RESUMO
This study was set up to demonstrate whether prognostic classification based on the secondary age-adjusted International Prognostic Index (sAA-IPI) for recurring aggressive non-Hodgkin lymphoma (NHL) or the prognostic score for recurring Hodgkin lymphoma (HL) can be improved by including the midtreatment results of fluorine-18-fluorodeoxy-glucose-positron emission tomography (FDG-PET). Clinical data on patients with recurring lymphoma who were treated with second-line chemotherapy (DHAP-VIM-DHAP) followed by autologous stem cell transplantation (ASCT) were collected and combined with the results of FDG-PET performed before and after 2 cycles of reinduction chemotherapy. PET responses after 2 courses were scored as complete remission (CR), partial remission (PR), or no response (NR). A multivariate analysis was performed to design a predictive model. The number of patients (101 of 117) included those (78 patients with aggressive NHL and 23 patients with HL) that could be analyzed according to protocol. Of these, 80 patients were chemosensitive and 77 received transplants. Both secondary clinical risk score (P<.001) and FDG-PET response (P<.001) were independent predictive factors for the total evaluable group of patients with lymphoma and for patients with NHL alone. The combined use of the clinical risk score and FDG-PET response after 2 chemotherapy courses identified at least 4 categories of patients with a failure-free survival varying between 5% to 100% after transplantation (P<.001). These data indicate that the secondary clinical risk score in conjunction with FDG-PET response provides a more accurate prognostic instrument for the outcome of second-line treatment at least in patients with recurring NHL.
Assuntos
Fluordesoxiglucose F18 , Doença de Hodgkin/diagnóstico , Linfoma não Hodgkin/diagnóstico , Recidiva Local de Neoplasia/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/tratamento farmacológico , Humanos , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Recidiva Local de Neoplasia/terapia , Valor Preditivo dos Testes , Prognóstico , Indução de Remissão , Fatores de Risco , Sensibilidade e Especificidade , Taxa de Sobrevida , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) appears to be an excellent tool for evaluating early response to chemotherapy in lymphoma patients. As only chemosensitive patients with relapsed lymphoma may benefit from ablative therapy and autologous stem cell transplantation (ASCT), PET may be used to select patients for ASCT. A prospective study was performed to investigate the optimal time point of pre-transplantation PET, using different PET-parameters. DESIGN AND METHODS: Three serial whole-body attenuation-corrected FDG-PET scans were performed in 39 consecutive patients with relapsed lymphoma (28 with aggressive non-Hodgkin's lymphoma and 11 with Hodgkin's disease) eligible for second-line chemotherapy followed by ASCT: PET1 before treatment, PET2 after two cycles of induction chemotherapy and PET3 after a third cycle of chemotherapy just before ASCT in cases with an abnormal PET2. Visual analysis and standardized uptake value (SUV) parameters were obtained for each scan. The follow-up lasted a minimum of 6 months after ASCT. RESULTS: PET2 normalized in 43% (17/39) of the patients, and PET3 normalized in 27% (6/22). Persistent abnormal FDG-uptake was observed in 41% of the patients: 15% showed partial remission and 26% stable or even progressive abnormalities. With a median follow-up of 22 months (range 6-55) 54% of all patients relapsed after ASCT. The results demonstrated that those patients who showed a complete response after the second and third cycles of chemotherapy had a 2-year progression-free survival of 71% and 58%, respectively, while those who showed no response, all relapsed shortly after ASCT. Analysis of the SUV parameters did not reveal additional information compared to that yielded by the visual assessment. INTERPRETATION AND CONCLUSIONS: Two serial PET scans predict outcome after ASCT more precisely than one interim PET in patients with relapsed lymphoma.
Assuntos
Linfoma/diagnóstico , Tomografia por Emissão de Pósitrons/métodos , Progressão da Doença , Fluordesoxiglucose F18 , Humanos , Valor Preditivo dos Testes , Prognóstico , RecidivaRESUMO
OBJECTIVE: The herpes simplex virus thymidine kinase (HSVtk) gene has frequently been applied as a reporter gene for monitoring transgene expression in animal models. In clinical gene therapy protocols, however, extremely low expression levels of the transferred gene are generally observed. Consequently, sensitive and selective radiotracers for imaging are required. This study describes the in-vitro evaluation of 2'-[18F]fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil (18F-FEAU) as a candidate tracer for HSVtk imaging with positron emission tomography (PET). METHODS: In cellular accumulation experiments, the potential of 18F-FEAU as a PET tracer for HSVtk was compared to the known acyclic guanosine derivatives 9-[(3-[18F]fluoro-1-hydroxy-2-propoxy)methyl]guanine (18F-FHPG) and 9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine (18F-FHBG), and the thymidine derivatives 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT), 2'-deoxy-2'-[18F]fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (18F-FMAU) and 2'-deoxy-2'-[18F]fluoro-5-iodo-1-beta-D-arabinofuranosyluracil (18F-FIAU). For this purpose, C6 control cells and HSVtk-expressing C6tk cells were incubated with the different tracers for various periods of time and cellular uptake and initial uptake rates were analysed. The initial rate of tracer uptake was determined from the slope of the plot of tracer uptake versus incubation time. RESULTS: After 2 h of tracer incubation, the C6tk/C6 accumulation ratio was 1.6 for 18F-FLT, 2.4 for F-FMAU, 5.5 for 18F-FHPG, 10.3 for 18F-FIAU, 40.8 for 18F-FHBG and 84.5 for 18F-FEAU. The initial tracer uptake rate in C6tk cells was in the order FLT>FMAU>FEAU>FIAU>FHBG>FHPG, whereas the initial tracer uptake rate in C6 control cells was FLT>FMAU>FIAU>FEAU approximately = FHBG approximately = FHPG. The highest HSVtk specific uptake was observed for FEAU. CONCLUSION: This study indicates that the high uptake rate of FEAU together with its high selectivity make this tracer an excellent candidate as a PET tracer for HSVtk gene expression.
Assuntos
Arabinofuranosiluracila/análogos & derivados , Perfilação da Expressão Gênica/métodos , Glioma/diagnóstico por imagem , Glioma/metabolismo , Timidina Quinase/genética , Timidina Quinase/metabolismo , Proteínas Virais/genética , Proteínas Virais/metabolismo , Animais , Arabinofuranosiluracila/farmacocinética , Linhagem Celular Tumoral , Radioisótopos de Flúor/farmacocinética , Glioma/genética , Taxa de Depuração Metabólica , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , TransfecçãoRESUMO
UNLABELLED: Although the herpes simplex virus thymidine kinase gene has been frequently applied as a reporter gene for monitoring gene transfection in animals, it has some intrinsic limitations for use in humans. In our search for a reporter gene that lacks these limitations, we have evaluated the feasibility of the human norepinephrine transporter (hNET) as a reporter gene in combination with the reporter probe 11C-m-hydroxyephedrine (mHED) for PET. METHODS: An adenoviral vector (AdTrack-hNET) containing the hNET gene as reporter gene and the enhanced green fluorescent protein (EGFP) as a substitute for a therapeutic gene was constructed. After COS-7, A2780, and U373 cells were transiently transduced with AdTrack-hNET, hNET protein expression, EGFP fluorescence, and cellular uptake of 11C-mHED were determined. In rats, U373 tumor xenografts were grown and transiently transduced with either AdTrack-hNET or an AdTrack-Luc control adenovirus. Intratumoral accumulation of 11C-mHED was determined by PET and ex vivo biodistribution. The tumors were subsequently examined for EGFP fluorescence. RESULTS: 11C-mHED uptake was positively correlated with AdTrack-hNET viral titer and hNET protein expression. However, large differences in transfection efficiency between cell lines were observed. The highest 11C-mHED uptake was found in hNET transfected U373 cells, in which tracer uptake was >70-fold higher than that in control cells. 11C-mHED accumulation could be inhibited by desipramine, a potent inhibitor of hNET. In all cell lines, 11C-mHED uptake was positively correlated with EGFP fluorescence, implying that imaging of hNET with 11C-mHED would enable monitoring of a coexpressed therapeutic gene. In the animal model, gene transfection efficiencies were very low, as determined by EGFP fluorescence. Still, a significantly higher 11C-mHED uptake in hNET transduced tumors than that in control tumors was demonstrated by ex vivo biodistribution studies. PET with a clinical camera could visualize 1 of 3 hNET transduced tumors, indicating that the transfection efficiency was near the detection limit. CONCLUSION: These results indicate that monitoring of gene therapy using the hNET/11C-mHED reporter gene/probe is feasible, but further investigation with regard to the sensitivity of the technique is required.
Assuntos
Radioisótopos de Carbono/farmacologia , Meios de Contraste/farmacologia , Efedrina/análogos & derivados , Terapia Genética/métodos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Tomografia por Emissão de Pósitrons/métodos , Adenoviridae/genética , Animais , Células COS , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Desipramina/farmacologia , Efedrina/farmacologia , Genes Reporter , Proteínas de Fluorescência Verde/metabolismo , Humanos , Modelos Químicos , Transplante de Neoplasias , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Sensibilidade e Especificidade , Fatores de Tempo , TransfecçãoRESUMO
OBJECTIVES: Positron emission tomography (PET) scanning may provide information on changes in the density and affinity of airway beta-adrenoceptors in lung diseases. However, the injection of a radiolabeled beta-blocker results in a pulmonary PET signal that reflects the binding of the ligand in the alveoli and not in the airways. Better discrimination between alveolar and airway beta-adrenoceptors may be possible with an inhaled radioligand. DESIGN: A nebulizer was used to administer the antagonist S-11C-CGP12388 in aerosol form. Eight volunteers inhaled the tracer twice, at baseline and after pretreatment with a beta-adrenergic drug. In both PET scan studies, a dynamic scan of the lungs was followed by a whole-body scan to assess the inhaled dose. Pulmonary uptake was quantified using a region-of-interest-based analysis. SETTING: University hospital. PARTICIPANTS: Healthy volunteers. INTERVENTIONS: Pretreatment consisted either of inhaled salbutamol (400 microg, 20 min before the scan), or orally administered pindolol (3 x 5 mg during a period of 16 h before PET scanning). RESULTS: Drug pretreatment did not affect pulmonary deposition of the radioligand. The agonist salbutamol accelerated the monoexponential washout of 11C not only in the peripheral lung (mainly alveoli), but also in the central lung (mainly airways) and in the main bronchi. An even larger increase of the washout rate was induced by the antagonist pindolol. CONCLUSION: The similar effects of pindolol and salbutamol on tracer kinetics suggest that accelerated washout is due to the blockade of beta-adrenoceptors. Thus, the interaction of drugs with airway beta-adrenoceptors can be visualized using PET scanning and an inhaled radioligand.
Assuntos
Antagonistas Adrenérgicos beta/farmacocinética , Benzimidazóis/farmacocinética , Radioisótopos de Carbono/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Sistema Respiratório/diagnóstico por imagem , Administração por Inalação , Administração Oral , Antagonistas Adrenérgicos beta/administração & dosagem , Adulto , Albuterol/administração & dosagem , Albuterol/farmacocinética , Benzimidazóis/administração & dosagem , Tamanho Corporal , Radioisótopos de Carbono/administração & dosagem , Feminino , Humanos , Masculino , Pindolol/administração & dosagem , Pindolol/farmacocinética , Valores de Referência , Sistema Respiratório/metabolismoRESUMO
UNLABELLED: While searching for a PET method to determine the density and occupancy of the dopamine D(3) receptor, we found evidence that suggested that the dopamine D(3) antagonist GR218231 could be a substrate of the P-glycoprotein efflux pump. P-glycoprotein protects the brain against toxic substances and xenobiotics, but it also hampers the delivery of various drugs into the brain. In this study, we aimed to explore whether radiolabeled GR218231 could be applied as a PET tracer for monitoring P-glycoprotein activity in the blood-brain barrier. Such an imaging technique could be useful for the development of new drugs and novel strategies to deliver drugs to the brain and for identification of undesirable drug-drug interactions. METHODS: As a potential PET tracer, GR218231 was labeled with (11)C by reaction of the newly synthesized desmethyl precursor with (11)C-methyl triflate. The biodistribution of (11)C-GR218231 was determined in rats. To assess specific binding to the dopamine D(3) receptor, blocking experiments with unlabeled GR218231 (0.2 and 2.5 mg/kg) were performed. To demonstrate the influence of P-glycoprotein on cerebral uptake of (11)C-GR218231, the efflux pump was modulated with 50 mg/kg cyclosporine A. The sensitivity of (11)C-GR218231 for P-glycoprotein modulation was assessed in dose-response studies, using escalating cyclosporine A dosages. RESULTS: (11)C-GR218231 was prepared in 53% +/- 8% decay-corrected radiochemical yield and had a specific activity of 15 +/- 10 GBq/micromol (mean +/- SD). Biodistribution studies in rats revealed a low and homogeneous uptake in the brain. Pretreatment of the animals with unlabeled GR218231 did not demonstrate any specific binding. Modulation of P-glycoprotein with cyclosporine A caused a 12-fold higher (11)C-GR218231 uptake in the brain, indicating that the low cerebral tracer uptake was caused by the P-glycoprotein efflux pump in the blood-brain barrier. Cyclosporine A dose-escalation studies showed a dose-dependent sigmoidal increase in (11)C-GR218231 uptake in brain and spleen (median effective dose [ED(50)], 23.3 +/- 0.6 and 38.4 +/- 2.4 mg/kg, respectively), whereas a dose-dependent decrease was observed in the pancreas (ED(50), 36.0 +/- 4.4 mg/kg). CONCLUSION: Although (11)C-GR218231 is unsuited for dopamine D(3) receptor imaging with PET, it appears to be an attractive PET tracer for visualization and quantification of P-glycoprotein activity in the blood-brain barrier.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Antagonistas dos Receptores de Dopamina D2 , Receptores de Dopamina D2/metabolismo , Sulfonas/farmacocinética , Tetra-Hidronaftalenos/farmacocinética , Animais , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacocinética , Marcação por Isótopo/métodos , Masculino , Taxa de Depuração Metabólica , Especificidade de Órgãos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Wistar , Receptores de Dopamina D3 , Sulfonas/química , Tetra-Hidronaftalenos/química , Distribuição TecidualRESUMO
The p53 protein is mutated in 50% of all human tumors and plays a key role in apoptosis, cell cycle, and the expression of several genes. We investigated if p53 mutations influence the herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV)-induced bystander effect (BE). Additionally, we studied some of the underlying mechanisms. GCV sensitivity and BE were studied in a human ovarian carcinoma cell line transfected with an empty vector (A2780/cmv) or a vector containing a p53 hotspot mutation at codon 175 (A2780/m175) or 248 (A2780/m248). In addition, expression levels of two nucleoside analogue transporters, multidrug resistance-related protein 4 and 5 (MRP4/MRP5), were determined. Finally, differences in gap junctional intercellular communication (GJIC) were studied by determining connexin 43 (Cx43) expression and by modulating GJIC with 18-alpha-glycyrrhetinic acid. Our results showed that compared to A2780/cmv, GCV sensitivity was significantly decreased in A2780/m175 and A2780/m248. Additionally, a significant BE (relative increase in cell kill) was found in A2780/cmv and A2780/m248. In contrast, an increased survival was observed in A2780/m175. No MRP4 or MRP5 expression was detected. However, all A2780 cell lines expressed Cx43. Modulating the GJIC significantly decreased the BE in A2780/cmv and A2780/ m248. In conclusion, HSV-tk/GCV-induced BE is influenced by p53 mutations. Differences in GJIC could be one of the underlying mechanisms.
Assuntos
Antineoplásicos/farmacologia , Efeito Espectador , Ganciclovir/farmacologia , Simplexvirus/enzimologia , Timidina Quinase/genética , Proteína Supressora de Tumor p53/genética , Animais , Western Blotting , Efeito Espectador/fisiologia , Comunicação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Junções Comunicantes/efeitos dos fármacos , Glioma/metabolismo , Glioma/patologia , Humanos , Imuno-Histoquímica , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ratos , Simplexvirus/genética , Timidina Quinase/metabolismo , TransfecçãoRESUMO
Imaging of P-glycoprotein (P-gp) function in the blood-brain barrier (BBB) may support development of strategies, which will improve drug delivery to the brain. [(11)C]verapamil has been developed as a positron emission tomography (PET) tracer, to image P-gp function in vivo. Ideally, for the purpose of brain imaging, tracers should have a log P between 0.9 and 2.5. The beta-receptor antagonist carvedilol is a P-gp substrate with a log P=2.0, and can be labeled with [(11)C]. The aim of this study was to determine whether the P-gp substrate [(11)C]carvedilol can be used as a PET tracer for visualisation and quantification of the P-gp function in the BBB. Cellular [(11)C]carvedilol accumulation in GLC(4), GLC(4)/P-gp, and GLC(4)/Adr cells increased three-fold in the GLC(4)/P-gp cells after pretreatment with cyclosporin A (CsA) whereas no effect of MK571 could be determined in the GLC(4)/Adr cells. Ex vivo [(11)C]carvedilol biodistribution studies showed that [(11)C]carvedilol uptake in the brain was increased by CsA. [(11)C]carvedilol uptake in other organs was not affected by CsA. Autoradiography studies of rat brains showed that [(11)C]carvedilol was homogeneously distributed over the brain and that pretreatment with CsA increased [(11)C]carvedilol uptake. In vivo PET experiments were performed with and without P-gp modulation by CsA. P-gp mediated transport was quantified by Logan analysis of the PET data, calculating the distribution volume (DV) of [(11)C]carvedilol in the brain. Logan analysis resulted in excellent fits, revealing that [(11)C]carvedilol is not trapped in the brain. Brain DV of [(11)C]carvedilol showed a dose-dependent increase of maximal three-fold after CsA pretreatment. Above 15 mg kg(-1), no change in DV was found. Compared to [(11)C]verapamil less CsA was needed to reach maximal DV, suggesting that [(11)C]carvedilol kinetics is a more sensitive tool to in vivo measure P-gp function.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Encéfalo/diagnóstico por imagem , Carbazóis/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Propanolaminas/farmacocinética , Animais , Encéfalo/metabolismo , Radioisótopos de Carbono , Carvedilol , Linhagem Celular Tumoral , Humanos , Masculino , Ratos , Distribuição TecidualRESUMO
The permeability of the blood-brain barrier (BBB) is one of the factors determining the bioavailability of drugs in the brain. The BBB only allows passage of lipophilic drugs by passive diffusion. However, some lipophilic drugs hardly enter the brain. The transmembrane protein P-glycoprotein (P-gp) is one of the carrier systems that is responsible for transportation of drugs out of the brain. P-Glycoprotein affects the pharmacokinetics of many drugs and can be inhibited by administration of modulators or competitive substrates. Identification and classification of central nervous system (CNS) drugs as P-gp substrates or inhibitors are of crucial importance in drug development. Positron emission tomography (PET) studies can play an important role in the screening process as a follow-up of high-throughput in vitro assays. Several rodent studies have shown the potential value of PET to measure the effect of P-gp on the pharmacokinetics and brain uptake of radiolabeled compounds. P-Glycoprotein-mediated effects were observed for two 5-HT(1a) receptor ligands, [(18)F]MPPF vs. [carbonyl-(11)C]WAY100635. Under control conditions, the specific brain uptake of [(18)F]MPPF is five- to eightfold lower than that of [(11)C]WAY100635. After cyclosporin A (CsA) modulation, [(18)F]MPPF uptake in the rat brain increased five- to tenfold. Cerebral uptake of [carbonyl-(11)C]WAY100635 was also increased by modulation, but in general the increase was lower than that observed for [(18)F]MPPF (two- to threefold). Brain uptake of the beta-adrenergic receptor ligands [(11)C]carazolol and [(18)F]fluorocarazolol was increased in P-gp knockout mice and CsA-treated rats. Both the specific and nonspecific binding of [(18)F]fluorocarazolol were doubled by CsA. Cerebral uptake of [(11)C]carazolol in rats was much lower than that of [(18)F]fluorocarazolol and no specific binding was measured. After CsA modulation, the uptake of [(11)C]carazolol increased five- to sixfold, but this uptake was not receptor-mediated. Quantitative PET studies in rodents on P-gp functionality demonstrated a dose-dependent increase of radioligands after administration of CsA. Studies with [(11)C]verapamil and [(11)C]carvedilol showed that complete modulation was achieved at 50 mg/kg CsA. The distribution volume of [(11)C]carvedilol increased from 0.25 in the control study to 1.0 after full modulation with CsA. By quantitative PET measurement of P-gp function, the dose of modulators required to increase the concentration of CNS drugs may be determined, which may result in improved drug therapy.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fármacos do Sistema Nervoso Central/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Roedores/metabolismo , Animais , Humanos , Ligação ProteicaRESUMO
This paper focuses on the influence of chemoresistance on the herpes simplex virus (HSV-tk)/ganciclovir (GCV)-induced bystander effect (BE), as studied in a human small cell lung cancer (SCLC) cell line (GLC4) and its sublines with in vitro acquired resistance to adriamycin (GLC4/ADR), mitoxantrone (GLC4/MITO) and cisplatin (GLC4/CDDP). Chemoresistance for adriamycin, mitoxantrone and cisplatin significantly changed GCV sensitivity. A significant BE was found in all GLC4 cell lines. Compared to the parental GLC4 cell line, the BE was significantly higher only for the GLC4/ADR cell line. No expression of the nucleoside transporters MRP4 and MRP5 was detected. In all cell lines expression of connexin 43 was found, but modulation of gap junctional intercellular communication (GJIC) by 18-alpha-glycyrrhetinic acid did not significantly change the BE in any of the GLC4 cell lines. In conclusion, chemoresistance can influence the HSV-tk/GCV-induced BE, which seems not to be related to differences in MRP4/MRP5 expression or to differences in GJIC.
Assuntos
Carcinoma de Células Pequenas/terapia , Ganciclovir/farmacologia , Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Simplexvirus/genética , Timidina Quinase/genética , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/enzimologia , Carcinoma de Células Pequenas/genética , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/fisiologia , Linhagem Celular Tumoral , Conexina 43/biossíntese , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ganciclovir/farmacocinética , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/fisiologia , Ácido Glicirretínico/farmacologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/biossíntese , Simplexvirus/enzimologia , Timidina Quinase/biossíntese , Timidina Quinase/metabolismoRESUMO
Parkinson's disease (PD) is associated with a loss of neurons from the midbrain. The cause of PD is unknown, but it is established that certain neurotoxins can cause similar syndromes. The brain is normally protected from these noxious blood-borne chemicals by the blood-brain barrier which includes specialized proteins on the inside of blood vessels in the brain. These act as molecular efflux pumps and P-glycoprotein (P-gp) is an abundant representative. Vulnerability to PD appears codetermined by the genotype for the P-gp gene. We hypothesized that PD patients have reduced P-gp function in the blood-brain barrier. We used positron emission tomography to measure brain uptake of [(11)C]-verapamil, which is normally extruded from the brain by P-gp. Here, we show significantly elevated uptake of [(11)C]-verapamil (18%) in the midbrain of PD patients relative to controls. This is the first evidence supporting a dysfunctional blood-brain barrier as a causative mechanism in PD.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/fisiopatologia , Mesencéfalo/fisiopatologia , Doença de Parkinson/fisiopatologia , Idoso , Barreira Hematoencefálica/metabolismo , Feminino , Humanos , Masculino , Mesencéfalo/irrigação sanguínea , Mesencéfalo/diagnóstico por imagem , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Verapamil/metabolismoRESUMO
PURPOSE: The beta-adrenoceptor (beta-AR) plays an important role in heart failure. Recently, the new tracer (S)-[11C]CGP12388 has been developed. It displays excellent properties for investigation of the cardiac beta-ARs in vivo with positron emission tomography (PET). Furthermore, the simple production method allows its use in a routine clinical setting. The aim of this study was to investigate whether decreased myocardial beta-AR density in patients with idiopathic dilated cardiomyopathy (IDC) can be estimated using (S)-[11C]CGP12388 PET. METHODS: Myocardial beta-AR density was investigated in six patients with IDC and six age-matched healthy controls, using (S)-[11C]CGP12388 PET. RESULTS: Beta-AR densities of 5.4+/-1.3 pmol/g (mean +/- SD) were observed in patients; these values were significantly lower than those observed in healthy controls (8.4+/-1.5 pmol/g, p<0.005). CONCLUSION: This study indicates that PET with (S)-[11C]CGP12388 is applicable for the measurement of myocardial beta-AR density in patients. A highly significant reduction in beta-AR density was found in patients with IDC compared with healthy controls.
Assuntos
Benzimidazóis/farmacocinética , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/metabolismo , Miocárdio/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Receptores Adrenérgicos beta/metabolismo , Adulto , Idoso , Radioisótopos de Carbono/farmacocinética , Regulação para Baixo , Feminino , Coração/diagnóstico por imagem , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
UNLABELLED: Choosing the optimal treatment for an individual with squamous cell carcinoma of the head and neck is a difficult challenge because of the unpredictable clinical behavior of this malignancy. A reliable method for assessing the clinical behavior and predicting the radiocurability of tumors would assist in the therapy strategy and prognosis. This study evaluated whether quantitative PET using l-[1-(11)C]-tyrosine (TYR) has predictive value for survival and therapy outcome in patients with primary squamous cell carcinoma of the larynx. METHODS: Thirty-four patients with histologically confirmed laryngeal carcinomas underwent dynamic (11)C-TYR PET before receiving definitive therapy. Various methods for quantification of tumor activity were used: assessment of protein synthesis rate (PSR), calculation of standardized uptake value, and estimation of tumor-to-nontumor ratio. Treatment consisted of radiotherapy (n = 20) or surgery (n = 14). The median follow-up was 40 mo. RESULTS: All malignancies were identified correctly, with no false-negative results. Cumulative survival was compared between patients with tumor PSR equal to or higher than the median (2.0 nmol/mL/min) and those with tumor PSR lower than the median and was found not to be significantly different (P = 0.07). When the radiotherapy group was evaluated separately, the difference in survival was significant (P = 0.03; 5-y survival, 30% vs. 73%) and high (11)C-TYR uptake correlated with poor prognosis. In multivariate analysis, PSR was an independent predictor for survival. Because differences (P = 0.08) between patients with and patients without recurrence were not significant, no predictive value of PSR for disease recurrence could be demonstrated. CONCLUSION: Prediction of survival of patients undergoing radiotherapy for laryngeal squamous cell carcinoma is feasible primarily by using (11)C-TYR PET to quantify activity before treatment.
Assuntos
Radioisótopos de Carbono , Carcinoma de Células Escamosas/diagnóstico por imagem , Neoplasias Laríngeas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Tirosina , Adulto , Idoso , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/radioterapia , Feminino , Humanos , Neoplasias Laríngeas/metabolismo , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/radioterapia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
UNLABELLED: Our objective was to study 2 radioligands for visualization of sigma-receptors with PET. METHODS: Two radioligands-sigma(1)-selective (11)C-1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine ((11)C-SA4503) and nonsubtype-selective 1-(4-2'-(18)F-fluoroethoxy-3-methoxyphenethyl)-4-(3-(4-fluorophenyl)propyl)piperazine ((18)F-FE-SA5845)-were evaluated for tumor imaging. RESULTS: Binding studies to rat glioma cells (C6) and human nonsmall cell lung cancer cells (N417) indicated interaction of (18)F-FE-SA5845 with 2 sites and interaction of (11)C-SA4503 with a single site. Specific binding of (18)F-FE-SA5845 was 93% +/- 2% and that of (11)C-SA4503 was 78% +/- 6% of the total cellular uptake of radioactivity. Uptake of the (18)F-labeled ligand, but not that of the (11)C-labeled ligand, appeared to be related to the growth phase of the cells. Biodistribution experiments in C6 tumor-bearing nude rats (Ham HSD RNU rnu) indicated tumor-to-plasma ratios of 13.3 for (11)C-SA4503 and 8.0 for (18)F-FE-SA5845 and tumor-to-muscle ratios of 5.0 for (11)C-SA4503 and 4.9 for (18)F-FE-SA5845, 60 min after injection, which were reduced to values ranging from 1.4 to 2.0 after pretreatment of animals with haloperidol (2 micromol/kg). Tumor uptake of (18)F-FE-SA5845 showed a negative correlation with tumor size (P < 0.0001), in contrast to that of (11)C-SA4503, suggesting that tissue binding of the former ligand is related to cellular proliferation. A study with (11)C-SA4503 in a human volunteer indicated high uptake in liver, kidney, and heart but relatively low background in thorax and lower abdomen. CONCLUSION: Both (18)F-FE-SA5845 and (11)C-SA4503 demonstrate specific binding to sigma-receptors in vivo and may be useful for the detection of pulmonary and abdominal tumors. However, the (18)F-labeled compound may be better for tumor staging than the (11)C-labeled drug.
Assuntos
Glioma/diagnóstico por imagem , Glioma/metabolismo , Piperazinas/farmacocinética , Receptores sigma/metabolismo , Idoso , Animais , Radioisótopos de Carbono/farmacocinética , Linhagem Celular Tumoral , Estudos de Viabilidade , Feminino , Humanos , Taxa de Depuração Metabólica , Especificidade de Órgãos , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Nus , Distribuição TecidualRESUMO
UNLABELLED: The objective of this study was to compare 18F-3'-fluoro-3'-deoxy-L-thymidine (FLT) PET with clinical TNM staging, including that by 18F-FDG PET, in patients with non-small cell lung cancer (NSCLC). METHODS: Patients with NSCLC underwent whole-body 18F-FDG PET and whole-body 18F-FLT PET, using a median of 360 MBq of 18F-FDG (range, 160-500 MBq) and a median of 210 MBq of 18F-FLT (range, 130-420 MBq). 18F-FDG PET was performed 90 min after 18F-FDG injection, and 18F-FLT PET was performed 60 min after 18F-FLT injection. Two viewers independently categorized the localization and intensity of tracer uptake for all lesions. All 18F-FDG PET and 18F-FLT PET lesions were compared. Staging with 18F-FLT PET was compared with clinical TNM staging based on the findings of history, physical examination, bronchoscopy, CT, and 18F-FDG PET. From 8 patients, standardized uptake values (SUVs) were calculated. Maximal SUV and mean SUV were calculated. RESULTS: Sixteen patients with stage IB-IV NSCLC and 1 patient with strong suspicion of NSCLC were investigated. Sensitivity on a lesion-by-lesion basis was 80% for the 8 patients who received treatment before 18F-FLT PET and 27% for the 9 patients who did not receive pretreatment, using 18F-FDG PET as the reference standard. Compared with clinical TNM staging, staging by 18F-FLT PET was correct for 8 of 17 patients: 5 of 9 patients in the group with previous therapy and 3 of 8 patients in the group without previous therapy. The maximal SUV of 18F-FLT PET, at a median of 2.7 and range of 0.8-4.5, was significantly lower than that of 18F-FDG PET, which had a median of 8.0 and range of 3.7-18.8 (n = 8; P = 0.012). The mean SUV of 18F-FLT PET, at a median of 2.7 and range of 1.4-3.3, was significantly lower than that of 18F-FDG PET, which had a median of 6.2 and range of 2.8-13.9 (n = 6; P = 0.027). CONCLUSION: 18F-FLT PET is not useful for staging and restaging NSCLC.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/patologia , Didesoxinucleosídeos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias/métodos , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Cintilografia , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
This review focuses on positron emission tomography (PET)-imaging of receptors in the sympathetic and the parasympathetic systems of heart and lung and highlights the human applications of PET. For the alpha-adrenoceptor, only [11C]GB67 (N2-[6-[(4-amino-6,7-dimethoxy-2-quinazolinyl)(methyl)amino]hexyl]-N2-[11C]methyl-2-furamide hydrochloride) has been developed. Its potential for application in patients needs to be assessed. For both the beta-adrenergic and the muscarinic systems, potent PET radioligands have been prepared and evaluated in patients. It has been possible to measure receptor densities quantitatively in human heart [[11C]MQNB: [11C]methylquinuclidinyl benzilate, [11C]CGP12177: S-(3'-t-butylamino-2'-hydroxypropoxy)-benzimidazol-2-[11C]one and [11C]CGP12388: (S)-4-(3-(2'-[11C]isopropylamino)-2-hydroxypropoxy)-2H-benzimidazol-2-one] and qualitatively in lung [[11C]VC002: N-[11C]-methyl-piperidin-4-yl-2-cyclohexyl-2-hydroxy-2-phenylacetate and [11C]CGP12177]. Besides these subtype nonselective radioligands, the development of compounds that are selective for one subtype are ongoing and have not found successful application in humans yet.
Assuntos
Tomografia por Emissão de Pósitrons/métodos , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/metabolismo , Tórax/diagnóstico por imagem , Agonistas alfa-Adrenérgicos/metabolismo , Antagonistas Adrenérgicos alfa/metabolismo , Agonistas Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/metabolismo , Animais , Benzimidazóis/metabolismo , Carbazóis/metabolismo , Radioisótopos de Carbono , Etanolaminas/metabolismo , Fumarato de Formoterol , Humanos , Propanolaminas/metabolismo , Ensaio Radioligante , Tórax/metabolismoRESUMO
UNLABELLED: Early discrimination between benign and malignant pleural diseases is vital for the treatment and prognosis of a patient. Imaging is traditionally performed with CT or MRI, with an accuracy of 50%-75%. PET has proven to be superior as a diagnostic tool in several malignancies. In this prospective study, PET results in patients with pleural abnormalities on CT were compared with histologic results. METHODS: Eligible patients had pleural thickening on CT and were medically fit for surgical diagnostic procedures. All patients underwent PET. Qualitative assessment led to a PET score of 1 (definitely normal), 2 (probably normal), 3 (probably abnormal), or 4 (definitely abnormal). PET scores of 1 or 2 indicated a negative PET finding, whereas PET scores of 3 or 4 indicated a positive PET finding. Pathologic verification techniques included thoracocentesis, thoracoscopy, or open pleural biopsy at thoracotomy. RESULTS: Thirty-two patients were enrolled, 19 with malignant and 13 with benign pleural disease. PET was true positive in 18 and true negative in 12 patients, with an accuracy and negative predictive value of 94% and 92%, respectively. PET was false negative in a patient with a slowly growing malignant solitary fibrous tumor and false positive in a patient with infectious pleuritis. Median standardized uptake values calculated for 7 patients with malignant and benign pleural diseases were 6.28 and 1.69, respectively. Patients with a PET score of 1 or 2 survived significantly longer than patients with a PET score of 3 or 4. CONCLUSION: Qualitative assessment of pleural thickening with PET accurately discriminates between malignant and benign pleural thickening, with a high accuracy and negative predictive value.
Assuntos
Fluordesoxiglucose F18 , Neoplasias Pleurais/diagnóstico por imagem , Tomografia Computadorizada de Emissão/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pleurais/patologia , Radiografia , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Inducible NO synthase (iNOS) is overexpressed in inflammatory bowel diseases. An antisense oligonucleotide with good hybridization properties for iNOS mRNA was selected using RT-PCR. The oligonucleotide was reliably labeled with fluorine-18 using N-(4-[(18)F]fluorobenzyl)-2-bromoacetamide. Cellular uptake and efflux of oligonucleotide complexed with FuGENE-6 were rapid, unlike naked oligonucleotide, which hardly accumulated. However, neither uptake nor efflux showed any selectivity for iNOS expressing cells. The oligonucleotide showed a high level of non-specific binding, which may have obscured its specific hybridization to iNOS mRNA.
Assuntos
Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Oligonucleotídeos Antissenso/farmacocinética , RNA Mensageiro/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Estudos de Viabilidade , Radioisótopos de Flúor/farmacocinética , Perfilação da Expressão Gênica/métodos , Humanos , Marcação por Isótopo/métodos , Óxido Nítrico Sintase Tipo II , Oligonucleotídeos Antissenso/síntese química , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinéticaRESUMO
Permeability of the blood-brain barrier (BBB) is one of the factors determining the bioavailability of therapeutic drugs. The BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. However, many lipophilic drugs show negligible brain uptake. They are substrates for transporters such as P-glycoprotein (P-gp), multidrug-resistance associated protein (MRP) and organic anion transporting polypeptides (OATPs). The action of these carrier systems results in rapid efflux of xenobiotics from the central nervous system (CNS). Classification of candidate drugs as substrates or inhibitors of such carrier proteins is of crucial importance in drug development. Positron emission tomography (PET) can play an important role in the screening process by providing in vivo information, after the putative drug has passed in vitro tests. Although radiolabeled probes for MRP and OATP function are not yet available, many radiotracers have been prepared to study P-glycoprotein function in vivo with PET. These include alkaloids ((11)C-colchicine), antineoplastic agents ((11)C-daunorubicin, (18)F-paclitaxel), modulators of L-type calcium channels ((11)C-(+/-)verapamil, (11)C-R(+)-verapamil), beta-adrenoceptor antagonists ((11)C-(S)-carazolol, (18)F-(S)-1'-fluorocarazolol, (11)C-carvedilol), serotonin 5-HT(1A) receptor antagonists ((18)F-MPPF), opioid receptor antagonists ((11)C-loperamide, (11)C-carfentanyl), and various (64)Cu-labeled copper complexes. Studies in experimental animals have indicated that it is possible to assess P-glycoprotein function in the BBB and its effect on the uptake and binding of drugs within the intact CNS, using suitable P-gp modulators labeled with positron emitters. Provided that radiopharmaceuticals (and P-gp modulators) can be developed for human use, several exciting fields of study may be explored, viz. (i) direct evaluation of the effect of modulators on the cerebral uptake of therapeutic drugs; (ii) assessment of mechanisms underlying drug resistance in epilepsy; (iii) examination of the role of the BBB in the pathophysiology of neurodegenerative and affective disorders; and (iv) exploration of the relationship between polymorphisms of transporter genes and the pharmacokinetics of test compounds within the CNS.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/metabolismo , Preparações Farmacêuticas/metabolismo , Tomografia Computadorizada de Emissão/métodos , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Sistema Nervoso Central/diagnóstico por imagem , Humanos , Preparações Farmacêuticas/química , Ligação Proteica/fisiologiaRESUMO
Beta-adrenoceptors are predominantly located in the cerebral cortex, nucleus accumbens and striatum. At lower densities, they are also present in amygdala, hippocampus and cerebellum. Beta-2 sites regulate glial proliferation during ontogenic development, after trauma and in neurodegenerative diseases. The densities of beta-1 adrenoceptors are changed by stress, in several mood disorders (depression, excessive hostility, schizophrenia) and during treatment of patients with antidepressants. A technique for beta-adrenoceptor imaging in the human brain is not yet available. Although 24 (ant)agonists have been labeled with either (11)C or (18)F and some of these are successful myocardial imaging agents, only two (S-1'-(18)F-fluorocarazolol and S-1'-(18)F-fluoroethylcarazolol) could actually visualize beta-adrenoceptors within the central nervous system. Unfortunately, these radiopharmaceuticals showed a positive Ames test. They may be mutagenic and cannot be employed for human studies. Screening of more than 150 beta-blockers described in the literature yields only two compounds (exaprolol and L643,717) which can still be radiolabeled and evaluated for beta-adenoceptor imaging. However, other imaging techniques could be examined. Cerebral beta-adrenoceptors might be labeled after temporary opening of the blood-brain barrier (BBB) and simultaneous administration of a hydrophilic ligand such as S-(11)C-CGP12388. Another approach to target beta-adrenoceptor ligands to the CNS is esterification of a myocardial imaging agent (such as (11)C-CGP12177), resulting in a lipophilic prodrug which can cross the BBB and is split by tissue esterases. BBB opening is not feasible in healthy subjects, but the prodrug approach may be successful and deserves to be explored.