Monitoring Cell Death in Regorafenib-Treated Experimental Colon Carcinomas Using Annexin-Based Optical Fluorescence Imaging Validated by Perfusion MRI

Kazmierczak, Philipp M.; Burian, Egon; Eschbach, Ralf; Hirner-Eppeneder, Heidrun; Moser, Matthias; Havla, Lukas; Eisenblätter, Michel; Reiser, Maximilian; Nikolaou, Konstantin; Cyran, Clemens C.

doi:10.1371/journal.pone.0138452

Cited by 10 publications

(7 citation statements)

References 34 publications

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“…Molecular changes play an important regulatory role in the development of malignant tumors. Cell surface Connexins or membrane proteins can induce the transcription initiation activity of downstream oncogenes, which promotes aberrant activation of the cell cycle in colonic epithelial cells and leads to excessive proliferation of cancer cells[ 14 ]. Accumulating experimental data indicate that phosphatidylserine exposition is associated with apoptosis and other cell death programs[ 15 - 17 ], which renders it an attractive target in imaging overall cell death.…”

Section: Discussionmentioning

confidence: 99%

Expression of annexin A5 in serum and tumor tissue of patients with colon cancer and its clinical significance

Sun

Zhao

et al. 2017

WJG

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AIMTo investigate the expression of annexin A5 in serum and tumor tissue of patients with colon cancer and to analyze its clinical significance.METHODSNinety-three patients with colon cancer treated at our hospital between February 2013 and March 2016 were included in an observation group, and 40 healthy individuals were included in a control group. Enzyme-linked immunosorbent assay was performed to determine the serum level of annexin A5, while immunohistochemistry was performed to determine the expression of annexin A5 in cancer tissues.RESULTSThe serum level of annexin A5 was 0.184 ± 0.043 ng/mL in the observation group, which was significantly higher than that in the control group (P < 0.05). Annexin A5 expression was detected in 79.31% of the patients with lymph node metastasis, which was significantly higher than that in patients without lymph node metastasis (P < 0.05). Moreover, annexin A5 expression was detected in 86.96% of the patients with stage III to IV disease, which was significantly higher than that in patients with stage I to II disease (P < 0.05). The serum level of annexin A5 was 0.215 ± 0.044 ng/mL in patients whose tumors were positive for annexin A5 expression, which was significantly higher than that in patients whose tumors were negative for annexin A5 expression (P < 0.05). The serum level of annexin A5 was correlated with annexin A5 expression in colon cancer tissues (r = 0.312, P < 0.05). When a cutoff value of > 0.148 ng/mL for serum level of annexin A5 was used in the diagnosis of colon cancer, the sensitivity was 83.90%, and the specificity was 57.50%.CONCLUSIONFor patients with colon cancer, annexin A5 expression in cancer tissues is related to lymph node metastasis and tumor grade. Serum level of annexin A5 is related to annexin A5 expression in cancer tissues and is of diagnostic relevance.

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Section: Discussionmentioning

confidence: 99%

Expression of annexin A5 in serum and tumor tissue of patients with colon cancer and its clinical significance

Sun

Zhao

et al. 2017

WJG

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“…Thus, approaches aiming to image whole-tumour apoptosis for the purposes of assessing therapeutic response (to chemotherapy, targeted therapies, and radiotherapy) were embraced. These imaging methods include MRI [ 20 , 33 ], magnetic resonance spectroscopy (MRS) [ 34 ], USS [ 35 ], novel fluorescence imaging [ 36 ], scintigraphy [ 11 , 18 ] and PET [ 6 , 10 , 16 , 17 ]. Studies using [ 99m Tc]Annexin V, in particular, led the way for nuclear imaging of apoptosis [ 11 , 19 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

“…There has been a handful of pre-clinical and clinical PET imaging studies attempting to image molecular and biochemical events of the apoptotic process [ 6 – 14 ]. Studies with [ 18 F]ML-10 [ 9 , 15 – 17 ] and [ 99m Tc]Annexin V [ 11 , 12 , 18 – 20 ] showed promising results in humans. A study of [ 18 F]ML-10 [ 9 ] — a member of the aposense family of biomarkers that measures ‘apoptotic imprint’ — in human subjects reported favourable dosimetry and biodistribution, and binding to apoptotic sites in testicular tissue of mice, confirmed by terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) of apoptotic cells; initial studies reported correlation of early changes of tumour [ 18 F]ML-10, and later changes in anatomical tumour dimension following radiotherapy [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer

Dubash

Merchant

Heinzmann

et al. 2018

Eur J Nucl Med Mol Imaging

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BackgroundEffective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy.ResultsBreast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes.ConclusionThis study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer.Electronic supplementary materialThe online version of this article (10.1007/s00259-018-4098-9) contains supplementary material, which is available to authorized users.

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“…Several approaches have been suggested to address these potential confounding factors for interpreting therapeutic response using apoptosis imaging, including diffusion-weighted MR imaging ( 20 ), perfusion MR imaging ( 21 ), and acquiring an 18 F-labeled fluorodeoxyglucose PET scan ( 2 ). In this report, we show another approach to assess the presence of viable tumor cells at the time of [ 18 F]ML-10 PET using 23 Na MRI.…”

Section: Discussionmentioning

confidence: 99%

[18F]ML-10 PET: Initial Experience in Glioblastoma Multiforme Therapy Response Assessment

et al. 2016

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The ability to assess tumor apoptotic response to therapy could provide a direct and prompt measure of therapeutic efficacy. 18F-labeled 2-(5-fluoro-pentyl)-2-methyl-malonic acid ([18F]ML-10) is proposed as a positron emission tomography (PET) apoptosis imaging radiotracer. This manuscript presents initial experience using [18F]ML-10 PET to predict therapeutic response in 4 patients with human glioblastoma multiforme. Each patient underwent [18F]ML-10 PET and contrast-enhanced magnetic resonance imaging (MRI) before (baseline) and at ∼2–3 weeks after therapy (early-therapy assessment). All PET and MRI data were acquired using a Siemens BioGraph mMR integrated PET/MRI scanner. PET acquisitions commenced 120 minutes after injection with 10 mCi of [18F]ML-10. Changes in [18F]ML-10 standard uptake values were assessed in conjunction with MRI changes. Time-to-progression was used as the outcome measure. One patient, ML-10 #4, underwent additional sodium-23 (23Na) MRI at baseline and early-therapy assessment. Siemens 3 T Magnetom Tim Trio scanner with a dual-tuned (1H-23Na) head coil was used for 23Na-MRI, acquiring two three-dimensional single-quantum sodium images at two echo times (TE). Volume-fraction-weighted bound sodium concentration was quantified through pixel-by-pixel subtraction of the two single-quantum sodium images. In the cases presented, [18F]ML-10 uptake changes were not clearly related to time-to-progression. We suggest that this may be because the tumors are undergoing varying rates of cell death and growth. Acquisition of complementary measures of tumor cell proliferation or viability may aid in the interpretation of PET apoptosis imaging.

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Monitoring Cell Death in Regorafenib-Treated Experimental Colon Carcinomas Using Annexin-Based Optical Fluorescence Imaging Validated by Perfusion MRI

Cited by 10 publications

References 34 publications

Expression of annexin A5 in serum and tumor tissue of patients with colon cancer and its clinical significance

Expression of annexin A5 in serum and tumor tissue of patients with colon cancer and its clinical significance

Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer

[18F]ML-10 PET: Initial Experience in Glioblastoma Multiforme Therapy Response Assessment

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