Angiogenic tumor markers,antiangiogenic agents and radiation therapy

There are many exciting avenues to pursue in angiogenesis-related cancer research. Until now, conventional therapy has targeted neoplastic cells within a tumor. However, tumor vasculature is emerging as a new cancer target. Antiangiogenic drugs are unique in having highly specific targets, while simultaneously carrying the potential to be effective against a wide breadth of cancer types. They also act synergistically with cytotoxic therapy. Currently, this combination of new antiangiogenic treatments with traditional cytotoxic treatments such as radiotherapy, may provide a powerful means of combating cancer. Strategic combination therapy, selecting for tumor type and angiogenic profile, may result in the realization of the promise and potential of antiangiogenic therapy.     

Design of clinical trials of radiation combined with antiangiogenic therapy

Clinical trials showing longer survival when chemotherapy is combined with antiangiogenic agents (AAs) have led to growing interest in designing combined modality protocols that exploit abnormalities in tumor vasculature. Approved agents include bevacizumab, a recombinant monoclonal antibody that binds to vascular endothelial growth factor, and two small molecule multitargeted tyrosine kinase inhibitors of angiogenesis (SU11248 and BAY-43-9006) that have been approved for therapy of renal cancer. Targeting tumor vasculature has a strong biological rationale in radiation therapy, and preclinical studies consistently show an increase in radiosensitization with combined treatment. Preclinical studies indicate that excessive damage to tumor vasculature can result in radioresistance in some situations, and early clinical data suggest that treatment sequencing may be important when combining AAs with radiation. Radiation itself appears to antagonize any hypoxia that can be induced by long-term administration of AAs. The optimal biological doses of AAs with radiotherapy are unknown, and surrogate markers of efficacy remain to be validated. Early clinical trials should therefore include studies designed to identify mechanisms of interaction and increases in tumor hypoxia. This review highlights preclinical and early clinical data that are relevant for clinical trial design. Optimal radiation planning and delivery is required to minimize the volume of irradiated normal organs and to establish safe dose-volume parameters for phase II-III clinical trials.     

Angiogenesis and antiangiogenic therapy

Current Problems in Cancer 2002;26:1-60.     

Current state of knowledge regarding the use of antiangiogenic agents with radiation therapy

Angiogenesis has been a central theme of oncologic research for several years. Recently, improved understanding of its mechanisms has led to the development of several antiangiogenic agents. Some have demonstrated their effectiveness in large randomized studies; however, no antiangiogenic agent has yet been approved for treatment in combination with radiotherapy. Numerous preclinical studies and a few small clinical trials have recently reported encouraging results. The objective of this article is to review the concept of targeted antiangiogenic agents and the early clinical results of their use in combination with radiation therapy.     

The impact on oncology of the interaction of radiation therapy and radiobiology

The quantitative analysis of the cell dose-survival curves, the randomness of cell killing by radiation, the probabilistic basis of the response to irradiation of tumors and normal tissues, the understanding of the biological mechanisms underlying to this response, the rationale for dose-time and fractionation in radiotherapy, the introduction of the concepts of tumor control probability (TCP) and biologically effective dose (BED), the relationships TCP-dose, BED-α,β, BED-fraction size and BED-treatment time, the problems associated with the accelerated regeneration of surviving tumor clonogens during the course of fractionated radiotherapy, the new demands of knowledge on oncology and radiation biology derived from heterogeneous dose distributions in conformal radiation therapy programs and the definition of the biological basis of normal tissues tolerance to reirradiation are, probably, the most important contributions of radiobiology to clinical radiotherapy in the last twenty five years. Radiotherapy is today a scientific discipline based on the interplay of mathematics, physics, biology and oncology. The knowledge of the basic concepts of radiobiology is essential for daily radiotherapy practices and for all oncologists. The most efficient use of multimodality treatments in cancer therapy cannot be done without a clear understanding of these principles. Opening Conference, XIII Congress of the Spanish Association of Radiotherapy and Oncology, Cadiz, October 4–7, 2005.     

The horizon of antiangiogenic therapy for colorectal cancer

Vascular endothelial growth factor (VEGF) plays a crucial role in the growth and metastatic spread of cancer. Bevacizumab (Avastin) is the first commercially available VEGF inhibitor, earning U.S. Food and Drug Administration (FDA) approval in February 2004. In combination with fluorouracil (5-FU)-based chemotherapy, this agent significantly prolongs overall and progression-free survival of patients with metastatic colorectal cancer. This review details the emerging role of the drug, its unique side effects, and other practical considerations related to bevacizumab therapy. Ongoing trials attempting to define additional indications for bevacizumab as well as the development of other promising angiogenesis inhibitors are also reviewed.     

The combination of antiangiogenic therapy with other modalities

Angiogenesis is critical for a number of physiologic and pathophysiologic processes, and several angiogenesis inhibitors are now in clinical trials for the treatment of cancer. Antiangiogenic therapy offers a number of potential benefits including lack of drug resistance for some agents, synergistic interaction with other modalities, lack of significant toxicity compared with conventional agents, and a potent antitumor effect. However, no angiogenesis inhibitor has been approved for clinical use. Although antiangiogenic agents offer great therapeutic potential, preclinical and early clinical trial results suggest that these agents will have a delayed onset of activity and may induce stabilization of disease, and not regression, in patients with advanced disease. Studies suggest that regulation of angiogenesis in various capillary beds may be differentially regulated, suggesting that antiangiogenic therapy may require organ-specific optimization. By combining antiangiogenic agents with each other and/or with other modalities used in the treatment of cancer, the limitations of each therapeutic approach will be overcome, leading to enhanced efficacy with diminished toxicity. However, the optimal strategies forthe use, monitoring, and validation of antiangiogenic agents in the clinic remains unclear. Before these agents can be integrated into clinical practice, a better understanding of their mechanism of action and regulation is     

肿瘤血管生成及抗血管生成基因治疗

肿瘤的侵袭和转移明显影响患者的预后,而肿瘤的血管生成是肿瘤生长、侵袭、转移的基本条件.因而抑制肿瘤血管生成是治疗肿瘤的关键.本文就肿瘤血管生成的调控及抗肿瘤血管生成基因治疗的研究进展作一综述.     

Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized by neovascularization, which plays an important role in the growth and progression of HCC. Angiogenesis provides a target for novel prognostic and therapeutic approaches to HCC. Assessment of microvessel density using immunohistochemical staining for specific endothelial cell markers such as CD34 has been shown to provide prognostic information independent of conventional pathological parameters in HCC patients. Recent studies have unveiled the important angiogenic factors involved in the regulation of angiogenesis in HCC, although the exact molecular pathways are far from clear. Current data suggest that vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis of HCC. Tumor expression of VEGF has been shown to correlate with tumor invasiveness and prognosis in patients with HCC. VEGF is an important molecular target for antiangiogenic therapy. Studies in animal models have demonstrated the efficacy of antiangiogenic agents such as anti-VEGF antibody and antagonists of VEGF receptors in suppressing hepatocarcinogenesis and growth of HCC. Antiangiogenic therapy has already entered clinical trials in HCC patients and holds the promise of providing an effective novel treatment for HCC, which is of great clinical significance because there is no existing effective systemic therapy for HCC.     

Angiogenesis and antiangiogenic therapy for malignant gliomas

Angiogenesis is crucial to the growth of malignant gliomas. Therefore, antiangiogenic therapy represents a new, promising therapeutic modality for malignant gliomas. This study was designed to define the malignant glioma cases most suitable for antiangiogenic therapy in humans and to demonstrate the efficacy of antiangiogenic therapy in animals. Protein expression of the most potent angiogenic factor, vascular endothelial growth factor (VEGF), and its specific natural inhibitor, soluble Flt-1, as well as vessel architecture, including vessel density, area, and diameter, was evaluated in human malignant glioma samples (24 glioblastomas, 13 anaplastic astrocytomas). Among these, VEGF >1000ng/ml, VEGF/soluble Fltl ratio >1, vessel density >30, and vessel area >7% were prognostic factors for malignant gliomas. Based on these results, we per formed three different antiangiogenic experiments targeted to inhibit VEGF expression in a human malignant glioma (U87) mouse model: anti-VEGF neutralized antibody intraperitoneal injection; interferon-beta intramusclar injection; and transfection of an endogenous nonspecific angiogenesis inhibitor, thrombospondin-1, into glioma cells caused inhibition of VEGF secretion and/or mRNA expression and resulted in glioma growth inhibition of 70%, 84%, and 50%, respectively, compared with control. We conclude that malignant gliomas with high degrees of VEGF expression and vessel areas are good candidates for antiangiogenic therapy, especially that designed to inhibit VEGF expression.     

Angiogenesis and antiangiogenic therapy in non-Hodgkin's lymphoma

Angiogenesis, the growth of new blood vessels, requires dynamic expansion, assembly and stabilization of vascular endothelial cells in response to proangiogenic stimuli. Antiangiogenic strategies have become an important therapeutic modality for solid tumors. While many aspects of postnatal pathological angiogenesis have been extensively studied in the context of nonhematopoietic neoplasms, the precise role of these processes in lymphoma pathogenesis is under active investigation. Lymphoma growth and progression is potentiated by at least two distinct angiogenic mechanisms: autocrine stimulation of tumor cells via expression of vascular endothelial growth factor (VEGF) and VEGF receptors by lymphoma cells, as well as paracrine influences of proangiogenic tumor microenvironment on both local neovascular transformation and recruitment of circulating bone marrow-derived progenitors. Lymphoma-associated infiltrating host cells including hematopoietic monocytes, T cells and mesenchymal pericytes have increasingly been associated with the pathogenesis and prognosis of lymphoma, in part providing perivascular guidance and support to neoangiogenesis. Collectively, these distinct angiogenic mechanisms appear to be important therapeutic targets in selected non-Hodgkin's lymphoma (NHL) subtypes. Understanding these pathways has led to the introduction of antiangiogenic treatment strategies into the clinic where they are currently under assessment in several ongoing studies of NHL patients.     

Copper chelation as an antiangiogenic therapy

Angiogenesis is now recognized as a crucial process in tumor development. Copper appears to act as an essential cofactor for several angiogenic growth factors, and both copper metabolism and ceruloplasmin expression are upregulated in many tumors. The role of copper chelators has been investigated in animal models with promising results. New therapies for Wilson's disease (a disease of copper accumulation) have enabled clinical trials of copper chelation to be undertaken. Here we discuss the evidence for a role of copper in angiogenesis and possible mechanisms of action of anticopper agents.     

抗血管生成药治疗肝细胞癌的研究进展

肝细胞癌（HCC）是一种血管丰富的癌症,抗血管生成药可通过阻断血管生成因子,抑制内皮细胞扩增及预防细胞外基质和血管基底膜降解等机制而发挥治疗肝癌的作用,加上其临床相对优良的安全性可能为肝癌治疗提供了治疗新途径。     

VEGF抑制与肿瘤转移抗血管生成治疗的启示

【缩写】FDA(Food and Drug Administration):食品药品监督管理局;VEGF(vascular endothelial growth factor):血管内皮生长因子;VEGFR2(VEGF-receptor2):血管内皮生长因子受体2;SCID(severe combined immunode-ficiency):重症联合免疫缺陷;PNET(pancreatic neuroendocrine tumor):胰腺神经内分泌肿瘤     

乳腺癌抗血管生成治疗的研究进展

新生血管生成是恶性肿瘤的增殖过程中的关键步骤,因此抗血管生成已成为抗肿瘤治疗的重要策略和研究热点。本文就乳腺癌抗肿瘤血管生成治疗的研究背景、应用现状、未来展望作一综述。     

Progress in antiangiogenic gene therapy of cancer

BACKGROUND: Because tumors require angiogenesis for growth, inhibiting angiogenesis is a promising strategy for treating cancer patients. Although numerous endogenous angiogenesis inhibitors have been discovered, the clinical evaluation of these agents has been hindered by high dose requirements, manufacturing constraints, and relative instability of the corresponding recombinant proteins. Therefore the delivery of these proteins using gene therapy has become increasingly attractive. METHODS: Based on their own antiangiogenic gene therapy research, the authors evaluated the published experience with antiangiogenic gene therapy models using the National Library of Medicine's PubMed search service and the reference lists of the publications cited. RESULTS: Greater than 40 endogenous inhibitors of angiogenesis have been characterized. Thirteen have been employed in gene therapy models, all of which showed antitumor activity in experimental animals. Other approaches have inhibited the expression or activity of proangiogenic cytokines such as vascular endothelial growth factor. The ideal gene delivery vector would target tumor tissue preferentially to minimize systemic toxicity of the transgene product. However, the low toxicity profile of endogenous inhibitors of angiogenesis has allowed the success of systemic antiangiogenic gene therapy in a number of preclinical models, in which normal host tissues act as a "factory" to produce high circulating concentrations of antiangiogenic proteins. CONCLUSIONS: Difficulties with the large-scale use of antiangiogenic agents have hindered their investigation in clinical trials. Antiangiogenic gene therapy offers the potential for cancer patients to manufacture their own antiangiogenic proteins. This strategy has been increasingly successful in preclinical models and represents an exciting new approach to cancer therapy.     

The potential of antiangiogenic therapy in non-small cell lung cancer.

The long-term prognosis for patients with advanced non-small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small-molecule VEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.