the positive clinical results with improved strategies. This review discusses the experimental results surrounding the current status of our understanding of the mechanism of action of VEGF signaling inhibitors, and the potential for utilizing these agents in the future so that clinical benefits will be measured in years rather than months.     

Monoclonal Antibodies Targeting Vascular Endothelial Growth Factor

The use of monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) pathway has been a significant addition to cancer therapy. One of the VEGF family members, VEGF-A (commonly referred to as VEGF), has been demonstrated to be important in angiogenesis. Although the mechanism of action of these antibodies is still under study, the anti-VEGF antibody bevacizumab has been approved for treatment of various solid cancers including colorectal, lung, and breast cancers as well as glioblastoma and renal cell carcinoma. Addition of bevacizumab to chemotherapy as adjuvant therapy in colorectal cancer did not improve disease-free survival. Bevacizumab is being tested in other clinical settings such as adjuvant therapy, maintenance therapy, and in combination with both chemotherapy and other targeted agents such as the epidermal growth factor receptor kinase inhibitor erlotinib. In addition to bevacizumab, other antibody-based therapies targeting the VEGF pathway are being tested. Ramucirumab and IMC-18F1 are monoclonal antibodies that target the VEGF receptors VEGFR-2 and VEGFR-1, respectively. Aflibercept (VEGF-Trap), a peptide-antibody fusion targeting VEGF ligand, is being tested in clinical trials. Much research is focused on identifying biomarkers to predict which patients will benefit from anti-VEGF therapy. Recent results suggest that VEGF single nucleotide polymorphisms may be predictive of patient response to bevacizumab. Improved imaging modalities such as dynamic contrast-enhanced MRI (DCE-MRI) can better characterize the efficacy of anti-angiogenic agents. As anti-VEGF treatments such as bevacizumab have been integrated into the treatment of many different types of cancers, the development of bevacizumab-resistant tumors has become more common. Recent studies show that targeting other angiogenesis signaling pathways such as platelet-derived growth factor-C (PDGF-C), Bombina variagata peptide 8 (Bv8, also known as prokineticin-2), and VEGFR-3 may lead to enhanced response in anti-VEGF resistant tumors. In the future, tailored treatments consisting of combinations of chemotherapy, other targeted therapies, and anti-angiogenesis agents will hopefully result in better patient outcomes.     

Targeting Angiogenesis in Advanced Breast Cancer

Angiogenesis, the process of new blood vessel formation, is required for tumor growth and metastasis. There is substantial preclinical and clinical evidence supporting the central role of angiogenesis in tumor formation and metastasis. Thus, the inhibition of angiogenesis may provide more effective treatment for patients with advanced breast cancer. Several chemotherapeutic and hormonal agents routinely used in the treatment of advanced breast cancer have antiangiogenic properties. Novel antiangiogenic agents targeting the vascular endothelial growth factor (VEGF) ligand and receptor tyrosine kinase inhibitors are being developed. Recently, a large phase III clinical trial demonstrated a significant benefit in progression-free survival with the addition of anti-VEGF monoclonal antibody bevacizumab to paclitaxel for first-line treatment of advanced breast cancer. This study established that antiangiogenic therapy is effective in breast cancer, and additional studies of bevacizumab and other antiangiogenic agents are underway. This article reviews the evidence for the role of angiogenesis in breast cancer pathogenesis, the challenges of developing antiangiogenic agents, and current agents in clinical trials.     

Decreased peritherapeutic VEGF expression could be a predictor of responsiveness to first-line FOLFIRI plus bevacizumab in mCRC patients

Objective: Bevacizumab is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer (mCRC). Although chemotherapy plus bevacizumab has led to improve outcomes for mCRC patients and is a common choice for first-line treatment of mCRC, previous research has established no prominent biomarker that can help to select patients who may benefit from bevacizumab in order to improve cost-effectiveness and therapeutic outcomes. The aim of this study was to compare pre- and post-therapeutic VEGF immunohistochemical (IHC) expression in mCRC patients treated with FOLFIRI plus bevacizumab to identify its potential role as a predictive biomarker. Methods: A total of 57 mCRC patients who underwent FOLFIRI combined with bevacizumab chemotherapy as a first-line neoadjuvant regimen were enrolled and clinical outcome data analyzed. Results: Low post-therapeutic VEGF expression (P < 0.001) and decreased peri-therapeutic VEGF expression (P < 0.001) were significantly predictive factors of responders. Furthermore, the 6-month progression-free survival (PFS) rate in mCRC patients with decreased peri-therapeutic VEGF expression was significantly better than the rate for those patients with no peri-therapeutic VEGF expression alterations (P = 0.033). Conclusions: Decreased peri-therapeutic VEGF expression in mCRC patients could probably be used to predict responsiveness to bevacizumab and subsequent PFS in clinical practice.     

Differential drug class-specific metastatic effects following treatment with a panel of angiogenesis inhibitors

Inhibiting angiogenesis has become an important therapeutic strategy for cancer treatment but, like other current targeted therapies, benefits experienced for late-stage cancers can be curtailed by inherent refractoriness or by acquired drug resistance, requiring a need for better mechanistic understanding of such effects. Numerous preclinical studies have demonstrated that VEGF pathway inhibitors suppress primary tumour growth and metastasis. However, it has been recently reported that short-term VEGF and VEGFR inhibition can paradoxically accelerate tumour invasiveness and metastasis in certain models. Here we comprehensively compare the effects of both antibody and small molecule receptor tyrosine kinase (RTK) inhibitors targeting the VEGF-VEGFR pathway, using short-term therapy in various mouse models of metastasis. Our findings demonstrate that antibody inhibition of VEGF pathway molecules does not promote metastasis, in contrast to selected small molecule RTK inhibitors at elevated-therapeutic drug dosages. In particular, a multi-targeted RTK inhibitor, sunitinib, which most profoundly potentiated metastasis, also increased lung vascular permeability and promoted tumour cell extravasation. Mechanistically, sunitinib, but not anti-VEGF treatment, attenuated endothelial barrier function in culture and caused a global inhibition of protein tyrosine phosphorylation, including molecules important for maintaining endothelial cell-cell junctions. Together these findings indicate that, rather than a specific consequence of inhibiting the VEGF signalling pathway, pharmacological inhibitors of the VEGF pathway can have dose- and drug class-dependent side-effects on the host vasculature. These findings also advocate for the continued identification of mechanisms of resistance to anti-angiogenics and for therapy development to overcome it.     

Bevacizumab-Induced Hypertension

Bevacizumab, a recombinant humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF), has been approved in the US as first- and second-line treatment of colorectal cancer and in the first-line treatment of advanced non-small cell lung cancer. The US FDA has also granted approval for the use of bevacizumab for the treatment of patients with metastatic renal cell carcinoma and glioblastoma, and in Europe, it is also approved in metastatic breast cancer in combination with paclitaxel. Bevacizumab is under investigation in the first-line and adjuvant setting of almost all types of solid tumors. However, anti-VEGF therapy is associated with significant toxicity. The incidence of grade 3-4 hypertension differs among the various malignancies in which bevacizumab is administered, possibly because of drug interactions with co-administered chemotherapy drugs. Hypertension appears to be dose dependent, and it is under investigation as a biomarker for VEGF inhibition efficacy. There are three main theories concerning the underlying pathophysiology: (i) the nitric oxide theory; (ii) the renal impairment theory; and (iii) the pre-eclampsia-like theory. The correct evaluation of the levels of hypertension is of critical importance and home blood pressure monitoring seems to be the most effective technique. A baseline assessment and follow-up monitoring of blood pressure is considered necessary for all patients receiving bevacizumab. There are no evidence-based recommendations regarding which antihypertensives are more appropriate for the management of bevacizumab-related hypertension. It has been suggested that the benefits from antihypertensive treatment are largely independent of the drugs used, as long as they adequately lower blood pressure. Randomized prospective studies are necessary to provide data that will be useful for the development of specific guidelines for the management of bevacizumab-related hypertension. In the meantime, treatment of anti-VEGF-induced hypertension should follow current guidelines for diagnosis and management of hypertension in general.     

血管内皮细胞生长因子与大肠癌治疗

血管内皮细胞生长因子（VEGF）在大肠癌组织中高表达，与肿瘤血管生成，肿瘤细胞增殖、转移，肿瘤预后关系密切。目前各种针对VEGF及其受体开展的抑制肿瘤血管生成的药物研究广泛开展，有的已经批准上市，用于大肠癌的临床治疗，为大肠癌的治疗开辟了新的途径。     

Spotlight on Bevacizumab in Advanced Colorectal Cancer, Breast Cancer, and Non-Small Cell Lung Cancer

Bevacizumab (Avastin) is a humanized recombinant antibody that prevents vascular endothelial growth factor (VEGF) receptor binding, and inhibits angiogenesis and tumor growth.In patients receiving an irinotecan plus fluorouracil/leucovorin (IFL) regimen for first-line treatment of metastatic colorectal cancer, the addition of bevacizumab significantly increased overall survival by 4.7 months relative to IFL plus placebo. In the second-line treatment of advanced colorectal cancer, patients who received bevacizumab in combination with a fluorouracil/leucovorin plus oxaliplatin (FOLFOX4) regimen had an overall survival time that was 2 months longer than that in patients receiving FOLFOX4. Preliminary results indicated that bevacizumab significantly extended progression-free survival by 4.9 months in patients receiving paclitaxel for the first-line treatment of locally recurrent or metastatic breast cancer. The addition of bevacizumab to paclitaxel plus carboplatin in the first-line treatment of advanced non-small cell lung cancer (NSCLC) significantly prolonged overall survival by >2 months. Bevacizumab has acceptable tolerability in patients with advanced colorectal cancer, breast cancer, or NSCLC, with the majority of adverse events being generally mild and clinically manageable. Thus, bevacizumab provides a highly effective addition to standard chemotherapeutic regimens for advanced colorectal cancer, breast cancer, and NSCLC.     

Telomerase in Cancer Diagnosis and Therapy

Curing cancers is one of the most challenging tasks of modern medicine. The major problem is the heterogeneity of human tumours and thus finding a 'universal' target for cancer treatment. The discovery that the expression of the enzyme telomerase is a hallmark of immortality and cancer, and that it is found in the majority (>85%) of human tumours but is repressed in most normal cells, has therefore caused considerable excitement. These observations led to the design of potential telomerase inhibitors and ideas about targeting telomerase in the clinic. To date, several classes of telomerase inhibitory agents have been identified and are in preclinical development. However, the approach has not yet been tested clinically. Because of the proposed function of telomerase, and the understanding that replicative cell senescence or cell death result from progressive telomere shortening during successive cell divisions, even complete enzyme inhibition will not produce immediate cell death. Designing clinical trials for promising telomerase inhibitors requires consideration of the novel mechanism of action of these drugs. A lag period between initiation of treatment and occurrence of effects is likely, and thus anti-telomerase therapy might best be given in adjuvant treatment protocols after initial tumour debulking therapy and in combination with other cytostatic agents. The available knowledge of telomerase biology and its association with human tumours suggests that telomerase inhibition might prove a valuable addition to current cancer treatment regimens.     

Targeted Therapies for Solid Tumors

The therapeutic benefits of targeted clinical interventions with increased selectivity and fewer adverse effects hold great promise in the treatment of solid malignancies, both in monotherapy and in combination. Molecular targeted therapies offer increasingly customized solutions based on the targeting of multiple specific pathways essential for cancer development and metastasis, allowing the maintenance of quality of life while efficiently attacking the tumor. To date, several monoclonal antibodies (mAbs) and small-molecule inhibitors have been approved for the treatment of colorectal, breast, head and neck, non-small cell lung and renal cell cancer. A number of additional targeted therapies are currently being investigated in ongoing clinical trials in various tumor types such as lung, gastric, cervical, uterine melanoma, and brain tumors. This article describes current and newly developed targeted therapies in solid tumors, with a special focus on tyrosine kinase inhibitors. These include mAbs and small-molecule inhibitors that aim to specifically disrupt receptor signaling pathways, which are essential for proliferation, survival and migration of tumor cells.     

The possible role of chemotherapy in antiangiogenic drug resistance

The use of antiangiogenic drugs for cancer treatment was welcomed because of the hypothesis that they would be much less likely to lose their therapeutic activity as a result of tumor-acquired resistance over time. Unfortunately, the clinical experience has shown that acquired resistance to antiangiogenic therapeutic strategies is possible since many patients whose tumors initially respond to drugs such as bevacizumab (a monoclonal antibody against VEGF), sorafenib, or sunitinib (tyrosine kinase inhibitors targeting VEGF receptors and PDGF receptors) or metronomic chemotherapy (e.g. low dose cyclophosphamide) become nonresponsive, often within months of therapy initiation. Indeed, the role of associated antineoplastic chemotherapy in antiangiogenic resistance seems to be ignored by the previous studies and the real part played by these drugs has to be written yet. The studies undertaken on antiangiogenic resistance mainly involved mechanisms directly related to the antiangiogenic drugs alone and as such lead one to ask whether the acquired resistance to angiogenesis pathway-targeting might also be mediated by the chemotherapeutic drugs usually associated (at least into the clinic) with these types of drugs. The proposed hypothesis is concerning the possibility that the acquired resistance to antiangiogenic therapy could be actively and heavily modulated by the choice of the associated chemotherapeutic drug. The chemotherapeutic compounds may delay or accelerate the process through the induction, upregulation or downregulation of pro-angiogenic or anti-angiogenic factors or their receptors in the tumor, endothelial and other type of cells of the tumor microenvironment. In conclusion, the consequences of our hypothesis could be promptly translated into the preclinical studies and verified in clinical trials, involving cancer patients resistant to chemotherapy plus antiangiogenic drug schedules.     

Mechanistic Rationale and Clinical Evidence for the Efficacy of Proteasome Inhibitors against Indolent and Mantle Cell Lymphomas

Recent advances in understanding the complex biology of the ubiquitin-proteasome pathway have led to the identification of many potentially 'drugable' targets within this pathway. One such inhibitor, bortezomib (formerly known as PS341), has proven to be an effective reversible inhibitor of the chymotryptic protease in the 26S proteasome. Proteasome inhibitors represent a new approach for the treatment of many forms of cancer, especially select hematological malignancies. The proteasome plays an important role in regulating the availability of different intracellular proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the proteasome is associated with a remarkable panoply of different biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard chemotherapy and radiation therapy. Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory multiple myeloma. In addition, bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring bortezomib in different histologies of NHLs and in combination with conventional chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity profile of this drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ bortezomib in the conventional treatment of lymphoma. The apparent lack of activity in different subtypes of lymphoma, such as small lymphocytic lymphoma/chronic lymphocytic leukemia and diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine bortezomib with standard therapies for indolent NHLs, raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.     

Gene therapy for colorectal cancer: therapeutic potential

Colorectal cancer is a leading cause of cancer mortality in Western countries. Gene therapy has been proposed as a potential novel treatment modality for colorectal cancer, but it is still in an early stage of development. The preclinical data have been promising and numerous clinical trials are underway. This brief review aims to summarise the current status of clinical trials of different gene therapy strategies, including immune stimulation, mutant gene correction, prodrug activation and oncolytic virus therapy, for patients with colorectal cancer. Data from phase I trials have proven the safety of the reagents but have not yet demonstrated significant therapeutic benefit. In order to achieve this and extend the scope of the treatment, continuing efforts should be made to improve the antitumour potency, efficiency of gene delivery and accuracy of gene targeting.     

Triple-negative breast cancer: Novel therapies and new directions

Triple-negative breast cancer (TNBC) accounts for approximately 15% of breast cancer diagnoses, and exhibits substantial overlap with basal-type and BRCA1-positive breast cancer. In recent years, a greater understanding of the biology of this disease has led to the development of numerous and varied therapeutic approaches. Neoadjuvant trials using conventional cytotoxic agents such as cisplatin have demonstrated TNBC to be a relatively chemo-sensitive disease. In the current review, focus is directed towards novel targeted strategies for TNBC. Recent trials have shown the poly(ADP-ribosyl)ation polymerase (PARP) inhibitors BSI-201 and olaparib to be highly effective in TNBC and BRCA1/2-positive disease, respectively. Efforts to assess the role of antiangiogenic agents such as bevacizumab and sunitinib in TNBC are ongoing. Finally, preclinical studies provide a signal of potential activity with use of heat shock protein 90 (Hsp90) and Src inhibitors in this breast cancer subtype.     

Spotlight on Bevacizumab in Metastatic Colorectal Cancel

Bevacizumab (Avastin((R))) is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that is used to inhibit VEGF function in vascular endothelial cells and thereby inhibit tumor angiogenesis, upon which solid tumors depend for growth and metastasis.The addition of bevacizumab to fluoropyrimidine-based chemotherapy, with or without irinotecan or oxaliplatin, in both the first- and second-line treatment of metastatic colorectal cancer, significantly increased median progression-free survival or time to disease progression in most randomized controlled trials. Bevacizumab was generally, but not always, associated with a survival advantage; in phase III trials, the increases in median overall survival attributable to bevacizumab were 4.7 months with first-line therapy and 2.1 months with second-line therapy. In some studies, patients experienced clinical improvement without an apparent overall survival benefit. Bevacizumab had acceptable tolerability, with the majority of adverse events being generally mild and clinically manageable. However, from the UK National Health Service perspective, bevacizumab was not considered to be cost effective in combination with bolus fluorouracil/leucovorin (folinic acid) or irinotecan/bolus fluorouracil/leucovorin. Additional pharmacoeconomic analyses from different perspectives and using clinical data for combinations with the more efficacious infusional fluorouracil/leucovorin plus oxaliplatin or irinotecan chemotherapy regimens are required. Although cost effectiveness may be a concern, the combination of bevacizumab and fluoropyrimidine-based chemotherapy has potential in the treatment of metastatic colorectal cancer.     

Ataxia-telangiectasia mutated and the Mre11-Rad50-NBS1 complex: promising targets for radiosensitization

Radiotherapy plays a central part in cancer treatment, and use of radiosensitizing agents can greatly enhance this modality. Although studies have shown that several chemotherapeutic agents have the potential to increase the radiosensitivity of tumor cells, investigators have also studied a number of molecularly targeted agents as radiosensitizers in clinical trials based on reasonably promising preclinical data. Recent intense research into the DNA damage-signaling pathway revealed that ataxia-telangiectasia mutated (ATM) and the Mre11-Rad50-NBS1 (MRN) complex play central roles in DNA repair and cell cycle checkpoints and that these molecules are promising targets for radiosensitization. Researchers recently developed three ATM inhibitors (KU-55933, CGK733, and CP466722) and an MRN complex inhibitor (mirin) and showed that they have great potential as radiosensitizers of tumors in preclinical studies. Additionally, we showed that a telomerase-dependent oncolytic adenovirus that we developed (OBP-301 [telomelysin]) produces profound radiosensitizing effects by inhibiting the MRN complex via the adenoviral E1B55kDa protein. A recent Phase I trial in the United States determined that telomelysin was safe and well tolerated in humans, and this agent is about to be tested in combination with radiotherapy in a clinical trial based on intriguing preclinical data demonstrating that telomelysin and ionizing radiation can potentiate each other. In this review, we highlight the great potential of ATM and MRN complex inhibitors, including telomelysin, as radiosensitizing agents.     

Potential of anti-inflammatory agents for treatment of atherosclerosis

Chronic inflammation is a central pathogenic mechanism of atherosclerosis induction and progression. Vascular inflammation is associated with accelerated onset of late atherosclerosis complications. Atherosclerosis-related inflammation is mediated by a complex cocktail of pro-inflammatory cytokines, chemokines, bioactive lipids, and adhesion molecules, and blocking the key pro-atherogenic inflammatory mechanisms can be beneficial for treatment of atherosclerosis. Therapeutic agents that specifically target some of the atherosclerosis-related inflammatory mechanisms have been evaluated in preclinical and clinical studies. The most promising anti-inflammatory compounds for treatment of atherosclerosis include non-specific anti-inflammatory drugs, phospholipase inhibitors, blockers of major inflammatory cytokines, leukotrienes, adhesion molecules, and pro-inflammatory signaling pathways, such as CCL2-CCR2 axis or p38 MAPK pathway. Ongoing studies attempt evaluating therapeutic utility of these anti-inflammatory drugs for treatment of atherosclerosis. The obtained results are important for our understanding of atherosclerosis-related inflammatory mechanisms and for designing randomized controlled studies assessing the effect of specific anti-inflammatory strategies on cardiovascular outcomes.     

VEGF in neoplastic angiogenesis

Solid tumor progression largely depends on vascularization and angiogenesis in the malignant tissue. The most prominent among all proangiogenic factors is vascular endothelium growth factor (VEGF). VEGF suppression leads to retrogression of neoplastic vessels and tumor growth restriction. Clinical trials of complex antiangiogenic and chemical therapy of different neoplastic tumors have shown promising results. Nowadays bevacizumab is widely used in breast cancer, colorectal cancer and II-IV stage of malignancy gliomas treatment. Unfortunately, in the majority of cases antiangiogenic treatment led not to full recovery, but only to tumor development restriction. Resistance mechanisms include potentiating of alternative proangiogenic signaling pathways and activation of malignant cell invasive population.     

Current trends in the pharmacotherapy of diabetic retinopathy

Diabetic retinopathy (DR) is one of the most debilitating disorders of microvasculature of the retina and one of the leading causes of vision loss among the working class worldwide. At present, intravitreal anti-inflammatory (corticosteroids) and anti-angiogenesis (anti-Vascular Endothelial Growth Factor) agents are being used as wide options for the pharmacotherapy of DR and diabetic macular edema (DME). Anti-inflammatory agents (Triamcinolone acetonide and other agents) have shown evidence-based clinical benefits in various randomized clinical trials for the treatment of DR and DME, and also shown improvement in best corrected visual acuity. However, direct intravitreal injections are associated with serious side-effects like cataract and elevation of Intra Ocular Pressure. Despite this, corticosteroid therapy has been effective for DR and DME, therefore current focus is on the development of novel intravitreal steroid delivery devices that release a small quantity over a prolonged period of time. In addition to corticosteroids, anti-angiogenic agents are found to be effective for the treatment of DR and DME. The most popular target of these agents is the subfamily of proteins known as VEGF, whose over-expression is believed to play a role in numerous diseases including DR and Age-related Macular Degeneration. Intravitreal bevacizumab (Avastin?) and Ranibizumab (Lucentis?) are gaining popularity as a clinical adjunct to panretinal photocoagulation in patients with proliferative DR. Moreover, Lucentis has been recently approved by the United States Food and Drug Administration for macular edema following retinal vein occlusion. Further, systemic agents (specially, hypoglycemic, hypolipidemic and anti-hypertensive agents) have shown beneficial results in reducing the progression of DR. In conclusion, it can be stated that for the present scenario systematic use of available pharmacotherapy as an adjunct to laser photocoagulation, which is gold standard therapy, can be a useful tool in the prevention of vision loss from DR and related disorders. This article summarizes the up-to-date developments in the pharmacotherapy of DR. Method- Literature search was done on online database, Pubmed, Google Scholar, clinitrials.gov and browsing through individual ophthalmology journals and leading pharmaceutical company websites.     

Mechanisms of neovascularization and resistance to anti-angiogenic therapies in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most malignant brain tumor and highly resistant to intensive combination therapies. GBM is one of the most vascularized tumors and vascular endothelial growth factor (VEGF) produced by tumor cells is a major factor regulating angiogenesis. Successful results of preclinical studies of anti-angiogenic therapies using xenograft mouse models of human GBM cell lines encouraged clinical studies of anti-angiogenic drugs, such as bevacizumab (Avastin), an anti-VEGF antibody. However, these clinical studies have shown that most patients become resistant to anti-VEGF therapy after an initial response. Recent studies have revealed some resistance mechanisms against anti-VEGF therapies involved in several types of cancer. In this review, we address mechanisms of angiogenesis, including unique features in GBMs, and resistance to anti-VEGF therapies frequently observed in GBM. Enhanced invasiveness is one such resistance mechanism and recent works report the contribution of activated MET signaling induced by inhibition of VEGF signaling. On the other hand, tumor cell-originated neovascularization including tumor-derived endothelial cell-induced angiogenesis and vasculogenic mimicry has been suggested to be involved in the resistance to anti-VEGF therapy. Therefore, these mechanisms should be targeted in addition to anti-angiogenic therapies to achieve better results for patients with GBM.