RESUMO
PURPOSE: Tumor hypoxia contributes to radiation resistance. A noninvasive assessment of tumor hypoxia would be valuable for prognostication and possibly selection for hypoxia-targeted therapies. 18F-pentafluorinated etanidazole (18F-EF5) is a nitroimidazole derivative that has demonstrated promise as a positron emission tomography (PET) hypoxia imaging agent in preclinical and clinical studies. However, correlation of imageable hypoxia by 18F-EF5 PET with clinical outcomes after radiation therapy remains limited. METHODS AND MATERIALS: Our study prospectively enrolled 28 patients undergoing radiation therapy for localized lung or other tumors to receive pretreatment 18F-EF5 PET imaging. Depending on the level of 18F-EF5 tumor uptake, patients underwent functional manipulation of tumor oxygenation with either carbogen breathing or oral dichloroacetate followed by repeated 18F-EF5 PET. The hypoxic subvolume of tumor was defined as the proportion of tumor voxels exhibiting higher 18F-EF5 uptake than the 95th percentile of 18F-EF5 uptake in the blood pool. Tumors with a hypoxic subvolume ≥ 10% on baseline 18F-EF5 PET imaging were classified as hypoxic by imaging. A Cox model was used to assess the correlation between imageable hypoxia and clinical outcomes after treatment. RESULTS: At baseline, imageable hypoxia was demonstrated in 43% of all patients (12 of 28), including 6 of 16 patients with early-stage non-small cell lung cancer treated with stereotactic ablative radiation therapy and 6 of 12 patients with other cancers. Carbogen breathing was significantly associated with decreased imageable hypoxia, while dichloroacetate did not result in a significant change under our protocol conditions. Tumors with imageable hypoxia had a higher incidence of local recurrence at 12 months (30%) than those without (0%) (P < .01). CONCLUSIONS: Noninvasive hypoxia imaging by 18F-EF5 PET identified imageable hypoxia in about 40% of tumors in our study population. Local tumor recurrence after highly conformal radiation therapy was higher in tumors with imageable hypoxia.
Assuntos
Etanidazol/análogos & derivados , Radioisótopos de Flúor , Hidrocarbonetos Fluorados , Recidiva Local de Neoplasia/diagnóstico por imagem , Neoplasias/radioterapia , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Radioterapia Conformacional , Hipóxia Tumoral , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Neoplasias/mortalidade , Modelos de Riscos Proporcionais , Estudos ProspectivosRESUMO
We evaluated the relationship between pre-treatment positron emission tomography (PET) using the hypoxic tracer 18F-[2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3- pentafluoropropyl) acetamide] (18F-EF5) and the response of preclinical tumor models to a range of fractionated radiotherapies. Subcutaneous HT29, A549 and RKO tumors grown in nude mice were imaged using 18F-EF5 positron emission tomography (PET) in order to characterize the extent and heterogeneity of hypoxia in these systems. Based on these results, 80 A549 tumors were subsequently grown and imaged using 18F-EF5 PET, and then treated with one, two, or four fraction radiation treatments to a total dose of 10-40 Gy. Response was monitored by serial caliper measurements of tumor volume. Longitudinal post-treatment 18F-EF5 PET imaging was performed on a subset of tumors. Terminal histologic analysis was performed to validate 18F-EF5 PET measures of hypoxia. EF5-positive tumors responded more poorly to low dose single fraction irradiation relative to EF5-negative tumors, however both groups responded similarly to larger single fraction doses. Irradiated tumors exhibited reduced 18F-EF5 uptake one month after treatment compared to control tumors. These findings indicate that pre- treatment 18F-EF5 PET can predict the response of tumors to single fraction radiation treatment. However, increasing the number of fractions delivered abrogates the difference in response between tumors with high and low EF5 uptake pre-treatment, in agreement with traditional radiobiology.
Assuntos
Neoplasias Experimentais/radioterapia , Tomografia por Emissão de Pósitrons/métodos , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/radioterapia , Animais , Carcinoma/diagnóstico por imagem , Carcinoma/radioterapia , Hipóxia Celular , Linhagem Celular Tumoral , Fracionamento da Dose de Radiação , Etanidazol/análogos & derivados , Etanidazol/análise , Radioisótopos de Flúor/análise , Xenoenxertos , Humanos , Hidrocarbonetos Fluorados/análise , Masculino , Camundongos , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Dosagem Radioterapêutica , Tela Subcutânea , Carga TumoralRESUMO
[reaction: see text] Pd-catalyzed silylstannylation of acetylenes tolerates a variety of reactive functional groups (aldehydes, nonterminal acetylenes, epoxides, activated and unactivated olefins), providing easy access to precursors that can be converted into carbocyclic and heterocyclic compounds via free radical or Heck reactions. Examples of the synthesis of pyrrolidines, bicyclic beta-lactams, hydrindanes, and tetrahydrofurans are described.
RESUMO
Tumor hypoxia is a negative prognostic factor and its precise imaging is of great relevance to therapy planning. The present review summarizes various strategies of probe design for imaging hypoxia with a variety of techniques such as PET, SPECT and fluorescence imaging. Synthesis of some important probes that are used for preclinical and clinical imaging and their mechanism of binding in hypoxia are also discussed.