Biomedical subjects

László Balkay

Publications and source records attributed to László Balkay.

16 recordsLinked to original sources

PubMed2006

Na+/Ca2+ exchanger inhibitors modify the accumulation of tumor-diagnostic PET tracers in cancer cells.

AIM: To establish the effects of Na(+)/Ca(2+) exchanger (NCX) blockers on 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)FDG) and (11)C-choline accumulation in different cancer cells. METHODS: The tumor cells were incubated with NCX inhibitors, and the uptakes of (18)FDG and (11)C-choline were measured. Flow cytometric measurements of intracellular Ca(2+) and Na(+) concentrations were carried out. The presence of the NCX antigen in the cancer cells was proved by Western blotting, flow cytometry and confocal laser scanning microscopy. RESULTS: The NCX is expressed at a noteworthy level in the cytosol and on the cytoplasmic membrane of the examined cells. Incubation of the cells with three chemically unrelated NCX blockers (bepridil, KB-R7943 or 3',4'-dichlorobenzamil hydrochloride) resulted in an increase in the intracellular Ca(2+) concentration, with a simultaneous decrease in the intracellular Na(+) concentration. The treatment with the NCX inhibitors increased the energy consumption of the tumor cells by 50-100%. Thapsigargin abolished the NCX-induced (18)FDG accumulation in the cells. The NCX blockers applied decreased the (11)C-choline accumulation of all the investigated cancer cells by 60-80% relative to the control. CONCLUSION: A possible masking effect of NCX medication must be taken into consideration during the diagnostic interpretation of PET scans.

Bepridil↗

PubMed2006

Paclitaxel modifies the accumulation of tumor-diagnostic tracers in different ways in P-glycoprotein-positive and negative cancer cells.

AIM: To study how paclitaxel treatment modifies the accumulation of tumor-diagnostic radiotracers in P-glycoprotein (P-gp) positive and negative cancer cells. METHODS: The accumulations of different P-gp substrates, including rhodamine 123, daunorubicin and [(99m)Tc]hexakis-2-methoxybutyl isonitrile ((99m)Tc-MIBI), were measured in P-gp-positive (A2780AD) and P-gp-negative human ovarian carcinoma cells (A2780) and JY human lymphoid B cells. The uptakes of the tumor-diagnostic tracers (11)C-choline and 2-[(18)F]fluoro-2-deoxy-d-glucose ((18)FDG) were measured in the same cell lines. The P-gp expression and function were demonstrated by flow-cytometry. RESULTS: The (18)FDG measurements revealed that the glucose metabolic rate was significantly higher (p<0.01) in the P-gp-positive A2780AD cells than in the P-gp-negative cells. Paclitaxel (1-70microM) increased the (18)FDG uptake (up to 200%) of both P-gp-positive and P-gp-negative cells, whereas it did not modulate their (11)C-choline uptake. Paclitaxel reinstated the (99m)Tc-MIBI accumulation of the A2780AD cells (to 1500% of the control) in a concentration-dependent manner, while it increased the uptake of the P-gp-negative cells to a lesser extent (to a maximum of 200% of the control). CONCLUSION: Paclitaxel modifies the uptake of tumor-diagnostic tracers in both P-gp-dependent and independent manners. Interpretation of the multifactorial effects of paclitaxel may promote a correct in vivo diagnosis of P-gp-positive and P-gp-negative tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Biphasic accumulation kinetics of [99mTc]-hexakis-2-methoxyisobutyl isonitrile in tumour cells and its modulation by lipophilic P-glycoprotein ligands.

AIM: To study the accumulation and washout kinetics of [99mTc]-hexakis-2-methoxyisobutyl isonitrile (99mTc-MIBI) in MDR positive and MDR negative tumour cells and how this is modified by lipophilic P-glycoprotein ligands. METHODS: The tumour cells were incubated in the presence and absence of the ligands and the uptakes of 99mTc-MIBI, rhodamine 123 and 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) were measured. RESULTS: The accumulation of 99mTc-MIBI in the tumour cells followed biphasic kinetics. Verapamil and cyclosporin A increased the membrane fluidity and significantly enhanced the 99mTc-MIBI uptake of the MDR negative cells, while the rhodamine 123 uptake was not affected. Verapamil significantly increased the uptake of rhodamine 123 and 18FDG but did not modify that of 99mTc-MIBI in the MDR positive cells. Cyclosporin A significantly increased the 18FDG uptake of the MDR positive and negative tumour cells; these effects were ouabain-sensitive. Depolarization of the cytoplasmic membrane, acidification of the extracellular medium and the administration of CCCP decreased the accumulation of 99mTc-MIBI and rhodamine 123 uptake in the tumour cells. CONCLUSIONS: Lipophilic P-glycoprotein ligands modified the biphasic accumulation kinetics of the 99mTc-MIBI uptakes of MDR negative and positive tumour cells in different and complex ways and could therefore mask the P-glycoprotein pump-dependent changes in tracer accumulation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Effects of vinpocetine on the redistribution of cerebral blood flow and glucose metabolism in chronic ischemic stroke patients: a PET study.

The pharmacological effects of the neuroprotective drug vinpocetine, administered intravenously in a 14-day long treatment regime, on the cerebral blood flow and cerebral glucose metabolism in chronic ischemic stroke patients (n=13) were studied with positron emission tomography in a double-blind design. The regional and global cerebral metabolic rates of glucose (CMRglc) and cerebral blood flow (CBF) as well as vital physiological parameters, clinical performance scales, and transcranial Doppler parameters were measured before and after the treatment period in patient groups treated with daily intravenous infusion with or without vinpocetine. While the global CMRglc values did not change markedly as a result of the infusion treatment with (n=6) or without (n=7) vinpocetine, the global CBF increased and regional CMRglc and CBF values showed marked changes in several brain structures in both cases, with more accentuated changes when the infusion contained vinpocetine. In the latter case the highest rCBF changes were observed in those structures in which the highest regional uptake of labelled vinpocetine was measured in other PET studies (thalamus and caudate nucleus: increases amounting to 36% and 37%, respectively). The findings indicate that a 2-week long intravenous vinpocetine treatment can contribute effectively to the redistribution of rCBF in chronic ischemic stroke patients. The effects are most pronounced in those brain regions with the highest uptake of the drug.

Brain Chemistry↗

PubMed2005

Effects of miltefosine on membrane permeability and accumulation of [99mTc]-hexakis-2-methoxyisobutyl isonitrile, 2-[18F]fluoro-2-deoxy-D-glucose, daunorubucin and rhodamine123 in multidrug-resistant and sensitive cells.

Miltefosine is a phospholipid analog that exhibits antineoplastic activity against breast cancer metastases, but its mechanism of action remains uncertain. The aim of this study was to investigate the transport mechanism for the removal of miltefosine and [99mTc]-hexakis-2-methoxyisobutyl isonitrile (99mTc-MIBI) from multidrug-resistant cells. The P-glycoprotein pump function, cell viability, and 99mTc-MIBI and 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) uptakes were measured in NIH 3T3 (3T3) and NIH 3T3MDR1 G185 (3T3MDR1) mouse fibroblasts and human lymphoid B JY cells. Miltefosine treatment increased the permeability and fluidity of these tumor cells in a concentration-dependent manner. The multidrug-sensitive cells were 3-4 times more sensitive to miltefosine than the multidrug-resistant ones. The extent of 99mTc-MIBI accumulation in the P-glycoprotein-expressing cells increased in the presence of miltefosine, whereas the rhodamine123 and daunorubicin uptakes of the cells did not change significantly. In the 3T3MDR1 cells verapamil reinstated the rhodamine123 and daunorubicin accumulation, but not the 99mTc-MIBI uptake. Cyclosporin A reinstated the uptakes of 99mTc-MIBI, daunorubicin and rhodamine123 by the 3T3MDR1 cells. In a concentration-dependent manner miltefosine decreased the extents of 99mTc-MIBI, rhodamine123, daunorubicin and 18FDG accumulation in the JY and 3T3 cells. Our findings indicate a common transport mechanism for 99mTc-MIBI and miltefosine, which is distinct from that for rhodamine123 and daunorubicin in MDR cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Detection of prostate cancer with 11C-methionine positron emission tomography.

PURPOSE: We studied the detection of primary prostate cancer with positron emission tomography (PET) using C-labeled methionine (MET) in patients with increased prostate specific antigen (PSA) levels and repeatedly negative biopsies. MATERIALS AND METHODS: A total of 20 consecutive patients with increased serum PSA and negative repeat biopsies were included in the study. Patient age ranged from 52 to 75 years (average 65). PSA levels ranged from 3.49 to 28.6 ng/ml (average 9.36). Dynamic PET images were obtained from the prostate region using C-labeled MET. Suspicious accumulations of the tracer were anatomically localized using magnetic resonance images and were used as guidance during the next biopsy. RESULTS: PET was positive in 15 (75%) patients, in 7 of whom (46.7%) the next repeat biopsy verified carcinoma. The overall detection rate was 35% (7 of 20) and 46.7% (7 of 15) in the whole group and in the positive PET group, respectively. All 5 of 5 patients with negative MET PET had negative biopsies. CONCLUSIONS: MET PET of the prostate with short dynamic scanning and multicore biopsy is a useful method to ensure a high detection rate of prostate cancer in patients with increased PSA and repeat negative biopsies.

Aged↗

PubMed2003

In vivo and in vitro multitracer analyses of P-glycoprotein expression-related multidrug resistance.

P-glycoprotein (Pgp) is an ABC (ATP binding cassette) transporter that is often overexpressed in tumours, contributing significantly to their multidrug resistance. In this study, we explored whether the radiotracers used in tumour diagnostics can be used for in vivo visualisation of Pgp-related multidrug resistance. We also examined the effects of different Pgp modulators on the accumulation of these radioligands in tumours with or without Pgp expression. In a SCID BC-17 mouse model, cells of the drug-sensitive KB-3-1 (MDR(-)) and the KB-V1 Pgp-expressing (MDR(+)) human epidermoid carcinoma cell lines were inoculated to yield tumours in opposite flanks. For in vivo scintigraphic (biodistribution) and positron emission tomography (PET) examinations, the mice were injected with technetium-99m hexakis-2-methoxybutylisonitrile ((99m)Tc-MIBI), carbon-11 labelled methionine and fluorine-18 fluoro-2-deoxy- d-glucose ((18)FDG). For validation, in vitro cell studies with (99m)Tc-MIBI,( 99m)Tc-tetrofosmin, [(11)C]methionine and (18)FDG were carried out using a gamma counter. The expression and function of the MDR product were proved by immunohistochemistry and spectrofluorimetry. (99m)Tc-MIBI uptake was significantly lower in KB-V1 cells as compared with KB-3-1-derived tumours in vivo (Pgp(+)/Pgp(-) =0.61+/-0.13; P<0.01) and cells in vitro (Pgp(+)/Pgp(-) =0.08+/-0.01; P<0.001).()Cyclosporin A reversed (99m)Tc-MIBI uptake in the Pgp+ cells, while verapamil failed to modify it. (18)FDG uptake was significantly higher in KB-V1 tumours (Pgp(+)/Pgp(-) =1.36+/-0.05; P<0.01) and cells (Pgp(+)/Pgp(- )=1.52+/-0.12; P<0.001). Whereas cyclosporin A eliminated the difference between FDG uptake in MDR(+) and MDR(-) cell lines, verapamil significantly increased it. When the animals were treated with verapamil, the ratio of (99m)Tc-MIBI uptake in the MDR(+) tumours to that in the MDR(-) tumours decreased to 0.38+/-0.05 ( P<0.01), while the ratio of (18)FDG uptake increased to 2.1+/-0.3 ( P<0.001). There were no significant differences in the [(11)C]methionine uptake in the MDR(+) and MDR(-) tumours and cell lines, nor was [(11)C]methionine accumulation modified by cyclosporin A. Parallel administration of (18)FDG and (99m)Tc-MIBI combined with verapamil treatment seems to be a good candidate as a non-invasive marker for the diagnosis of MDR-related Pgp expression in tumours.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Cortical projection of peripheral vestibular signaling.

The cerebral projection of vestibular signaling was studied by using PET with a special differential experimental protocol. Caloric vestibular stimulation (CVS)-induced regional cerebral blood flow (rCBF) changes were investigated in two populations. Butanol perfusion scans were carried out on six healthy volunteers and on six patients following the removal of tumors from the right cerebello pontine angle. The complete loss of the vestibular function postoperatively allowed a comparison of the rCBF changes in the populations with or without this input and offered a promising functional approach whereby to delineate the cortical region most responsive to pure vestibular input. The activations by left-sided and right-sided CVS were determined for both the healthy volunteers and the patient population. Statistical analysis of the data obtained following left-sided CVS did not reveal any cerebral region for which there was a significant difference in CVS-induced response by these two populations. In the case of right-sided CVS, however, the statistical comparison of the CVS-related responses demonstrated a single contralateral area characterized by a significantly different degree of response. This cortical area corresponds to part of the cortical region described recently which can be activated by both CVS and neck vibration. It appears to be anatomically identical to the aggregate of the somatosensory area SII and the retroinsular cortex described in primates, a region identified by other investigators as an analog of the parietoinsular vestibular cortex.

Brain Mapping↗

PubMed2002

[Spatial standardization of [15O]-butanol PET images using T1-weighted MRI data].

Population averaged brain activation studies require the spatial standardization of the individual perfusion PET images. This procedure is usually supported by T1-weighted MRI images. The authors developed a segmentation technique to improve the automatized transformation of the individual MRI images into Talairach space. It was for the first time in Hungary that population averages of standardized T1-weighted MRI and [15O]-butanol PET images of the brain were created after validation of the procedure using data from 23 healthy volunteers. The newly developed method offers a solution for the automatized processing of primary data from brain activation experiments prior to statistical analysis.

Adult↗

PubMed2002

[Comparative analysis of quantitative evaluation methods for FDG-PET scans].

The comparative analysis of two kinetic methods most frequently applied for the quantization of the results of FDG-PET brain scans was performed applying PET investigations and computer simulations. The analysis of the measured data and computer simulation demonstrated that the applicability of the results of SUV-methods to estimate glucose metabolic rates (GMR) as calculated by the Phelps-method (the most advanced method ) depended on the selected cerebral region. The distorted estimation was explained by the fact that the simpler models neglect dephosphorylation of the FDG-6P, and they also disregard the contribution of the intravascular activity to the tissue radioactivity. The simulations revealed the lack of a general and close positive correlation between SUV and GMR data; under special circumstances they might even change in an inverse manner.

Computer Simulation↗

PubMed2002

[The PET scan in neuro-oncology--indications, differential diagnosis and clinical application].

Results of 157 PET (positron emission tomography) studies in 102 patients with known or presumed intracranial (ic.) tumors are reviewed. In 106 studies [18F]-2-fluoro-2-deoxy-D-glucose (FDG) and in 51 cases [11C]-methionine (MET) was used as the PET tracer. CT and MRI imaging accompanied the PET studies in each case. Results of pre- and/or postoperative studies are compared. PET was concluded to have a fundamental role in the precise differential diagnosis in case of ic. space-occupying pathologies since it is capable of providing information that is not obtainable or may be equivocal based solely on CT and/or MRI investigations. However, it is also mandatory to be aware of the limits of PET.

Adolescent↗

PubMed2002

[FDG-PET-scan in subarachnoid hemorrhage].

Ruptured aneurysms cause subarachnoidal hemorrhage (SAH) that may or may not result in neurological sequelae. Acute SAH has been shown to reduce cerebral blood flow and metabolism. An important question is whether or not the SAH induced vasospasm without clinical symptoms leads to cerebral ischemia? Using postoperative [18F]-fluorodeoxyglucose positron emission tomography in patients with vasospasm diagnosed by transcranial Doppler without clinical changes, hypermetabolism was detected as an indicator of diffuse compensated ischemia in 6 cases. In 2 patients with neurological deficit reduced glucose metabolism was observed in the frontal and temporal-basal cortex.

Adult↗

PubMed2002

[The role of PET scan among cardiologic imaging methods].

The PET technique has been available for myocardial viability studies in Hungary since 1994. The early comparative results showed that FDG-PET identified more potentially reversible myocardial damages than [201Tl]-scintigraphy, defining the viability either by preserved metabolic activity of 50% or by metabolism-perfusion mismatch. According to the follow up of revascularized patients in our cases, FDG-PET had a positive predictive value for functional recovery at 80%. In our opinion, it is the detection of glucose metabolism that predicts with the greatest accuracy segments of hibernating myocardial tissue that will recover after revascularization. Unlike dobutamine echocardiography, PET can detect viable ventricular segments in the myocardium of lost contractile material often seen in the histological studies of chronically ischemic myocardium. The FDG-PET method can be regarded as the gold standard of myocardial viability.

Adult↗

PubMed2002

[In vivo investigation of the A2A adenosine receptor distribution using the [11C]-CSC radioligand].

A 11C labeled selective adenosine A2A antagonist, (E)-8-(3-chlorostyryl)-1,3-dimethyl-7-[11C]-methylxanthine [(11C)-CSC] was prepared reacting (E)-8-(3-chlorostyryl)-1,3,-dimethylxanthine and [11C]-methyl iodide. A primary evaluation of [11C]-CSC as a potential tracer for mapping adenosine A2A receptors by positron emission tomography (PET) was also presented. Autoradiographic studies were carried out on Swiss mice. A high level accumulation of radioactivity was observed in the striatum and medulla oblongata in accordance with previous findings on the specific spatial distribution of A2A adenosine receptors. Dynamic PET studies on rabbits showed a fast brain uptake of CSC, reaching a maximum in less than 2 minutes. Competition experiments with the unlabeled ligand proved [11C]-CSC to bind specifically to the appropriate receptor.

Animals↗

PubMed2002

[The [18F]-FNECA serves as a suitable radioligand for PET investigation of purinergic receptor expression].

The well known and widely used P1 adenosine agonist, 5'-N-ethyl-carboxamidoadenosine (NECA), was labelled with 18F isotope for the in vivo PET investigation of A1, A2 and A3 adenosine receptor expression. The precursor 2-[18F]fluoroethylamine was reacted with 2',3'-O-isopropylideneadenosine-5'-uronic acid. Specific activity of the [18F]-FNECA was (2.3 +/- 1.1) TBq/mmol (60 Ci/mmol). Dynamic PET measurements were carried out in rabbits to study the in vivo kinetics of the receptor saturation with the labelled ligand. The time dependent accumulation was followed up in the heart, lungs, liver, brain and testis. The radiotracer uptake was rapid and reached its maximum in less than two minutes in the heart and testes after v. injection of the radiopharmaceutical, while it took about 6 minutes in the brain, lungs and liver. High [18F]-FNECA accumulation was detected in the intestines, too. The specific binding of the [18F]-FNECA was tested in competition experiments in brain and heart sections using autoradiographic technique. The outlined synthesis provided sufficient amounts of [18F]-FNECA to map adenosine receptor expression under physiological conditions.

Adenosine-5'-(N-ethylcarboxamide)↗

PubMed2002

A1 and A2 adenosine receptor activation inversely modulates potassium currents and membrane potential in DDT1 MF-2 smooth muscle cells.

Adenosine receptors are widely distributed in mammalian tissues and have been possibly involved through transmembrane potential changes in cell function regulation. The effect of A1 and A2A adenosine receptor ligands on transmembrane potential measured with flow cytometry and potassium conductance measured by the patch-clamp technique was investigated in DDT1 MF-2 smooth muscle cells. The A1 adenosine-receptor agonist CPA (50 nM) and the A2A adenosine-receptor agonist CGS 21680 (50 nM) elicited a rapid and maintained increase and decrease in the potassium conductance, respectively, and a concomitant hyperpolarization and depolarization of the membrane, respectively. These effects were eliminated by subtype-selective adenosine receptor antagonists (DPCPX, CSC, ZM 241385, all 1 microM). The ligand induced membrane potential changes were reversible. Based on these detected membrane potential changes along with the published voltage dependence of the adenylyl cyclase, the regulation of cAMP production by A1- and A2A-receptor activation is suggested to be mediated through the induced early hyperpolarization and depolarization. The interaction between the effects of these receptor subtypes allows for a complex regulation mechanism.

Animals↗