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1.
NMR Biomed ; 26(2): 151-63, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22777834

RESUMO

Cediranib is a small-molecule pan-vascular endothelial growth factor receptor inhibitor. The tumor response to short-term cediranib treatment was studied using dynamic contrast-enhanced and diffusion-weighted MRI at 7 T, as well as (18) F-fluoromisonidazole positron emission tomography and histological markers. Rats bearing subcutaneous HT29 human colorectal tumors were imaged at baseline; they then received three doses of cediranib (3 mg/kg per dose daily) or vehicle (dosed daily), with follow-up imaging performed 2 h after the final cediranib or vehicle dose. Tumors were excised and evaluated for the perfusion marker Hoechst 33342, the endothelial cell marker CD31, smooth muscle actin, intercapillary distance and tumor necrosis. Dynamic contrast-enhanced MRI-derived parameters decreased significantly in cediranib-treated tumors relative to pretreatment values [the muscle-normalized initial area under the gadolinium concentration curve decreased by 48% (p=0.002), the enhancing fraction by 43% (p=0.003) and K(trans) by 57% (p=0.003)], but remained unchanged in controls. No change between the pre- and post-treatment tumor apparent diffusion coefficients in either the cediranib- or vehicle-treated group was observed over the course of this study. The (18) F-fluoromisonidazole mean standardized uptake value decreased by 33% (p=0.008) in the cediranib group, but showed no significant change in the control group. Histological analysis showed that the number of CD31-positive vessels (59 per mm(2) ), the fraction of smooth muscle actin-positive vessels (80-87%) and the intercapillary distance (0.17 mm) were similar in cediranib- and vehicle-treated groups. The fraction of perfused blood vessels in cediranib-treated tumors (81 ± 7%) was lower than that in vehicle controls (91 ± 3%, p=0.02). The necrotic fraction was slightly higher in cediranib-treated rats (34 ± 12%) than in controls (26 ± 10%, p=0.23). These findings suggest that short-term treatment with cediranib causes a decrease in tumor perfusion/permeability across the tumor cross-section, but changes in vascular morphology, vessel density or tumor cellularity are not manifested at this early time point.


Assuntos
Fluordesoxiglucose F18 , Gadolínio DTPA , Neoplasias Experimentais/diagnóstico , Neoplasias Experimentais/tratamento farmacológico , Tomografia por Emissão de Pósitrons/métodos , Quinazolinas/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Meios de Contraste , Células HT29 , Humanos , Compostos Radiofarmacêuticos , Ratos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Med Phys ; 37(1): 329-38, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20175496

RESUMO

PURPOSE: Bioluminescence imaging is a research tool for studying gene expression levels in small animal models of human disease. Bioluminescence light, however, is strongly scattered in biological tissue and no direct image of the light-emitting reporter probe's location can be obtained. Therefore, the authors have developed a linear image reconstruction method for bioluminescence tomography (BLT) that recovers the three-dimensional spatial bioluminescent source distribution in small animals. METHODS: The proposed reconstruction method uses third-order simplified spherical harmonics (SP3) solutions to the equation of radiative transfer for modeling the bioluminescence light propagation in optically nonuniform tissue. The SP3 equations and boundary conditions are solved with a finite-difference (FD) technique on a regular grid. The curved geometry of the animal surface was taken into account with a blocking-off region method for regular grids. Coregistered computed tomography (CT) and magnetic resonance (MR) images provide information regarding the geometry of the skin surface and internal organs. The inverse source problem is defined as an algebraic system of linear equations for the unknown source distribution and is iteratively solved given multiview and multispectral boundary measurements. The average tissue absorption parameters, which are used for the image reconstruction process, were calculated with an evolution strategy (ES) from in vivo measurements using an implanted pointlike source of known location and spectrum. Moreover, anatomical information regarding the location of the internal organs and other tissue structures within the animal's body are provided by coregistered MR images. RESULTS: First, the authors recovered the wavelength-dependent absorption coefficients (average error of 14%) with the ES under ideal conditions by using a numerical mouse model. Next, they reconstructed the average absorption coefficient of a small animal by using an artificial implanted light source and the validated ES. Last, they conducted two in vivo animal experiments and recovered the spatial location of the implanted light source and the spatial distribution of a bioluminescent reporter system located in the kidneys. The source reconstruction results were coregistered to CT and MR images. They further found that accurate bioluminescence image reconstructions could be obtained when segmenting a voidlike cyst with low-scattering and absorption parameters, whereas inaccurate image reconstructions were obtained when assuming a uniform optical parameter distribution instead. The image reconstructions were completed within 23 min on a 3 GHz Intel processor. CONCLUSIONS: The authors demonstrated on in vivo examples that the combination of anatomical coregistration, accurate optical tissue properties, multispectral acquisition, and a blocking-off FD-SP3 solution of the radiative transfer model significantly improves the accuracy of the BLT reconstructions.


Assuntos
Algoritmos , Medições Luminescentes/métodos , Imageamento por Ressonância Magnética/métodos , Técnica de Subtração , Tomografia Óptica/métodos , Tomografia Computadorizada por Raios X/métodos , Imagem Corporal Total/métodos , Animais , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
3.
J Biomed Opt ; 14(2): 024045, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19405773

RESUMO

The procedures we propose make possible the mapping of two-dimensional (2-D) bioluminescence image (BLI) data onto a skin surface derived from a three-dimensional (3-D) anatomical modality [magnetic resonance (MR) or computed tomography (CT)] dataset. This mapping allows anatomical information to be incorporated into bioluminescence tomography (BLT) reconstruction procedures and, when applied using sources visible to both optical and anatomical modalities, can be used to evaluate the accuracy of those reconstructions. Our procedures, based on immobilization of the animal and a priori determined fixed projective transforms, should be more robust and accurate than previously described efforts, which rely on a poorly constrained retrospectively determined warping of the 3-D anatomical information. Experiments conducted to measure the accuracy of the proposed registration procedure found it to have a mean error of 0.36+/-0.23 mm. Additional experiments highlight some of the confounds that are often overlooked in the BLT reconstruction process, and for two of these confounds, simple corrections are proposed.


Assuntos
Algoritmos , Interpretação de Imagem Assistida por Computador/métodos , Medições Luminescentes/métodos , Imageamento por Ressonância Magnética/métodos , Tomografia Óptica/métodos , Tomografia Computadorizada por Raios X/métodos , Imagem Corporal Total/métodos , Animais , Aumento da Imagem/métodos , Medições Luminescentes/instrumentação , Medições Luminescentes/veterinária , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/veterinária , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Técnica de Subtração/instrumentação , Técnica de Subtração/veterinária , Tomografia Óptica/instrumentação , Tomografia Óptica/veterinária , Tomografia Computadorizada por Raios X/instrumentação , Tomografia Computadorizada por Raios X/veterinária , Imagem Corporal Total/instrumentação , Imagem Corporal Total/veterinária
4.
Phys Med Biol ; 53(20): 5867-82, 2008 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-18827321

RESUMO

Dedicated small-animal imaging devices, e.g. positron emission tomography (PET), computed tomography (CT) and magnetic resonance imaging (MRI) scanners, are being increasingly used for translational molecular imaging studies. The objective of this work was to determine the positional accuracy and precision with which tumors in situ can be reliably and reproducibly imaged on dedicated small-animal imaging equipment. We designed, fabricated and tested a custom rodent cradle with a stereotactic template to facilitate registration among image sets. To quantify tumor motion during our small-animal imaging protocols, 'gold standard' multi-modality point markers were inserted into tumor masses on the hind limbs of rats. Three types of imaging examination were then performed with the animals continuously anesthetized and immobilized: (i) consecutive microPET and MR images of tumor xenografts in which the animals remained in the same scanner for 2 h duration, (ii) multi-modality imaging studies in which the animals were transported between distant imaging devices and (iii) serial microPET scans in which the animals were repositioned in the same scanner for subsequent images. Our results showed that the animal tumor moved by less than 0.2-0.3 mm over a continuous 2 h microPET or MR imaging session. The process of transporting the animal between instruments introduced additional errors of approximately 0.2 mm. In serial animal imaging studies, the positioning reproducibility within approximately 0.8 mm could be obtained.


Assuntos
Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Técnica de Subtração , Animais , Linhagem Celular Tumoral , Masculino , Ratos , Ratos Nus , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
5.
Cancer Cell ; 19(5): 575-86, 2011 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-21575859

RESUMO

Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.


Assuntos
PTEN Fosfo-Hidrolase/deficiência , Fosfatidilinositol 3-Quinase/metabolismo , Neoplasias da Próstata/enzimologia , Receptores Androgênicos/metabolismo , Transdução de Sinais , Antagonistas de Androgênios/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Retroalimentação Fisiológica , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Proteínas Nucleares/metabolismo , PTEN Fosfo-Hidrolase/genética , Inibidores de Fosfoinositídeo-3 Quinase , Fosfoproteínas Fosfatases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/metabolismo , Receptores Androgênicos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transcrição Gênica , Transfecção , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
6.
PLoS One ; 2(8): e810, 2007 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-17726540

RESUMO

BACKGROUND: The EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer. METHODOLOGY/PRINCIPAL FINDINGS: To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFR(T790M) alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFR(L858R+T790M)-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFR(T790M)-expressing animals develop tumors with longer latency than EGFR(L858R+T790M)-bearing mice and in the absence of additional kinase domain mutations. CONCLUSIONS/SIGNIFICANCE: These new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFR(T790M) alone or in conjunction with drug-sensitive EGFR kinase domain mutations.


Assuntos
Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Benzoquinonas/farmacologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/metabolismo , Genótipo , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Lactamas Macrocíclicas/farmacologia , Camundongos , Camundongos Transgênicos
7.
Mol Imaging ; 6(2): 108-20, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17445505

RESUMO

Multimodality scanners that allow the acquisition of both functional and structural image sets on a single system have recently become available for animal research use. Although the resultant registered functional/structural image sets can greatly enhance the interpretability of the functional data, the cost of multimodality systems can be prohibitive, and they are often limited to two modalities, which generally do not include magnetic resonance imaging. Using a thin plastic wrap to immobilize and fix a mouse or other small animal atop a removable bed, we are able to calculate registrations between all combinations of four different small animal imaging scanners (positron emission tomography, single-photon emission computed tomography, magnetic resonance, and computed tomography [CT]) at our disposal, effectively equivalent to a quadruple-modality scanner. A comparison of serially acquired CT images, with intervening acquisitions on other scanners, demonstrates the ability of the proposed procedures to maintain the rigidity of an anesthetized mouse during transport between scanners. Movement of the bony structures of the mouse was estimated to be 0.62 mm. Soft tissue movement was predominantly the result of the filling (or emptying) of the urinary bladder and thus largely constrained to this region. Phantom studies estimate the registration errors for all registration types to be less than 0.5 mm. Functional images using tracers targeted to known structures verify the accuracy of the functional to structural registrations. The procedures are easy to perform and produce robust and accurate results that rival those of dedicated multimodality scanners, but with more flexible registration combinations and while avoiding the expense and redundancy of multimodality systems.


Assuntos
Animais de Laboratório , Restrição Física/métodos , Tomografia/métodos , Animais , Osso e Ossos/anatomia & histologia , Camundongos , Movimento , Reprodutibilidade dos Testes , Tomografia/instrumentação
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