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1.
Exp Hematol ; 17(11): 1067-71, 1989 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-2583250

RESUMO

Addition of carbamylcholine, a cholinergic analogue, to bone marrow cultures enhanced megakaryocytic and granulocytic growth by 60% and 42%, respectively. When carbamylcholine was added to spleen cells cultured in the presence of pokeweed mitogen, the resulting conditioned medium (PWM-SCM) increased the number of megakaryocytic and granulocytic colonies to 159% +/- 6% and 146% +/- 10%, respectively, compared to control cultures stimulated by PWM-SCM alone. To determine if this cholinergic augmentation of colony formation was direct or mediated via accessory marrow cells, cyclosporin A (CyA), a potent T-lymphocyte function inhibitor known to suppress the production of colony-stimulating activity (CSA) by spleen cell cultures, was added to marrow cultures. CyA (3 micrograms/ml) abrogated the enhancement of megakaryocytic and granulocyte-macrophage colony growth but had no effect on colony formation when added alone. To confirm the role of T-lymphocytes in the augmented proliferation of megakaryocytopoiesis and granulocytopoiesis, bone marrow cells from T-lymphocyte-deficient nude mice were cultured in the presence of carbamylcholine. No significant change was observed in the number of megakaryocyte colony-forming units (CFU-M) and committed granulocyte-macrophage colony-forming units (CFU-C) derived from the marrow of nude mice when cultured in the presence of carbamylcholine. The data suggest that carbamylcholine-induced enhancement of megakaryocytopoiesis and granulocytopoiesis in culture is indirect, requiring a T-lymphocyte population.


Assuntos
Carbacol/farmacologia , Granulócitos/fisiologia , Hematopoese/efeitos dos fármacos , Megacariócitos/fisiologia , Linfócitos T/fisiologia , Animais , Células da Medula Óssea , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Ciclosporinas/farmacologia , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus
2.
Int J Radiat Biol ; 75(2): 245-51, 1999 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10072186

RESUMO

PURPOSE: The present study investigated in vitro radio-enhancement by gemcitabine (dFdC) in two head and neck squamous cell carcinomas with different intrinsic cellular radiosensitivity. MATERIALS AND METHODS: Radiosensitive (SCC61, SF2=0.16) and radioresistant (SQD9, SF2=0.49) human head and neck squamous cell carcinomas were used. Confluent cells were incubated with dFdC and irradiated in drug-free medium with a single dose of 250 kV X-rays (0-12Gy). Cell survival curves were corrected for the toxicity of the drug alone. RESULTS: In both cell lines, radio-enhancement was observed with 5 microM dFdC incubated for 3 h prior to irradiation. Dose modification factors (DMF) at a surviving fraction level of 0.5 reached 1.3 (95% CI 1.1-1.6) and 1.5 (95% CI 1.4-1.5) for SQD9 and SCC61 cells, respectively. Radio-enhancement was associated with a modest increase in the alpha term of the linear-quadratic model. In SQD9 cells, radio-enhancement increased with dFdC incubation time. At 24h, DMF reached a value of 1.5 (95% CI 0.9-3.2). In SCC61 cells at 24h, DMF reached a value of 1.1 (95% CI 0.9-1.2). In both cell lines, radio-enhancement increased with dFdC concentration up to 5-10 microM from which values it levelled off up to 100 microM. CONCLUSIONS: The data indicated that dFdC induced a modest radio-enhancement in both cell lines. For a short incubation time, dFdC did not radio-enhance preferentially the more radio-resistant cells, whereas the opposite was observed for a longer time. In both cell lines, radio-enhancement was saturated above a dFdC concentration of 5-10 microM.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Desoxicitidina/análogos & derivados , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Radiossensibilizantes/farmacologia , Carcinoma de Células Escamosas/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/efeitos da radiação , Terapia Combinada , Desoxicitidina/farmacologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Tolerância a Radiação , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos da radiação , Gencitabina
3.
Eur J Nucl Med Mol Imaging ; 35(7): 1282-9, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18317752

RESUMO

PURPOSE: The aim of this study was to assess the pharmacokinetics, biodistribution and metabolism of [(18)F]EF3, a labelled 2-nitroimidazole hypoxia marker, in ten patients with head and neck cancer. METHODS: [(18)F]EF3 was administered intravenously (group 1, n=5, mean dose+/-SD: 324+/-108 MBq; group 2, n=5, mean dose+/-SD: 1,134+/-138 MBq) to patients (nine male, one female). Blood and urine samples and whole-body PET scans were obtained from 20 s to 4-6 h. Radioactivity was determined in several regions of interest. RESULTS: No serious adverse event was reported. [(18)F]EF3 concentration in blood exhibited a bi-exponential decline. [(18)F]EF3 was mainly eliminated in the urine. By 7 h 40 min after injection, 53+/-14% of the injected dose was collected in the urine. There was no significant difference between the low- and high-dose groups. A progressive accumulation occurred also in the colon, indicating a hepatobiliary excretion. Except in organs involved in the elimination of [(18)F]EF3, the tumour-to-organ ratio remained close to or below unity in muscle, lungs, heart and brain at various times after injection. In one patient, tumour hypoxia was observed with a tumour-to-blood ratio ranging from 1.4 to 1.9. Last, [(18)F]EF3 remained very stable after injection, with percentage of native tracer above 87% in the serum and 84% in the urine. CONCLUSION: Administration of [(18)F]EF3 in head and neck cancer patients is feasible and safe. Uptake and retention in tumour was observed, indicating the presence of hypoxia.


Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Hipóxia/diagnóstico por imagem , Nitroimidazóis/farmacocinética , Adulto , Idoso , Carcinoma de Células Escamosas/diagnóstico por imagem , Feminino , Humanos , Neoplasias Laríngeas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Neoplasias Faríngeas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
4.
Eur J Nucl Med Mol Imaging ; 33(5): 553-6, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16523307

RESUMO

In the framework of the preclinical validation of the hypoxic tracer [(18)F]EF3, a comparison was performed between uptake of [(18)F]EF3 and EF5 adducts detected by immunofluorescence in MCa-4, FSA, FSAII, Sa-NH and NFSA tumour-bearing mice. Mice were allowed to breath carbogen (5% CO(2), 95% O(2)), 21% oxygen or 10% oxygen. A significant correlation (r (2)=0.57; p<0.01) was found between the [(18)F]EF3 tumour-to-muscle ratio and the fluorescence intensity of EF5.


Assuntos
Etanidazol/análogos & derivados , Fibrossarcoma/diagnóstico por imagem , Fibrossarcoma/metabolismo , Hidrocarbonetos Fluorados/metabolismo , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/metabolismo , Nitroimidazóis/farmacocinética , Oxigênio/metabolismo , Animais , Hipóxia Celular , Avaliação Pré-Clínica de Medicamentos , Etanidazol/metabolismo , Imunofluorescência , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C3H , Especificidade de Órgãos , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
5.
Blood ; 72(4): 1187-92, 1988 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3167202

RESUMO

Murine bone marrow cells were separated on discontinuous Percoll gradients and assayed for their ability to give rise to megakaryocyte colonies. Ninety-one percent of the megakaryocyte progenitors (CFU-M) sedimented at densities between 1.070 and 1.080 g/mL. Six percent of CFU-M were found at densities between 1.060 and 1.070 g/mL, 2% between 1.050 and 1.060 g/mL, whereas less than 1% had a density either lower than 1.050 g/mL or higher than 1.080 g/mL. The number of doublings and endomitoses achieved by progenitors of density classes higher than 1.050 g/mL were similar. However, colonies derived from CFU-M of densities less than 1.050 g/mL (LD-CFU-M) had a higher probability of polyploidization and a lower probability of cell division in vitro. The inverse correlation found between the number of cells per colony and their DNA content was invariate regardless of the density class of the progenitors. The heterogeneity of the ploidy of cells within colonies increased continuously with increasing cell numbers per colony. The study if a short-period exposure of LD-CFU-M to acute thrombocytopenia could modify the ploidy of their progeny, mice were given rabbit antimouse platelet serum while control animals received normal rabbit serum. Twenty-four hours after injection, marrow was cultured. After a five-day culture period, no change in the number of colonies, doublings, ploidy, and heterogeneity of ploidy were observed between control and thrombocytopenic animals. The data suggests that LD-CFU-M are a distinct category of CFU-M, perhaps more mature than the common CFU-M.


Assuntos
Separação Celular/métodos , Centrifugação com Gradiente de Concentração , Células-Tronco Hematopoéticas/citologia , Megacariócitos/citologia , Doença Aguda , Animais , Medula Óssea/patologia , Contagem de Células , Ensaio de Unidades Formadoras de Colônias , Células-Tronco Hematopoéticas/patologia , Megacariócitos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mitose , Trombocitopenia/sangue , Trombocitopenia/patologia
6.
Eur J Nucl Med Mol Imaging ; 31(9): 1263-72, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15197503

RESUMO

The 2-nitroimidazole derivative 2-(2-nitroimidazol-1-yl)- N-(3,3,3-trifluoropropyl)acetamide (EF3) is a marker which forms adducts into hypoxic cells. Radiosynthesis of [(18)F]EF3 was recently performed by our group. Our aim was to study the pharmacokinetics, biodistribution, metabolism and specificity for hypoxia of [(18)F]EF3. MCa-4, SCC VII, NFSA, FSA, FSA II or Sa-NH tumour-bearing C3H mice were injected intravenously with [(18)F]EF3 and allowed to breathe air, 10% O(2) or carbogen until sacrifice 5-770 min after injection. Radioactivity was measured ex vivo in various organs, including urine and faeces. Selected organs were additionally processed to measure tracer metabolites with high-performance liquid chromatography. The half-life in blood was 73.9 min. [(18)F]EF3 was eliminated mainly via the kidneys, with 75% of the injected activity found in the urine by 12 h 50 min. The biodistribution was fast and homogeneous except in the brain and the bone, where it was significantly lower, and in the liver and the kidney, where it was significantly higher. In most organs, the exceptions being the gastrointestinal and urinary tract, tissue-to-blood ratios were below or close to unity. In tumours, a relative accumulation of the tracer was observed with time, which, at 220 min after injection, depended on tumour strain and oxygenation conditions, i.e. 10% O(2) significantly increased the tumour-to-muscle ratio whereas carbogen decreased it. [(18)F]EF3 was rapidly metabolised in the kidney and the liver. [(18)F]EF3 is a promising tracer for detection of tumour hypoxia. A phase I study in head and neck cancer patients is in progress at our institution.


Assuntos
Carcinoma/diagnóstico por imagem , Carcinoma/metabolismo , Fibrossarcoma/diagnóstico por imagem , Fibrossarcoma/metabolismo , Nitroimidazóis/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Animais , Hipóxia Celular , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C3H , Especificidade de Órgãos , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
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