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1.
PLoS One ; 9(4): e95456, 2014.
Article in English | MEDLINE | ID: mdl-24787744

ABSTRACT

To relate exposure to adverse health effects, it is necessary to know where particles in the submicron range deposit in the respiratory tract. The possibly higher vulnerability of children requires specific inhalation studies. However, radio-aerosol deposition experiments involving children are rare because of ethical restrictions related to radiation exposure. Thus, an in vivo study was conducted using three baboons as a child respiratory tract model to assess regional deposition patterns (thoracic region vs. extrathoracic region) of radioactive polydisperse aerosols ([d16-d84], equal to [0.15 µm-0.5 µm], [0.25 µm-1 µm], or [1 µm-9 µm]). Results clearly demonstrated that aerosol deposition within the thoracic region and the extrathoraic region varied substantially according to particle size. High deposition in the extrathoracic region was observed for the [1 µm-9 µm] aerosol (72% ± 17%). The [0.15 µm-0.5 µm] aerosol was associated almost exclusively with thoracic region deposition (84% ± 4%). Airborne particles in the range of [0.25 µm-1 µm] showed an intermediate deposition pattern, with 49% ± 8% in the extrathoracic region and 51% ± 8% in the thoracic region. Finally, comparison of baboon and human inhalation experiments for the [1 µm-9 µm] aerosol showed similar regional deposition, leading to the conclusion that regional deposition is species-independent for this airborne particle sizes.


Subject(s)
Aerosols/pharmacokinetics , Models, Animal , Respiratory System/metabolism , Animals , Child , Humans , Papio , Particle Size
3.
Acta Otolaryngol ; 130(12): 1421-4, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20735322

ABSTRACT

CONCLUSION: In our experience PET-CT cannot yet reliably predict the need for surgical neck dissection in patients with N0 neck. According to the results of PET-CT the neck dissection should be extended towards unusual lymph node areas. OBJECTIVE: To analyze the value of PET-CT for the initial N staging, comparing PET-CT data with histopathological results of the modified radical neck dissection. METHODS: Fifty patients with previously untreated head and neck squamous cell carcinoma were eligible for inclusion in this study. Modified radical unilateral or bilateral neck dissection was performed in all patients. PET-CT findings and histological findings were compared to determine their diagnostic sensitivity, specificity, accuracy, positive predictive value, and negative predictive value. RESULTS: In all, 105 levels had pathologically diagnosed metastases: PET-CT was positive in 87 levels and negative in 18 levels. Also, 399 levels had negative postoperative histology findings: PET-CT was positive in 24 levels and negative in 375 levels. The false-positive over-staged and the false-negative under-staged rates were 27% and 12%, respectively.


Subject(s)
Carcinoma, Squamous Cell/pathology , Fluorodeoxyglucose F18 , Hypopharyngeal Neoplasms/pathology , Laryngeal Neoplasms/pathology , Oropharyngeal Neoplasms/pathology , Polymerase Chain Reaction , Tomography, X-Ray Computed , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/surgery , Female , Humans , Hypopharyngeal Neoplasms/surgery , Laryngeal Neoplasms/surgery , Lymph Nodes/pathology , Lymphatic Metastasis/pathology , Male , Middle Aged , Neck Dissection , Neoplasm Staging , Oropharyngeal Neoplasms/surgery , Sensitivity and Specificity
5.
Eur J Nucl Med Mol Imaging ; 36(8): 1256-64, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19300998

ABSTRACT

PURPOSE: Multidrug resistance, aggressiveness and accelerated choline metabolism are hallmarks of malignancy and have motivated the development of new PET tracers like (18)F-FCH, an analogue of choline. Our aim was to study the relationship of multidrug resistance of cultured glioma cell lines and (18)F-FCH tracer uptake. METHODS: We used an in vitro multidrug-resistant (MDR) glioma model composed of sensitive parental U87MG and derived resistant cells U87MG-CIS and U87MG-DOX. Aggressiveness, choline metabolism and transport were studied, particularly the expression of choline kinase (CK) and high-affinity choline transporter (CHT1). FCH transport studies were assessed in our glioblastoma model. RESULTS: As expected, the resistant cell lines express P-glycoprotein (Pgp), multidrug resistance-associated protein isoform 1 (MRP1) and elevated glutathione (GSH) content and are also more mobile and more invasive than the sensitive U87MG cells. Our results show an overexpression of CK and CHT1 in the resistant cell lines compared to the sensitive cell lines. We found an increased uptake of FCH (in % of uptake per 200,000 cells) in the resistant cells compared to the sensitive ones (U87MG: 0.89 +/- 0.14; U87MG-CIS: 1.27 +/- 0.18; U87MG-DOX: 1.33 +/- 0.13) in line with accelerated choline metabolism and aggressive phenotype. CONCLUSIONS: FCH uptake is not influenced by the two ATP-dependant efflux pumps: Pgp and MRP1. FCH would be an interesting probe for glioma imaging which would not be effluxed from the resistant cells by the classic MDR ABC transporters. Our results clearly show that FCH uptake reflects accelerated choline metabolism and is related to tumour aggressiveness and drug resistance.


Subject(s)
Choline/analogs & derivatives , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Glioblastoma/metabolism , Animals , Biological Transport , Cell Line, Tumor , Choline/metabolism , Choline Kinase/metabolism , Gene Expression Regulation, Neoplastic , Glioblastoma/diagnosis , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Phenotype , Symporters/metabolism
6.
Eur J Nucl Med Mol Imaging ; 35(7): 1290-8, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18338166

ABSTRACT

PURPOSE: The aim of this study was to determine whether (99m)Tc-glucarate ((99m)Tc-GLA) is a powerful and discriminant tumour necrosis marker. MATERIALS AND METHODS: The induction of apoptosis and secondary necrosis (by a chemotherapeutic agent) and necrosis (by intense hyperthermia) was studied on an in vitro and in vivo leukaemic cell line model (U937). The percentage of apoptosis/necrosis in vitro was determined by flow cytometry after staining cells with annexin-V-fluorescein/propidium iodide. The uptake of (99m)Tc-GLA was studied after treatments that produce an optimal of necrosis cells or apoptotic cells. Three populations of interest: viable, apoptotic and necrotic cells were sorted by flow cytometry. The uptake and the intracellular distribution of (99m)Tc-GLA on each population have been studied. We also investigated the influence of necrosis on (99m)Tc-GLA uptake in a model of U937 xenografts in nude mice. RESULTS: The accumulation of (99m)Tc-GLA in untreated and apoptotic cells was lower than in necrotic cells. Cell sorting discriminated each cellular population and showed a 14% accumulation in necrotic cells and no more than a 3% in apoptotic cells. In apoptotic and viable cells, (99m)Tc-GLA is distributed between the cytosolic/membrane and the nucleus fractions. In necrotic cells, (99m)Tc-GLA is mainly found in the nucleus fraction. In vivo investigations showed a higher (99m)Tc-GLA uptake in necrotic tumour than in apoptotic and control ones. CONCLUSIONS: (99m)Tc-GLA may be a useful agent to specifically evaluate tumour necrosis and may be helpful for the follow-up of patients with cancer.


Subject(s)
Glucaric Acid/analogs & derivatives , Lymphoma, Large B-Cell, Diffuse/diagnostic imaging , Lymphoma, Large B-Cell, Diffuse/pathology , Organotechnetium Compounds , Animals , Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis , Cell Survival , Etoposide/therapeutic use , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Mice , Mice, Nude , Necrosis , Neoplasm Transplantation , Radionuclide Imaging , Radiopharmaceuticals , Transplantation, Heterologous , U937 Cells
7.
Coron Artery Dis ; 19(2): 89-97, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18300745

ABSTRACT

AIMS: The authors tested the value of stress single-photon emission computed tomography (SPECT) imaging performed systematically for detecting angiographic restenosis in asymptomatic patients who underwent direct percutaneous coronary intervention (PCI) for acute ST segment elevation myocardial infarction (STEMI). Angiographic restenosis of the infarct-related artery after direct PCI for STEMI is often silent and the strategy for follow-up evaluation of asymptomatic patients remains debated. METHODS: A total of 149 patients successfully treated by direct PCI (96% stenting) for STEMI with no symptoms during the follow-up systematically underwent both rest thallium 201/stress Tc 99m setamibi myocardial perfusion imaging and coronary angiogram at 6 months. Patients were followed up for 2.5+/-0.5 years after 6 months control for cardiac events. RESULTS: In the 149 patients, the sensitivity, specificity, positive and negative predictive values and accuracy of SPECT imaging were 48, 61, 35, 72 and 57%, respectively, for detecting binary angiographic restenosis defined as > or =50% diameter stenosis. Whether stress testing was maximal or performed after withheld anti-ischemic drugs did not improve the results. Reversible ischemia at SPECT in the infarct territory did not predict long-term cardiac events. CONCLUSION: These data suggest a poor correlation between stress SPECT imaging and angiographic restenosis at 6 months in patients treated by direct PCI for STEMI who remain asymptomatic at follow-up. The long-term clinical prognostic value of SPECT reversible ischemia in the infarct territory appears also limited in this peculiar subset of patients. These findings should be taken into account in the strategy of the clinical follow-up of this population.


Subject(s)
Angioplasty, Balloon, Coronary/rehabilitation , Coronary Restenosis/diagnostic imaging , Myocardial Infarction/surgery , Tomography, Emission-Computed, Single-Photon , Aged , Exercise Test , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myocardial Ischemia , Predictive Value of Tests , Prognosis
8.
Dis Colon Rectum ; 50(7): 962-70, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17468975

ABSTRACT

PURPOSE: This study was designed to assess the feasibility of a combined colorimetric and radioisotopic technique in the detection of the sentinel lymph node in colorectal cancer. METHODS: This prospective dual-center study included 64 patients. Using endoscopy on D0, a radiolabeled colloid was injected into the peritumoral submucosa, followed by a lymphoscintigraphy. Intraoperatively, on D1, lymphatic mapping was performed by using a visual method and radioguided detection after subserosal peritumoral injection of patent blue. Twenty-nine patients were injected only with the patent blue, 18 patients only with the radioactive tracer, and the other 17 patients benefited from both techniques. RESULTS: The detection rate was 92 percent. The average number of sentinel nodes harvested was 2.8. Twenty-four of 59 patients were pN+ (40 percent) and in 12 cases the sentinel lymph node was histologically negative, although there was a positive nonsentinel node (false-negative rate, 50 percent). The false-negative rate for the combined, radioisotopic, and colorimetric techniques were 63, 60, and 36 percent, respectively. In four patients, the sentinel node was the only metastatic site (4/24, 17 percent), and in two of these four patients, the sentinel lymph node presented with micrometastases (<2 mm). The radioisotopic technique allowed us to highlight a lateral drainage of two rectal cancers (2/13, 15 percent). The concordance between the blue and radioactive sentinel nodes was 43 percent. CONCLUSIONS: The addition of a radioisotopic method using submucosal injection does not improve the false-negative rate. The sentinel lymph node technique in colorectal cancer is feasible, although the false-negative rate is such that the technique should still be considered as experimental.


Subject(s)
Colorectal Neoplasms/diagnostic imaging , Colorectal Neoplasms/pathology , Coloring Agents , Rosaniline Dyes , Sentinel Lymph Node Biopsy/methods , Aged , Aged, 80 and over , Colonoscopy , Colorimetry , Coloring Agents/administration & dosage , False Negative Reactions , Female , Follow-Up Studies , Humans , Injections, Intralesional , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Male , Middle Aged , Neoplasm Staging/methods , Predictive Value of Tests , Prospective Studies , Radionuclide Imaging , Retroperitoneal Space , Rosaniline Dyes/administration & dosage
9.
Eur J Nucl Med Mol Imaging ; 33(10): 1206-13, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16763818

ABSTRACT

PURPOSE: Intensive proliferation and a high degree of migration and invasion are characteristic features of malignant glioblastomas, associated with a poor prognosis. Phosphatidylinositol-3-kinase (Pi3-K) and protein kinase C (PKC) are two phosphorylated proteins involved in glioblastoma cell progression. Phosphorylated focal adhesion protein kinase (FAK) has also been reported to be involved in tumour progression. In a recent study, we demonstrated a correlation between phosphorylated FAK, proliferation rate and 99mTc-(V)-dimercaptosuccinate [(V)-DMSA] uptake. We hypothesised that 99mTc-(V)-DMSA could be a potential imaging agent to evaluate glioblastoma aggressiveness. The aim of the present study was to assess the relationship between 99mTc-(V)-DMSA incorporation rate and modulation of Pi3-K and PKC activity. METHODS: Proliferation, migration and invasion capacities in the presence of protein kinase modulators-staurosporine (PKC inhibitor), 4-phorbol 12-myristate 13-acetate (PMA; PKC activator) and LY294002 (Pi3-K inhibitor)-were correlated with 99mTc-(V)-DMSA cell accumulation in an in vitro model of several malignant glioma cells: G111 (grade II), U-87-MG (grade III) and G152 (grade IV). RESULTS: In all cell lines tested, LY294002 and staurosporine treatment inhibited cell proliferation, migration and invasion. In contrast, treatment with PMA stimulated tumour aggressiveness. 99mTc-(V)-DMSA uptake was strongly correlated with the % of cellular proliferation (r=0.8462) and the % of cellular migration (r=0.9081), and to a lesser extent with the % of cellular invasion (r=0.7761). CONCLUSION: Our results clearly demonstrated that 99mTc-(V)-DMSA reflects Pi3-K and PKC activity and is correlated with tumour aggressiveness. 99mTc-(V)-DMSA could be a reliable in vivo marker providing additional information on the biological status of malignant glioblastoma.


Subject(s)
Glioblastoma/diagnostic imaging , Glioblastoma/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase C/metabolism , Technetium Tc 99m Dimercaptosuccinic Acid/pharmacokinetics , Cell Line, Tumor , Enzyme Activation , Glioblastoma/pathology , Humans , Neoplasm Invasiveness , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Statistics as Topic
10.
Curr Cancer Drug Targets ; 6(3): 181-96, 2006 May.
Article in English | MEDLINE | ID: mdl-16712456

ABSTRACT

A major field of interest in nuclear medicine is in vivo tumor characterization and measurement of biological processes at cellular and molecular levels by means of positron emission tomography (PET) or single photon emission computed tomography (SPECT). Functional imaging with radiopharmaceuticals represents a useful noninvasive tool to evaluate the biological status of the tumor and its progression. The properties of radiopharmaceuticals are exploited for initial staging of cancer, assessment of recurrent or residual disease and, more recently, considerable progress has been made in the field of the evaluation of tumor response to treatment. PET and SPECT can both detect changes in tumor activity caused by therapy or disease progression before any detectable change in tumor volume. Measurement of tumor response to therapy using PET and SPECT is the subject of intense investigations because it may result in individualization of treatment and may have a prognostic value for long-term outcome. This review focuses on the various methods used to monitor anticancer therapy with a variety of clinically approved or investigational tracers. We summarize the mechanisms of radiopharmaceutical uptake based on certain physiological activities affected by treatment: proliferation, apoptosis, hypoxia, angiogenesis and multidrug resistance (MDR).


Subject(s)
Neoplasms/diagnostic imaging , Radiopharmaceuticals , Animals , Apoptosis/drug effects , Cell Proliferation , DNA, Neoplasm/biosynthesis , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Humans , Hypoxia/diagnostic imaging , Neoplasms/metabolism , Neoplasms/pathology , Neovascularization, Pathologic/diagnostic imaging , Radionuclide Imaging
11.
Eur J Cancer ; 42(8): 1004-13, 2006 May.
Article in English | MEDLINE | ID: mdl-16564690

ABSTRACT

In vitro and in vivo studies have demonstrated inhibition of glioblastoma growth by imatinib mesylate (Gleevec). Imatinib is an inhibitor of the tyrosine kinase activities of platelet-derived growth factor receptor (PDGF-r), which is involved in glioblastoma aggressiveness. In this study, we have investigated the link between 99mTc-(V)-DMSA, an imaging agent used in Single Photon Emission Computed Tomography, cellular accumulation and the biological effects of imatinib mediated by PDGF-r in a human glioblastoma cell line U87-MG. Cells treated with imatinib showed significant decreases in proliferation, invasion, migration and PDGF-rbeta expression. 99mTc-(V)-DMSA cellular uptake studies showed that the specific action of imatinib on PDGF-r signal pathway, in the human glioblastoma cell line U87-MG, could be followed by radioactive tracer. Furthermore, strong correlations between cellular 99mTc-(V)-DMSA uptake and the effect of imatinib therapy on U87-MG proliferation (r=0.896), invasion (r=0.621) and migration (r=0.822) were obtained, likewise for 99mTc-(V)-DMSA uptake and PDGF-r expression (r=0.958). Our results show that the biological effects of imatinib therapy on tumour cells properties are linked to PDGF-r phosphorylation and could be traced with 99mTc-(V)-DMSA, which also seems to be a potential tracer to evaluate the response to imatinib therapy in glioblastoma.


Subject(s)
Antineoplastic Agents/therapeutic use , Glioblastoma/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Radiopharmaceuticals , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Technetium Tc 99m Dimercaptosuccinic Acid , Benzamides , Blotting, Western , Cell Line, Tumor , Cell Proliferation , Humans , Imatinib Mesylate , Protein Kinase Inhibitors/therapeutic use , Radiopharmaceuticals/pharmacokinetics , Technetium Tc 99m Dimercaptosuccinic Acid/pharmacokinetics , Tomography, Emission-Computed, Single-Photon/methods
12.
Surg Radiol Anat ; 27(6): 482-6, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16211322

ABSTRACT

The two essential regulating mechanisms of the middle ear pressure are the trans-mucosal gas exchange in the middle ear and the ventilation function of the eustachian tube (ET). The physiological mechanism of these both functions is not yet clear. The purpose of this study was to evaluate the role of the ET pressure equilibrium function by ventilation scintigraphy with technetium-99m. The rabbit animal model in vivo was used to study the presence and role of the ventilation of the tympanic cavity via auditory tube. The obtained results did not show any ventilation function of the ET despite active opening by muscle movement. In our experience, ventilation scintigraphy with technetium-99m is not a reliable method to study the auditory tube pressure equilibrium function in physiological conditions.


Subject(s)
Eustachian Tube/physiology , Radiopharmaceuticals , Sodium Pertechnetate Tc 99m , Aerosols , Animals , Deglutition/physiology , Ear, Middle/physiology , Eustachian Tube/diagnostic imaging , Imaging, Three-Dimensional/methods , Male , Models, Animal , Nasal Cavity/diagnostic imaging , Nasopharynx/diagnostic imaging , Nasopharynx/physiology , Pressure , Rabbits , Radionuclide Imaging , Radiopharmaceuticals/administration & dosage , Sodium Pertechnetate Tc 99m/administration & dosage , Tomography, X-Ray Computed/methods
13.
Cancer Biother Radiopharm ; 20(4): 391-400, 2005 Aug.
Article in English | MEDLINE | ID: mdl-16114987

ABSTRACT

The main cause of the multidrug resistance (MDR) of glioma cells is the overexpression of MRP-1, often associated with high levels of glutathione (GSH). We investigated whether MRP-1-related GSH content can influence (99m)Tc-glucarate entry by comparing its uptake with that of (99m)Tc-sestamibi (MIBI), an MRP- 1 probe, in an in vitro model of a sensitive cell line (U-87-MG) and a resistant derived cell line expressing MRP-1 (U-87-MG-R). Drug resistance was assessed by immunoblotting, GSH measurement, and Alamar Blue assay. To correlate MDR phenotype with tracer accumulation, uptakes were performed with and without modulators and after GSH depletion. Similar accumulation of (99m)Tc-glucarate was observed in the two cell lines, and the use of MDR reversals did not enhance its uptake. Our results clearly demonstrate that (99m)Tc-glucarate uptake is not related to MRP-1 expression or GSH levels. In contrast, (99m)Tc- MIBI accumulation is inversely proportional to the cell MDR phenotype. The combination of (99m)Tc-glucarate and (99m)Tc-MIBI may be a useful tool for the noninvasive detection of malignant sites and their chemoresistance status.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/biosynthesis , Carcinoma/pathology , Glioma/pathology , Glucaric Acid/analogs & derivatives , Glutathione/metabolism , Organotechnetium Compounds/pharmacokinetics , Blotting, Western , Cell Line, Tumor , Cell Survival , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Glucaric Acid/pharmacokinetics , Humans , In Vitro Techniques , Kinetics , Neoplasm Metastasis , Phenotype , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Time Factors
14.
Cancer Biother Radiopharm ; 20(3): 249-59, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15989470

ABSTRACT

The emergence of multidrug resistance (MDR) is a major obstacle to successful chemotherapy of malignant glioma tumors. Overexpression of the multidrug resistance-associated protein isoform 1 (MRP1), associated with a high level of intracellular glutathione (GSH), is a well-characterized mechanism of MDR in glioma cells. Previously, we have investigated the role of GSH and MRP1 in the accumulation of two radiopharmaceuticals classically used in nuclear medicine: (99m)Tc-sestamibi (MIBI) and (99m)Tc-tetrofosmin (TFOS), in a model of glioma cell lines. Although the involvement of GSH in MRP1-mediated transport of the two radiopharmaceuticals has been demonstrated, the exact transport mechanisms involving phase II (conjugation) and phase III (efflux) detoxification of these lipophilic cations has not been fully elucidated. To clarify the difference of release kinetics observed between MIBI and TFOS, we have studied the efficiency of formation of monogluthationyl conjugates mediated by glutathione S-transferses (GSTs). Our results clearly demonstrate that, in our model, the main efflux mechanism for radiopharmaceuticals is on monoglutathionyl-conjugates of MIBI (MIBI-SG) and TFOS (TFOS-SG). These mechanisms involving MRP1, and the phase II of detoxification is not efficient for TFOS in resistant glioma cells. A relatively slower catalytic efficiency of formation of TFOS-SG conjugate (0.006%.s(-1)) prevents its expulsion, contrary to MIBI (0.133%.s(-1)), suggesting that TFOS should be interesting in the detection and management of patients with high-grade glioma.


Subject(s)
Glioma/metabolism , Glioma/radiotherapy , Multidrug Resistance-Associated Proteins/metabolism , Organophosphorus Compounds/pharmacokinetics , Organotechnetium Compounds/pharmacokinetics , Technetium Tc 99m Sestamibi/analogs & derivatives , Technetium Tc 99m Sestamibi/pharmacokinetics , Catalysis , Cell Line, Tumor , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Glutathione/metabolism , Humans , Kinetics , Organophosphorus Compounds/metabolism , Organotechnetium Compounds/metabolism , Phenotype , Technetium Tc 99m Sestamibi/metabolism
15.
Eur J Nucl Med Mol Imaging ; 32(7): 820-7, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15785954

ABSTRACT

PURPOSE: Although a number of prognostic indicators have been developed, it is still difficult to predict the biological behaviour of all cancer types.( 99m)Tc-(V)-DMSA (V DMSA) uptake and focal adhesion kinase (FAK) expression and activation level could be potential agents for this purpose. We hypothesised the existence of a correlation between V DMSA, whose uptake is linked to phosphate ions, essential compounds for tumour growth and cell proliferation, and the adhesion protein FAK, whose elevated expression and level of constitutive activation are implicated in cancer progression. The aim of this study was to assess the relationship between V DMSA incorporation rate and FAK expression and activation by phosphorylation on tyrosine 397 residue. METHODS: We determined V DMSA uptake in six different cancer cell lines and we measured FAK expression and activation by using Western Blotting analysis. Correlations with factors known to be associated with poor prognosis, such as invasive potential, resistance to chemotherapy and proliferation rate, were also investigated. RESULTS: The cell lines exhibited different V DMSA incorporation rates. In addition, these cells showed the same FAK expression, but various degrees of activation. A correlation was observed between V DMSA uptake and level of FAK phosphorylation and between V DMSA or constitutive FAK activation and proliferation rate. However, no correlation was shown between these parameters and the other factors tested, i.e. invasive potential and anticancer drug resistance. CONCLUSION: The results of this in vitro study clearly demonstrate that phosphorylation of FAK, proliferation rate and V DMSA uptake are closely related. Because proliferation and a high level of constitutive FAK activation are linked to cancer progression, it can be assumed that in vivo V DMSA uptake reflects tumour aggressiveness.


Subject(s)
Cell Line, Tumor/pathology , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Radiopharmaceuticals , Technetium Tc 99m Dimercaptosuccinic Acid , Antineoplastic Agents/pharmacology , Blotting, Western , Cell Proliferation , Humans , In Vitro Techniques , Ions , Kinetics , Neoplasm Invasiveness , Neoplasm Metastasis , Phosphates/chemistry , Phosphorylation , Prognosis , Radiopharmaceuticals/pharmacokinetics , Technetium Tc 99m Dimercaptosuccinic Acid/pharmacokinetics , Time Factors , Tyrosine/chemistry
16.
Chest ; 127(2): 443-8, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15705980

ABSTRACT

STUDY OBJECTIVES: The objective of this study was to evaluate the feasibility of the sentinel lymph node (SLN) biopsy in peripheral clinically stage I or II non-small cell lung cancer (NSCLC) using (99m)Tc colloid and a hand-held gamma detection probe, associated with a blue dye technique. DESIGN: Prospective study. SETTING: Royal Brompton Hospital, London, UK; and Hopital Nord, Saint Etienne, France. METHODS: After thoracotomy, a total of 2 mL patent blue dye mixed with 1,600 muCi (99m)Tc-albumin or (99m)Tc-colloid was injected into each quadrant of lung tissue immediately surrounding the tumor. Routine lymphadenectomy was carried out. The first lymph nodes to stain blue or radioactive, if any, were considered SLNs. RESULTS: Twenty-four patients were evaluated. We successfully identified 17 SLNs in 13 patients (detection rate, 54.2%). Mean time from injection to identification of SLNs was 18 min (range, 5 to 30 min). In nine cases, the SLN was blue and radioactive, in six cases only blue, and in two cases only radioactive. The pathologic status of the SLN reflected the pathologic status of other nodes of the routine lymphadenectomy except one case of false-negative SLN (14%). Four SLNs were in N2 stations (23.5%). CONCLUSIONS: The sentinel node mapping in NSCLC with blue dye and radioisotopic techniques is feasible, but the detection rate has to be improved. This technique is an accurate method of identifying the first node draining a tumor, although it is not yet sufficiently sensitive to have a role in reducing the extent of nodal dissection.


Subject(s)
Carcinoma, Non-Small-Cell Lung/diagnostic imaging , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Rosaniline Dyes , Sentinel Lymph Node Biopsy , Technetium Tc 99m Aggregated Albumin , Technetium Tc 99m Sulfur Colloid , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/surgery , Feasibility Studies , Female , Gamma Cameras , Humans , Lung Neoplasms/surgery , Lymph Node Excision , Male , Middle Aged , Neoplasm Staging , Prospective Studies , Radionuclide Imaging , Sensitivity and Specificity
17.
Cancer Biother Radiopharm ; 19(4): 411-21, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15453956

ABSTRACT

In our previous studies, we demonstrated a possible effect of cellular glutathione (GSH) depletion on plasma-membrane permeability and fluidity in glioma-cell lines. We therefore investigated the effect of GSH modulation on accumulation of two radiotracers, Tc-99m-sestamibi (MIBI) and Tc-99m-tetrofosmin (TFOS), and on plasma-membrane cholesterol content in sensitive U-87-MG and resistant U-87-MG-CIS and U-87-MG-MEL (MRP1 positive) human glioma-cell lines. GSH depletion was mediated by BSO pretreatment and addition of N-acetylcysteine reversed the effect. MIBI and TFOS uptakes, total cholesterol, and cholesteryl-ester contents were evaluated under each condition. In contrast with TFOS, MIBI accumulation was inversely proportional to the cell multidrug resistance phenotype. Similar cholesterol contents were observed in all cell lines, demonstrating that MRP1 did not modify lipid membrane composition. A decrease of intracellular GSH allows an increase of plasma-membrane cholesterol and a decrease of cholesteryl-ester content, which in turn results in spectacular TFOS uptake. The GSH status of the cells plays an important role in the plasma membrane cholesterol composition and TFOS uptake, which appears to be particularly sensitive to this modification. In contrast with MIBI, TFOS is not an MRP1 probe in glioma cells, and therefore appears to be a suitable tracer in this indication.


Subject(s)
Cholesterol Esters/metabolism , Glioma/drug therapy , Glutathione/analysis , Membrane Lipids/metabolism , Multidrug Resistance-Associated Proteins/analysis , Organophosphorus Compounds/pharmacokinetics , Organotechnetium Compounds/pharmacokinetics , Technetium Tc 99m Sestamibi/pharmacokinetics , Biological Transport , Buthionine Sulfoximine/pharmacology , Cell Line, Tumor , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Glioma/metabolism , Humans , Membrane Lipids/analysis
18.
Eur J Nucl Med Mol Imaging ; 31(10): 1421-7, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15205924

ABSTRACT

PURPOSE: Pentavalent 99mTc-dimercaptosuccinic acid [99mTc-(V)DMSA or (V)DMSA] is a marker of phosphate transport, entering cells specifically through type III NaPi co-transporters. Phosphate ion is known to be involved in cell metabolism, including the apoptotic cell death process. As phosphate accumulation decreases during apoptosis, we investigated the influence of type III NaPi co-transporter activity on (V)DMSA uptake during this type of cell death. METHODS: Uptake of (V)DMSA and phosphate was compared in a leukaemic cell line (U937) in vitro model after induction of apoptosis by a chemotherapeutic agent, etoposide (VP16). (V)DMSA biodistribution in nude mice during apoptosis was also investigated in a U937 xenograft in vivo model. The percentage of apoptosis in vitro and ex vivo was determined with annexin V fluorescein by flow cytometry. RESULTS: The in vitro results showed that, in parallel with the decrease in phosphate uptake during apoptosis, (V)DMSA accumulation is negatively correlated with the percentage of apoptosis. Biodistribution studies showed decreased accumulation of (V)DMSA in tumours after treatment with VP16. Animal studies also confirmed an inverse correlation between percentage of apoptosis in tumours and (V)DMSA uptake. CONCLUSION: The activity of type III NaPi co-transporter is inhibited during the early stages of apoptosis, leading to differential incorporation of (V)DMSA in viable cells and apoptotic cells both in vitro and in vivo.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Etoposide/administration & dosage , Leukemia/metabolism , Symporters/metabolism , Technetium Tc 99m Dimercaptosuccinic Acid/pharmacokinetics , Animals , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Leukemia/diagnostic imaging , Leukemia/drug therapy , Metabolic Clearance Rate , Mice , Mice, Nude , Organ Specificity , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Sodium-Phosphate Cotransporter Proteins , Tissue Distribution
19.
Eur J Nucl Med Mol Imaging ; 31(1): 77-84, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14557898

ABSTRACT

In vivo studies have demonstrated that pentavalent technetium-99m dimercaptosuccinic acid [(99m)Tc-(V)-DMSA] may be a useful tumour imaging agent. Several studies have suggested that (99m)Tc-(V)-DMSA uptake may be related to the structural similarity between the (99m)Tc-(V)-DMSA core and the PO(4)(3-) anion. As phosphate ions enter cells via NaPi cotransporters, we investigated whether (99m)Tc-(V)-DMSA uptake is mediated by NaPi cotransporters. (99m)Tc-(V)-DMSA and phosphate uptake kinetics were compared in three cancer cell lines (MCF-7, G152 and MG-63) under several conditions (with and without sodium and NaPi cotransporter inhibitor and at different pH). Determination of molecular NaPi cotransporter mRNA expression was performed by reverse-transcriptase polymerase chain reaction (Rt-PCR) assay. Results obtained in the presence of NaPi inhibitor, in sodium-free medium and at alkaline pH showed that (99m)Tc-(V)-DMSA accumulation is linked to NaPi cotransporter functionality. MCF-7 and G152 exhibited the same tracer uptake, whereas MG-63 showed the highest phosphate accumulation and the lowest (99m)Tc-(V)-DMSA uptake. These results were in accordance with mRNA NaPi expression, i.e. all cell lines expressed NaPi type III but MG-63 also co-expressed NaPi type I. The total level of NaPi cotransporter was highly correlated with phosphate accumulation, while the level of type III was related to (99m)Tc-(V)-DMSA uptake. We have demonstrated that (99m)Tc-(V)-DMSA uptake is specifically mediated by NaPi type III in cancer cells.


Subject(s)
Biomarkers, Tumor/metabolism , Neoplasms/diagnostic imaging , Neoplasms/metabolism , Phosphates/pharmacokinetics , Potassium Compounds/pharmacokinetics , Symporters/metabolism , Technetium Tc 99m Dimercaptosuccinic Acid/pharmacokinetics , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/metabolism , Cell Line, Tumor/diagnostic imaging , Cell Line, Tumor/metabolism , Glioblastoma/diagnostic imaging , Glioblastoma/metabolism , Humans , Hydrogen-Ion Concentration , Kinetics , Metabolic Clearance Rate , Osteosarcoma/diagnostic imaging , Osteosarcoma/metabolism , Phosphorus Radioisotopes/pharmacokinetics , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Sodium/metabolism , Sodium-Phosphate Cotransporter Proteins , Sodium-Phosphate Cotransporter Proteins, Type I
20.
Cancer Biother Radiopharm ; 18(5): 791-801, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14629827

ABSTRACT

The main causes of multidrug resistance (MDR) are overexpression of P-glycoprotein (P-gp) and multidrug resistance-associated protein isoform 1 (MRP1) often associated with high levels of glutathione (GSH). We investigated whether MDR phenotype can influence Tc-99m-(V)-DMSA [pentavalent technetium-99m-dimercaptosuccinic acid] entry by comparing its uptake with that of Tc-99m-sestamibi (MIBI) on an in vitro model of sensitive (MCF-7) and variant resistant cell lines. Drug resistance was assessed by immunoblotting, GSH measurement, and 3-[4,5-dimethylthiazol-2-yl]-2,5,diphenyl tetrazolium bromide (MTT) assay. To correlate MDR phenotype with tracer accumulation, uptakes were performed with and without P-gp and MRP1 inhibitors and after GSH modulation. Similar accumulation of Tc-99m-(V)-DMSA was observed in all cell lines and the use of MDR reversals did not enhance its uptake. Our results demonstrate clearly that Tc-99m-(V)-DMSA uptake is not related to either P-gp and MRP1 expression, or GSH levels. In contrast, Tc-99m-MIBI accumulation is inversely proportional to the cell MDR phenotype. The combination of Tc-99m-(V)-DMSA and Tc-99m-MIBI may be a useful tool for noninvasive detection of malignant sites and their chemoresistance status.


Subject(s)
Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Technetium Tc 99m Dimercaptosuccinic Acid/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Biological Transport/drug effects , Cell Line, Tumor , Doxorubicin/pharmacology , Glutathione/metabolism , Glutathione/pharmacology , Humans , Kinetics , Technetium Tc 99m Sestamibi/metabolism
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