DOI:10.1259/bjr/34932557

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY

摘要:

The field of angiogenesis research has evolved to become one of the most rapidly growing biomedical disciplines. The interest in basic angiogenesis research is sparked by the translational therapeutic potential aimed at developing anti-angiogenesis as a novel therapeutic modality for tumours and a number of non-oncological diseases, such as rheumatoid arthritis, psoriasis, diabetic retinopathy and age-dependent macula degeneration. The molecular determinants of the angiogenic cascade have been characterized in great detail over the last few years. Likewise, intense ongoing efforts are aimed at identifying and validating additional vascular specific determinants that may be exploited as therapeutic targets for pro-angiogenic and anti-angiogenic therapy. At the same time, a large number of angiomodulatory compounds are in various phases of clinical trials. These include the neutralizing vascular endothelial growth factor (VEGF) antibody Avastin, which has successfully passed phase III clinical trials for the combination with chemotherapy in colorectal cancers. In view of the dramatic progress in basic angiogenesis research, surprisingly little is known about the nature of the neovasculature in human tumours. The inclusion and exclusion criteria of clinical trials of anti-angiogenic compounds are devoid of angiogenesis-related parameters and reliable biomarkers to trace the efficacy of an anti-angiogenic intervention are largely missing. Based on a brief review of the biology of the angiogenic cascade, this review provides an overview of the current concepts of the angiogenic vasculature in human tumours and discusses some key unanswered questions in translating angiogenesis research into the clinic.

DOI:10.1259/bjr/68078705

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY

摘要:

Tumour angiogenesis is triggered by various signals characteristic of the tumour microenvironment, including low oxygen tension, low extracellular pH and low glucose concentration. Tumour microvasculature is chaotic, producing perfusion heterogeneities which can be visualized by MRI and other modalities. Inefficient perfusion in tumours produces regions of transient and chronic hypoxia. Tumour hypoxia is associated with adverse clinical outcomes and reduced patient survival. Hypoxia may be a factor in activation of extracellular matrix-degrading proteases, and some studies have correlated primary tumour hypoxia with likelihood of tumour cell dissemination. Exposure to hypoxia either induces or selects for cells that are hyperglycolytic, and this in turn produces local acidosis which is also a common feature of solid tumours. Increased glucose uptake in hyperglycolyzing tumour cells is the basis of lesion-visualization in positron emission tomography using18F-fluorodeoxyglucose. Tumour acidity can reduce the effectiveness of weak-base drugs, but can be exploited to increase the anti-tumour activity of weak-acid chemotherapeutics. Evidence linking tumour acidity with increased activity of several extracellular matrix-degrading enzyme systems is examined. High levels of lactate, another end-product of glycolysis, in primary lesions have been correlated with increased likelihood of metastasis. In the numerous studies correlating hypoxia, acidity and lactate with metastasis, the direction of the causality has not been adequately established. We hypothesize that adoption of a hyperglycolytic phenotype is a necessary feature of carcinogenesis itself, and confers a survival and proliferative advantage to tumour cells over surrounding normal cells. Empirical evidence supporting this “acid-mediated tumour invasion” model is discussed.

DOI:10.1259/bjr/12913493

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY

摘要:

The tumour vasculature is an attractive target for therapy because of its accessibility to blood-borne anticancer agents and the reliance of most tumour cells on an intact vascular supply for their survival. For convenience, therapeutic targeting of the tumour vasculature can be divided into antiangiogenic approaches, which target the process of new blood vessel development and antivascular approaches, which target the established tumour vasculature. Many agents are now in clinical trial for the treatment of cancer by these methods. The main aim of this article is to describe the vascular effects of some of these agents and identify suitable end-points for measuring efficacy in early clinical trials. For drugs which are active below their maximum tolerated dose (MTD), measurement of vascular end-points is required to determine the most effective dosing/scheduling protocols. In addition, many of the current and developing antiangiogenic agents have additional mechanisms of action unrelated to angiogenesisper se, requiring measurement of vascular end-points to understand their mechanisms of action. Measurement of tumour microvascular density (MVD) from tumour biopsies is a common method for assessing the efficacy of antiangiogenic drugs. The limitations of this method and alternative end-points, which take into account vascular function, are discussed. Pre-clinical data regarding tumour response to the antivascular agent combretastatin A-4 3-0-phosphate (CA-4-P) are discussed in the context of guiding clinical trial planning. Finally, the accessibility of vascular end-points for clinical imaging is addressed.

DOI:10.1259/bjr/30165281

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY

摘要:

Perfusion CT is a technique that can be readily incorporated into the existing CT protocols that continue to provide the mainstay for anatomical imaging in oncology to provide anin vivomarker of tumour angiogenesis. By capturing physiological information reflecting the tumour vasculature, perfusion CT can be useful for diagnosis, risk-stratification and therapeutic monitoring. However, a wide range of perfusion CT techniques have evolved and the various commercial implementations advocate different acquisition protocols and processing methods. Acquisition choices include first pass studies or delayed imaging, temporal resolution versus image noise, and single location sequences or multiple spiral acquisitions. Data processing may be semi-quantitative or, using either compartmental analysis or deconvolution, produce results that are quantified in absolute physiological terms such as perfusion, blood volume and permeability. This article discusses the advantages and disadvantages of the more common CT perfusion protocols and offers proposals that could allow for easier comparison between studies employing different techniques.

DOI:10.1259/bjr/18486642

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY

DOI:10.1259/bjr/86364648

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY

摘要:

Surrogate markers of clinical outcome are important in anticancer drug research, since clinical criteria of response develop only slowly and may be confounded by other processes than drug effect. The need for surrogate outcome markers is especially great with newer agents that may act by tumour stabilization as opposed to shrinkage. Neoplastic angiogenesis is associated with a number of detectable changes at molecular and microcirculatory levels. Therefore, direct study of angiogenic molecular biology and tumour circulation before during and after treatment may offer useful surrogate markers for vascular-targeted therapies. The main advantage of radiotracer imaging with positron emission tomography (PET) is its functional specificity. This article will review two main areas: (a) the methodology behind PET imaging of tumour blood supply with15O-oxygen labelled compounds; and (b) newer tracers in development as markers of angiogenetic biology.

DOI:10.1259/bjr/30399077

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY

摘要:

Selective antiangiogenesis and vascular targeting drugs hold out the promise of improved efficacy and tolerability for anticancer treatments. Early phase 1 drug trials have shown good tolerability for antiangiogenesis agents with biological activity below the maximum tolerated dose. Advanced clinical trials have demonstrated that morphological assessments of tumour response are of limited value in gauging the efficacy of treatment. MRI is a versatile technique which is sensitive to contrast mechanisms that can be affected by antivascular treatments; this use for MRI has been validated in xenografts and humans. Dynamic contrast-enhanced MRI (DCE-MRI), which demonstrates tissue perfusion and permeability, is being used clinically as a pharmacodynamic indicator of biological activity for antivascular cancer drugs. Early data show that DCE-MRI studies can define the biologically active dose and predict the efficacy of treatment on the basis of changes observed. MRI with macromolecular contrast media (MMCM) depicts microvessel permeability and fractional plasma volume. Xenograft studies with MMCM have shown great promise for evaluating antivascular treatments but this has not been used clinically. Intrinsic susceptibility-weighted MRI, which is sensitive to blood oxygenation and flow, is emerging as a technique that may be able to monitor vascular targeting therapies.

DOI:10.1259/bjr/15334380

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY

摘要:

The imaging of angiogenesis in human disease represents an exciting prospect for those involved in the drug development process. With an increasing focus on the therapeutic modulation of angiogenesis in man, the development of technologies capable of monitoring angiogenic drug interventions non-invasively should be welcomed.

DOI:10.1259/bjr/42249357

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY

DOI:10.1259/bjr/15255885

出版商:British Institute of Radiology    

年代:2003

数据来源: WILEY