Optical Imaging of Apoptosis as a Biomarker of Tumor Response to Chemotherapy

Schellenberger, Eyk; Bogdanov, Alexei A.; Petrovsky, Alexander; Ntziachristos, Vasilis; Weissleder, Ralph; Josephson, Lee

doi:10.1016/s1476-5586(03)80050-7

Cited by 119 publications

(88 citation statements)

References 32 publications

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“…Laxman et al (6), for example, developed a recombinant luciferase reporter molecule that amplifies luminescence in apoptotic cells by specific cleavage of a Asp-Glu-Val-Asp fragment by caspase 3, which can be used in animal studies. Fluorescence detection using an annexin V probe tagged with a cyanine dye has been demonstrated by Schellenberger et al (7) and Petrovsky et al (8). Imaging of drug targets has also been demonstrated recently in a study that monitored MMP2 suppression after Prinomastat treatment with fluorescent activatable probes (9).…”

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confidence: 99%

“…The second focus was to investigate how fluorescence molecular tomography (FMT) compares with planar imaging technologies currently used for small-animal optical imaging. We investigated the performance of this technique with phantoms and in vivo with previously validated phosphatidylserine-sensing and control fluorochromes based on modified annexins (7). We hypothesized that FMT could accurately visualize treatment response to chemotherapy and attain significant utility to drug discovery by combining the simplicity and versatility of fluorescent probes with 3D visualization and quantification capacity.…”

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confidence: 99%

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Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V–Cy5.5 conjugate

Ntziachristos

Schellenberger

Ripoll

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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In vivo imaging of treatment responses at the molecular level could have a significant impact on the speed of drug discovery and ultimately lead to personalized medicine. Strong interest has been shown in developing quantitative fluorescence-based technologies with good molecular specificity and sensitivity for noninvasive 3D imaging through tissues and whole animals. We show herein that tumor response to chemotherapy can be accurately resolved by fluorescence molecular tomography (FMT) with a phosphatidylserinesensing fluorescent probe based on modified annexins. We observed at least a 10-fold increase of fluorochrome concentration in cyclophosphamide-sensitive tumors and a 7-fold increase of resistant tumors compared with control studies. FMT is an optical imaging technique developed to overcome limitations of commonly used planar illumination methods and demonstrates higher quantification accuracy validated by histology. It is further shown that a 3-fold variation in background absorption heterogeneity may yield 100% errors in planar imaging but only 20% error in FMT, thus confirming tomographic imaging as a preferred tool for quantitative investigations of fluorescent probes in tissues. Tomographic approaches are found essential for small-animal optical imaging and are potentially well suited for clinical drug development and monitoring. drug discovery ͉ quantification ͉ three-dimensional T he ability to noninvasively image molecular processes in vivo is an emerging reality with different reporter and detection approaches (1, 2). Molecular imaging has been heralded to lead to earlier detection than current anatomical imaging approaches, which typically detect late-stage abnormalities. Another important prospect of molecular imaging is the ability to examine and quantify treatment responses in vivo by monitoring specific primary molecules or downstream targets. Therapeutic efficacy could then be probed dynamically on timescales of hours to days. This ability is in contrast to the mainstay of today's healthcare with traditionally late end points of drug efficacy, a practice that often impairs prompt revision and exclusion of ineffective treatment strategies with potentially lethal results.Drug-induced apoptosis is considered a generic biomarker of monitoring the effects of chemotherapeutic drugs (3), antihormonal therapeutics (4), or antiangiogenic therapies (5). Of several different detection methods, optical imaging is emerging as an important alternative to techniques using ionizing radiation and offers the advantages of stable fluorochromes, easier to perform chemistries, and portable and cost-effective imaging practices. Laxman et al. (6), for example, developed a recombinant luciferase reporter molecule that amplifies luminescence in apoptotic cells by specific cleavage of a Asp-Glu-Val-Asp fragment by caspase 3, which can be used in animal studies. Fluorescence detection using an annexin V probe tagged with a cyanine dye has been demonstrated by Schellenberger et al. (7) and Petrovsky et al. (8). Imagin...

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confidence: 99%

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confidence: 99%

Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V–Cy5.5 conjugate

Ntziachristos

Schellenberger

Ripoll

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

334

206

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“…However, it has the risk of exposing patients to radiation. NIRF-annexin V had been used for imaging cell death induced by chemotherapy [27]. To our knowledge there is no report on detecting cell death induced by ischemia and reperfusion injury in the myocardium.…”

Section: Discussionmentioning

confidence: 99%

Imaging Myocardial Ischemia and Reperfusion Injury via Cy5.5-Annexin V

Tian

Pan

2012

Nucl Med Mol Imaging

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Aim The aim of this article is to present the results of an imaging study of myocardial apoptosis induced by ischemia/reperfusion injury. Methods Twenty nude mice were randomly divided into an experimental group (10 mice) and control group (10 mice). In the experimental group, myocardial apoptosis was induced by ligation of the left anterior descending coronary artery (LAD) for 30 min. This was followed by reperfusion for 90 min. In the control group, the heart was exposed for the same length of time as in the experimental group. Cy5. 5-annexin V (25 μg) was injected into both sets of mice after the onset of reperfusion. At 90 min post-injection, the mice were imaged. The region of interest (ROI) was obtained, and the fluorescence intensity of the ROI was quantified. The animals were sacrificed, and myocardial apoptosis was assayed by TUNEL assay. Results Fluorescence intensity in the ischemia/reperfusion hearts was significantly higher than that in the control group (P<0.05). In the TUNEL assay, more apoptotic cells were observed in the experimental group than in the control group, correlating with imaging results. Conclusion Fluorescence imaging of Cy5.5-annexin V in a mouse model of myocardial ischemia/reperfusion can be used in vivo as a noninvasive means of detecting ischemia/reperfusion-induced apoptotic cells in the heart.

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“…To demonstrate the probe specificity, nude mice each bearing a cyclophosphamide (CPA) chemosensitive Lewis lung carcinoma (LLC) and a chemoresistant LLC (CR-LLC) were tested. 26 After injection with active annexin V, the LLC of CPA-treated mice had significant elevations of the tumor-annexinV ratio (TAR; tumor NIRF/background NIRF), but only a moderate increase was obtained for the CR-LLC indicating that active Cy-annexin V and surface reflectance fluorescence imaging provide a nonradioactive, semiquantitative method of determining chemosensitivity in LLC xenografts. The method maybe used to image pharmacologic responses in other animal models and, potentially, may permit the clinical imaging of apoptosis with noninvasive or minimally invasive instrumentation.…”

Section: Imaging Apoptosis With Nirf Probesmentioning

confidence: 98%

Molecular optical imaging: Applications leading to the development of present day therapeutics

Shah

Weissleder

2005

Neurotherapeutics

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Summary:A number of advances in the molecular imaging field have led to the sensing of specific molecular targets and pathways in living animals. In the optical imaging field, these include the designing of biocompatible near-infrared fluorochromes, development of targeted and activatable "smart" imaging probes, and engineering of activatable fluorescent and bioluminescent proteins. The current advances in molecular optical imaging will help in early disease diagnoses, functioning of a number of pathways and finally help speed drug discovery. In this review, we will describe the near infrared fluorescent and bioluminescence imaging modalities and how these techniques have been employed in current research. Furthermore, we will also shed some light on the use of these imaging modalities in neurotherapeutics, for example imaging different parameters of vector-mediated gene expression in glioma tumors and stem cell tracking in vivo.

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Optical Imaging of Apoptosis as a Biomarker of Tumor Response to Chemotherapy

Cited by 119 publications

References 32 publications

Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V–Cy5.5 conjugate

Visualization of antitumor treatment by means of fluorescence molecular tomography with an annexin V–Cy5.5 conjugate

Imaging Myocardial Ischemia and Reperfusion Injury via Cy5.5-Annexin V

Molecular optical imaging: Applications leading to the development of present day therapeutics

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