Base de dados : MEDLINE
Pesquisa : D01.268.271.110 [Categoria DeCS]
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  1 / 273 MEDLINE  
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[PMID]:28658304
[Au] Autor:Kodaira S; Li HK; Konishi T; Kitamura H; Kurano M; Hasegawa S
[Ad] Endereço:Radiation Measurement Research Team, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
[Ti] Título:Validating α-particle emission from 211At-labeled antibodies in single cells for cancer radioimmunotherapy using CR-39 plastic nuclear track detectors.
[So] Source:PLoS One;12(6):e0178472, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recently, 211At has received increasing attention as a potential radionuclide for cancer radioimmunotherapy. It is a α-particle emitter, which is extremely effective against malignant cells. We demonstrate a method to verify the efficiency of 211At-labeled trastuzumab antibodies (211At-trastuzumab) against HER2 antigens, which has not been determined for radioimmunotherapy. A CR-39 plastic nuclear detector is used for measuring the position and the linear energy transfer (LET) of individual 211At α- particle tracks. The tracks and 211At-trastuzumab-binding cells were co-visualized by using the geometric information recorded on the CR-39. HER2-positive human gastric cancer cells (NCI-N87), labelled with 211At-trastuzumab, were dropped on the centre of the CR-39 plate. Microscope images of the cells and the corresponding α-tracks acquired by position matching were obtained. In addition, 3.5 cm × 3.5 cm macroscopic images of the whole plate were acquired. The distribution of number of α-particles emitted from single cells suggests that 80% of the 211At-trastuzumab-binding cells emitted α-particles. It also indicates that the α-particles may strike the cells several times along their path. The track-averaged LET of the α-particles is evaluated to be 131 keV/µm. These results will enable quantitative evaluation of delivered doses to target cells, and will be useful for the in vitro assessment of 211At-based radioimmunotherapeutic agents.
[Mh] Termos MeSH primário: Partículas alfa/uso terapêutico
Anticorpos Monoclonais/uso terapêutico
Astato/química
Plásticos/química
Polietilenoglicóis/química
Radioimunoterapia/métodos
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Plastics); 25656-90-0 (CR 39); 30IQX730WE (Polyethylene Glycols); XI595HAL7H (Astatine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170629
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0178472


  2 / 273 MEDLINE  
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[PMID]:28514062
[Au] Autor:Li HK; Morokoshi Y; Nagatsu K; Kamada T; Hasegawa S
[Ad] Endereço:Radiation and Cancer Biology Team, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
[Ti] Título:Locoregional therapy with α-emitting trastuzumab against peritoneal metastasis of human epidermal growth factor receptor 2-positive gastric cancer in mice.
[So] Source:Cancer Sci;108(8):1648-1656, 2017 Aug.
[Is] ISSN:1349-7006
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Peritoneal metastasis of gastric cancer (PMGC) is incurable and thus has an extremely poor prognosis. We have found, however, that locoregionally administered trastuzumab armed with astatine-211 ( At-trastuzumab) is effective against human epidermal growth factor receptor 2 (HER2)-positive PMGC in a xenograft mouse model. We first observed that At-trastuzumab can specifically bind and effectively kill NCI-N87 (N87) cells, which are HER2-positive human metastatic GC cells, both in vitro and in s.c. tumors. We established a PMGC mouse model using N87 xenografts stably expressing luciferase to test α-particle radioimmunotherapy with At-trastuzumab against PMGC. Biodistribution analysis in this PMGC mouse model revealed that the i.p. administration of At-trastuzumab (1 MBq) was a more efficient means of delivery of At into metastatic tumors than i.v. injection; the maximum tumor uptake with i.p. administration was over 60% injected dose per gram of tissue (%ID/g) compared to approximately 18%ID/g with i.v. injection. Surprisingly, a single i.p. injection of At-trastuzumab (1 MBq) was sufficient to completely eradicate intraperitoneally disseminated HER2-positive GC xenografts in two of six treated mice by inducing DNA double-strand breaks, and to drastically reduce the tumor burden in another three mice. No bodyweight loss, leukocytopenia, or significant biochemical changes in liver or kidney function were observed in the treatment group. Accordingly, locoregionally administered At-trastuzumab significantly prolonged the survival time of HER2-positive PMGC mice compared with control treatments. Our results provide a proof-of-concept demonstration that locoregional therapy with At-trastuzumab may offer a new treatment option for HER2-positive PMGC.
[Mh] Termos MeSH primário: Astato/química
Neoplasias Peritoneais/tratamento farmacológico
Neoplasias Peritoneais/secundário
Compostos Radiofarmacêuticos/administração & dosagem
Neoplasias Gástricas/tratamento farmacológico
Trastuzumab/administração & dosagem
[Mh] Termos MeSH secundário: Administração Intravenosa
Animais
Linhagem Celular Tumoral
Seres Humanos
Injeções Intraperitoneais
Camundongos
Neoplasias Peritoneais/metabolismo
Radioimunoterapia
Compostos Radiofarmacêuticos/química
Compostos Radiofarmacêuticos/farmacologia
Receptor ErbB-2/antagonistas & inibidores
Receptor ErbB-2/metabolismo
Neoplasias Gástricas/metabolismo
Distribuição Tecidual
Trastuzumab/química
Trastuzumab/farmacologia
Resultado do Tratamento
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Radiopharmaceuticals); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); P188ANX8CK (Trastuzumab); XI595HAL7H (Astatine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170518
[St] Status:MEDLINE
[do] DOI:10.1111/cas.13282


  3 / 273 MEDLINE  
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[PMID]:27765860
[Au] Autor:Langen B; Rudqvist N; Helou K; Forssell-Aronsson E
[Ad] Endereço:Department of Radiation Physics, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden britta.langen@gu.se.
[Ti] Título:Microarray Studies on 211At Administration in BALB/c Nude Mice Indicate Systemic Effects on Transcriptional Regulation in Nonthyroid Tissues.
[So] Source:J Nucl Med;58(2):346-353, 2017 Feb.
[Is] ISSN:1535-5667
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Targeted α-therapy is a promising treatment option for various types of malignant tumors. Radiolabeled cancer-seeking agents, however, undergo degradation, resulting in a certain percentage of free radionuclide in the body. The radiohalogen At accumulates in various tissues, with specifically high uptake in the thyroid. When normal thyroid function is disturbed because of ionizing radiation (IR) exposure, deleterious effects can occur in tissues that depend on thyroid hormone (TH) regulation for normal physiologic function. However, knowledge of systemic effects is still rudimentary. We previously reported similarities in transcriptomic regulation between the thyroid and other tissues despite large differences in absorbed dose from At. Here, we present supportive evidence on systemic effects after At administration. METHODS: Expression microarray data from the kidney cortex and medulla, liver, lungs, and spleen were used from previous studies in which mice were intravenously injected with 0.064-42 kBq of At and killed after 24 h or injected with 1.7 kBq of At and killed after 1, 6, or 168 h. Controls were mock-treated and killed after 24 h. Literature-based gene signatures were used to evaluate the relative impact from IR- or TH-induced regulation. Thyroid- and TH-associated upstream regulators as well as thyroid-related diseases and functions were generated using functional analysis software. RESULTS: Responses in IR- or TH-associated gene signatures were tissue-specific and varied over time, and the relative impact of each gene signature differed between the investigated tissues. The liver showed a clear dominance of TH-responding genes. In the kidney cortex, kidney medulla, and lungs, the TH-associated signature was detected to at least an extent similar to the IR-associated signature. The spleen was the single tissue showing regulation of only IR-associated signature genes. Various thyroid-associated diseases and functions were inferred from the data: L-triiodothyronine, TH, TH receptor, and triiodothyronine (reverse) were inferred as upstream regulators with differences in incidence and strength of regulation depending on tissue type. CONCLUSION: These findings indicate that transcriptional regulation in various nonthyroid tissues was-in part-induced by thyroid (hormone)-dependent signaling. Consideration of the systemic context between tissues could contribute to normal tissue risk assessment and planning of remedial measures.
[Mh] Termos MeSH primário: Astato/administração & dosagem
Regulação da Expressão Gênica/genética
Regulação da Expressão Gênica/efeitos da radiação
Especificidade de Órgãos/genética
Ativação Transcricional/genética
Ativação Transcricional/efeitos da radiação
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta à Radiação
Camundongos Endogâmicos BALB C
Camundongos Nus
Análise de Sequência com Séries de Oligonucleotídeos/métodos
Especificidade de Órgãos/efeitos da radiação
Dose de Radiação
Compostos Radiofarmacêuticos/efeitos da radiação
Glândula Tireoide/fisiologia
Glândula Tireoide/efeitos da radiação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Radiopharmaceuticals); XI595HAL7H (Astatine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170501
[Lr] Data última revisão:
170501
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161022
[St] Status:MEDLINE
[do] DOI:10.2967/jnumed.116.176958


  4 / 273 MEDLINE  
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[PMID]:27688477
[Au] Autor:Bäck T; Chouin N; Lindegren S; Kahu H; Jensen H; Albertsson P; Palm S
[Ad] Endereço:Department of Radiation Physics, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden tom.back@radfys.gu.se.
[Ti] Título:Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with At-MX35-F(ab') : Influence of Absorbed Tumor Dose and Effect on Long-Term Survival.
[So] Source:J Nucl Med;58(4):598-604, 2017 Apr.
[Is] ISSN:1535-5667
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Mice bearing subcutaneous tumors (50 mm , NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with At-MX35-F(ab') at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Effects on tumor growth after fractionated α-radioimmunotherapy with At-MX35-F(ab') was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (≤60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after α-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Having observed complete eradication of solid tumor xenografts, we conclude that targeted α-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival.
[Mh] Termos MeSH primário: Partículas alfa/uso terapêutico
Anticorpos Monoclonais/uso terapêutico
Astato/uso terapêutico
Transformação Celular Neoplásica
Neoplasias Ovarianas/radioterapia
Dose de Radiação
Radioimunoterapia/métodos
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/farmacocinética
Peso Corporal/efeitos da radiação
Linhagem Celular Tumoral
Proliferação Celular/efeitos da radiação
Feminino
Seres Humanos
Camundongos
Camundongos Nus
Neoplasias Ovarianas/metabolismo
Neoplasias Ovarianas/patologia
Radiometria
Análise de Sobrevida
Fatores de Tempo
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); XI595HAL7H (Astatine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170523
[Lr] Data última revisão:
170523
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161001
[St] Status:MEDLINE
[do] DOI:10.2967/jnumed.116.178327


  5 / 273 MEDLINE  
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[PMID]:27145158
[Au] Autor:Dekempeneer Y; Keyaerts M; Krasniqi A; Puttemans J; Muyldermans S; Lahoutte T; D'huyvetter M; Devoogdt N
[Ad] Endereço:a Vrije Universiteit Brussel, In Vivo Cellular and Molecular Imaging , Brussels , Belgium.
[Ti] Título:Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle.
[So] Source:Expert Opin Biol Ther;16(8):1035-47, 2016 Aug.
[Is] ISSN:1744-7682
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: The combination of a targeted biomolecule that specifically defines the target and a radionuclide that delivers a cytotoxic payload offers a specific way to destroy cancer cells. Targeted radionuclide therapy (TRNT) aims to deliver cytotoxic radiation to cancer cells and causes minimal toxicity to surrounding healthy tissues. Recent advances using α-particle radiation emphasizes their potential to generate radiation in a highly localized and toxic manner because of their high level of ionization and short range in tissue. AREAS COVERED: We review the importance of targeted alpha therapy (TAT) and focus on nanobodies as potential beneficial vehicles. In recent years, nanobodies have been evaluated intensively as unique antigen-specific vehicles for molecular imaging and TRNT. EXPERT OPINION: We expect that the efficient targeting capacity and fast clearance of nanobodies offer a high potential for TAT. More particularly, we argue that the nanobodies' pharmacokinetic properties match perfectly with the interesting decay properties of the short-lived α-particle emitting radionuclides Astatine-211 and Bismuth-213 and offer an interesting treatment option particularly for micrometastatic cancer and residual disease.
[Mh] Termos MeSH primário: Partículas alfa/uso terapêutico
Neoplasias/radioterapia
Anticorpos de Domínio Único/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Astato
Seres Humanos
Veículos Farmacêuticos
Radioisótopos/administração & dosagem
Radioisótopos/uso terapêutico
Anticorpos de Domínio Único/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Pharmaceutical Vehicles); 0 (Radioisotopes); 0 (Single-Domain Antibodies); XI595HAL7H (Astatine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160505
[St] Status:MEDLINE
[do] DOI:10.1080/14712598.2016.1185412


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[PMID]:27061979
[Au] Autor:Ayed T; Pilmé J; Tézé D; Bassal F; Barbet J; Chérel M; Champion J; Maurice R; Montavon G; Galland N
[Ad] Endereço:CEISAM, CNRS UMR 6230, Université de Nantes, 2 Rue de la Houssinière, BP 92208, F-44322 Nantes Cedex 3, France.
[Ti] Título:(211)At-labeled agents for alpha-immunotherapy: On the in vivo stability of astatine-agent bonds.
[So] Source:Eur J Med Chem;116:156-164, 2016 Jun 30.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:The application of (211)At to targeted cancer therapy is currently hindered by the rapid deastatination that occurs in vivo. As the deastatination mechanism is unknown, we tackled this issue from the viewpoint of the intrinsic properties of At-involving chemical bonds. An apparent correlation has been evidenced between in vivo stability of (211)At-labeled compounds and the At-R (R = C, B) bond enthalpies obtained from relativistic quantum mechanical calculations. Furthermore, we highlight important differences in the nature of the At-C and At-B bonds of interest, e.g. the opposite signs of the effective astatine charges, which implies different stabilities with respect to the biological medium. Beyond their practical use for rationalizing the labeling protocols used for (211)At, the proposed computational approach can readily be used to investigate bioactive molecules labeled with other heavy radionuclides.
[Mh] Termos MeSH primário: Astato/química
Astato/uso terapêutico
Imunoterapia/métodos
[Mh] Termos MeSH secundário: Estabilidade de Medicamentos
Marcação por Isótopo
Modelos Moleculares
Conformação Molecular
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
XI595HAL7H (Astatine)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170516
[Lr] Data última revisão:
170516
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160411
[St] Status:MEDLINE


  7 / 273 MEDLINE  
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[PMID]:26791409
[Au] Autor:Aneheim E; Gustafsson A; Albertsson P; Bäck T; Jensen H; Palm S; Svedhem S; Lindegren S
[Ad] Endereço:Department of Radiation Physics, Gothenburg University , Gula Stråket 2B, 41345 Gothenburg, Sweden.
[Ti] Título:Synthesis and Evaluation of Astatinated N-[2-(Maleimido)ethyl]-3-(trimethylstannyl)benzamide Immunoconjugates.
[So] Source:Bioconjug Chem;27(3):688-97, 2016 Mar 16.
[Is] ISSN:1520-4812
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Effective treatment of metastasis is a great challenge in the treatment of different types of cancers. Targeted alpha therapy utilizes the short tissue range (50-100 µm) of α particles, making the method suitable for treatment of disseminated occult cancers in the form of microtumors or even single cancer cells. A promising radioactive nuclide for this type of therapy is astatine-211. Astatine-211 attached to tumor-specific antibodies as carrier molecules is a system currently under investigation for use in targeted alpha therapy. In the common radiolabeling procedure, astatine is coupled to the antibody arbitrarily on lysine residues. By instead coupling astatine to disulfide bridges in the antibody structure, the immunoreactivity of the antibody conjugates could possibly be increased. Here, the disulfide-based conjugation was performed using a new coupling reagent, maleimidoethyl 3-(trimethylstannyl)benzamide (MSB), and evaluated for chemical stability in vitro. The immunoconjugates were subsequently astatinated, resulting in both high radiochemical yield and high specific activity. The MSB-conjugate was shown to be stable with a long shelf life prior to the astatination. In a comparison of the in vivo distribution of the new immunoconjugate with other tin-based immunoconjugates in tumor-bearing mice, the MSB conjugation method was found to be a viable option for successful astatine labeling of different monoclonal antibodies.
[Mh] Termos MeSH primário: Astato/química
Benzamidas/química
Imunoconjugados/química
[Mh] Termos MeSH secundário: Animais
Camundongos
Camundongos Endogâmicos BALB C
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzamides); 0 (Immunoconjugates); XI595HAL7H (Astatine)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160122
[St] Status:MEDLINE
[do] DOI:10.1021/acs.bioconjchem.5b00664


  8 / 273 MEDLINE  
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[PMID]:26761207
[Au] Autor:Nafee SS; Shaheen SA; Al-Ramady AM
[Ad] Endereço:Physics Department, Faculty of Science, King Abdulaziz University, Jeddah, 20589, Saudi Arabia.
[Ti] Título:Nuclear Data Evaluation for Mass Chain A=217:Odd-Proton Nuclei.
[So] Source:PLoS One;11(1):e0146182, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Thallium (81(217)Tl, Bismuth (83(217)Bi), Astatine (85(217)At), Francium (87(217)Fr), Actinium (89(217)Ac) and Protactinium (91(217)Pa) are of odd-proton numbers among the mass chain A = 217. In the present work, the half-lives and gamma transitions for the six nuclei have been studied and adopted based on the recently published interactions or unevaluated nuclear data sets XUNDL. The Q (α) has been updated based on the recent published work of the Atomic Mass Evaluation AME2012 as well. Moreover, the total conversion electrons as well as the K-Shell to L-Shell, L-Shell to M-Shell and L-Shell to N-Shell Conversion Electron Ratios have been calculated using BrIcc code v2.3. An updated skeleton decay scheme for each of the above nuclei has been presented here. The decay hindrance factors (HF) calculated using the ALPHAD program, which is available from Brookhaven National Laboratory's website, have been calculated for the α- decay data sets for (221)Fr-, (221)Ac- and (221)Pa-α-decays.
[Mh] Termos MeSH primário: Partículas alfa
Prótons
[Mh] Termos MeSH secundário: Actínio/química
Astato/química
Bismuto/química
Elétrons
Frâncio/química
Raios gama
Meia-Vida
Probabilidade
Protoactínio/química
Radioisótopos
Síncrotrons
Tálio/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Protons); 0 (Radioisotopes); 0S6855V29M (Protactinium); 15TEQ7D2QF (Francium); AD84R52XLF (Thallium); NIK1K0956U (Actinium); U015TT5I8H (Bismuth); XI595HAL7H (Astatine)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160114
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0146182


  9 / 273 MEDLINE  
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[PMID]:26702785
[Au] Autor:Makvandi M; Lieberman BP; LeGeyt B; Hou C; Mankoff DA; Mach RH; Pryma DA
[Ad] Endereço:Radiological Chemistry and Biology Laboratories, Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104. Electronic address: makvandi@mail.med.upenn.edu.
[Ti] Título:The pre-clinical characterization of an alpha-emitting sigma-2 receptor targeted radiotherapeutic.
[So] Source:Nucl Med Biol;43(1):35-41, 2016 Jan.
[Is] ISSN:1872-9614
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: The sigma-2 receptor is a protein with a Heme binding region and is capable of receptor-mediated endocytosis. It is overexpressed in many cancers making it a potential vector for therapeutic drug delivery. Our objective was to introduce an alpha-emitting radionuclide, astatine-211, into a selective sigma-2 ligand moiety to provide cytotoxic capabilities without adversely altering the pharmacological characteristics. In this study we investigated the in vitro/in vivo tumor targeting and estimated dosimetry of alpha-emitting sigma-2 ligand, 5-(astato-(211)At)-N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide ((211)At-MM3), in a pre-clinical human breast cancer model. METHODS: Astatine-211 was produced in a cyclotron and isolated by dry distillation. Radiosynthesis of (211)At-MM3 was performed using a tin precursor through radioastatodestannylation. In vitro sigma-2 binding experiments using (211)At-MM3 were carried out in live EMT6 and MDA-MB-231 breast cancer cells and liver homogenate tissue. In vivo biodistribution experiments were performed using EMT6 mouse breast cancer cells in BALB/c female mice. Approximately 370 kBq of (211)At-MM3 was administered intravenously and at time points of 5 min, 1, 2, 4, 8, and 24 h organs/tissue were harvested. Estimated human dosimetry was extrapolated from biodistribution data using OLINDA/EXM (VU e-Innovations). RESULTS: Astatine-211 was successfully produced and isolated in quantities suitable for in vitro and small animal in vivo experiments. Radiosynthesis of (211)At-MM3 was reproducible with high radiochemical purity. Astatine-211-MM3 exhibited picomolar affinity to the sigma-2 receptor in contrast to the iodinated analog that had nanomolar affinity. Prolonged tumor targeting was measured through biodistribution studies with a maximal tumor to muscle ratio of 9.02 at 4h. Estimated human dosimetry revealed doses of up to 370 MBq in an adult female patient were below organ radiation limits with the potential to provide a high therapeutic dose to tumors. CONCLUSION: The sigma-2 receptor could serve as a suitable targeting platform for designing radiotherapeutics. (211)At-MM3 showed tumor targeting properties in vitro/in vivo and favorable estimated human dosimetry establishing the proof of concept for future development as a radiotherapeutic for the treatment of breast cancer.
[Mh] Termos MeSH primário: Partículas alfa/uso terapêutico
Terapia de Alvo Molecular/métodos
Receptores sigma/metabolismo
[Mh] Termos MeSH secundário: Animais
Astato/uso terapêutico
Benzamidas/química
Benzamidas/metabolismo
Benzamidas/farmacocinética
Benzamidas/uso terapêutico
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Neoplasias da Mama/radioterapia
Linhagem Celular Tumoral
Transformação Celular Neoplásica
Feminino
Seres Humanos
Camundongos
Radiometria
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Benzamides); 0 (Receptors, sigma); 0 (sigma-2 receptor); XI595HAL7H (Astatine)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151226
[St] Status:MEDLINE


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[PMID]:26460999
[Au] Autor:Cederkrantz E; Andersson H; Bernhardt P; Bäck T; Hultborn R; Jacobsson L; Jensen H; Lindegren S; Ljungberg M; Magnander T; Palm S; Albertsson P
[Ad] Endereço:Department of Radiation Physics, Institute for Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
[Ti] Título:Absorbed Doses and Risk Estimates of (211)At-MX35 F(ab')2 in Intraperitoneal Therapy of Ovarian Cancer Patients.
[So] Source:Int J Radiat Oncol Biol Phys;93(3):569-76, 2015 Nov 01.
[Is] ISSN:1879-355X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Ovarian cancer is often diagnosed at an advanced stage with dissemination in the peritoneal cavity. Most patients achieve clinical remission after surgery and chemotherapy, but approximately 70% eventually experience recurrence, usually in the peritoneal cavity. To prevent recurrence, intraperitoneal (i.p.) targeted α therapy has been proposed as an adjuvant treatment for minimal residual disease after successful primary treatment. In the present study, we calculated absorbed and relative biological effect (RBE)-weighted (equivalent) doses in relevant normal tissues and estimated the effective dose associated with i.p. administration of (211)At-MX35 F(ab')2. METHODS AND MATERIALS: Patients in clinical remission after salvage chemotherapy for peritoneal recurrence of ovarian cancer underwent i.p. infusion of (211)At-MX35 F(ab')2. Potassium perchlorate was given to block unwanted accumulation of (211)At in thyroid and other NIS-containing tissues. Mean absorbed doses to normal tissues were calculated from clinical data, including blood and i.p. fluid samples, urine, γ-camera images, and single-photon emission computed tomography/computed tomography images. Extrapolation of preclinical biodistribution data combined with clinical blood activity data allowed us to estimate absorbed doses in additional tissues. The equivalent dose was calculated using an RBE of 5 and the effective dose using the recommended weight factor of 20. All doses were normalized to the initial activity concentration of the infused therapy solution. RESULTS: The urinary bladder, thyroid, and kidneys (1.9, 1.8, and 1.7 mGy per MBq/L) received the 3 highest estimated absorbed doses. When the tissue-weighting factors were applied, the largest contributors to the effective dose were the lungs, stomach, and urinary bladder. Using 100 MBq/L, organ equivalent doses were less than 10% of the estimated tolerance dose. CONCLUSION: Intraperitoneal (211)At-MX35 F(ab')2 treatment is potentially a well-tolerated therapy for locally confined microscopic ovarian cancer. Absorbed doses to normal organs are low, but because the effective dose potentially corresponds to a risk of treatment-induced carcinogenesis, optimization may still be valuable.
[Mh] Termos MeSH primário: Anticorpos Monoclonais/farmacocinética
Astato/farmacocinética
Imunoconjugados/farmacocinética
Fragmentos Fab das Imunoglobulinas/metabolismo
Neoplasias Ovarianas/radioterapia
Neoplasias Peritoneais/radioterapia
Radioimunoterapia/métodos
[Mh] Termos MeSH secundário: Partículas alfa/uso terapêutico
Elétrons/uso terapêutico
Feminino
Seres Humanos
Rim/diagnóstico por imagem
Rim/metabolismo
Pulmão/diagnóstico por imagem
Pulmão/metabolismo
Recidiva Local de Neoplasia
Neoplasia Residual
Neoplasias Ovarianas/metabolismo
Neoplasias Ovarianas/patologia
Neoplasias Peritoneais/secundário
Terapia com Prótons
Dosagem Radioterapêutica
Eficiência Biológica Relativa
Medição de Risco
Estômago/diagnóstico por imagem
Estômago/metabolismo
Glândula Tireoide/diagnóstico por imagem
Glândula Tireoide/metabolismo
Distribuição Tecidual
Tomografia Computadorizada de Emissão de Fóton Único/métodos
Bexiga Urinária/diagnóstico por imagem
Bexiga Urinária/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Immunoconjugates); 0 (Immunoglobulin Fab Fragments); XI595HAL7H (Astatine)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151014
[St] Status:MEDLINE



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