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1.
Chem Commun (Camb) ; 60(26): 3507-3510, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38385843

RESUMO

For specific imaging of bacterial infections we aimed at targeting the exclusive bacterial iron transport system via siderophore-based radiotracers. De novo synthesis and radiolabeling yielded the salmochelin-based PET radiotracer [68Ga]Ga-RMA693, which showed a favourable biodistribution and a bacteria-specific uptake in an animal model of Escherichia coli infection.


Assuntos
Enterobactina , Tomografia por Emissão de Pósitrons , Animais , Distribuição Tecidual , Enterobactina/metabolismo , Enterobactina/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Bactérias/metabolismo , Radioisótopos de Gálio
2.
Arch Pharm (Weinheim) ; 355(12): e2200388, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36161669

RESUMO

The calcium-activated potassium channel 3.1 (KCa 3.1) is overexpressed in many tumor entities and has predictive power concerning disease progression and outcome. Imaging of the KCa 3.1 channel in vivo using a radiotracer for positron emission tomography (PET) could therefore establish a potentially powerful diagnostic tool. Senicapoc shows high affinity and excellent selectivity toward the KCa 3.1 channel. We have successfully pursued the synthesis of the 18 F-labeled derivative [18 F]3 of senicapoc using the prosthetic group approach with 1-azido-2-[18 F]fluoroethane ([18 F]6) in a "click" reaction. The biological activity of the new PET tracer was evaluated in vitro and in vivo. Inhibition of the KCa 3.1 channel by 3 was demonstrated by patch clamp experiments and the binding pose was analyzed by docking studies. In mouse and human serum, [18 F]3 was stable for at least one half-life of [18 F]fluorine. Biodistribution experiments in wild-type mice were promising, showing rapid and predominantly renal excretion. An in vivo study using A549-based tumor-bearing mice was performed. The tumor signal could be delineated and image analysis showed a tumor-to-muscle ratio of 1.47 ± 0.24. The approach using 1-azido-2-[18 F]fluoroethane seems to be a good general strategy to achieve triarylacetamide-based fluorinated PET tracers for imaging of the KCa 3.1 channel in vivo.


Assuntos
Neoplasias , Canais de Potássio Cálcio-Ativados , Animais , Humanos , Camundongos , Radioisótopos de Flúor/metabolismo , Compostos Radiofarmacêuticos/farmacologia , Compostos Radiofarmacêuticos/metabolismo , Distribuição Tecidual , Canais de Potássio Cálcio-Ativados/metabolismo , Relação Estrutura-Atividade , Tomografia por Emissão de Pósitrons/métodos , Neoplasias/metabolismo
3.
Mol Imaging Biol ; 24(3): 359-364, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34755247

RESUMO

PURPOSE: Multimodal molecular imaging allows a direct coregistration of different images, facilitating analysis of the spatial relation of various imaging parameters. Here, we further explored the relation of proliferation, as measured by [18F]FLT PET, and water diffusion, as an indicator of cellular density and cell death, as measured by diffusion-weighted (DW) MRI, in preclinical tumor models. We expected these parameters to be negatively related, as highly proliferative tissue should have a higher density of cells, hampering free water diffusion. PROCEDURES: Nude mice subcutaneously inoculated with either lung cancer cells (n = 11 A549 tumors, n = 20 H1975 tumors) or colorectal cancer cells (n = 13 Colo205 tumors) were imaged with [18F]FLT PET and DW-MRI using a multimodal bed, which was transferred from one instrument to the other within the same imaging session. Fiducial markers allowed coregistration of the images. An automatic post-processing was developed in MATLAB handling the spatial registration of DW-MRI (measured as apparent diffusion coefficient, ADC) and [18F]FLT image data and subsequent voxel-wise analysis of regions of interest (ROIs) in the tumor. RESULTS: Analyses were conducted on a total of 76 datasets, comprising a median of 2890 data points (ranging from 81 to 13,597). Scatterplots showing [18F]FLT vs. ADC values displayed various grades of relations (Pearson correlation coefficient (PCC) varied from - 0.58 to 0.49, median: -0.07). When relating PCC to tumor volume (median: 46 mm3, range: 3 mm3 to 584 mm3), lung tumors tended to have a more pronounced negative spatial relation of [18F]FLT and ADC with increasing tumor size. However, due to the low number of large tumors (> ~ 200 mm3), this conclusion has to be treated with caution. CONCLUSIONS: A spatial relation of water diffusion, as measured by DW-MRI, and cellular proliferation, as measured by [18F]FLT PET, cannot be detected in the experimental datasets investigated in this study.


Assuntos
Fluordesoxiglucose F18 , Neoplasias Pulmonares , Animais , Didesoxinucleosídeos , Imagem de Difusão por Ressonância Magnética/métodos , Fluordesoxiglucose F18/metabolismo , Xenoenxertos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Camundongos , Camundongos Nus , Tomografia por Emissão de Pósitrons/métodos , Água
4.
RSC Adv ; 11(48): 30295-30304, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-35480282

RESUMO

Expression of the Ca2+ activated potassium channel 3.1 (KCa3.1) channel (also known as the Gàrdos channel) is dysregulated in many tumor entities and has predictive power with respect to patient survival. Therefore, a positron emission tomography (PET) tracer targeting this ion channel could serve as a potential diagnostic tool by imaging the KCa3.1 channel in vivo. It was envisaged to synthesize [18F]senicapoc ([18F]1) since senicapoc (1) shows high affinity and excellent selectivity towards the KCa3.1 channels. Because problems occurred during 18F-fluorination, the [18F]fluoroethoxy senicapoc derivative [18F]28 was synthesized to generate an alternative PET tracer targeting the KCa3.1 channel. Inhibition of the KCa3.1 channel by 28 was confirmed by patch clamp experiments. In vitro stability in mouse and human serum was shown for 28. Furthermore, biodistribution experiments in wild type mice were performed. Since [18F]fluoride was detected in vivo after application of [18F]28, an in vitro metabolism study was conducted. A potential degradation route of fluoroethoxy derivatives in vivo was found which in general should be taken into account when designing new PET tracers for different targets with a [18F]fluoroethoxy moiety as well as when using the popular prosthetic group [18F]fluoroethyl tosylate for the alkylation of phenols.

5.
Cancers (Basel) ; 12(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32752204

RESUMO

Cadherins mediate cohesive contacts between isotypic cells by homophilic interaction and prevent contact between heterotypic cells. Breast cancer cells neighboring endothelial cells (ECs) atypically express vascular endothelial (VE)-cadherin. To understand this EC-induced VE-cadherin expression in breast cancer cells, MCF7 and MDA-MB-231 cells expressing different endogenous cadherins were co-cultured with ECs and analyzed for VE-cadherin at the transcriptional level and by confocal microscopy, flow cytometry, and immunoblotting. After losing their endogenous cadherins and neo-expression of VE-cadherin, these cells integrated into an EC monolayer without compromising the barrier function instantly. However, they induced the death of nearby ECs. EC-derived extracellular vesicles (EVs) contained soluble and membrane-anchored forms of VE-cadherin. Only the latter was re-utilized by the cancer cells. In a reporter gene assay, EC-adjacent cancer cells also showed a juxtacrine but no paracrine activation of the endogenous VE-cadherin gene. This cadherin switch enabled intimate contact between cancer and endothelial cells in a chicken chorioallantoic membrane tumor model showing vasculogenic mimicry (VM). This EV-mediated, EC-induced cadherin switch in breast cancer cells and the neo-expression of VE-cadherin mechanistically explain the mutual communication in the tumor microenvironment. Hence, it may be a target to tackle VM, which is often found in breast cancers of poor prognosis.

6.
Recent Results Cancer Res ; 216: 493-507, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32594396

RESUMO

Understanding the (molecular) mechanisms underlying tumor progression is fundamental for developing and improving cancer diagnosis and therapy. Positron emission tomography (PET) is a method to non-invasively and longitudinally provide such information. Depending on the radioactive tracer employed, a range of molecular processes can be visualized. Preclinical PET has fundamentally contributed to the establishment of novel imaging, diagnostic, and therapy approaches in the clinical situation. It is a valuable tool to corroborate in vivo imaging findings with conventional ex vivo tissue analysis. Here, we provide an overview of challenges and applications of preclinical PET in the field of oncology.


Assuntos
Tamanho Corporal , Modelos Animais de Doenças , Tomografia por Emissão de Pósitrons , Animais , Neoplasias/diagnóstico por imagem
7.
Adv Exp Med Biol ; 1225: 71-87, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030648

RESUMO

The tumour microenvironment (TME) surrounding tumour cells is a highly dynamic and heterogeneous composition of immune cells, fibroblasts, precursor cells, endothelial cells, signalling molecules and extracellular matrix (ECM) components. Due to the heterogeneity and the constant crosstalk between the TME and the tumour cells, the components of the TME are important prognostic parameters in cancer and determine the response to novel immunotherapies. To improve the characterization of the TME, novel non-invasive imaging paradigms targeting the complexity of the TME are urgently needed.The characterization of the TME by molecular imaging will (1) support early diagnosis and disease follow-up, (2) guide (stereotactic) biopsy sampling, (3) highlight the dynamic changes during disease pathogenesis in a non-invasive manner, (4) help monitor existing therapies, (5) support the development of novel TME-targeting therapies and (6) aid stratification of patients, according to the cellular composition of their tumours in correlation to their therapy response.This chapter will summarize the most recent developments and applications of molecular imaging paradigms beyond FDG for the characterization of the dynamic molecular and cellular changes in the TME.


Assuntos
Imagem Molecular , Neoplasias/terapia , Microambiente Tumoral , Humanos , Imunoterapia , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Microambiente Tumoral/efeitos dos fármacos
8.
J Am Chem Soc ; 142(11): 5252-5265, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32105452

RESUMO

In this work, we investigate the potential of highly sulfated synthetic glycomimetics to act as inhibitors of viral binding/infection. Our results indicate that both long-chain glycopolymers and short-chain glycooligomers are capable of preventing viral infection. Notably, glycopolymers efficiently inhibit Human Papillomavirus (HPV16) infection in vitro and maintain their antiviral activity in vivo, while the glycooligomers exert their inhibitory function post attachment of viruses to cells. Moreover, when we tested the potential for broader activity against several other human pathogenic viruses, we observed broad-spectrum antiviral activity of these compounds beyond our initial assumptions. While the compounds tested displayed a range of antiviral efficacies, viruses with rather diverse glycan specificities such as Herpes Simplex Virus (HSV), Influenza A Virus (IAV), and Merkel Cell Polyomavirus (MCPyV) could be targeted. This opens new opportunities to develop broadly active glycomimetic inhibitors of viral entry and infection.


Assuntos
Resinas Acrílicas/uso terapêutico , Alcanossulfonatos/uso terapêutico , Antivirais/uso terapêutico , Galactosídeos/uso terapêutico , Manosídeos/uso terapêutico , Infecções por Papillomavirus/tratamento farmacológico , Resinas Acrílicas/síntese química , Alcanossulfonatos/síntese química , Animais , Antivirais/síntese química , Linhagem Celular Tumoral , Feminino , Galactosídeos/síntese química , Humanos , Manosídeos/síntese química , Camundongos Endogâmicos BALB C , Vírus/efeitos dos fármacos
10.
Mol Ther ; 27(5): 933-946, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30879952

RESUMO

Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Gangliosídeos/genética , Receptores de Antígenos Quiméricos/genética , Sarcoma de Ewing/tratamento farmacológico , Antígenos de Superfície/efeitos dos fármacos , Antígenos de Superfície/genética , Benzamidas/farmacologia , Compostos de Bifenilo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Gangliosídeos/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Indóis/farmacologia , Morfolinas , Regiões Promotoras Genéticas/genética , Piridonas/farmacologia , Receptores de Antígenos Quiméricos/imunologia , Sarcoma de Ewing/genética , Sarcoma de Ewing/imunologia , Sarcoma de Ewing/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
11.
J Nucl Med ; 59(7): 1063-1069, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29476002

RESUMO

Noninvasive monitoring of tumor therapy response helps in developing personalized treatment strategies. Here, we performed sequential PET and diffusion-weighted MRI to evaluate changes induced by a FOLFOX-like combination chemotherapy in colorectal cancer xenografts, to identify the cellular and molecular determinants of these imaging biomarkers. Methods: Tumor-bearing CD1 nude mice, engrafted with FOLFOX-sensitive Colo205 colorectal cancer xenografts, were treated with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) weekly. On days 1, 2, 6, 9, and 13 of therapy, tumors were assessed by in vivo imaging and ex vivo analyses. In addition, HCT116 xenografts, which did not respond to the FOLFOX treatment, were imaged on day 1 of therapy. Results: In Colo205 xenografts, FOLFOX induced a profound increase in uptake of the proliferation PET tracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) accompanied by increases in markers for proliferation (Ki-67, thymidine kinase 1) and for activated DNA damage response (γH2AX), whereas the effect on cell death was minimal. Because tracer uptake was unaltered in the HCT116 model, these changes appear to be specific for tumor response. Conclusion: We demonstrated that 18F-FLT PET can noninvasively monitor cancer treatment-induced molecular alterations, including thymidine metabolism and DNA damage response. The cellular or imaging changes may not, however, be directly related to therapy response as assessed by volumetric measurements.


Assuntos
Artefatos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Didesoxinucleosídeos/metabolismo , Timidina/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transporte Biológico/efeitos dos fármacos , Transformação Celular Neoplásica , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Imagem de Difusão por Ressonância Magnética , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Células HCT116 , Humanos , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Camundongos , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico
12.
Mol Imaging Biol ; 20(2): 194-199, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28971330

RESUMO

PURPOSE: We recently reported that high thymidine phosphorylase (TP) expression is accompanied by low tumor thymidine concentration and high 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) uptake in four untreated lung cancer xenografts. Here, we investigated whether this relationship also holds true for a broader range of tumor models. PROCEDURES: Lysates from n = 15 different tumor models originating from n = 6 institutions were tested for TP and thymidylate synthase (TS) expression using western blots. Results were correlated to [18F]FLT accumulation in the tumors as determined by positron emission tomography (PET) measurements in the different institutions and to previously published thymidine concentrations. RESULTS: Expression of TP correlated positively with [18F]FLT SUVmax (ρ = 0.549, P < 0.05). Furthermore, tumors with high TP levels possessed lower levels of thymidine (ρ = - 0.939, P < 0.001). CONCLUSIONS: In a broad range of tumors, [18F]FLT uptake as measured by PET is substantially influenced by TP expression and tumor thymidine concentrations. These data strengthen the role of TP as factor confounding [18F]FLT uptake.


Assuntos
Didesoxinucleosídeos/farmacocinética , Neoplasias Experimentais/enzimologia , Timidina Fosforilase/metabolismo , Animais , Didesoxinucleosídeos/química , Humanos , Camundongos , Timidina/metabolismo
13.
EJNMMI Res ; 7(1): 99, 2017 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-29247446

RESUMO

CORRECTION: Unfortunately, the original version of Figs. 4, 5 and 6b in the article [1] contained errors in the n numbers as indicated on the columns. Please note that column heights and error bars in the original figures and data in the ESM tables are correct and statistical tests are valid. These corrections do not affect any results or conclusions in this article.

14.
Eur J Neurosci ; 45(7): 975-986, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28194885

RESUMO

Bioluminescence imaging in transgenic mice expressing firefly luciferase in Doublecortin+ (Dcx) neuroblasts might serve as a powerful tool to study the role of neurogenesis in models of brain injury and neurodegeneration using non-invasive, longitudinal in vivo imaging. Therefore, we aimed to use BLI in B6(Cg)-Tyrc-2J/J Dcx-Luc (Doublecortin-Luciferase, Dcx-Luc) mice to investigate its suitability to assess neurogenesis in a unilateral injection model of Parkinson's disease. We further aimed to assess the blood brain barrier leakage associated with the intranigral 6-OHDA injection to evaluate its impact on substrate delivery and bioluminescence signal intensity. Two weeks after lesion, we observed an increase in bioluminescence signal in the ipsilateral hippocampal region in both, 6-OHDA and vehicle injected Dcx-Luc mice. At the same time, no corresponding increase in Dcx+ neuroblast numbers could be observed in the dentate gyrus of C57Bl6 mice. Blood brain barrier leakage was observed in the hippocampal region and in the degenerating substantia nigra of C57Bl6 mice in vivo using T1 weighted Magnetic Resonance Imaging with Gadovist® and ex vivo using Evans Blue Fluorescence Reflectance Imaging and mouse Immunoglobulin G staining. Our data suggests a BLI signal dependency on blood brain barrier permeability, underlining a major pitfall of substrate/tracer dependent imaging in invasive disease models.


Assuntos
Barreira Hematoencefálica/metabolismo , Neurogênese , Imagem Óptica/métodos , Doença de Parkinson/diagnóstico por imagem , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Permeabilidade Capilar , Giro Denteado/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética , Proteína Duplacortina , Azul Evans/farmacocinética , Luminescência , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organometálicos/farmacocinética , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Substância Negra/diagnóstico por imagem
15.
Oncoimmunology ; 6(1): e1250050, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28197367

RESUMO

Activated and in vitro expanded natural killer (NK) cells have substantial cytotoxicity against many tumor cells, but their in vivo efficacy to eliminate solid cancers is limited. Here, we used chimeric antigen receptors (CARs) to enhance the activity of NK cells against Ewing sarcomas (EwS) in a tumor antigen-specific manner. Expression of CARs directed against the ganglioside antigen GD2 in activated NK cells increased their responses to GD2+ allogeneic EwS cells in vitro and overcame resistance of individual cell lines to NK cell lysis. Second-generation CARs with 4-1BB and 2B4 co-stimulatory signaling and third-generation CARs combining both co-stimulatory domains were all equally effective. By contrast, adoptive transfer of GD2-specific CAR gene-modified NK cells both by intratumoral and intraperitoneal delivery failed to eliminate GD2-expressing EwS xenografts. Histopathology review revealed upregulation of the immunosuppressive ligand HLA-G in tumor autopsies from mice treated with NK cells compared to untreated control mice. Supporting the relevance of this finding, in vitro co-incubation of NK cells with allogeneic EwS cells induced upregulation of the HLA-G receptor CD85j, and HLA-G1 expressed by EwS cells suppressed the activity of NK cells from three of five allogeneic donors against the tumor cells in vitro. We conclude that HLA-G is a candidate immune checkpoint in EwS where it can contribute to resistance to NK cell therapy. HLA-G deserves evaluation as a potential target for more effective immunotherapeutic combination regimens in this and other cancers.

16.
Cancer Res ; 77(8): 1831-1841, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28137769

RESUMO

The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, noninvasive imaging by PET with [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) was used for the assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([18F]FET) in conjunction with MRI. We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4- to 1.7-fold, with [18F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of [18F]DPA-714 (14%) and [18F]BR-351 (11%) volumes along the tumor rim could be identified. [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multitracer and multimodal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this noninvasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages. Cancer Res; 77(8); 1831-41. ©2017 AACR.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Glioma/diagnóstico por imagem , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Radioisótopos de Flúor , Glioma/metabolismo , Glioma/patologia , Metaloproteinases da Matriz/metabolismo , Camundongos , Camundongos Nus , Microglia/patologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Receptores de GABA/metabolismo , Microambiente Tumoral
17.
Theranostics ; 7(1): 40-50, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28042315

RESUMO

The positron emission tomography (PET) tracer 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been proposed to measure cell proliferation non-invasively in vivo. Hence, it should provide valuable information for response assessment to tumor therapies. To date, [18F]FLT uptake has found limited use as a response biomarker in clinical trials in part because a better understanding is needed of the determinants of [18F]FLT uptake and therapy-induced changes of its retention in the tumor. In this systematic review of preclinical [18F]FLT studies, comprising 174 reports, we identify the factors governing [18F]FLT uptake in tumors, among which thymidine kinase 1 plays a primary role. The majority of publications (83 %) report that decreased [18F]FLT uptake reflects the effects of anticancer therapies. 144 times [18F]FLT uptake was related to changes in proliferation as determined by ex vivo analyses. Of these approaches, 77 % describe a positive relation, implying a good concordance of tracer accumulation and tumor biology. These preclinical data indicate that [18F]FLT uptake holds promise as an imaging biomarker for response assessment in clinical studies. Understanding of the parameters which influence cellular [18F]FLT uptake and retention as well as the mechanism of changes induced by therapy is essential for successful implementation of this PET tracer. Hence, our systematic review provides the background for the use of [18F]FLT in future clinical studies.


Assuntos
Didesoxinucleosídeos/administração & dosagem , Monitoramento de Medicamentos/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Animais , Avaliação Pré-Clínica de Medicamentos
18.
Cancer Res ; 76(24): 7089-7095, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27923827

RESUMO

Molecular imaging with the PET tracer 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) allows assessment of the proliferative state of organs in vivo Although used primarily in the oncology clinic, it can also shed light on the proliferation of other tissues, as demonstrated here for monitoring hematopoietic organs that recover after myelosuppressive chemotherapy. In the NMRI nude mouse model, we observed up to a 4.5-fold increase in [18F]FLT uptake in bone marrow and spleen on days 2, 3, and 5 after treatment with gemcitabine, a chemotherapeutic agent that is powerfully myelosuppressive in the model. Specifically, we observed (i) a reduced spleen weight; (ii) reduced bone marrow cell counts and proliferation (BrdUrd flow cytometry, spleen IHC; 6 hours/day 1); and (iii) reduced leukocytes in peripheral blood (day 5). In conclusion, our results show how [18F]FLT PET can provide a powerful tool to noninvasively visualize the proliferative status of hematopoietic organs after myelosuppressive therapy. Cancer Res; 76(24); 7089-95. ©2016 AACR.


Assuntos
Antineoplásicos/toxicidade , Medula Óssea/diagnóstico por imagem , Desoxicitidina/análogos & derivados , Hematopoese/efeitos dos fármacos , Tomografia por Emissão de Pósitrons/métodos , Baço/diagnóstico por imagem , Animais , Desoxicitidina/toxicidade , Didesoxinucleosídeos , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Humanos , Camundongos , Camundongos Nus , Compostos Radiofarmacêuticos , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
19.
Cancer Res ; 76(24): 7096-7105, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27784748

RESUMO

3'-Deoxy-3'-[18F]fluorothymidine positron emission tomography ([18F]FLT-PET) and diffusion-weighted MRI (DW-MRI) are promising approaches to monitor tumor therapy response. Here, we employed these two imaging modalities to evaluate the response of lung carcinoma xenografts in mice after gemcitabine therapy. Caliper measurements revealed that H1975 xenografts responded to gemcitabine treatment, whereas A549 growth was not affected. In both tumor models, uptake of [18F]FLT was significantly reduced 6 hours after drug administration. On the basis of the gemcitabine concentration and [18F]FLT excretion measured, this was presumably related to a direct competition of gemcitabine with the radiotracer for cellular uptake. On day 1 after therapy, [18F]FLT uptake was increased in both models, which was correlated with thymidine kinase 1 (TK1) expression. Two and 3 days after drug administration, [18F]FLT uptake as well as TK1 and Ki67 expression were unchanged. A reduction in [18F]FLT in the responsive H1975 xenografts could only be noted on day 5 of therapy. Changes in ADCmean in A549 xenografts 1 or 2 days after gemcitabine did not seem to be of therapy-related biological relevance as they were not related to cell death (assessed by caspase-3 IHC and cellular density) or tumor therapy response. Taken together, in these models, early changes of [18F]FLT uptake in tumors reflected mechanisms, such as competing gemcitabine uptake or gemcitabine-induced thymidylate synthase inhibition, and only reflected growth-inhibitory effects at a later time point. Hence, the time point for [18F]FLT-PET imaging of tumor response to gemcitabine is of crucial importance. Cancer Res; 76(24); 7096-105. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Desoxicitidina/análogos & derivados , Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Animais , Western Blotting , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Didesoxinucleosídeos , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Humanos , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Camundongos , Camundongos Nus , Compostos Radiofarmacêuticos , Ensaios Antitumorais Modelo de Xenoenxerto , Gencitabina
20.
EJNMMI Res ; 6(1): 63, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27515446

RESUMO

BACKGROUND: Recent studies have shown that 3'-deoxy-3'-[(18)F] fluorothymidine ([(18)F]FLT)) uptake depends on endogenous tumour thymidine concentration. The purpose of this study was to investigate tumour thymidine concentrations and whether they correlated with [(18)F]FLT uptake across a broad spectrum of murine cancer models. A modified liquid chromatography-mass spectrometry (LC-MS/MS) method was used to determine endogenous thymidine concentrations in plasma and tissues of tumour-bearing and non-tumour bearing mice and rats. Thymidine concentrations were determined in 22 tumour models, including xenografts, syngeneic and spontaneous tumours, from six research centres, and a subset was compared for [(18)F]FLT uptake, described by the maximum and mean tumour-to-liver uptake ratio (TTL) and SUV. RESULTS: The LC-MS/MS method used to measure thymidine in plasma and tissue was modified to improve sensitivity and reproducibility. Thymidine concentrations determined in the plasma of 7 murine strains and one rat strain were between 0.61 ± 0.12 µM and 2.04 ± 0.64 µM, while the concentrations in 22 tumour models ranged from 0.54 ± 0.17 µM to 20.65 ± 3.65 µM. TTL at 60 min after [(18)F]FLT injection, determined in 14 of the 22 tumour models, ranged from 1.07 ± 0.16 to 5.22 ± 0.83 for the maximum and 0.67 ± 0.17 to 2.10 ± 0.18 for the mean uptake. TTL did not correlate with tumour thymidine concentrations. CONCLUSIONS: Endogenous tumour thymidine concentrations alone are not predictive of [(18)F]FLT uptake in murine cancer models.

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