RESUMO
INTRODUCTION: Good manufacturing practice (GMP)-compliant production of radiopharmaceuticals for parenteral application requires great efforts in maintenance of clean room infrastructure and equipment in order to reliably guarantee the constant hygienic quality of the product (sterility). Terminal sterilization of the product is not always possible due to short half-life or due to thermal instability of the compound. The typical method for sterilization in these cases is sterile filtration prior to dispensing (distribution of product solution from bulk to patient vials). Therefore, aseptic processing techniques have to be in place in order to ensure sterility. Still, there remains some risk of microbial contamination of the product, and hence a risk for the patient to suffer from infection. Due to the short half-life of the labeling radionuclides, this aspect is aggravated by only retrospectively possible testing for sterility. This work investigated the potential of [18F]-radiation to intrinsically inactivate microorganisms (MO) that might have slipped through the aseptic process. METHODS: Defined numbers of viable cells of different bacterial strains and molds were incubated with defined amounts of [18F]-activity. After decay of radiation the number of surviving viable cells was determined, D10-values were calculated and evaluated. RESULTS: The MOs tested exhibit a broad range of [18F]-radiation susceptibility, D10-values range from a sensitive 114MBq/mL (46Gy) to a durable 2,048MBq/mL (790Gy). CONCLUSION: The intrinsic [18F]-radiation in radiopharmaceuticals is no safe measure to generally ensure sterility of the product solution in terms of "autosterilization", because of dependence on various parameters. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This work presents for the first time experimental data on the influence of [18F]-radiation on MOs. The results suggest, that aseptic processing techniques are essential and that results of determination of sterility in radiopharmaceuticals should be considered with care (emphasis on importance of media fill campaigns).
Assuntos
Radioisótopos de Flúor , Viabilidade Microbiana/efeitos dos fármacos , Compostos Radiofarmacêuticos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/efeitos da radiação , Marcação por Isótopo , Cinética , Viabilidade Microbiana/efeitos da radiação , Compostos Radiofarmacêuticos/químicaRESUMO
Syntheses of [carbonyl-11C]2-(2-benzoylphenoxy)-N-phenylacetamide, a radiolabeled inhibitor of human immunodeficiency virus type 1 (HIV 1) reverse transcriptase, were achieved by applying palladium-mediated cross-coupling reactions with insertion of [11C]carbon monoxide. Our interest was focused for the present on a comparison of the Stille and Suzuki methods, using trimethylphenylstannane or phenylboronic acid as alternative coupling reagents, respectively. The Suzuki variant gave a much higher amount of [11C]CO radioactivity trapped in the reaction mixture, but a significant loss of product occurred due to adsorption phenomena on the potassium carbonate present in the heterogeneous reaction mixture. The labeled product was isolated in only 20% yield (based on trapped [11C]CO, not corrected for decay). According to Stille, the reaction provided a product that could be isolated more easily but it did not increase the final yield of the target compound due to a low trapping efficiency for [11C]CO. Both methods were performed in an overall synthesis time of 30min, starting from [11C]CO2, and gave a product with a specific radioactivity of at least 30GBq/micromol. The Stille method as well as the Suzuki reaction allowed the synthesis of a radiochemically pure product in aqueous acetonitrile.
Assuntos
Acetamidas/síntese química , Acetanilidas , Fármacos Anti-HIV/síntese química , Benzofenonas/síntese química , Radioisótopos de Carbono/isolamento & purificação , Inibidores da Transcriptase Reversa/síntese química , Acetamidas/isolamento & purificação , Fármacos Anti-HIV/isolamento & purificação , Benzofenonas/isolamento & purificação , Monóxido de Carbono/química , Catálise , Paládio , Radioquímica/métodos , Inibidores da Transcriptase Reversa/isolamento & purificaçãoRESUMO
The usefulness of 18F-labelled carbohydrates, especially 2-deoxy-2-[18F]fluoro-D-glucose, to study pathophysiological processes in man non-invasively using positron-emission-tomography (PET) led to a widespread investigation of different 18F-labelled sugars and sugar derivatives. In consideration of the short half-life of fluorine-18 (T(1/2) = 110 min) synthetic strategies concerning precursor design, labelling conditions and deprotection of the intermediate compounds were developed to guarantee an efficient high radiochemical yield synthesis for diagnostic purposes. Besides some aspects of medical application of 2-deoxy-2-[18F]fluoro-D-glucose, a few synthetic strategies are described reflecting development work on promising 18F-labelled sugars for diagnostic purposes during the last two decades.
Assuntos
Carboidratos , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Carboidratos/química , Fluordesoxiglucose F18/síntese química , Fluordesoxiglucose F18/química , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Tomografia Computadorizada de Emissão/métodosRESUMO
The dramatic expansion of clinical gene therapy trials requires the development of noninvasive clinical monitoring procedures, which provide information about expression levels, expression kinetics, and spatial distribution of transduced therapeutic genes. With the development of such procedures, invasive sampling of tissue probes from patients potentially could be reduced significantly. In this study, an experimental platform for the rational design and in vitro testing of suitable receptor-ligand couples as components of future transduction tag systems for noninvasive gene therapy monitoring applications was developed. Initially, the feasibility of the delta LNGFR/nerve growth factor (NGF) transduction tag system was investigated; this system employs a mutated version of the low-affinity nerve growth factor receptor (p75mut or delta LNGFR) lacking the entire cytoplasmic domain. Specific binding of 125I-radiolabeled NGF was demonstrated for two stable delta LNGFR-transduced cell lines, but not for delta LNGFR-negative parental control cell lines. An additional binding analysis performed in a MicroImager directly confirmed binding of radiolabeled ligands (125I-NGF, 125I-anti-p75 monoclonal antibody) to the p75mut expressed on intact target cells, but not on control cells. Subsequent binding studies employing NGF radiolabeled with the positron-emitting isotope 124I demonstrated a specific binding for LNGFR+ PC12 cells. Consequently, the first in vitro proof of a transduction tag approach based on the specificity of the 124I-NGF/LNGFR interaction was provided, which opens up the possibility for future noninvasive positron emission tomography monitoring in clinical gene therapy trials.
Assuntos
Terapia Genética/métodos , Fator de Crescimento Neural/genética , Receptor de Fator de Crescimento Neural/genética , Retroviridae/genética , Transdução Genética , Células 3T3 , Animais , Anticorpos Monoclonais/metabolismo , Sítios de Ligação de Anticorpos , Linhagem Celular , Regulação Neoplásica da Expressão Gênica , Marcadores Genéticos , Radioisótopos do Iodo/metabolismo , Camundongos , Fator de Crescimento Neural/biossíntese , Células PC12 , Ratos , Receptor de Fator de Crescimento Neural/biossíntese , Receptor de Fator de Crescimento Neural/imunologia , Deleção de Sequência/genética , Tomografia Computadorizada de Emissão/métodosRESUMO
PURPOSE: To evaluate the carbon 11 ethanol kinetics with positron emission tomography after intratumoral injection of the tracer and assess its redistribution and dilution in patients who have hepatocellular carcinomas and who were scheduled for treatment with percutaneous ethanol injection. MATERIALS AND METHODS: The study included eight patients with hepatocellular carcinomas. 11C ethanol was administered via a puncture needle positioned with ultrasonographic guidance. Parametric images based on the Fourier transformation were created for further analysis of the local distribution patterns of the tracer. The ratio of the 45-minute postinjection standardized uptake value to the 5-minute postinjection standardized uptake value was used for the evaluation of ethanol dilution. RESULTS: Five of eight tumors demonstrated almost constant uptake values after the initial distribution phase. In contrast, a rapid elimination of the 11C ethanol from the tumor was documented in three of eight tumors. The 45 minute-to-5 minute ratio was 0.18-0.67 (median value, 0.56) in the tumors. The time-activity curves of the normal liver parenchyma increased slowly but steadily with time owing to a low ethanol elimination from the tumor. Fourier transformation demonstrated inhomogeneous parts on the amplitude images in seven of eight tumors and random redistribution on the phase images in six of eight tumors. CONCLUSION: Inhomogeneous drug distribution and drug dilution in the target area are likely to be the major limiting parameters for therapy response.
Assuntos
Radioisótopos de Carbono , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Etanol/administração & dosagem , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Tomografia Computadorizada de Emissão , Idoso , Etanol/farmacocinética , Etanol/uso terapêutico , Feminino , Humanos , Injeções Intralesionais , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Ultrassonografia de IntervençãoRESUMO
The aim of the study was the evaluation of the detectability of treated liver metastases using one FDG-PET measurement. The study includes 42 patients (80 lesions) from different primary tumours. Standardized Uptake Values (SUV) as well as the tumour to liver Ratio (T/L) were used for evaluation. A T/L > 1.0 was considered to be pathological. Clinical follow-up data for at least 6 months were used as a reference. The median value of the FDG-uptake was 2.9 SUV in all liver metastases. The sensitivity based on a T/L ratio exceeding 1.0 was 82.5% (66/80 lesions). 25 of 80 (31%) lesions had a ratio T/L higher than 2.0 and were clearly visualized by PET. Negative results with a ratio T/L < 1.0 were raised in 14 of 80 treated metastatic lesions (17.5%). Although these metastases were hypometabolic, they were correctly classified due to the image correlation with computed tomography (CT) or magnetic resonance (MR) images or due to a baseline FDG-study prior to the onset of therapy. False positive results were not noted in this study. FDG-PET is a reliable method for the evaluation of treated liver metastases. A baseline FDG study prior to therapy is preferable for the interpretation.
Assuntos
Fluordesoxiglucose F18 , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Glicemia/análise , Estudos de Avaliação como Assunto , Humanos , Neoplasias Hepáticas/sangue , Tomografia Computadorizada de Emissão/métodosRESUMO
UNLABELLED: Prediction of chemotherapy response is still a problem in oncological patients. METHODS: Studies with PET and 18F-fluorouracil (FU) were used for measurements of drug concentrations in patients with liver metastases from colorectal carcinoma. The PET data obtained before onset of FU chemotherapy were correlated to the growth rate of the metastases after therapy. The final evaluation included 25 metastases obtained in 17 patients. CT preceded the first chemotherapeutic cycle and was repeated within 3-11 mo after onset of treatment. The uptake of the cytostatic agent was evaluated in the liver metastases using the SUV at 120 min after tracer infusion. Tumor growth rate of the metastases was calculated based on CT volumetric data. RESULTS: The trapping of 18F-FU was highly variable even for multiple metastases in the same patients. Six metastases with high 18F-FU uptake values exceeding 3.0 SUV correlated with negative growth rate values, 5 of 25 metastases with intermediate uptake values ranging from 2.0-3.0 SUV were associated with almost stable growth rate values nearly zero and 14 of 25 metastases with low uptake values <2.0 SUV demonstrated positive growth rate values. Only metastases with a 18F-FU uptake exceeding 3.0 SUV at 120 min postinjection demonstrated a response to therapy. A significant correlation of 0.86 (p < 0.001) was found between the 18F-FU uptake values in the metastases measured before chemotherapy and the growth rate of the lesions after treatment. CONCLUSION: The data show, that FU chemotherapy outcome can be predicted using a single PET study with 18F-FU before onset to therapy.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/patologia , Radioisótopos de Flúor , Fluoruracila/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/secundário , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Valor Preditivo dos Testes , Prognóstico , Fatores de TempoRESUMO
UNLABELLED: Intra-arterial chemotherapy can potentially increase drug delivery at the tumor sites and has therefore been used for the therapy of metastatic colorectal cancer. METHODS: Dynamic PET and [18F]fluorouracil (18F-FU) were used in patients with liver metastases from colorectal cancer to examine the pharmacokinetics of the drug up to 120 min after intravenous and intra-arterial injection of the same dose of fluorouracil (FU). All patients included in the study (n = 15) had surgically implanted catheters in the gastroduodenal artery. Dynamic PET studies (up to 5 min) with 15O-labeled water were performed for the evaluation of the access to the lesions immediately before the 18F-FU study using both administration routes. The final evaluation included 24 metastases, obtained from 15 patients. RESULTS: Of 24 lesions, 21 (87.5%) showed an improved access using the intra-arterial approach, and 20 (83.3%) demonstrated a better FU influx after intra-arterial 18F-FU infusion. Metastases reached the highest 18F-FU concentrations after intra-arterial administration, with a maximum standardized uptake values of 18.75 for the FU influx and of 5.03 for FU trapping. Of 24 metastases, eight (33.3%) demonstrated enhanced FU trapping after the intra-arterial administration. Cluster analysis revealed a group of metastases (n = 6) with a nonperfusion-dependent FU transport using the intravenous application. Of these six lesions, five (83.3%) did not show any enhancement of the 18F-FU trapping after intra-arterial application. The data gave evidence for at least one different, energy-dependent transport system, which can be saturated even after intravenous administration of the drug. CONCLUSION: The data show that the main limiting factor for a therapy response is the very high and rapid elimination of the cytostatic agent out of the tumor cells. Furthermore, it was not possible to predict the pharmacokinetics of FU after intra-arterial application using an intravenous PET study. It may be possible, using intravenous PET double-tracer studies, to identify metastases having a nonperfusion-dependent transport system and exclude them from an intra-arterial treatment protocol.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/secundário , Radioisótopos de Flúor , Fluordesoxiglucose F18 , Fluoruracila/farmacocinética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Radioisótopos de Oxigênio , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Antimetabólitos Antineoplásicos/administração & dosagem , Neoplasias Colorretais/diagnóstico por imagem , Fluoruracila/administração & dosagem , Humanos , Injeções Intra-Arteriais , Injeções Intravenosas , Neoplasias Hepáticas/diagnóstico por imagem , Fatores de Tempo , ÁguaRESUMO
UNLABELLED: This study evaluates the performance of the newly developed high-resolution whole-body PET scanner ECAT EXACT HR+. METHODS: The scanner consists of four rings of 72 bismuth germanate block detectors each, covering an axial field of view of 15.5 cm with a patient port of 56.2 cm. A single block detector is divided into an 8 x 8 matrix, giving a total of 32 rings with 576 detectors each. The dimensions of a single detector element are 4.39 x 4.05 x 30 mm3. The scanner is equipped with extendable tungsten septa for two-dimensional two-dimensional measurements, as well as with three 68Ge line sources for transmission scans and daily quality control. The spatial resolution, scatter fraction, count rate, sensitivity, uniformity and accuracy of the implemented correction algorithms were evaluated after the National Electrical Manufacturers Association protocol using the standard acquisition parameters. RESULTS: The transaxial resolution in the two-dimensional mode is 4.3 mm (4.4 mm) in the center and increases to 4.7 mm (4.8 mm) tangential and to 8.3 mm (8.0 mm) radial at a distance of r = 20 cm from the center. The axial slice width measured in the two-dimensional mode varies between 4.2 and 6.6 mm FWHM over the transaxial field of view. In the three-dimensional mode the average axial resolution varies between 4.1 mm FWHM in the center and 7.8 mm at r = 20 cm. The scatter fraction is 17.1% (32.5%) for a lower energy discriminator level of 350 keV. The maximum true event count rate of 263 (345) kcps was measured at an activity concentration of 142 (26.9) kBq/ml. The total system sensitivity for true events is 5.7 (27.7) cps/Bq/ml. From the uniformity measurements, we obtained a volume variance of 3.9% (5.0%) and a system variance of 1.6% (1.7%). The implemented three-dimensional scatter correction algorithm reveals very favorable properties, whereas the three-dimensional attenuation correction yields slightly inaccurate results in low- and high-density regions. CONCLUSION: The ECAT EXACT HR+ has an excellent, nearly isotropic spatial resolution, which is advantageous for brain and small animal studies. While the relatively low slice sensitivity may hamper the capability for performing fast dynamic two-dimensional studies, the scanner offers a sufficient sensitivity and count rate capacity for fully three-dimensional whole-body imaging.
Assuntos
Câmaras gama/normas , Tomografia Computadorizada de Emissão/instrumentação , Adenocarcinoma Folicular/diagnóstico por imagem , Adenocarcinoma Folicular/secundário , Algoritmos , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Desenho de Equipamento , Estudos de Avaliação como Assunto , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/secundário , Sensibilidade e Especificidade , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Tomografia Computadorizada de Emissão/normasRESUMO
UNLABELLED: This study was performed to investigate the effect of the new chemotherapeutic agent gemcitabine on glucose transport and metabolism in prostate carcinoma in vitro and in vivo. METHODS: After transplantation of rat prostate adenocarcinoma cells, dynamic PET measurements with fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose (18FDG) were performed in 15 animals before and 1 day after therapy with 90 mg/kg of body weight (n = 8) and 180 mg/kg of body weight (n = 7) gemcitabine. In the second examination, the animals received a simultaneous injection of 18FDG and [3H]thymidine. Quantitative evaluation of the PET data was done using the standardized uptake value (SUV) as well as a three-compartment pharmacokinetic model. Furthermore, the incorporation of [3H]thymidine into the DNA was determined. In vitro measurements of the FDG, 3-O-methylglucose and thymidine uptake were performed immediately and 4 hr after a 24-hr incubation period with different doses of gemcitabine. RESULTS: FDG-SUV and the metabolic rate of FD 3 utilization did not change significantly after therapy. However, the values for the transport rate constants K1 and K2 increased significantly. The incorporation of thymidine into the DNA of treated tumors showed an 80% decline as compared with a control group. In the cell culture experiments, a dose-dependent increase of FDG (up to 178%) and 3-O-methylglucose uptake (up to 305%) was demonstrated. The thymidine uptake showed a 96% decline in the nucleic acid fraction and an increase of up to 337% in the cytoplasmic fraction. CONCLUSION: The more global measures of FDG metabolism as SUV and metabolic rate of FDG utilization were unchanged after therapy, while DNA synthesis and cell viability declined. However, in vitro and in vivo evidence of an enhancement of glucose transport is presented, indicating that quantification by modelling may be superior for the evaluation of metabolic effects during chemotherapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxiglucose/análogos & derivados , Radioisótopos de Flúor , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão , Adenocarcinoma/diagnóstico por imagem , Animais , Transporte Biológico , DNA de Neoplasias/efeitos dos fármacos , Desoxicitidina/uso terapêutico , Desoxiglucose/farmacocinética , Fluordesoxiglucose F18 , Glucose/metabolismo , Masculino , Transplante de Neoplasias , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ribonucleotídeo Redutases/antagonistas & inibidores , Timidina , Trítio , Células Tumorais Cultivadas , GencitabinaRESUMO
UNLABELLED: Using different tracers of tumor metabolism, the application of PET for monitoring gene therapy with the suicide gene herpes simplex virus thymidine kinase (HSVtk) is investigated in this in vitro study. METHODS: Morris hepatoma cells were transfected with a retroviral vector bearing the HSVtk gene, and different clones were established by selection with the neomycin analog G418. Thereafter, uptake measurements using fluorodeoxyglucose (FDG), 3-O-methylglucose, aminoisobutyric acid and methionine were performed in a thymidine kinase (TK)-expressing cell line and in control cells bearing the empty vector in the presence of different concentrations of ganciclovir (GCV). These experiments were done up to 48 hr after the onset of therapy. The values were expressed as Bq/well or as Bq/10(5) cells. RESULTS: During GCV treatment therapy, a decrease of the uptake/well was measured for all tracers in the TK-expressing cell line. After normalization to the viable cell number, the uptake for FDG and 3-O-methylglucose increases up to 195% after 24 hr incubation with GCV. A high-pressure liquid chromatography analysis revealed a decline of the FDG-6-phosphate fraction after 48 hr incubation with GCV. Consequently, a normalization of FDG uptake was observed after this incubation period, whereas the 3-O-methylglucose uptake was still increased. Experiments performed with different amounts of TK-expressing cells and control cells showed that these effects are dependent on the percentage of TK-expressing cells. The aminoisobutyric acid uptake decreases to 47%, while the methionine uptake decreases in the acid-insoluble fraction (to 17%) and increases in the acid-soluble fraction (to 150%). CONCLUSION: These data indicate that combinations of the PET tracers used in these experiments may be applied for monitoring gene therapy with HSVtk. The increase in FDG and 3-O-methylglucose uptake in vitro is interpreted as stress reaction of the tumor cells. However, an uncoupling of transport and phosphorylation was observed after 48 hr incubation. The amino acid uptake experiments point to an inhibition of protein synthesis as well as of the neutral amino acid transport.
Assuntos
Antivirais/farmacologia , Ganciclovir/farmacologia , Terapia Genética , Neoplasias Hepáticas Experimentais/terapia , Simplexvirus/genética , Timidina Quinase/genética , 3-O-Metilglucose/farmacocinética , Ácidos Aminoisobutíricos/farmacocinética , Animais , Radioisótopos de Carbono , Divisão Celular/efeitos dos fármacos , Desoxiglucose/análogos & derivados , Desoxiglucose/farmacocinética , Relação Dose-Resposta a Droga , Fluordesoxiglucose F18 , Expressão Gênica , Técnicas de Transferência de Genes , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/metabolismo , Metionina/farmacocinética , Ratos , Tomografia Computadorizada de Emissão , Células Tumorais CultivadasRESUMO
UNLABELLED: This study investigates the application of PET with specific substrates for the assessment of enzyme activity after transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene. METHODS: After transfection of a rat hepatoma cell line with a retroviral vector containing the HSV-tk gene, different clones were established by G418 selection. Uptake measurements were performed up to 48 hr in a TK-expressing cell line and in a control cell line using thymidine (TdR; measured under therapy conditions), fluorodeoxycytidine (FdCyt) and ganciclovir (GCV). Additionally, bystander experiments and inhibition/competition studies were done. RESULTS: In TK-expressing cells GCV treatment caused an increased (up to 250%) TdR uptake in the acid-soluble fraction and a decrease to 5.5% in the acid-insoluble fraction. The FdCyt uptake was higher in the TK-expressing cells than in controls with a maximum after 4 hr (12-fold and 3-fold higher in the acid-insoluble and acid-soluble fraction). GCV accumulated up to 180-fold more in the acid-insoluble and 26-fold more in the acid-soluble fraction. GCV uptake occurred mainly by the nucleoside transport systems. Bystander experiments revealed a relation between growth inhibition or GCV uptake and the amount of TK-expressing cells. GCV uptake and growth inhibition were correlated with r = 0.96. CONCLUSION: Assessment of GCV accumulation may serve as an indicator of the enzyme activity and of therapy outcome. TdR may be useful to measure therapy effects on DNA synthesis, whereas the potential of FdCyt has to be investigated in further studies.
Assuntos
Genes Virais , Terapia Genética , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/terapia , Simplexvirus/genética , Timidina Quinase/genética , Tomografia Computadorizada de Emissão , Animais , Antivirais/farmacologia , Sobrevivência Celular , Clonagem Molecular , DNA/biossíntese , DNA/efeitos dos fármacos , Desoxicitidina Monofosfato/análogos & derivados , Desoxicitidina Monofosfato/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Imunofluorescência , Ganciclovir/farmacologia , Neoplasias Hepáticas Experimentais/enzimologia , Contagem de Cintilação , Simplexvirus/enzimologia , Especificidade por Substrato , Trítio , Células Tumorais Cultivadas/diagnóstico por imagem , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/enzimologia , Proteínas ViraisRESUMO
The management of patients who have malignant lymphomas requires functional methods to differentiate residual soft tissue masses. Positron emission tomography (PET) was performed in patients with histologically proven malignant lymphomas prior to the onset of second-line chemotherapy to examine tumor viability. Twenty patients (68 malignant lesions and 3 benign lesions) with Hodgkin lymphomas (HL) as well as 26 patients (46 malignant lesions and 1 benign lesion) with non-Hodgkin lymphomas (NHL) were studied with fluorine-18-deoxyglucose (FDG). Oxygen-15-labelled water was used in addition in 14 patients with 25 lesions to obtain information on the tissue perfusion. PET with FDG is highly sensitive for the detection of viable tumor tissue, all malignant lesions being correctly classified in this study. We noted no statistically significant difference in FDG metabolism for Hodgkin and non-Hodgkin lymphomas. Even normal-sized lymph-node metastases (< 1 cm) were detected with PET and FDG. The possible limitations are inflammatory processes, which may obscure tumor detection because of the increased FDG uptake, as well as malignant lesions with low FDG uptake as a result of reduced perfusion. Comparison of tumor perfusion and FDG uptake showed a significant nonlinear correlation of r = 0.78 between the two parameters. Two patients with scar tissue and no evidence of malignancy were excluded from blood stem-cell support therapy as a result of the PET study. The data demonstrate that PET is a useful tool for making a diagnosis and deciding on therapy for malignant lymphomas.
Assuntos
Glicemia/metabolismo , Metabolismo Energético/fisiologia , Doença de Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/diagnóstico por imagem , Tomografia Computadorizada de Emissão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Desoxiglucose/análogos & derivados , Desoxiglucose/farmacocinética , Metabolismo Energético/efeitos dos fármacos , Fluordesoxiglucose F18 , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasia Residual/diagnóstico por imagem , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/patologia , Resultado do TratamentoRESUMO
Positron emission tomography (PET) is a noninvasive functional method for the study of solid tumor perfusion, metabolism and interaction with different therapeutic agents. The aim of the study was the investigation of the metabolism of hepatocellular carcinomas (HCC) and the kinetics during a treatment with intratumoral ethanol by PET. The ongoing study includes seven patients with child. A cirrhosis and HCC (UICC stage III-IVA; tumor size 3-6 cm). Dynamic PET studies (60 min) with 18F-fluordeoxyglucose (FDG) were performed prior to therapy to assess tumor viability. The evaluation of the FDG data demonstrated a liver-equivalent uptake in six of the tumors (well and moderately differentiated HCC), which were poorly delineated against the normal liver parenchyma. One moderately differentiated HCC showed an increased FDG metabolism, indicating no correlation between histology and metabolism. A dose of 37-80 MBq 11C-ethanol was applied together with a nonlabelled therapeutic dose of the drug via a puncture needle positioned under sonography. Five out of seven tumors demonstrated a high 11C uptake shortly after the end of the ethanol injection followed by constant 11C-ethanol concentration during the whole study period of 45 min. The PET data demonstrated no significant elimination of the 11C-ethanol from the tumor and no accumulation in the surrounding liver tissue. One case showed a decrease of the intra-tumoral 11C-ethanol concentration due to a punkture of a tumor vein, and in another case the surrounding liver parenchyma demonstrated significant 11C uptake in the early phase following paratumoral injection of the drug. In conclusion, PET is a useful tool for the study of the mechanism and the kinetics of percutaneous intratumoral ethanol injection of HCC.
Assuntos
Glicemia/metabolismo , Neoplasias Encefálicas/secundário , Carcinoma Hepatocelular/secundário , Etanol/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Tomografia Computadorizada de Emissão , Idoso , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/tratamento farmacológico , Radioisótopos de Carbono , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/tratamento farmacológico , Desoxiglucose/análogos & derivados , Desoxiglucose/metabolismo , Etanol/farmacocinética , Feminino , Fluordesoxiglucose F18 , Humanos , Injeções Intralesionais , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
Hematopoietic growth factors (HGF) such as G-CSF and GM-CSF stimulate cell growth of the bone marrow and thereby mitigate the myelotoxic effect of chemotherapy. Using 18F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) for therapy response monitoring of patients with small-cell lung cancer, both an extension and an intensification of thoracic bone marrow uptake were noted in patients treated with HGF (n = 5) compared to those patients without HGF supplementation (n = 11). FDG uptake was a very sensitive marker of stimulated hematopoiesis, and both the extension and the intensification of uptake have to be noted during HGF therapy.
Assuntos
Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Desoxiglucose/análogos & derivados , Radioisótopos de Flúor , Fatores de Crescimento de Células Hematopoéticas/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Medula Óssea/diagnóstico por imagem , Carcinoma de Células Pequenas/tratamento farmacológico , Desoxiglucose/farmacocinética , Método Duplo-Cego , Feminino , Fluordesoxiglucose F18 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia Computadorizada de EmissãoRESUMO
The nonphysiological, nonracemic, branched-chain alpha-acetamido-aminoisobutyric acid was labeled with the carbon isotope 11C with the intention to use it in conjunction with positron emission tomography (PET) to measure the kinetics of amino acid transport in vivo. It was produced by the reaction of the novel 11C-precursor N-[1-11C]acetylpyridinium chloride with alpha-aminoisobutyric acid. Typically, 2 GBq of alpha-(N-[1-11C]acetyl)-aminoisobutyric acid were isolated with a specific activity of 12 to 20 GBq. mumol-1 at the time of application, and with a radiochemical purity of > 98%. The chemical identity of alpha-(N-[1-11C]acetyl)-aminoisobutyric acid was confirmed by comparison with alpha-(N-[1-14C]acetyl)-aminoisobutyric acid that was independently prepared by a standard acetylation procedure of alpha-aminoisobutyric acid using [1-14C]acetic anhydride. In vivo, both labeled substrates were not metabolized. In cell-culture experiments, 84% of the substrate entered the cells by the sodium-dependent amino acid transport system A, whereas 16% was taken up by the sodium-independent system. The uptake of the radiotracer was measured 20 min and 40 min postinjection in tumor-bearing male Copenhagen rats for assessment of its in vivo biodistribution.
Assuntos
Adenocarcinoma/metabolismo , Aminoácidos/metabolismo , Aminobutiratos , Radioisótopos de Carbono , Neoplasias da Próstata/metabolismo , Adenocarcinoma/diagnóstico por imagem , Aminobutiratos/síntese química , Aminobutiratos/farmacocinética , Animais , Transporte Biológico , Linhagem Celular , Estudos de Viabilidade , Indicadores e Reagentes , Marcação por Isótopo/métodos , Cinética , Masculino , Neoplasias da Próstata/diagnóstico por imagem , Ratos , Fatores de Tempo , Distribuição Tecidual , Tomografia Computadorizada de Emissão/métodos , Células Tumorais CultivadasRESUMO
UNLABELLED: We report an attractive approach for the preparation of [1-11C]acetate. METHODS: The procedure involved the instantaneous hydrolysis of [1-11C]acetyl chloride back to [1-11C]acetic acid by simply trapping the volatile acid chloride in physiological saline. This delivered [1-11C]acetate immediately in pharmaceutical quality. RESULTS: An easy and quantitative gas phase separation of the radiopharmaceutical from any inorganic residue and organic contamination could be achieved. The preparation required a minimum of automation and afforded only 5 min for an amount of 15 GBq of [1-11C]acetate which was yet ready for injection. Multiple preparations could be performed within 1 day. CONCLUSION: The use of [1-11C]acetyl chloride as a precursor to [1-11C]acetate is of considerable practical importance lending itself to automation with ease and giving the target compound directly in sterile solution without the need for further care and purification.
Assuntos
Acetatos/síntese química , Radioisótopos de Carbono , Coração/diagnóstico por imagem , Humanos , Tomografia Computadorizada de EmissãoRESUMO
Up to 4 h after treatment of human SW 707 colon carcinoma cells with the antineoplastic drug 4-amino-N-(2'-aminophenyl)-benzamide (GOE 1734, dinaline), the effects of tumour cell metabolism and proliferation were examined in vitro. Four tracers which can be labelled with isotopes suitable for positron emission tomography (PET) were used for this purpose: alpha-aminoisobutyric acid (AIB) and methionine to study changes in amino acid transport and protein synthesis, thymidine to observe changes in tumour proliferation and 2-fluoro-2-deoxy-D-glucose (FDG) to estimate glucose metabolism. Dinaline showed an inhibition of the sodium-dependent and -independent uptake of AIB. The methionine uptake was found to increase shortly after therapy. Thymidine incorporation into DNA was impaired and the FDG uptake showed a maximally 2.2-fold enhancement. Inhibition of AIB uptake suggests changes in amino acid transport, whereas increased uptake of methionine and FDG points to an enhancement of protein synthesis and glycolysis caused by repair mechanisms. The cytostatic and antiproliferative effect of dinaline, observed in cell growth curves, could be demonstrated by the impaired thymidine incorporation into DNA. This study demonstrates that in vitro screening with radiotracers suitable for PET can help to clarify effects of new antineoplastic substances on tumour cell metabolism. These data may be applied to choose the appropriate time schedule for monitoring therapeutic effects on tumour tissue.
Assuntos
Ácidos Aminoisobutíricos , Antineoplásicos/uso terapêutico , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/tratamento farmacológico , Desoxiglucose/análogos & derivados , Metionina , Fenilenodiaminas/uso terapêutico , Timidina , Tomografia Computadorizada de Emissão , Radioisótopos de Carbono , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fluordesoxiglucose F18 , Humanos , Técnicas In Vitro , Trítio , Células Tumorais CultivadasRESUMO
UNLABELLED: Genetically modified mammalian cells that express the cytosine deaminase (CD) gene are able to convert the nontoxic prodrug 5-fluorocytosine (5-FC) to the toxic metabolite 5-fluorouracil (5-FU). PET with 18F-5-FC may be used for in vivo measurement of CD activity in genetically modified tumors. METHODS: A human glioblastoma cell line was stably transfected with the Escherichia coli CD gene. After incubation of lysates of CD-expressing cells and control cells with 3H-5-FC high-performance liquid chromatography (HPLC) was performed. The uptake of 5-FC was measured after various incubation times using therapeutic amounts of 5-FC. In addition, saturation and competition experiments with 5-FC and 5-FU were performed. Finally, the efflux was measured. RESULTS: We found that 3H-5-FU was produced in CD-expressing cells, whereas in the control cells only 3H-5-FC was detected. Moreover, significant amounts of 5-FU were found in the medium of cultured cells, which may account for the bystander effect observed in previous experiments. However, uptake studies revealed a moderate and nonsaturable accumulation of radioactivity in the tumor cells, suggesting that 5-FC enters the cells only through diffusion. Although a significant difference in 5-FC uptake was seen between CD-positive and control cells after 48 hr of incubation, no difference was observed after 2 hr of incubation. Furthermore, a rapid efflux could be demonstrated. CONCLUSION: 5-Fluorocytosine transport may be a limiting factor for this therapeutic procedure. Quantitation with PET has to rely more on dynamic studies and modeling, including HPLC analysis of the plasma, than on nonmodeling approaches.
Assuntos
Flucitosina/uso terapêutico , Fluoruracila/uso terapêutico , Terapia Genética/métodos , Glioblastoma/terapia , Nucleosídeo Desaminases/metabolismo , Pró-Fármacos/uso terapêutico , Cromatografia Líquida de Alta Pressão , Citosina Desaminase , Flucitosina/farmacocinética , Fluoruracila/metabolismo , Glioblastoma/metabolismo , Humanos , Técnicas In Vitro , Nucleosídeo Desaminases/genética , Pró-Fármacos/farmacocinética , Tomografia Computadorizada de Emissão , Transfecção , Trítio , Células Tumorais CultivadasRESUMO
The bacterial enzyme cytosine deaminase (CD) catalyzes the conversion of 5-fluorocytosine (5-FC) to the lethal 5-fluorouracil (5-FU) and so provides a useful system for selective killing of gene-modified mammalian tumor cells. Cloning of the CD gene from Escherichia coli and expression in human tumor cell lines enabled these cells to convert 3H-labeled 5-FC into 3H-5-FU. Two CD-expressing human tumor cell lines (adenocarcinoma cell line KM12 and glioblastoma cell line T1115) became 200-fold more sensitive to 5-FC than the nonexpressing parental cell lines. At least 90% of the cells are killed within 7 days. CD-expressing cells are able to kill nonexpressing cells when grown in the same culture flask (bystander effect). The CD gene may be used as a suicide system for in situ chemotherapy or as a safety mechanism abrogating the expression of other genes.