Imaging Angiogenesis: Applications and Potential for Drug Development

Department of Radiology, Massachusetts General Hospital, 100 Charles River Plaza, Boston, MA 02114, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 03/2005; 97(3):172-87. DOI: 10.1093/jnci/dji023
Source: PubMed


Recognition of the importance of angiogenesis to tumor growth and metastasis has led to efforts to develop new drugs that are targeted to angiogenic vasculature. Clinical trials of these agents are challenging, both because there is no agreed upon method of establishing the correct dosage for drugs whose mechanism of action is not primarily cytotoxic and because of the long time it takes to determine whether such drugs have a clinical effect. Therefore, there is a need for rapid and effective biomarkers to establish drug dosage and monitor clinical response. This review addresses the potential of imaging as a way to accurately and reliably assess changes in angiogenic vasculature in response to therapy. We describe the advantages and disadvantages of several imaging modalities, including positron emission tomography, x-ray computed tomography, magnetic resonance imaging, ultrasound, and optical imaging, for imaging angiogenic vasculature. We also discuss the analytic methods used to derive blood flow, blood volume, empirical semiquantitative hemodynamic parameters, and quantitative hemodynamic parameters from pharmacokinetic modeling. We examine the validity of these methods, citing studies that test correlations between data derived from imaging and data derived from other established methods, their reproducibility, and correlations between imaging-derived hemodynamic parameters and other pathologic indicators, such as microvessel density, pathology score, and disease outcome. Finally, we discuss which imaging methods are most likely to have the sensitivity and reliability required for monitoring responses to cancer therapy and describe ways in which imaging has been used in clinical trials to date.

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Available from: Homer Pien, Aug 02, 2014
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    • "Clinical grading of the microvascular parameters includes the number of mucosal blood vessels and the average microvessel diameter were semiquantitavely assessed independently by two oral medicine specialist and given a scale of 1–3 under the 545 nm light, with 3 given to the most intense vascularity observed, considering both the number and architecture of blood vessels in the oral lesions, and 1 having the least number of microvasculature.21,22,23 Upon completion of the optical measurements, tissue biopsies were obtained from the lesions by using either scalpel or punch technique under local anesthesia and samples were submitted for histopathological assessment. "
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    ABSTRACT: Optical spectroscopy devices are being developed and tested for the screening and diagnosis of oral precancer and cancer lesions. This study reports a device that uses white light for detection of suspicious lesions and green-amber light at 545 nm that detect tissue vascularity on patients with several suspicious oral lesions. The clinical grading of vascularity was compared to the histological grading of the biopsied lesions using specific biomarkers. Such a device, in the hands of dentists and other health professionals, could greatly increase the number of oral cancerous lesions detected in early phase. The purpose of this study is to correlate the clinical grading of tissue vascularity in several oral suspicious lesions using the Identafi(®) system with the histological grading of the biopsied lesions using specific vascular markers. Twenty-one patients with various oral lesions were enrolled in the study. The lesions were visualized using Identafi(®) device with white light illumination, followed by visualization of tissue autofluorescence and tissue reflectance. Tissue biopsied was obtained from the all lesions and both histopathological and immunohistochemical studies using a vascular endothelial biomarker (CD34) were performed on these tissue samples. The clinical vascular grading using the green-amber light at 545 nm and the expression pattern and intensity of staining for CD34 in the different biopsies varied depending on lesions, grading ranged from 1 to 3. The increase in vascularity was observed in abnormal tissues when compared to normal mucosa, but this increase was not limited to carcinoma only as hyperkeratosis and other oral diseases, such as lichen planus, also showed increase in vascularity. Optical spectroscopy is a promising technology for the detection of oral mucosal abnormalities; however, further investigations with a larger population group is required to evaluate the usefulness of these devices in differentiating benign lesions from potentially malignant lesions.International Journal of Oral Science advance online publication, 25 July 2014; doi:10.1038/ijos.2014.39.
    International Journal of Oral Science 07/2014; 6(3). DOI:10.1038/ijos.2014.39 · 2.53 Impact Factor
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    • "Dynamic contrast-enhanced magnetic resonance imaging (DCE- MRI), a noninvasive, clinical-imaging technique, provides information about microvascular permeability between the vascular space and extravascular extracellular space (EES) [1]. Applications of DCE- MRI include assessing the microvascular status of tumor tissue and characterizing tumor response to antiangiogenic treatment [2] [3] [4], differentiation of tumor histopathology [5], and prediction of clinical outcomes, including treatment response to chemotherapy [6]. "
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    ABSTRACT: This study compared three methods for analyzing DCE-MRI data with a reference region (RR) model: a linear least-square fitting with numerical analysis (LLSQ-N), a nonlinear least-square fitting with numerical analysis (NLSQ-N), and an analytical analysis (NLSQ-A). The accuracy and precision of estimating the pharmacokinetic parameter ratios KR and VR, where KR is defined as a ratio between the two volume transfer constants, K(trans,TOI) and K(trans,RR), and VR is the ratio between the two extracellular extravascular volumes, ve,TOI and ve,RR, were assessed using simulations under various signal-to-noise ratios (SNRs) and temporal resolutions (4, 6, 30, and 60s). When no noise was added, the simulations showed that the mean percent error (MPE) for the estimated KR and VR using the LLSQ-N and NLSQ-N methods ranged from 1.2% to 31.6% with various temporal resolutions while the NLSQ-A method maintained a very high accuracy (<1.0×10(-4) %) regardless of the temporal resolution. The simulation also indicated that the LLSQ-N and NLSQ-N methods appear to underestimate the parameter ratios more than the NLSQ-A method. In addition, seven in vivo DCE-MRI datasets from spontaneously occurring canine brain tumors were analyzed with each method. Results for the in vivo study showed that KR (ranging from 0.63 to 3.11) and VR (ranging from 2.82 to 19.16) for the NLSQ-A method were both higher than results for the other two methods (KR ranging from 0.01 to 1.29 and VR ranging from 1.48 to 19.59). A temporal downsampling experiment showed that the averaged percent error for the NLSQ-A method (8.45%) was lower than the other two methods (22.97% for LLSQ-N and 65.02% for NLSQ-N) for KR, and the averaged percent error for the NLSQ-A method (6.33%) was lower than the other two methods (6.57% for LLSQ-N and 13.66% for NLSQ-N) for VR. Using simulations, we showed that the NLSQ-A method can estimate the ratios of pharmacokinetic parameters more accurately and precisely than the NLSQ-N and LLSQ-N methods over various SNRs and temporal resolutions. All simulations were validated with in vivo DCE MRI data.
    Magnetic Resonance Imaging 04/2014; 32(7). DOI:10.1016/j.mri.2014.04.007 · 2.09 Impact Factor
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    • "In effect, a direct cell death occurs as a result of the production of reactive oxygen species. Besides the induction of apoptosis in tumor cells, the vasculature is damaged, which leads to an undersupply of the tumor with nutrients and ultimately determines the therapeutic success [3] [4]. A central process in the effective elimination of tumor cells is apoptosis [5]. "
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    ABSTRACT: In our study we wanted to elucidate a time frame for in vivo optical imaging of the therapeutic efficacy of photodynamic therapy (PDT) by using a multiplexed imaging approach for detecting apoptosis and vascularization. The internalization of the photosensitizer Foslip(®) into tongue-squamous epithelium carcinoma cells (CAL-27) was examined in vitro and in vivo. For detecting apoptosis, annexin V was covalently coupled to the near-infrared dye DY-734 and the spectroscopic properties and binding affinity to apoptotic CAL-27 cells were elucidated. CAL-27 tumor bearing mice were treated with PDT and injected 2 days and 2 weeks thereafter with DY-734-annexin V. PDT-induced changes in tumor vascularization were detected with the contrast agent IRDye(®) 800CW RGD up to 3 weeks after PDT. A perinuclear enrichment of Foslip(®) could be seen in vitro which was reflected in an accumulation in CAL-27 tumors in vivo. The DY-734-annexin V (coupling efficiency 30-50%) revealed a high binding affinity to apoptotic compared to non-apoptotic cells (17.2% vs. 1.2%) with a KD-value of 20 nm. After PDT-treatment, the probe showed a significantly higher (p <0.05) contrast in tumors at 2 days compared to 2 weeks after therapy (2-8 h post injection). A reduction of the vascularization could be detected after PDT especially in the central tumor areas. To detect the therapeutic efficacy of PDT, a multiplexed imaging approach is necessary. A detection of apoptotic cells is possible just shortly after therapy, whereas at later time points the efficacy can be verified by investigating the vascularization.
    Biomaterials 09/2013; 34(38). DOI:10.1016/j.biomaterials.2013.08.087 · 8.56 Impact Factor
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