Radiolabeled cholecystokinin/gastrin (CCK) receptor-targeting peptides are promising compounds for radiodiagnosis and radiotherapy of certain malignancies. This study evaluated the pharmacokinetic profile of a CCK-2 receptor-specific peptide, Demogastrin 1, labeled with technetium-99m ((99m)Tc-Demogastrin 1), in rats. To investigate the fate of (99m)Tc-Demogastrin 1 in the rat, biodistribution and elimination studies in vivo were performed, and elimination parameters in perfused rat liver and kidney were determined. Biodistribution studies showed that (99m)Tc-Demogastrin 1 was rapidly cleared from the blood and most organs. A significant amount of radioactivity was detected in the CCK-2 receptor-rich organs, such as the stomach. Low radioactivity was found in the CCK-1 receptor-rich organs. Radioactivity in bowels and stomach declined relatively slowly. High and long-term retention of radioactivity in the kidneys was observed. Elimination of (99m)Tc-Demogastrin 1 via the bile was negligible. A high and rapid renal excretion was observed in elimination experiments in vivo. In the perfused kidney, glomerular filtration was found to be the main renal excretion mechanism of (99m)Tc-Demogastrin 1. Demogastrin 1 was distributed preferentially to the organs expressing CCK-2 receptors. The decisive elimination route of (99m)Tc-Demogastrin 1 in rats was urinary excretion. A high and prolonged renal retention may limit potential clinical use of the compound.
- MeSH
- gastriny farmakokinetika MeSH
- izotopové značení metody MeSH
- játra metabolismus MeSH
- krysa rodu rattus MeSH
- ledviny metabolismus MeSH
- potkani Wistar MeSH
- radiofarmaka farmakokinetika MeSH
- receptor cholecystokininu B metabolismus MeSH
- technecium farmakokinetika MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: The humanized monoclonal antibody Nimotuzumab (h-R3) has demonstrated an exceptional and better clinical profile than other monoclonal antibodies for immunotherapy of epidermal growth factor receptor-overexpressing tumors. This work deals with the preparation and radiolabeling optimization of (177)Lu-Nimotuzumab and their preclinical evaluation. METHODS: Nimotuzumab was conjugated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), testing different molar ratios. The immunoconjugates were characterized. The radiolabeling with (177)Lu was optimized. Radioimmunoconjugates stability was tested in 2-[bis[2-[bis(carboxymethyl)amino]ethyl]amino]acetic acid (DTPA) excess and human serum. In vitro studies were performed in tumor model cell lines. Receptor-specific binding was tested by competitive inhibition. (177)Lu-Nimotuzumab in vivo studies were conducted in healthy and xenograft animals. RESULTS: Nimotuzumab conjugates were obtained with high purity. Radiolabeling yield and specific activities ranged from 63.6% to 94.5% and from 748 to 1142 MBq/mg, respectively. The stability in DTPA excess and human serum was 95.9% and 93.2% after 10 days, respectively. The radioimmunoconjugate showed specific receptor binding in tumor cell lines. Biodistribution in healthy animals showed the typical behavior of the immunoconjugates based on monoclonal antibodies. The study in xenografts mice demonstrated uptake of (177)Lu-Nimotuzumab in the tumor and reticuloendothelial organs. CONCLUSIONS: (177)Lu-Nimotuzumab was obtained with high purity and specific activities under optimal conditions without significant loss in immunoreactivity and might be a potential radioimmunoconjugate for radioimmunotherapy of tumors with epidermal growth factor receptor overexpression.
- MeSH
- časové faktory MeSH
- chelátory farmakologie MeSH
- erbB receptory biosyntéza MeSH
- heterocyklické sloučeniny farmakologie MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- imunokonjugáty terapeutické užití MeSH
- isothiokyanatany farmakologie MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lutecium terapeutické užití MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory terapie MeSH
- potkani Wistar MeSH
- radioimunoterapie metody MeSH
- radionuklidy terapeutické užití MeSH
- regulace genové exprese u nádorů MeSH
- transplantace nádorů MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Somatostatin analogs (SSA) are the standard diagnostic and treatment tools in the clinical management of patients with neuroendocrine tumors (NETs) expressing somatostatin receptors (SSTRs). Although symptomatic and biochemical control is obtained with SSA in the majority of functional NETs, antineoplastic effects of SSA are partial and of limited duration. The aim of this study was to quantify expression levels of five SSTR subtypes (SSTR1-SSTR5) and correlate them with the clinical outcomes of patients with NETs who underwent SSA therapy. The expression levels were analyzed using real-time polymerase chain reaction in a series of 22 metastatic NETs with a median time of 10 months on the SSA therapy (range 2-82 months). The median duration of disease stabilization in patients who developed progression (n = 14) was 9 months (range 3-92 months). The median survival period for all patients was 44 months (range 3-175 months). According to RECIST criteria, one (5%) partial objective tumor response was obtained, disease stabilization was achieved in 10 (45%) patients, and progressive disease was observed in 11 (50%). Analysis of mRNA expression of the SSTR subtypes showed that SSTR2 and SSTR5 were expressed in all of the studied NETs; SSTR1 and SSTR4 in all but 3 tumors (86%); and SSTR3 in only 10 NETs (49%). Interestingly, our preliminary data suggest that only the levels of SSTR4, though it has the lowest affinity for SSA of all SSTR subtypes, were significantly associated with the stabilization of disease during SSA therapy (p = 0.0357). These levels correlated with time to progression (p = 0.0015) and overall survival (p = 0.0017) in NET patients.
- MeSH
- antitumorózní látky hormonální terapeutické užití MeSH
- dospělí MeSH
- exprese genu účinky léků MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfatické metastázy MeSH
- messenger RNA genetika MeSH
- míra přežití MeSH
- nádory jater farmakoterapie genetika sekundární MeSH
- nádory mediastina farmakoterapie genetika sekundární MeSH
- následné studie MeSH
- neuroendokrinní nádory farmakoterapie genetika patologie MeSH
- oktreotid terapeutické užití MeSH
- peritoneální nádory farmakoterapie genetika sekundární MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- radioizotopy india diagnostické užití MeSH
- receptory somatostatinu genetika MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
(166)Ho is a beta-emitter (E(_max) = 1.84 MeV, T1/2 = 26.7 hours) with a mean penetration in the soft tissue of 2.2 mm and gamma-photons 81keV and 1380keV. In this paper, we present our experiences with preparation of (166)Ho-macroaggregates ((166)Ho-MA) for radiosynoviorhesis. Ho-MA were prepared by reacting the aqueous solution of holmium nitrate pentahydrate with sodium borohydride solution in 0.2 M NaOH. After centrifugation, washing, and drying at 105 degrees C, final fineness of 1-15 microm was attained using a homogenizer working at 70,000 rpm. Neutron activation was carried out in screwed titanium ampules in a nuclear reactor at the neutron flux 10E12-10E14 neutrons.cm-24.s-1. The irradiated samples were allowed to cool 24 hours before further manipulation. (166)Ho-MA were clinically tested on 20 patients suffering from gonarthrosis (15), rheumatoid arthritis (5), psoriatic arthritis (1), and gout arthropathy (1). (166)Ho-MA are currently produced under GMP and production facility allows producing radioactivity for 6 patients within one production run.
In this paper, the authors present their experience with the radioiodine therapy of thyroid functional autonomies. The aims of this study were to establish the efficacy and determine the adverse effects of radioiodine therapy of patients with thyroid functional autonomies. Over a period of 31 years (from 1974 to 2005) 868 patients (766 women, 102 men with the age from 33 to 86 years; average age, 58.5) with unifocal functional autonomy, multifocal functional autonomy, and disseminated functional autonomy, received at least one treatment of radioiodine in our Department of Nuclear Medicine. For diagnostics and the evaluation of the radioiodine therapeutic effect of functional autonomies, a thyroid scintigraphy is the basic and necessary procedure. We have also performed a thyroid ultrasonography, an assessment of a serum level of a total and free thyroxine, total tri-iodothyronine, thyroid-stimulating hormone (TSH), the radioiodine accumulation test, the estimation of the radioiodine effective half-life, and in some patients, thyrotrophin-releasing hormone (TRH)-TSH test. The follow-up examinations were done in all patients after 4-6 months, another examination after 1 year in 585 patients, and after 2 years in 284 patients. One therapeutic dose received 798 patients (91.9%) and it was sufficient for an elimination of functional autonomies. Some patients were retreated if there was the evidence of small or no treatment effect and no elimination of functional autonomies. Sixty-six (66) patients (7.6%) received two radioiodine treatments and 4 patients (0.5%) three treatments. Before radioiodine therapy, an average serum level of total thyroxine was 165.8 nmol/L, of free thyroxine 21.2 pmol/L, and of total triiodothyronine 3.3 nmol/L, and in all patients, TSH was suppressed. Before therapy, patient complaints were cardiovascular in 87%, neurological in 72%, hypermetabolic in 70%, and local in 31% of patients. After therapy, the average serum levels of total thyroxine were 110.9 nmol/L, free thyroxine 12.7 pmol/L, and total triiodothyronine 2.1 nmol/L with an improvement of symptoms in 91.5% of patients, no improvement in 8.2% and a worsening in 0.3% of patients. The suppression of TSH disappeared in 668 of treated patients (77%). An average volume reduction of thyroid of 40% was achieved in any type of functional autonomy after radioiodine treatment. Side-effects were minimal, and in some patients, presented as a transient neck pressure or pain and neck swelling. Postradiation hypothyroidism was diagnosed in 38 patients (4.4%). The results of this study show that the radioiodine therapy of the thyroid functional autonomies is safe, with a low incidence of adverse effects. It is effective, and for patients, is a nondemanding procedure.
- MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- nemoci štítné žlázy epidemiologie patologie radioterapie MeSH
- radiofarmaka škodlivé účinky terapeutické užití MeSH
- radioizotopy jodu škodlivé účinky terapeutické užití MeSH
- radiometrie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
The aim of this study was to evaluate adverse and therapeutic effects of applicated holmium-boro-macroaggregates (HBMAs) in the radiosynoviorthesis (RSO) of knees in patients suffering from chronic synovitis. We started RSO of the knees by means of a new radiopharmaceutical (RF) HBMA in patients with gonarthrosis, rheumatoid arthritis, chronic synovitis, psoriatic arthritis, and gout arthropathy. Seventeen (17) intra-articular injections were performed in 15 patients who were receiving a mean activity of 972 MBq (range, 904-1057) of 166Ho-HBMA. Patient inclusion to the study followed a series of inclusion and exclusion criterions. The patients were hospitalized for 3 days. Side-effects were evaluated during their hospital stay and again after 6-8 weeks. Static scintigraphy of knee joints and measurements of blood radioactivity were performed. Therapeutic effects were evaluated after 6-8 weeks and at 6 months. In 2 hours and 2 days following the application, we proved, by means of knee and inguinal scintigraphy, only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes in 4 patients. In the treated patients, no serious adverse effects occurred. Nine (9) patients were without complaints, 4 patients had slight knee exudation, and 2 patients had great exudation. Therapeutic effects were as follows: 2 patients were without pain, 9 were with lower pain, 3 were with the same pain, and 1 patient was with increased pain. Joint motion was improved in 7 patients, remained the same in 7 patients, and was impaired in 1 patient. Analgesics consumption was lower in 5 patients, the same in 9 patients, and greater in 1 patient. Knee exudation was absent in 2 patients, lower in 4 patients, the same in 6 patients, and greater in 3 patients. In 3 patients it was necessary to do surgical RSO. This RF can extend the range of clinically used radiopharmaceuticals for RSO and to supplement space between 90Y with high energy and 186Re with 169Er with lower beta energy. The energy of 166Ho is suitable for great and medium joints (i.e., knees, hips, shoulders, elbows, wrists, and ankles).
- MeSH
- časové faktory MeSH
- dospělí MeSH
- holmium škodlivé účinky terapeutické užití MeSH
- koleno patologie účinky záření MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- synovitida patologie radioterapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- klinické zkoušky MeSH
- MeSH
- kolenní kloub patologie účinky záření MeSH
- lidé MeSH
- retrospektivní studie MeSH
- synovitida radioterapie MeSH
- Check Tag
- lidé MeSH
- MeSH
- krysa rodu rattus MeSH
- ledviny MeSH
- nádory terapie MeSH
- oktreotid analogy a deriváty aplikace a dávkování farmakokinetika farmakologie MeSH
- radioaktivita MeSH
- radioizotopy ytria aplikace a dávkování MeSH
- somatostatin analogy a deriváty MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- MeSH
- arteria hepatica MeSH
- finanční podpora výzkumu jako téma MeSH
- imunoterapie adoptivní MeSH
- interleukin-2 farmakologie MeSH
- leukocyty MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové biomarkery MeSH
- nádory jater sekundární terapie MeSH
- převod jednotlivých krevních složek MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
