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Sample records for targeted radionuclide therapy

  1. Targeted Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    David Cheng

    2011-10-01

    Full Text Available Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.

  2. Targeted Radionuclide Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ersahin, Devrim, E-mail: devrimersahin@yahoo.com; Doddamane, Indukala; Cheng, David [Department of Diagnostic Radiology, School of Medicine, Yale University, 333 Cedar St., New Haven, CT 06520 (United States)

    2011-10-11

    Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.

  3. Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Ersahin, Devrim; Doddamane, Indukala; Cheng, David

    2011-01-01

    Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose

  4. Targeted radionuclide therapy

    African Journals Online (AJOL)

    target for which a speci c treatment/drug is intended (Fig. 1). eranostics .... Using an anti-CD20 antibody as a delivery device to target the follicular ... systems combine diagnostic imaging (Ga-68-DOTATATE PET/CT) .... Intra-articular injected ...

  5. Molecular Targets for Targeted Radionuclide Therapy

    International Nuclear Information System (INIS)

    Mather, S.J.

    2009-01-01

    Molecular targeted radionuclide cancer therapy is becoming of increasing importance, especially for disseminated diseases. Systemic chemotherapies often lack selectivity while targeted radionuclide therapy has important advantages as the radioactive cytotoxic unit of the targeting vector is specifically directed to the cancer, sparing normal tissues. The principle strategy to improve cancer selectivity is to couple therapeutic agents to tumour-targeting vectors. In targeted radionuclide therapy (TRT), the cytotoxic portion of the conjugates normally contains a therapeutic radiometal immobilised by a bifunctional chelator. The aim is therefore to use as ligand-targeted therapeutics vectors coupled to Auger-, alpha- and/or beta-emitting radionuclides. An advantage of using radiation instead of chemotherapeutics as the cytotoxic agent is the so called 'crossfire effect'. This allows sterilisation of tumour cells that are not directly targeted due to heterogeneity in target molecule expression or inhomogeneous vector delivery. However, before the targeting ligands can be selected, the target molecule on the tumour has to be selected. It should be uniquely expressed, or at least highly overexpressed, on or in the target cells relative to normal tissues. The target should be easily accessible for ligand delivery and should not be shed or down- regulated after ligand binding. An important property of a receptor (or antigen) is its potential to be internalized upon binding of the ligand. This provides an active uptake mechanism and allows the therapeutic agent to be trapped within the tumour cells. Molecular targets of current interest include: Receptors: G-protein coupled receptors are overexpressed on many major human tumours. The prototype of these receptors are somatostatin receptors which show very high density in neuroendocrine tumours, but there are many other most interesting receptors to be applied for TRT. The targeting ligands for these receptors are

  6. Research progess on treatment of cancer with targeted radionuclide therapy

    International Nuclear Information System (INIS)

    Luo Jiawen; Zhang Caixia

    2008-01-01

    The new development and situation of targeted radionuclide therapy in oncology is described, which include radioimmunotherapy, peptide receptor radionuclide therapy, gene therapy and radionuclide labled chemotherapeutics therapy. The application research on labled carrier of those therapy is emphasized. Meanwhile, the research progess of indomethacin and its combined with targeted radionuclide therapy is also described. (authors)

  7. Introduction to radiobiology of targeted radionuclide therapy

    Directory of Open Access Journals (Sweden)

    Jean-Pierre ePOUGET

    2015-03-01

    Full Text Available During the last decades, new radionuclide-based targeted therapies have emerged as efficient tools for cancer treatment. Targeted radionuclide therapies (TRT are based on a multidisciplinary approach that involves the cooperation of specialists in several research fields. Among them, radiobiologists investigate the biological effects of ionizing radiation, specifically the molecular and cellular mechanisms involved in the radiation response. Most of the knowledge about radiation effects concerns external beam radiation therapy (EBRT and radiobiology has then strongly contributed to the development of this therapeutic approach. Similarly, radiobiology and dosimetry are also assumed to be ways for improving TRT, in particular in the therapy of solid tumors which are radioresistant. However, extrapolation of EBRT radiobiology to TRT is not straightforward. Indeed, the specific physical characteristics of TRT (heterogeneous and mixed irradiation, protracted exposure and low absorbed dose rate differ from those of conventional EBRT (homogeneous irradiation, short exposure and high absorbed dose rate, and consequently the response of irradiated tissues might be different. Therefore, specific TRT radiobiology needs to be explored. Determining dose-effect correlation is also a prerequisite for rigorous preclinical radiobiology studies because dosimetry provides the necessary referential to all TRT situations. It is required too for developing patient-tailored TRT in the clinic in order to estimate the best dose for tumor control, while protecting the healthy tissues, thereby improving therapeutic efficacy. Finally, it will allow to determine the relative contribution of targeted effects (assumed to be dose-related and non-targeted effects (assumed to be non-dose-related of ionizing radiation. However, conversely to EBRT where it is routinely used, dosimetry is still challenging in TRT. Therefore, it constitutes with radiobiology, one of the main

  8. Radionuclide molecular target therapy for lung cancer

    International Nuclear Information System (INIS)

    Zhang Fuhai; Meng Zhaowei; Tan Jian

    2012-01-01

    Lung cancer harms people's health or even lives severely. Currently, the morbidity and mortality of lung cancer are ascending all over the world. Accounting for 38.08% of malignant tumor caused death in male and 16% in female in cities,ranking top in both sex. Especially, the therapy of non-small cell lung cancer has not been obviously improved for many years. Recently, sodium/iodide transporter gene transfection and the therapy of molecular target drugs mediated radionuclide are being taken into account and become the new research directions in treatment of advanced lung cancer patients with the development of technology and theory for medical molecular biology and the new knowledge of lung cancer's pathogenesis. (authors)

  9. Gene therapy and radionuclides targeting therapy in mammary carcinoma

    International Nuclear Information System (INIS)

    Song Jinhua

    2003-01-01

    Breast carcinoma's gene therapy is a hotspot in study of the tumor's therapy in the recent years. Currently the major therapy methods that in the experimentative and primary clinical application phases include immunological gene therapy, multidrug resistance gene therapy, antisense oligonucleotide therapy and suicide gene therapy. The gene targeting brachytherapy, which is combined with gene therapy and radiotherapy has enhanced the killer effects of the suicide gene and nuclide in tumor cells. That has break a new path in tumor's gene therapy. The further study in this field will step up it's space to the clinical application

  10. Targeted radionuclide therapy for solid tumors: An overview

    International Nuclear Information System (INIS)

    De Nardo, Sally J.; De Nardo, Gerald L.

    2006-01-01

    Although radioimmunotherapy (RIT) has been effective in non-Hodgkin's lymphoma (NHL) as a single agent, solid tumors have shown less clinically significant therapeutic response to RIT alone. The clinical impact of RIT or other forms of targeted radionuclide therapy for solid tumors depends on the development of a high therapeutic index (TI) for the tumor vs. normal tissue effect, and the implementation of RIT as part of synergistic combined modality therapy (CMRIT). Preclinical and clinical studies have provided a wealth of information, and new prototypes or paradigms have shed light on future possibilities in many instances. Evidence suggests that combination and sequencing of RIT in CMRIT appropriately can provide effective treatment for many solid tumors. Vascular targets provide RIT enhancement opportunities and nanoparticles may prove to be effective carriers for RIT combined with intracellular drug delivery or alternating magnetic frequency (AMF) induced thermal tumor necrosis. The sequence and timing of combined modality treatments will be of critical importance to achieve synergy for therapy while minimizing toxicity. Fortunately, the radionuclide used for RIT also provides a signal useful for nondestructive quantitation of the influence of sequence and timing of CMRIT on events in animals and patients. This can be readily accomplished clinically using quantitative high-resolution imaging (e.g., positron emission tomography [PET])

  11. Targeted radionuclide therapy for neuroendocrine tumours: principles and application.

    Science.gov (United States)

    Druce, Maralyn R; Lewington, Val; Grossman, Ashley B

    2010-01-01

    Neuroendocrine tumours comprise a group of neoplasms with variable clinical behaviour. Their growth and spread is often very slow and initially asymptomatic, and thus they are often metastatic at the time of diagnosis and incurable by surgery. An exciting therapeutic strategy for cytoreduction, both for stabilisation of tumour growth and inhibition of hormone production, is the use of targeted radionuclide therapy. Evidence from large-scale, randomised, placebo-controlled trials is very difficult to obtain in these rare diseases, but current data appear promising. It is timely to review the principles underlying the use of these therapies, together with the clinical outcomes to date and potential directions for future research. Copyright 2009 S. Karger AG, Basel.

  12. Production of 177Lu for targeted radionuclide therapy: Available options

    International Nuclear Information System (INIS)

    Dah, Ashutosh; Pillai, Maroor Raghavan Ambikalmajan; Knapp, Furn F. Jr.

    2015-01-01

    This review provides a comprehensive summary of the production of 177 Lu to meet expected future research and clinical demands. Availability of options represents the cornerstone for sustainable growth for the routine production of adequate activity levels of 177 Lu having the required quality for preparation of a variety of 177 Lu-labeled radiopharmaceuticals. The tremendous prospects associated with production of 177 Lu for use in targeted radionuclide therapy (TRT) dictate that a holistic consideration should evaluate all governing factors that determine its success. While both “direct” and “indirect” reactor production routes offer the possibility for sustainable 177 Lu availability, there are several issues and challenges that must be considered to realize the full potential of these production strategies. This article presents a mini review on the latest developments, current status, key challenges and possibilities for the near future. A broad understanding and discussion of the issues associated with 177 Lu production and processing approaches would not only ensure sustained growth and future expansion for the availability and use of 177 Lu-labeled radiopharmaceuticals, but also help future developments

  13. Current Status and Future Directions of Targeted Peptide Radionuclide Therapy

    International Nuclear Information System (INIS)

    Valkema, R.

    2009-01-01

    Current status: Peptide receptor radionuclide therapy (PRRT) is currently almost exclusively targeted at the somatostatin receptor (sst). Of the 5 receptor subtypes, sst2 is frequently very highly expressed at the cell surface of neuroendocrine tumors (NET). Octreotide is a small and stable derivative of native somatostatin, which can be very well labeled with therapeutic radionuclides such as the beta-emitters ''9''0Y, ''1''7''7Lu or the Auger emitter ''1''1''1In, chelated in DTPA or DOTA, linked to the peptide. All current therapeutic octreotide derivatives are agonists that are internalized in the cell. The affinity for the sst2 receptor is better for [DOTA,Tyr''3]octreotate than for [DOTA,Tyr''3]octreotide or [DTPA]octreotide. ''9''0Y is a pure beta-emitter, with a half-life of 2.7 days, a high energy of 2.270 MeV, and a maximum penetration in tissue of 12mm. ''1''7''7Lu with a half-life of 6.7 days emits a low abundance of gamma photons as well as beta particles of 497 keV, with a maximum tissue penetration of 2 mm. ''1''7''7Lu-[DOTA,Tyr''3]octreotate (Lu-DOTATE), ''9''0Y-[DOTA,Tyr''3]octreotate (Y-DOTATATE) and ''9''0Y-[DOTA,Tyr''3]octreotide (Y-DOTATOC) are today the most frequently used therapeutic radiopeptides. Main inclusion criteria: inoperable and/or metastatic NET, receptor-positivity in all known lesions demonstrated by sufficient uptake on ''1''1''1In-octreotide scintigraphy (intensity > liver parenchyma), life expectancy at least 3-6 months, sufficient bone marrow reserve (hemoglobin (HGB) ≥ 5 mmol/L, white blood cells (WBC) ≥ 2*10 9 /L, platelets (PLT) ≥ 75*10 12 /L), sufficient renal function (serum creatinine 40 mL/min), sufficient hepatic and cardiac reserve. Karnofski score ≥50. Efficacy: several groups have reported objective response rates (RECIST or WHO/SWOG; CT or MRI based). Complete remission (CR) is rarely seen, partial remission (PR; >50% shrinkage SWOG) in 7% - 37%, minor remission (MR, 25% - 50% shrinkage) in 13% - 17

  14. Inducement of radionuclides targeting therapy by gene transfection

    International Nuclear Information System (INIS)

    Luo Quanyong

    2001-01-01

    The author presents an overview of gene transfection methods to genetically induce tumor cells to express enhanced levels of cell surface antigens and receptors to intake radiolabeled antibody and peptide targeting and thus increase their therapeutic effect in radiotherapy. The current research include inducement of radioimmunotherapy through CEA gene transfection, inducement of iodine-131 therapy by sodium iodide symporter gene transfection and inducement of MIBG therapy by noradrenaline transporter gene transfection. These studies raise the prospect that gene-therapy techniques could be used to enable the treatment of a wide range of tumors with radiopharmaceuticals of established clinical acceptability

  15. Radioisotopes for imaging and radionuclide targeted therapy in nuclear medicine

    Czech Academy of Sciences Publication Activity Database

    Forsterová, Michaela; Zimová, Jana; Beran, Miloš

    -, - (2007), s. 76-77 ISSN N R&D Projects: GA AV ČR 1QS100480501 Institutional research plan: CEZ:AV0Z10480505 Keywords : metal radionuclides * bifunctional chelators Subject RIV: FR - Pharmacology ; Medidal Chemistry

  16. Patient-Specific Dosimetry and Radiobiological Modeling of Targeted Radionuclide Therapy Grant - final report

    Energy Technology Data Exchange (ETDEWEB)

    George Sgouros, Ph.D.

    2007-03-20

    The broad, long-term objectives of this application are to 1. develop easily implementable tools for radionuclide dosimetry that can be used to predict normal organ toxicity and tumor response in targeted radionuclide therapy; and 2. to apply these tools to the analysis of clinical trial data in order to demonstrate dose-response relationships for radionuclide therapy treatment planning. The work is founded on the hypothesis that robust dose-response relationships have not been observed in targeted radionuclide therapy studies because currently available internal dosimetry methodologies are inadequate, failing to adequately account for individual variations in patient anatomy, radionuclide activity distribution/kinetics, absorbed dose-distribution, and absorbed dose-rate. To reduce development time the previously available software package, 3D-ID, one of the first dosimetry software packages to incorporate 3-D radionuclide distribution with individual patient anatomy; and the first to be applied for the comprehensive analysis of patient data, will be used as a platform to build the functionality listed above. The following specific aims are proposed to satisfy the long-term objectives stated above: 1. develop a comprehensive and validated methodology for converting one or more SPECT images of the radionuclide distribution to a 3-D representation of the cumulated activity distribution; 2. account for differences in tissue density and atomic number by incorporating an easily implementable Monte Carlo methodology for the 3-D dosimetry calculations; 3. incorporate the biologically equivalent dose (BED) and equivalent uniform dose (EUD) models to convert the spatial distribution of absorbed dose and dose-rate into equivalent single values that account for differences in dose uniformity and rate and that may be correlated with tumor response and normal organ toxicity; 4. test the hypothesis stated above by applying the resulting package to patient trials of targeted

  17. Dosimetric model for antibody targeted radionuclide therapy of tumor cells in cerebrospinal fluid

    International Nuclear Information System (INIS)

    Millar, W.T.; Barrett, A.

    1990-01-01

    Although encouraging results have been obtained using systemic radioimmunotherapy in the treatment of cancer, it is likely that regional applications may prove more effective. One such strategy is the treatment of central nervous system leukemia in children by intrathecal instillation of targeting or nontargeting beta particle emitting radionuclide carriers. The beta particle dosimetry of the spine is assessed, assuming that the spinal cord and the cerebrospinal fluid compartment can be adequately represented by a cylindrical annulus. The radionuclides investigated were 90 Y, 131 I, 67 Cu, and 199 Au. It is shown that the radiation dose to the cord can be significantly reduced using short range beta particle emitters and that there is little advantage in using targeting carriers with these radionuclides. 199 Au and 67 Cu also have the advantage of having a suitable gamma emission for imaging, permitting pretherapy imaging and dosimetric calculations to be undertaken prior to therapy. If these methods prove successful, it may be possible to replace the external beam component used in the treatment of central nervous system leukemia in children by intrathecal radionuclide therapy, thus reducing or avoiding side effects such as growth and intellectual impairment

  18. Development and optimization of targeted radionuclide tumor therapy using folate based radiopharmaceuticals

    CERN Document Server

    Reber, Josefine Astrid

    The folate receptor (FR) has been used for a quarter of a century as a tumor-associated target for selective delivery of drugs and imaging agents to cancer cells. While several folic acid radioconjugates have been successfully employed for imaging purposes in (pre)clinical studies, a therapeutic application of folic acid radioconjugates has not yet reached the critical stage which would allow a clinical translation. Due to a substantial expression of the FR in the proximal tubule cells, radiofolates accumulate in the kidneys which are at risk of damage by particle-radiation. To improve this situation, we aimed to develop and evaluate strategies for the performance of FR-targeted radionuclide therapy by decreasing the renal uptake of radiofolates and thereby reducing potential nephrotoxic effects. Two different strategies were investigated. First, the combination of radiofolates with chemotherapeutic agents such as pemetrexed (PMX) and 5-fluorouracil (5-FU) and secondly, an approach based on radioiodinated fol...

  19. Targeted radionuclide therapy with astatine-211: Oxidative dehalogenation of astatobenzoate conjugates.

    Science.gov (United States)

    Teze, David; Sergentu, Dumitru-Claudiu; Kalichuk, Valentina; Barbet, Jacques; Deniaud, David; Galland, Nicolas; Maurice, Rémi; Montavon, Gilles

    2017-05-31

    211 At is a most promising radionuclide for targeted alpha therapy. However, its limited availability and poorly known basic chemistry hamper its use. Based on the analogy with iodine, labelling is performed via astatobenzoate conjugates, but in vivo deastatination occurs, particularly when the conjugates are internalized in cells. Actually, the chemical or biological mechanism responsible for deastatination is unknown. In this work, we show that the C-At "organometalloid" bond can be cleaved by oxidative dehalogenation induced by oxidants such as permanganates, peroxides or hydroxyl radicals. Quantum mechanical calculations demonstrate that astatobenzoates are more sensitive to oxidation than iodobenzoates, and the oxidative deastatination rate is estimated to be about 6 × 10 6 faster at 37 °C than the oxidative deiodination one. Therefore, we attribute the "internal" deastatination mechanism to oxidative dehalogenation in biological compartments, in particular lysosomes.

  20. Targeted radionuclide therapy with A 177Lu-labeled anti-HER2 nanobody.

    Science.gov (United States)

    D'Huyvetter, Matthias; Vincke, Cécile; Xavier, Catarina; Aerts, An; Impens, Nathalie; Baatout, Sarah; De Raeve, Hendrik; Muyldermans, Serge; Caveliers, Vicky; Devoogdt, Nick; Lahoutte, Tony

    2014-01-01

    RIT has become an attractive strategy in cancer treatment, but still faces important drawbacks due to poor tumor penetration and undesirable pharmacokinetics of the targeting vehicles. Smaller radiolabeled antibody fragments and peptides feature highly specific target accumulation, resulting in low accumulation in healthy tissue, except for the kidneys. Nanobodies are the smallest (MWnanobodies is predominantly dictated by the number of polar residues in the C-terminal amino acid tag. Three nanobodies were produced with different C-terminal amino-acid tag sequences (Myc-His-tagged, His-tagged, and untagged). Dynamic planar imaging of Wistar rats with 111In-DTPA-nanobodies revealed that untagged nanobodies showed a 70% drop in kidney accumulation compared to Myc-His-tagged nanobodies at 50 min p.i.. In addition, coinfusion of untagged nanobodies with the plasma expander Gelofusin led to a final reduction of 90%. Similar findings were obtained with different 177Lu-DTPA-2Rs15d nanobody constructs in HER2pos tumor xenografted mice at 1 h p.i.. Kidney accumulation decreased 88% when comparing Myc-His-tagged to untagged 2Rs15d nanobody, and 95% with a coinfusion of Gelofusin, without affecting the tumor targeting capacity. Consequently, we identified a generic method to reduce kidney retention of radiolabeled nanobodies. Dosimetry calculations of Gelofusin-coinfused, untagged 177Lu-DTPA-2Rs15d revealed a dose of 0.90 Gy/MBq that was delivered to both tumor and kidneys and extremely low doses to healthy tissues. In a comparative study, 177Lu-DTPA-Trastuzumab supplied 6 times more radiation to the tumor than untagged 177Lu-DTPA-2Rs15d, but concomitantly also a 155, 34, 80, 26 and 4180 fold higher radioactivity burden to lung, liver, spleen, bone and blood. Most importantly, nanobody-based targeted radionuclide therapy in mice bearing small estiblashed HER2pos tumors led to an almost complete blockade of tumor growth and a significant difference in event-free survival

  1. Production and dosimetric aspects of the potent Auger emitter Co-58m for targeted radionuclide therapy of small tumours

    DEFF Research Database (Denmark)

    Thisgaard, Helge; Elema, Dennis Ringkjøbing; Jensen, Mikael

    2011-01-01

    Based on theoretical calculations, the Auger emitter 58mCo has been identified as a potent nuclide for targeted radionuclide therapy of small tumors. During the production of this isotope, the coproduction of the long-lived ground state 58gCo is unfortunately unavoidable, as is ingrowth of the gr...

  2. uPAR Targeted Radionuclide Therapy with 177Lu-DOTA-AE105 Inhibits Dissemination of Metastatic Prostate Cancer

    DEFF Research Database (Denmark)

    Persson, Morten; Juhl, Karina; Rasmussen, Palle

    2014-01-01

    The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect...... of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific...... value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted 177Lu groups (p

  3. Production of {sup 177}Lu for targeted radionuclide therapy: Available options

    Energy Technology Data Exchange (ETDEWEB)

    Dah, Ashutosh [Isotope Production and Applications Division, Bhabha Atomic Research Centre (BARC), Mumbai (India); Pillai, Maroor Raghavan Ambikalmajan [Molecular Group of Companies. Kerala (India); Knapp, Furn F. Jr. [Medical Isotopes Program, Isotope Dept. Group, Oak Ridge National Laboratory (ORNL), Oak Ridge (United States)

    2015-06-15

    This review provides a comprehensive summary of the production of {sup 177}Lu to meet expected future research and clinical demands. Availability of options represents the cornerstone for sustainable growth for the routine production of adequate activity levels of {sup 177}Lu having the required quality for preparation of a variety of {sup 177}Lu-labeled radiopharmaceuticals. The tremendous prospects associated with production of {sup 177}Lu for use in targeted radionuclide therapy (TRT) dictate that a holistic consideration should evaluate all governing factors that determine its success. While both “direct” and “indirect” reactor production routes offer the possibility for sustainable {sup 177}Lu availability, there are several issues and challenges that must be considered to realize the full potential of these production strategies. This article presents a mini review on the latest developments, current status, key challenges and possibilities for the near future. A broad understanding and discussion of the issues associated with {sup 177}Lu production and processing approaches would not only ensure sustained growth and future expansion for the availability and use of {sup 177}Lu-labeled radiopharmaceuticals, but also help future developments.

  4. Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using {sup 125}I, an Auger electron emitter

    Energy Technology Data Exchange (ETDEWEB)

    Gardette, M.; Papon, J.; Bonnet, M.; Labarre, P.; Miot-Noirault, E.; Madelmont, J. C.; Chezal, J. M.; Moins, N. [UMR 990, INSERM, Universite d' Auvergne, Clermont-Ferrand (France); Desbois, N. [EA 3660, Universite de Bourgogne, Dijon (France); Wu, T. D.; Guerquin-Kern, J. L. [U 759 INSERM, Institute Curie, Orsay (France)

    2013-06-01

    The full text of the publication follows. The increasing incidence of melanoma and the lack of effective therapy on the disseminated form have led to an urgent need for new specific therapies. Several iodo-benzamides or analogs are known to possess specific affinity for melanoma tissue. New hetero-aromatic derivatives have been designed with a cytotoxic moiety and termed DNA intercalating agents. These compounds could be applied in targeted radionuclide therapy using {sup 125}I, Auger electrons emitter which gives high-energetic localized irradiation. Two iodinated acridine derivatives have been reported to present an in vivo kinetic profile conducive to application in targeted radionuclide therapy. The aim of the present study was to perform a preclinical evaluation of these compounds. The DNA intercalating property was confirmed for both compounds. After radiolabeling with {sup 125}I, the two compounds induced in vitro a significant radiotoxicity on B16F0 melanoma cells. The acridine compound, ICF01040, appeared more radio toxic than the acridone compound, ICF01035. While cellular uptake was similar for both compounds, SIMS analysis and in vitro protocol showed a stronger affinity for melanin with ICF01035, which was able to induce a predominant scavenging process in the melanosome and restrict access to the nucleus. Nevertheless, an important radiotoxicity was measured for the two compounds while the nuclear accumulation was low. Indeed, even if nuclear localization remains the main target sensitive to Auger electrons, the cell membrane remains sensitive to {sup 125}I decays. So, these compounds may induce secondary toxic effects of irradiation, such as membrane lipid damage. Conducted to current experiments are evaluate such hypothesis. Taken together, these results suggest that ICF01040 is a better candidate for application in targeted radionuclide therapy using {sup 125}I. The next step will be in vivo evaluation, where high tumoral vectorization gives

  5. Prostate specific membrane antigen- a target for imaging and therapy with radionuclides

    DEFF Research Database (Denmark)

    Bouchelouche, Kirsten; Choyke, Peter L; Capala, Jacek

    2010-01-01

    Prostate cancer continues to represent a major health problem, and yet there is no effective treatment available for advanced metastatic disease. Thus, there is an urgent need for the development of more effective treatment modalities that could improve the outcome. Because prostate specific...... membrane antigen (PSMA), a transmembrane protein, is expressed by virtually all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas, it is a very attractive target. Molecules targeting PSMA can be labelled with radionuclides...... to become both diagnostic and/or therapeutic agents. The use of PSMA binding agents, labelled with diagnostic and therapeutic radio-isotopes, opens up the potential for a new era of personalized management of metastatic prostate cancer....

  6. Development of Reagents for Application of At-211 to Targeted Radionuclide Therapy of Cancer

    International Nuclear Information System (INIS)

    Wilbur, D. Scott

    2011-01-01

    This grant covered only a period of 4 months as the major portion of the award was returned to DOE due to an award of funding from NIH that covered the same research objectives. A letter regarding the termination of the research is attached as the last page of the Final Report. The research conducted was limited due to the short period of this grant, but the results obtained in that period are outlined in the Final Report. The studies addressed in the research effort were directed at a problem that is of critical importance to the in vivo application of the alpha-particle emitting radionuclide At-211. That problem, low in vivo stability of many astatinated molecules, severely limits the use of At-211 in therapeutic applications. The advances sought in the studies were expected to expand the types of biomolecules that can be used as carriers of At-211, and provide improved in vivo targeting of the radiation dose compared with the dose delivered to normal tissue.

  7. Radionuclide Therapy. Chapter 19

    Energy Technology Data Exchange (ETDEWEB)

    Flux, G.; Du, Yong [Royal Marsden Hospital and Institute of Cancer Research, Surrey (United Kingdom)

    2014-12-15

    Cancer has been treated with radiopharmaceuticals since the 1940s. The radionuclides originally used, including 131I and 32P, are still in use. The role of the physicist in radionuclide therapy encompasses radiation protection, imaging and dosimetry. Radiation protection is of particular importance given the high activities of the unsealed sources that are often administered, and must take into account medical staff, comforters and carers, and, as patients are discharged while still retaining activity, members of the public. Regulations concerning acceptable levels of exposure vary from country to country. If the administered radiopharmaceutical is a γ emitter, then imaging can be performed which may be either qualitative or quantitative. While a regular system of quality control must be in place to prevent misinterpretation of image data, qualitative imaging does not usually rely on the image corrections necessary to determine the absolute levels of activity that are localized in the patient. Accurate quantitative imaging is dependent on these corrections and can permit the distribution of absorbed doses delivered to the patient to be determined with sufficient accuracy to be clinically beneficial.

  8. SU-E-T-345: Validation of a Patient-Specific Monte Carlo Targeted Radionuclide Therapy Dosimetry Platform

    International Nuclear Information System (INIS)

    Besemer, A; Bednarz, B

    2014-01-01

    Purpose: There is a compelling need for personalized dosimetry in targeted radionuclide therapy given that conventional dose calculation methods fail to accurately predict dose response relationships. To address this need, we have developed a Geant4-based Monte Carlo patient-specific 3D dosimetry platform for TRT. This platform calculates patient-specific dose distributions based on serial CT/PET or CT/SPECT images acquired after injection of the TRT agent. In this work, S-values and specific absorbed fractions (SAFs) were calculated using this platform and benchmarked against reference values. Methods: S-values for 1, 10, 100, and 1000g spherical tumors with uniform activity distributions of I-124, I-125, I-131, F-18, and Ra-223 were calculated and compared to OLINDA/EXM reference values. SAFs for monoenergetic photons of 0.01, 0.1, and 1 MeV and S factors for monoenergetic electrons of 0.935 MeV were calculated for the liver, kidneys, lungs, pancreas, spleen, and adrenals in the Zubal Phantom and compared with previously published values. Sufficient particles were simulated to keep the voxel statistical uncertainty below 5%. Results: The calculated spherical S-values agreed within a few percent of reference data from OLINDA/EXM for each radionuclide and sphere size. The comparison of photon SAFs and electron S-values with previously published values showed good agreement with the previously published values. The S-values and SAFs of the source organs agreed within 1%. Conclusion: Our platform has been benchmarked against reference values for a variety of radionuclides and over a wide range of energies and tumor sizes. Therefore, this platform could be used to provide accurate patientspecific dosimetry for use in radiopharmaceutical clinical trials

  9. New peptide receptor radionuclide therapy of invasive cancer cells: in vivo studies using 177Lu-DOTA-AE105 targeting uPAR in human colorectal cancer xenografts

    DEFF Research Database (Denmark)

    Persson, Morten; Rasmussen, Palle; Madsen, Jacob

    2012-01-01

    -of-concept for a theranostic approach as treatment modality in a human xenograft colorectal cancer model. MethodsA DOTA-conjugated 9-mer high affinity uPAR binding peptide (DOTA-AE105) was radiolabeled with 64Cu and 177Lu, for PET imaging and targeted radionuclide therapy study, respectively. Human uPAR-positive CRC HT-29...... for the first time the in vivo efficacy of an uPAR-targeted radionuclide therapeutic intervention on both tumor size and its content of uPAR expressing cells thus setting the stage for future translation into clinical use. © 2012 Elsevier Inc. All rights reserved....

  10. Dosimetry in radionuclide therapy

    International Nuclear Information System (INIS)

    Riccabona, G.

    2001-01-01

    While it is known that therapeutic effects of radionuclides are due to absorbed radiation dose and to radiosensitivity, individual dosimetry in 'Gy' is practiced rarely in clinical Nuclear Medicine but 'doses' are described in 'mCi' or 'MBq', which is only indirectly related to 'Gy' in the target. To estimate 'Gy', the volume of the target, maximum concentration of the radiopharmaceutical in it and residence time should be assessed individually. These parameters can be obtained usually only with difficulty, involving possibly also quantitative SPET or PET, modern imaging techniques (sonography, CT, MRT), substitution of y- or positron emitting radiotracers for β - emitting radiopharmaceuticals as well as whole-body distribution studies. Residence time can be estimated by obtaining data on biological half-life of a comparable tracer and transfer of these data in the physical characteristics of the therapeutic agent. With all these possibilities for gross dosimetry the establishment of a dose-response-relation should be possible. As distribution of the radiopharmaceutical in lesions is frequently inhomogenous and microdosimetric conditions are difficult to assess in vivo as yet, it could be observed since decades that empirically set, sometimes 'fixed' doses (mCi or MBq) can also be successful in many diseases. Detailed dosimetric studies, however, are work- and cost-intensive. Nevertheless, one should be aware at a time when more sophisticated therapeutic possibilities in Nuclear Medicine arise, that we should try to estimate radiation dose (Gy) in our new methods even as differences in individual radiosensitivity cannot be assessed yet and studies to define individual radiosensitivity in lesions should be encouraged. (author)

  11. αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-cyclam-RAFT-c(-RGDfK-)4.

    Science.gov (United States)

    Jin, Zhao-Hui; Furukawa, Takako; Degardin, Mélissa; Sugyo, Aya; Tsuji, Atsushi B; Yamasaki, Tomoteru; Kawamura, Kazunori; Fujibayashi, Yasuhisa; Zhang, Ming-Rong; Boturyn, Didier; Dumy, Pascal; Saga, Tsuneo

    2016-09-01

    The transmembrane cell adhesion receptor αVβ3 integrin (αVβ3) has been identified as an important molecular target for cancer imaging and therapy. We have developed a tetrameric cyclic RGD (Arg-Gly-Asp) peptide-based radiotracer (64)Cu-cyclam-RAFT-c(-RGDfK-)4, which successfully captured αVβ3-positive tumors and angiogenesis by PET. Here, we subsequently evaluated its therapeutic potential and side effects using an established αVβ3-positive tumor mouse model. Mice with subcutaneous U87MG glioblastoma xenografts received single administrations of 37 and 74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 (37 MBq/nmol), peptide control, or vehicle solution and underwent tumor growth evaluation. Side effects were assessed in tumor-bearing and tumor-free mice in terms of body weight, routine hematology, and hepatorenal functions. Biodistribution of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 with ascending peptide doses (0.25-10 nmol) and with the therapeutic dose of 2 nmol were determined at 3 hours and at various time points (2 minutes-24 hours) postinjection, respectively, based on which radiation-absorbed doses were estimated. The results revealed that (64)Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently slowed down the tumor growth. The mean tumor doses were 1.28 and 1.81 Gy from 37 and 74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4, respectively. Peptide dose study showed that the tumor uptake of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 dose dependently decreased at doses ≥1 nmol, indicating a saturation of αVβ3 with the administered therapeutic doses (1 and 2 nmol). Combined analysis of the data from tumor-bearing and tumor-free mice revealed no significant toxicity caused by 37-74 MBq of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 Our study demonstrates the therapeutic efficacy and safety of (64)Cu-cyclam-RAFT-c(-RGDfK-)4 for αVβ3-targeted radionuclide therapy. (64)Cu-cyclam-RAFT-c(-RGDfK-)4 would be a promising theranostic drug for cancer imaging and therapy. Mol Cancer Ther; 15(9); 2076-85. ©2016 AACR

  12. Production and dosimetric aspects of the potent Auger emitter 58mCo for targeted radionuclide therapy of small tumors

    International Nuclear Information System (INIS)

    Thisgaard, H.; Elema, D.R.; Jensen, M.

    2011-01-01

    Purpose: Based on theoretical calculations, the Auger emitter 58m Co has been identified as a potent nuclide for targeted radionuclide therapy of small tumors. During the production of this isotope, the coproduction of the long-lived ground state 58g Co is unfortunately unavoidable, as is ingrowth of the ground state following the isomeric decay of 58m Co. The impact of 58g Co as a β + - and γ-emitting impurity should be included in the dosimetric analysis. The purpose of this study was to investigate this critical part of dosimetry based on experimentally determined production yields of 58m Co and 58g Co using a low-energy cyclotron. Also, the cellular S-values for 58m Co have been calculated and are presented here for the first time. Methods: 58m Co was produced via the 58 Fe(p,n) 58m Co nuclear reaction on highly enriched 58 Fe metal. In addition, radiochemical separations of produced radio-cobalt from nat Fe target material were performed. The theoretical subcellular dosimetry calculations for 58m Co and 58g Co were performed using the MIRD formalism, and the impact of the increasing ground state impurity on the tumor-to-normal-tissue dose ratios (TND) per disintegration as a function of time after end of bombardment (EOB) was calculated. Results: 192 ± 8 MBq of 58m Co was produced in the irradiation corresponding to a production yield of 10.7 MBq/μAh. The activity of 58g Co was measured to be 0.85% ± 0.04% of the produced 58m Co activity at EOB. The radio-cobalt yields in the rapid separations were measured to be >97% with no detectable iron contaminations in the cobalt fractions. Due to the unavoidable coproduction and ingrowth of the long-lived ground state 58g Co, the TND and the potency of the 58m Co decrease with time after EOB. If a future treatment with a 58m Co labeled compound is not initiated before, e.g., 21 h after EOB, the resulting TND will be approximately 50% of the TND of 'pure' 58m Co as a result of the increased normal tissue dose from

  13. Theranostic Approach for Metastatic Pigmented Melanoma Using ICF15002, a Multimodal Radiotracer for Both PET Imaging and Targeted Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    Latifa Rbah-Vidal

    2017-01-01

    Full Text Available PURPOSE: This work reports, in melanoma models, the theranostic potential of ICF15002 as a single fluorinated and iodinated melanin-targeting compound. METHODS: Studies were conducted in the murine syngeneic B16BL6 model and in the A375 and SK-MEL-3 human xenografts. ICF15002 was radiolabeled with fluorine-18 for positron emission tomography (PET imaging and biodistribution, with iodine-125 for metabolism study, and iodine-131 for targeted radionuclide therapy (TRT. TRT efficacy was assessed by tumor volume measurement, with mechanistics and dosimetry parameters being determined in the B16BL6 model. Intracellular localization of ICF15002 was characterized by secondary ion mass spectrometry (SIMS. RESULTS: PET imaging with [18F]ICF15002 evidenced tumoral uptake of 14.33 ± 2.11%ID/g and 4.87 ± 0.93%ID/g in pigmented B16BL6 and SK-MEL-3 models, respectively, at 1 hour post inoculation. No accumulation was observed in the unpigmented A375 melanoma. SIMS demonstrated colocalization of ICF15002 signal with melanin polymers in melanosomes of the B16BL6 tumors. TRT with two doses of 20 MBq [131I]ICF15002 delivered an absorbed dose of 102.3 Gy to B16BL6 tumors, leading to a significant tumor growth inhibition [doubling time (DT of 2.9 ± 0.5 days in treated vs 1.8 ± 0.3 in controls] and a prolonged median survival (27 days vs 21 in controls. P53S15 phosphorylation and P21 induction were associated with a G2/M blockage, suggesting mitotic catastrophe. In the human SK-MEL-3 model, three doses of 25 MBq led also to a DT increase (26.5 ± 7.8 days vs 11.0 ± 3.8 in controls and improved median survival (111 days vs 74 in controls. CONCLUSION: Results demonstrate that ICF15002 fulfills suitable properties for bimodal imaging/TRT management of patients with pigmented melanoma.

  14. Therapy with radionuclides

    International Nuclear Information System (INIS)

    Biersack, H.J.; Hotze, A.L.

    1992-01-01

    Radioiodine therapy of benign and malignant thyroid diseases is a well-established procedure in Nuclear Medicine. However, the therapeutic use of radioisotopes in other diseases is relatively unknown among our refering physicians. The therapeutic effects of intraarticular (rheumatoid arthritis) and intracavitary (pleural and peritoneal carcinosis) applications yields good results. The radiophosphorus therapy in polycythemia vera rubra has always to be considered as an alternative to chemotherapy. The use of analgetics may be reduced by pain therapy of bone metastasis by injection of bone-seeking beta emitters like Rh-186 HEDP. Other procedures like therapeutic application of meta-iodo-benzylguanidine in neuroblastoma and malignant pheochromocytoma resulted in at least remissions of the disease. Radioimmunotherapy needs further evaluation before it can be recommended as a routine procedure. (orig.) [de

  15. SU-E-T-256: Optimizing the Combination of Targeted Radionuclide Therapy Agents Using a Multi-Scale Patient-Specific Monte Carlo Dosimetry Platform

    International Nuclear Information System (INIS)

    Besemer, A; Bednarz, B; Titz, B; Grudzinski, J; Weichert, J; Hall, L

    2014-01-01

    Purpose: Combination targeted radionuclide therapy (TRT) is appealing because it can potentially exploit different mechanisms of action from multiple radionuclides as well as the variable dose rates due to the different radionuclide half-lives. The work describes the development of a multiobjective optimization algorithm to calculate the optimal ratio of radionuclide injection activities for delivery of combination TRT. Methods: The ‘diapeutic’ (diagnostic and therapeutic) agent, CLR1404, was used as a proof-of-principle compound in this work. Isosteric iodine substitution in CLR1404 creates a molecular imaging agent when labeled with I-124 or a targeted radiotherapeutic agent when labeled with I-125 or I-131. PET/CT images of high grade glioma patients were acquired at 4.5, 24, and 48 hours post injection of 124I-CLR1404. The therapeutic 131I-CLR1404 and 125ICLR1404 absorbed dose (AD) and biological effective dose (BED) were calculated for each patient using a patient-specific Monte Carlo dosimetry platform. The optimal ratio of injection activities for each radionuclide was calculated with a multi-objective optimization algorithm using the weighted sum method. Objective functions such as the tumor dose heterogeneity and the ratio of the normal tissue to tumor doses were minimized and the relative importance weights of each optimization function were varied. Results: For each optimization function, the program outputs a Pareto surface map representing all possible combinations of radionuclide injection activities so that values that minimize the objective function can be visualized. A Pareto surface map of the weighted sum given a set of user-specified importance weights is also displayed. Additionally, the ratio of optimal injection activities as a function of the all possible importance weights is generated so that the user can select the optimal ratio based on the desired weights. Conclusion: Multi-objective optimization of radionuclide injection activities

  16. Radionuclide therapy of endocrine-related cancer

    International Nuclear Information System (INIS)

    Kratochwil, C.; Giesel, F.L.

    2014-01-01

    This article gives an overview of the established radionuclide therapies for endocrine-related cancer that already have market authorization or are currently under evaluation in clinical trials. Radioiodine therapy is still the gold standard for differentiated iodine-avid thyroid cancer. In patients with bone and lung metastases (near) total remission is seen in approximately 50 % and the 15-year survival rate for these patients is approximately 90 %. In contrast to the USA, meta-iodobenzylguanidine (MIBG) therapy has market approval in Europe. According to the current literature, in the setting of advanced stage neuroblastoma and malignant pheochromocytoma or paraganglioma, radiological remission can be achieved in > 30 % and symptom control in almost 80 % of the treated patients. Somatostatin receptor targeted radionuclide therapies (e.g. with DOTATATE or DOTATOC) demonstrated promising results in phase 2 trials, reporting progression-free survival in the range of 24-36 months. A first phase 3 pivotal trial for intestinal carcinoids is currently recruiting and another trial for pancreatic neuroendocrine tumors is planned. Radiopharmaceuticals based on glucagon-like peptide 1 (GLP1) or minigastrins are in the early evaluation stage for application in the treatment of insulinomas and medullary thyroid cancer. In general, radiopharmaceutical therapy belongs to the group of so-called theranostics which means that therapy is tailored for individual patients based on molecular imaging diagnostics to stratify target positive or target negative tumor phenotypes. (orig.) [de

  17. Radionuclides for therapy: a review

    International Nuclear Information System (INIS)

    Roesler, H.; Noelpp, U.; Triller, K.J.; Steffen, R.

    1986-01-01

    Progress in angiographic techniques has been a gradual evolutionary development which now permits the selective and superselective access to a tumor's vascular bed. A diagnostic angiographic procedure can be supplemented by a one-step, quick application of embolizing radioactive material. This endoarterial radionuclide embolizing tumor therapy has the maximum selectivity among radiotherapeutic methods, with the highest radiation doses to the tumor and neglectible exposure of normal tissue. Spread of radioactivity by diffusion or leaching can be prevented

  18. Application of a whole-body pharmacokinetic model for targeted radionuclide therapy to NM404 and FLT

    Science.gov (United States)

    Grudzinski, Joseph J.; Floberg, John M.; Mudd, Sarah R.; Jeffery, Justin J.; Peterson, Eric T.; Nomura, Alice; Burnette, Ronald R.; Tomé, Wolfgang A.; Weichert, Jamey P.; Jeraj, Robert

    2012-03-01

    We have previously developed a model that provides relative dosimetry estimates for targeted radionuclide therapy (TRT) agents. The whole-body and tumor pharmacokinetic (PK) parameters of this model can be noninvasively measured with molecular imaging, providing a means of comparing potential TRT agents. Parameter sensitivities and noise will affect the accuracy and precision of the estimated PK values and hence dosimetry estimates. The aim of this work is to apply a PK model for TRT to two agents with different magnitudes of clearance rates, NM404 and FLT, explore parameter sensitivity with respect to time and investigate the effect of noise on parameter precision and accuracy. Twenty-three tumor bearing mice were injected with a ‘slow-clearing’ agent, 124I-NM404 (n = 10), or a ‘fast-clearing’ agent, 18F-FLT (3‧-deoxy-3‧-fluorothymidine) (n = 13) and imaged via micro-PET/CT pseudo-dynamically or dynamically, respectively. Regions of interest were drawn within the heart and tumor to create time-concentration curves for blood pool and tumor. PK analysis was performed to estimate the mean and standard error of the central compartment efflux-to-influx ratio (k12/k21), central elimination rate constant (kel), and tumor influx-to-efflux ratio (k34/k43), as well as the mean and standard deviation of the dosimetry estimates. NM404 and FLT parameter estimation results were used to analyze model accuracy and parameter sensitivity. The accuracy of the experimental sampling schedule was compared to that of an optimal sampling schedule found using Cramer-Rao lower bounds theory. Accuracy was assessed using correlation coefficient, bias and standard error of the estimate normalized to the mean (SEE/mean). The PK parameter estimation of NM404 yielded a central clearance, kel (0.009 ± 0.003 h-1), normal body retention, k12/k21 (0.69 ± 0.16), tumor retention, k34/k43 (1.44 ± 0.46) and predicted dosimetry, Dtumor (3.47 ± 1.24 Gy). The PK parameter estimation of FLT

  19. Development and validation of a simple model for cellular and cell cluster dosimetry with practical application in targeted radionuclide therapy

    International Nuclear Information System (INIS)

    Bardies, M.; Myers, M.J.

    1992-01-01

    The authors have developed an analytical technique for calculating the mean absorbed dose to the cell nucleus from a variety of spatial distributions of cells and activities and a wide range of emitted energies and radionuclides. The dose to the nucleus has been calculated using this method from activity distributed (1) on the cell surface (2) throughout the cytoplasm (3) throughout a cluster of cells (micrometastasis) and (4) on the surface of the cluster of cells. The derived absorption factors have been based on the latest point kernels of Berger and have been validated against published estimates. They show good agreement and the model has the advantage of being easily adapted for revisions and extensions of available low energy data. Data sets may be derived with the absorbed fractions or the absorbed dose per emission as a function of the radial extent of the activity, and either the individual energies of the emissions or the totality of the emissions from a particular radio-nuclide. The practical applications of the model have included: (a) calculation of the absorbed dose to radioimmuno-targeted micrometastasis in the peritoneum; (b) calculations of doses to cells labelled on the surface with some novel emitters such as 67 Cu, 177 Lu, 153 Sm, 111 Ag, 186 Re, 188 Re as well as 131 I, 125 I and 90 Y; (c) comparison of doses to the cell nucleus from MIBG labelled with 125 I and 131 I and distributed in the cytoplasm of the cell; and (d) estimates of the absorbed dose to the cell nucleus from alpha emitters distributed on the surface of the cell

  20. Alpha Emitting Radionuclides and Radiopharmaceuticals for Therapy

    International Nuclear Information System (INIS)

    Chérel, Michel; Barbet, Jacques

    2013-01-01

    Today, cancer treatments mainly rely on surgery or external beam radiation to remove or destroy bulky tumors. Chemotherapy is given when tumours cannot be removed or when dissemination is suspected. However, these approaches cannot permanently treat all cancers and relapse occurs in up to 50% of the patients’ population. Radioimmunotherapy (RIT) and peptide receptor radionuclide therapy (PRRT) are effective against some disseminated and metastatic diseases, although they are rarely curative. Most preclinical and clinical developments in this field have involved electron-emitting radionuclides, particularly iodine-131, yttrium-90 and lutetium-177. The large range of the electrons emitted by these radionuclides reduces their efficacy against very small tumour cell clusters or isolated tumour cells present in residual disease and in many haematological tumours (leukaemia, myeloma). The range of alpha particles in biological tissues is very short, less than 0.1 mm, which makes alpha emitters theoretically ideal for treatment of such isolated tumour cells or micro-clusters of malignant cells. Thus, over the last decade, a growing interest for the use of alpha-emitting radionuclides has emerged. Research on targeted alpha therapy (TAT) began years ago in Nantes through cooperation between Subatech, a nuclear physics laboratory, CRCNA, a cancer research centre with a nuclear oncology team and ITU (Karlsruhe, Germany). CD138 was demonstrated as a potential target antigen for Multiple Myeloma, which is a target of huge clinical interest particularly suited for TAT because of the disseminated nature of the disease consisting primarily of isolated cells and small clusters of tumour cells mainly localized in the bone marrow. Thus anti-CD138 antibodies were labelled with bismuth-213 from actinium-225/bismuth-213 generators provided by ITU and used to target multiple myeloma cells. In vitro studies showed cell cycle arrest, synergism with chemotherapy and very little induction

  1. The low-energy β(-) and electron emitter (161)Tb as an alternative to (177)Lu for targeted radionuclide therapy.

    Science.gov (United States)

    Lehenberger, Silvia; Barkhausen, Christoph; Cohrs, Susan; Fischer, Eliane; Grünberg, Jürgen; Hohn, Alexander; Köster, Ulli; Schibli, Roger; Türler, Andreas; Zhernosekov, Konstantin

    2011-08-01

    The low-energy β(-) emitter (161)Tb is very similar to (177)Lu with respect to half-life, beta energy and chemical properties. However, (161)Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to (177)Lu. It also emits low-energy photons that are useful for gamma camera imaging. The (160)Gd(n,γ)(161)Gd→(161)Tb production route was used to produce (161)Tb by neutron irradiation of massive (160)Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) (161)Tb from the bulk of the (160)Gd target and from its stable decay product (161)Dy. (161)Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. (177)Lu. A (161)Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. Up to 15 GBq of (161)Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%-90% of the available (161)Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The (161)Tb obtained was of the quality required to prepare (161)Tb-DOTA-Tyr3-octreotate. We were able to produce (161)Tb in n.c.a. form by irradiating highly enriched (160)Gd targets; it can be obtained in the quantity and quality required for the preparation of (161)Tb-labeled therapeutic agents. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. New peptide receptor radionuclide therapy of invasive cancer cells: in vivo studies using 177Lu-DOTA-AE105 targeting uPAR in human colorectal cancer xenografts

    International Nuclear Information System (INIS)

    Persson, Morten; Rasmussen, Palle; Madsen, Jacob; Ploug, Michael; Kjaer, Andreas

    2012-01-01

    The proposition of uPAR as a potential target in cancer therapy is advanced by its predominant expression at the invasive front of colorectal cancer (CRC) and its value as prognostic biomarker for poor survival in this disease. In this study, we provide the first in vivo proof-of-concept for a theranostic approach as treatment modality in a human xenograft colorectal cancer model. Methods: A DOTA-conjugated 9-mer high affinity uPAR binding peptide (DOTA-AE105) was radiolabeled with 64 Cu and 177 Lu, for PET imaging and targeted radionuclide therapy study, respectively. Human uPAR-positive CRC HT-29 cells were inoculated in Nude mice and treated with 177 Lu-DOTA-AE105 once a visible tumor had formed. To evaluate the true effect of the targeted radiotherapy, two controls groups were included in this study, one receiving a 177 Lu-labeled non-binding control peptide and one receiving vehicle. All animals were treated day 0 and 7. A parallel 18 F-FLT PET/CT study was performed on day 0, 1, 3 and 6. Dosimetry calculations were based on a biodistribution study, where organs and tissue of interest were collected 0.5, 1.0, 2.0, 4.0 and 24 h post injection of 177 Lu-DOTA-AE105. Toxicity was assessed by recording mouse weight and by H and E staining of kidneys in each treatment group. Results: uPAR-positive HT-29 xenograft was clearly visualized by PET/CT imaging using 64 Cu-DOTA-AE105. Subsequently, these xenograft transplants were locally irradiated using 177 Lu-DOTA-AE105, where a significant effect on tumor size and the number of uPAR-positive cells in the tumor was found (p 18 F-FLT PET/CT imaging study revealed a significant correlation between 18 F-FLT tumor uptake and efficacy of the radionuclide therapy. A histological examination of the kidneys from one animal in each treatment group did not reveal any gross abnormalities and the general performance of all treated animals also showed no indications of radioactivity-induced toxicity. Conclusion: These findings

  3. Development of a new anti-cancer agent for targeted radionuclide therapy: β- radiolabeled RAFT-RGD

    International Nuclear Information System (INIS)

    Petitprin, A.

    2013-01-01

    β-emitters radiolabeled RAFT-RGD as new agents for internal targeted radiotherapy. The αvβ3 integrin is known to play an important role in tumor-induced angiogenesis, tumor proliferation, survival and metastasis. Because of its overexpression on neo-endothelial cells such as those present in growing tumors, as well as on tumor cells of various origins, αvβ3 integrin is an attractive molecular target for diagnosis and therapy of the rapidly growing and metastatic tumors. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets integrin αvβ3 in vitro and in vivo. RAFT-RGD has been used for tumor imaging and drug targeting. This study is the first to evaluate the therapeutic potential of the β-emitters radiolabeled tetrameric RGD peptide RAFT-RGD in a Nude mouse model of αvβ3 -expressing tumors. An injection of 37 MBq of 90 Y-RAFT-RGD or 177 Lu-RAFT-RGD in mice with αvβ3 -positive tumors caused a significant growth delay as compared with mice treated with 37 MBq of 90 Y-RAFT-RAD or 177 Lu-RAFT-RAD or untreated mice. In comparison, an injection of 30 MBq of 90 Y-RAFT-RGD had no efficacy for the treatment of αvβ3 -negative tumors. 90 Y-RAFT-RGD and 177 Lu-RAFT-RGD are potent αvβ3 -expressing tumor targeting agents for internal targeted radiotherapy. (author)

  4. Therapy for incorporated radionuclides: scope and need

    International Nuclear Information System (INIS)

    Smith, V.H.

    1981-03-01

    In the United States the recent termination of funding for research on therapy for incorporated radionuclides has virtually halted progress on improved or new agents and procedures for removing radioactivity from the body. Research was eliminated, but is still needed on new removal agents, improved delivery system, in vitro test systems, and the toxicology of treatments. For many radionuclides, no adequate therapy exists. The relationship between radionuclide removal and reduction in cancer risk is still unanswered. Without proper research support, needed improvements in the treatment for incorporated radionuclides in the US are uncertain

  5. Tumour therapy with radionuclides: assessment of progress and problems

    International Nuclear Information System (INIS)

    Carlsson, Joergen; Forssell Aronsson, Eva; Hietala, Sven-Ola; Stigbrand, Torgny; Tennvall, Jan

    2003-01-01

    Radionuclide therapy is a promising modality for treatment of tumours of haematopoietic origin while the success for treatment of solid tumours so far has been limited. The authors consider radionuclide therapy mainly as a method to eradicate disseminated tumour cells and small metastases while bulky tumours and large metastases have to be treated surgically or by external radiation therapy. The promising therapeutic results for haematological tumours give hope that radionuclide therapy will have a breakthrough also for treatment of disseminated cells from solid tumours. New knowledge related to this is continuously emerging since new molecular target structures are being characterised and the knowledge on pharmacokinetics and cellular processing of different types of targeting agents increases. There is also improved understanding of the factors of importance for the choice of appropriate radionuclides with respect to their decay properties and the therapeutic applications. Furthermore, new methods to modify the uptake of radionuclides in tumour cells and normal tissues are emerging. However, we still need improvements regarding dosimetry and treatment planning as well as an increased knowledge about the tolerance doses for normal tissues and the radiobiological effects on tumour cells. This is especially important in targeted radionuclide therapy where the dose rates often are lower than 1 Gy/h

  6. Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

    Science.gov (United States)

    Widel, M

    2017-01-01

    For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included.

  7. Evaluation of cytotoxic and tumor targeting capability of (177)Lu-DOTATATE-nanoparticles: a trailblazing strategy in peptide receptor radionuclide therapy.

    Science.gov (United States)

    Arora, Geetanjali; Dubey, Priyanka; Shukla, Jaya; Ghosh, Sourabh; Bandopadhyaya, Gurupad

    2016-06-01

    We propose an innovative strategy of nanoparticle-mediated-peptide receptor radionuclide therapy (PRRT) employing PLGA-nanoparticles together with anti-β-hCG antibodies that can protect kidneys from radiation damage while simultaneously enhancing its tumor targeting and cytotoxic ability for somatostatin receptor (SSR) positive tumors. PEG-coated-(177)Lu-DOTATATE-PLGA-nanoparticles (PEG-LuD-NP) were formulated and characterized. In vitro toxicity of these particles was tested on human glioblastoma cell line U87MG over a radiation dose range of 19-78 Gy, using MTT assay and flow cytometry. To further enhance cytotoxicity and test the feasibility of active tumor targeting, apoptosis-inducing anti-β-hCG monoclonal antibodies were employed in vitro, after confirming expression of β-hCG on U87MG. In vivo tumor targeting ability of these particles, in comparison to uncoated particles and un-encapsulated (177)Lu-DOTATATE, was assessed by intravenous administration in tumor-induced wistar rats. Rats were first imaged in a gamma camera followed by euthanasia for organ extraction and counting in gamma counter. The particles were spherical in shape with mean diameter of 300 nm. Highest cytotoxicity that could be achieved with PEG-LuD-NP, on radio-resistant U87MG cells, was 35.8 % due to complex cellular response triggered by ionizing radiation. Interestingly, synergistic action of antibodies and PEG-LuD-NP doubled the cytotoxicity (80 %). PEG-LuD-NP showed the highest tumor uptake (4.3 ± 0.46 % ID/g) as compared to (177)Lu-DOTATATE (3.5 ± 0.31 %) and uncoated-(177)Lu-DOTATATE-nanoparticles (3.4 ± 0.35 %) in tumor-inoculated wistar rats (p targeting SSR positive tumors for enhanced cytoxicity and reduced renal radiation dose associated with conventional PRRT. To our knowledge of literature, this is the first study to establish in vitro and in vivo efficacy profile of nanoparticles in PRRT providing a stepping-stone for undergoing and future research

  8. Radionuclide therapy practice and facilities in Europe

    International Nuclear Information System (INIS)

    Hoefnagel, C.A.; Clarke, S.E.M.; Fischer, M.; Chatal, J.F.; Lewington, V.J.; Nilsson, S.; Troncone, L.; Vieira, M.R.

    1999-01-01

    Using a questionnaire the EANM Task Group Radionuclide Therapy in 1993 collected data on the current practice of radionuclide therapy in European countries. Subsequently, at the request of the EANM Executive Committee, the EANM Radionuclide Therapy Committee has made an inventory of the distribution of facilities for radionuclide therapy and undertaken an assessment of the total number of patients treated throughout Europe and of the types of treatment provides, with the aim of supporting the development of policy to adjust the available capacity to the needs by the year 2000. For this purpose, a second, more detailed questionnaire was sent out the members and national advisors of the Committee (see below), who gathered the data for each country that was a member of the EANM at the time. It is concluded that a wide bariation in therapy practice exists across Europe, particularly in the utilisation of radionuclide therapy, the requirement and availability of proper isolation facilities and the background training of those undertaking therapy. More uniform guidelines and legislation are required, although changes in legislation may have a significant impact in some countries. Although there is wide variation in the therapies used in each country, one the whole it appears that there is an underutilisation of nuclear medicine as a therapeutic modality. A rapidly increasing role may be expected, in particular for oncological indications requiring high-dose radionuclide treatment. Therefore there is an urgent need for a greater number of isolation beds in dedicated centers throughout Europe

  9. In vitro radionuclide therapy and in vivo scintigraphic imaging of alpha fetoprotein producing hepatocellular carcinoma by targeted sodium iodide symporter gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kwang Il; Lee, Yong Jin; Lee, Tae Sup; Song, Inho; Cheon, Gi Jeong; Lim, Sang Moo; Kang, Joo Hyun [Korea Institute of Radiological and Medical and Medical Sciences, Seoul (Korea, Republic of); Chung, June Key [Seoul National Univ. College of Medicine, Seoul (Korea, Republic of)

    2012-03-15

    This study aimed to develop a gene expression targeting method for specific imaging and therapy of alpha fetoprotein (AFP) producing hepatocellular carcinoma (HCC) cells, using an adenovirus vector containing the human sodium/iodide symporter (hNIS) gene driven by an AFP enhancer/promoter. The recombinant adenovirus vector, AdAFPhNIS (containing the hNIS gene driven by human AFP enhancer/promoter) was prepared. After in vitro infection by the adenovirus, hNIS gene expression in AFP producing cells and in AFP nonproducing cells was investigated using {sup 125}I uptake assay and semi quantitative reverse transcription polymerase chain reaction (RT-PCR). The killing effect of {sup 131}I vitro clonogenic assay. In addition, tumor bearing mice were intravenously injected with the adenovirus, and scintigraphic images were obtained. The expression of hNIS was efficiently demonstrated by {sup 125}I uptake assay in AFP producing cells, but not in AFP nonproducing cells. AFP producing HCC targeted gene expression was confirmed at the mRNA level. Furthermore, in vitro clonogenic assay showed that hNIS gene expression induced by AdAFPhNIS infection in AFP producing cells caused more sensitivity to {sup 131}I than that in AFP nonproducing cells. Injected intravenously in HuH-7 tumor xenografts mice by adenovirus, the functional hNIS gene expression was confirmed in tumor by in vivo scintigraphic imaging. An AFP producing HCC was targeted with an adenovirus vector containing the hNIS gene using the AFP enhancer/promoter in vitro and in vivo. These findings demonstrate that AFP producing HCC specific molecular imaging and radionuclide gene therapy are feasible using this recombinant adenovirus vector system.

  10. In vitro radionuclide therapy and in vivo scintigraphic imaging of alpha fetoprotein producing hepatocellular carcinoma by targeted sodium iodide symporter gene expression

    International Nuclear Information System (INIS)

    Kim, Kwang Il; Lee, Yong Jin; Lee, Tae Sup; Song, Inho; Cheon, Gi Jeong; Lim, Sang Moo; Kang, Joo Hyun; Chung, June Key

    2012-01-01

    This study aimed to develop a gene expression targeting method for specific imaging and therapy of alpha fetoprotein (AFP) producing hepatocellular carcinoma (HCC) cells, using an adenovirus vector containing the human sodium/iodide symporter (hNIS) gene driven by an AFP enhancer/promoter. The recombinant adenovirus vector, AdAFPhNIS (containing the hNIS gene driven by human AFP enhancer/promoter) was prepared. After in vitro infection by the adenovirus, hNIS gene expression in AFP producing cells and in AFP nonproducing cells was investigated using 125 I uptake assay and semi quantitative reverse transcription polymerase chain reaction (RT-PCR). The killing effect of 131 I vitro clonogenic assay. In addition, tumor bearing mice were intravenously injected with the adenovirus, and scintigraphic images were obtained. The expression of hNIS was efficiently demonstrated by 125 I uptake assay in AFP producing cells, but not in AFP nonproducing cells. AFP producing HCC targeted gene expression was confirmed at the mRNA level. Furthermore, in vitro clonogenic assay showed that hNIS gene expression induced by AdAFPhNIS infection in AFP producing cells caused more sensitivity to 131 I than that in AFP nonproducing cells. Injected intravenously in HuH-7 tumor xenografts mice by adenovirus, the functional hNIS gene expression was confirmed in tumor by in vivo scintigraphic imaging. An AFP producing HCC was targeted with an adenovirus vector containing the hNIS gene using the AFP enhancer/promoter in vitro and in vivo. These findings demonstrate that AFP producing HCC specific molecular imaging and radionuclide gene therapy are feasible using this recombinant adenovirus vector system

  11. Targeted radionuclide therapy with RAFT-RGD radiolabelled with {sup 90}Y or {sup 177}Lu in a mouse model of αvβ3-expressing tumours

    Energy Technology Data Exchange (ETDEWEB)

    Bozon-Petitprin, A.; Bacot, S.; Ahmadi, M.; Marti-Batlle, D.; Perret, P.; Broisat, A.; Riou, L.M. [INSERM, U1039, Grenoble (France); Universite de Grenoble, UMR-S1039, Grenoble (France); Gauchez, A.S.; Bourre, J.C.; Fagret, D.; Vuillez, J.P. [INSERM, U1039, Grenoble (France); Universite de Grenoble, UMR-S1039, Grenoble (France); CHRU Grenoble, Hopital Michallon, Service de Medecine Nucleaire, Grenoble (France); Claron, M.; Boturyn, D. [CNRS, UMR 5250, Departement de Chimie Moleculaire, Grenoble (France); Ghezzi, Catherine [INSERM, U1039, Grenoble (France); Universite de Grenoble, UMR-S1039, Grenoble (France); INSERM U1039, Radiopharmaceutiques biocliniques, Batiment Jean Roget, Domaine de la Merci, Faculte de Medecine, La Tronche (France)

    2014-08-28

    The αvβ3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK]){sub 4} (RAFT-RGD), specifically targets the αvβ3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with β{sup -} emitters in a nude mouse model of αvβ3 integrin-expressing tumours. Biodistribution and SPECT/CT imaging studies were performed after injection of {sup 90}Y-RAFT-RGD or {sup 177}Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvβ3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with {sup 90}Y-RAFT-RGD or {sup 177}Lu-RAFT-RGD and {sup 90}Y-RAFT-RAD or {sup 177}Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvβ3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvβ3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. Injection of 37 MBq of {sup 90}Y-RAFT-RGD into mice with large αvβ3-positive tumours or 37 MBq of {sup 177}Lu-RAFT-RGD into mice with small αvβ3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of {sup 90}Y-RAFT-RAD or 37 MBq of {sup 177}Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of {sup 90}Y-RAFT-RGD had no effect on the growth of αvβ3-negative tumours. {sup 90}Y-RAFT-RGD and {sup 177}Lu-RAFT-RGD are potent agents targeting αvβ3-expressing tumours for internal targeted radiotherapy. (orig.)

  12. Targeted radionuclide therapy with RAFT-RGD radiolabelled with (90)Y or (177)Lu in a mouse model of αvβ3-expressing tumours.

    Science.gov (United States)

    Bozon-Petitprin, A; Bacot, S; Gauchez, A S; Ahmadi, M; Bourre, J C; Marti-Batlle, D; Perret, P; Broisat, A; Riou, L M; Claron, M; Boturyn, D; Fagret, D; Ghezzi, Catherine; Vuillez, J P

    2015-02-01

    The αvβ3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvβ3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with β(-) emitters in a nude mouse model of αvβ3 integrin-expressing tumours. Biodistribution and SPECT/CT imaging studies were performed after injection of (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvβ3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD and (90)Y-RAFT-RAD or (177)Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvβ3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvβ3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. Injection of 37 MBq of (90)Y-RAFT-RGD into mice with large αvβ3-positive tumours or 37 MBq of (177)Lu-RAFT-RGD into mice with small αvβ3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of (90)Y-RAFT-RAD or 37 MBq of (177)Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of (90)Y-RAFT-RGD had no effect on the growth of αvβ3-negative tumours. (90)Y-RAFT-RGD and (177)Lu-RAFT-RGD are potent agents targeting αvβ3-expressing tumours for internal targeted radiotherapy.

  13. Single Photon Emission Computed Tomography/Positron Emission Tomography Imaging and Targeted Radionuclide Therapy of Melanoma: New Multimodal Fluorinated and Iodinated Radiotracers

    International Nuclear Information System (INIS)

    Maisonial, A.; Papon, J.; Bayle, M.; Vidal, A.; Auzeloux, Ph.; Rbah, L.; Bonnet-Duquennoy, M.; Miot-Noirault, E.; Galmier, M.J.; Borel, M.; Madelmont, J.C.; Moins, N.; Chezal, J.M.; Kuhnast, B.; Boisgard, R.; Dolle, F.; Tavitian, B.; Boisgard, R.; Tavitian, B.; Askienazy, S.

    2011-01-01

    This study reports a series of 14 new iodinated and fluorinated compounds offering both early imaging ( 123 I, 124 I, 18 F) and systemic treatment ( 131 I) of melanoma potentialities. The biodistribution of each 125 I-labeled tracer was evaluated in a model of melanoma B16F0-bearing mice, using in vivo serial γ scintigraphic imaging. Among this series, [ 125 I]56 emerged as the most promising compound in terms of specific tumoral uptake and in vivo kinetic profile. To validate our multimodality concept, the radiosynthesis of [ 18 F]56 was then optimized and this radiotracer has been successfully investigated for in vivo PET imaging of melanoma in B16F0- and B16F10-bearing mouse model. The therapeutic efficacy of [ 131 I]56 was then evaluated in mice bearing subcutaneous B16F0 melanoma, and a significant slow down in tumoral growth was demonstrated. These data support further development of 56 for PET imaging ( 18 F, 124 I) and targeted radionuclide therapy ( 131 I) of melanoma using a single chemical structure. (authors)

  14. Radionuclide therapy for true polycythemia

    International Nuclear Information System (INIS)

    Afanasieva, N.I.; Grushka, G.V.; Vasiliev, L.Ya.

    2005-01-01

    remission was achieved in 102 (67%). In these patients, the general condition improved, angina and thrombophlebitis course became more favorable, and ability to work improved. Mean remission duration after the first course of treatment with P-32 was 42 months and 26 months after two courses. Mean life span made up 9.3 years. Thus, radionuclide therapy for true polycythemia with P-32 improves the quality of life and increases mean life span in the patients. (author)

  15. Application of the linear-quadratic model with incomplete repair to radionuclide directed therapy

    International Nuclear Information System (INIS)

    Millar, W.T.; Glasgow Univ.

    1991-01-01

    The LQ model has now been extended to include a general time varying dose rate profile, and the equations can be readily evaluated if an exponential radiation damage repair process is assumed. These equations are applicable to radionuclide directed therapy, including brachytherapy. Kinetic uptake data obtained during radionuclide directed therapy may therefore be used to determine the radiobiological dosimetry of the target and non-target tissues. Also, preliminary tracer studies may be used to pre-plan the radionuclide directed therapy, provided that tracer and therapeutic amounts of the radionuclide carrier are identically processed by the tissues. It is also shown that continuous radionuclide therapy will induce less damage in late-responding tissues than 2 Gy/fraction external beam therapy if the ratio of the maximum dose rate and the sublethal damage repair half-life in the tissue is less than 1.0 Gy. Similar inequalities may be derived for β-particle radionuclide directed therapy. (author)

  16. Production and dosimetric aspects of the potent Auger emitter {sup 58m}Co for targeted radionuclide therapy of small tumors

    Energy Technology Data Exchange (ETDEWEB)

    Thisgaard, H.; Elema, D.R.; Jensen, M. [PET and Cyclotron Unit, Nuclear Medicine Department, Odense University Hospital, Sdr. Boulevard 29, DK-5000 Odense, Denmark and Institute of Clinical Research, University of Southern Denmark, Winsloewparken 19, DK-5000 Odense (Denmark); The Hevesy Laboratory, Risoe National Laboratory for Sustainable Energy, Technical University of Denmark, P.O. Box 49, DK-4000 Roskilde (Denmark)

    2011-08-15

    Purpose: Based on theoretical calculations, the Auger emitter {sup 58m}Co has been identified as a potent nuclide for targeted radionuclide therapy of small tumors. During the production of this isotope, the coproduction of the long-lived ground state {sup 58g}Co is unfortunately unavoidable, as is ingrowth of the ground state following the isomeric decay of {sup 58m}Co. The impact of {sup 58g}Co as a {beta}{sup +}- and {gamma}-emitting impurity should be included in the dosimetric analysis. The purpose of this study was to investigate this critical part of dosimetry based on experimentally determined production yields of {sup 58m}Co and {sup 58g}Co using a low-energy cyclotron. Also, the cellular S-values for {sup 58m}Co have been calculated and are presented here for the first time. Methods: {sup 58m}Co was produced via the {sup 58}Fe(p,n){sup 58m}Co nuclear reaction on highly enriched {sup 58}Fe metal. In addition, radiochemical separations of produced radio-cobalt from {sup nat}Fe target material were performed. The theoretical subcellular dosimetry calculations for {sup 58m}Co and {sup 58g}Co were performed using the MIRD formalism, and the impact of the increasing ground state impurity on the tumor-to-normal-tissue dose ratios (TND) per disintegration as a function of time after end of bombardment (EOB) was calculated. Results: 192 {+-} 8 MBq of {sup 58m}Co was produced in the irradiation corresponding to a production yield of 10.7 MBq/{mu}Ah. The activity of {sup 58g}Co was measured to be 0.85% {+-} 0.04% of the produced {sup 58m}Co activity at EOB. The radio-cobalt yields in the rapid separations were measured to be >97% with no detectable iron contaminations in the cobalt fractions. Due to the unavoidable coproduction and ingrowth of the long-lived ground state {sup 58g}Co, the TND and the potency of the {sup 58m}Co decrease with time after EOB. If a future treatment with a {sup 58m}Co labeled compound is not initiated before, e.g., 21 h after EOB, the

  17. Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting {sup 223}Ra-dichloride

    Energy Technology Data Exchange (ETDEWEB)

    Pacilio, Massimiliano [Azienda Ospealiera San Camillo Forlianini, Rome (Italy). Dept. of Medical Physics; Ventroni, Guido; Mango, Lucio [Azienda Ospealiera San Camillo Forlianini, Rome (Italy). Dept. of Nuclear Medicin; De Vincentis, Giuseppe; Di Castro, Elisabetta; Frantellizzi, Viviana; Follacchio, Giulia Anna; Garkavaya, Tatiana [Rome Univ. (Italy). Dept. of Radiological, Oncological and Anatomo Pathological Sciences; Cassano, Bartolomeo; Lorenzon, Leda [Rome Univ. (Italy). Postgraduate School of Medical Physics; Pellegrini, Rosanna; Pani, Roberto [Rome Univ. (Italy). Dept. of Molecular Medicine; Ialongo, Pasquale [Azienda Ospealiera San Camillo Forlianini, Rome (Italy). Dept. of Radiology

    2016-01-15

    percent uptake of {sup 99m}Tc and {sup 223}Ra (activity extrapolated to t = 0) were significantly correlated. The feasibility of in vivo quantitative imaging in {sup 223}Ra therapy was confirmed. The lesion uptake of {sup 223}Ra-dichloride was significantly correlated with that of {sup 99m}Tc-MDP. The D{sub RBE} to lesions per unit administered activity was much higher than that of other bone-seeking radiopharmaceuticals, but considering a standard administration of 21 MBq (six injections of 50 kBq/kg to a 70-kg patient), the mean cumulative value of D{sub RBE} was about 19 Gy, and was therefore in the range of those of other radiopharmaceuticals. The macrodosimetry of bone metastases in treatments with {sup 223}Ra-dichloride is feasible, but more work is needed to demonstrate its helpfulness in predicting clinical outcomes. (orig.)

  18. A model for inverse dose-rate effects - low dose-rate hyper-sensibility in response to targeted radionuclide therapy

    International Nuclear Information System (INIS)

    Murray, I.; Mather, S.J.

    2015-01-01

    Full text of publication follows. The aim of this work was to test the hypothesis that the Linear-Quadratic (LQ) model of cell survival, developed for external beam radiotherapy (EBRT), could be extended to targeted radionuclide therapy (TRT) in order to predict dose-response relationships in a cell line exhibiting low dose hypersensitivity (LDH). Methods: aliquots of the PC-3 cancer cell line were treated with either EBRT or an in-vitro model of TRT (Irradiation of cell culture with Y-90 EDTA over 24, 48, 72 or 96 hours). Dosimetry for the TRT was calculated using radiation transport simulations with the Monte Carlo PENELOPE code. Clonogenic as well as functional biological assays were used to assess cell response. An extension of the LQ model was developed which incorporated a dose-rate threshold for activation of repair mechanisms. Results: accurate dosimetry for in-vitro exposures of cell cultures to radioactivity was established. LQ parameters of cell survival were established for the PC-3 cell line in response to EBRT. The standard LQ model did not predict survival in PC-3 cells exposed to Y 90 irradiation over periods of up to 96 hours. In fact cells were more sensitive to the same dose when irradiation was carried out over 96 hours than 24 hours. I.e. at a lower dose-rate. Deviations from the LQ predictions were most pronounced below a threshold dose-rate of 0.5 Gy/hr. These results led to an extension of the LQ model based upon a dose-rate dependent sigmoid model of single strand DNA repair. This extension to the model resulted in predicted cell survival curves that closely matched the experimental data. Conclusion: the LQ model of cell survival to radiation has been shown to be largely predictive of response to low dose-rate irradiation. However, in cells displaying LDH, further adaptation of the model was required. (authors)

  19. Radionuclide Therapies in Molecular Imaging and Precision Medicine.

    Science.gov (United States)

    Kendi, A Tuba; Moncayo, Valeria M; Nye, Jonathon A; Galt, James R; Halkar, Raghuveer; Schuster, David M

    2017-01-01

    This article reviews recent advances and applications of radionuclide therapy. Individualized precision medicine, new treatments, and the evolving role of radionuclide therapy are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Therapy of Patients with Malignant Glioma with Targeted A-Radionuclide Therapy Using 213Bi-DOTA-[Thi8, Met (Oo)11]-Substanz P

    International Nuclear Information System (INIS)

    Forrer, F.; Mueller-Brand, J.; Cordier, D.; Merlo, A.; Morgenstern, A.; Bruchertseifer, F.; Maecke, H.R.

    2009-01-01

    The prognosis of patients with malignant glioma is very poor. New therapy options are mandatory. Substance P is the main ligand of neurokinin type 1 (NK-1) receptors, which are consistently over-expressed in malignant gliomas and surrounding tumor vessels. Administration of 90 Y-DOTA-[Thi 8 , Met (O o ) 11 ]-Substanz P was shown to be feasible and safe. However, in critically located tumors, the mean tissue range of 5 mm of 90 Y may lead to unacceptable damage of adjacent, functional critical areas of the brain. We report a phase I study with locally administered 213 Bi labeled DOTA-[Thi 8 , Met (O o ) 11 ]-Substanz P in patients with malignant glioma. By using a direct, intratumoral injection, the problem of the short physical half life of Bismuth-213 can be circumvent. To date, 5 patients with malignant glioma (2 Grade IV, 1 Grade III and 2 grade II) without previous treatment were included. One to three catheter systems were placed stereotactically into the tumor. After a diagnostic injection with 111 In-DOTA-[Thi 8 , Met (O o ) 11 ]-Substanz P and subsequent dosimetry, totally 30 to 138 mCi of 213 Bi-DOTA-[Thi8, Met (O o ) 11 ]-Substanz P was injected intratumorally performing 3 to 4 applications over 2 days. SPECT/CT was used to assess the biodistribution. Follow up was performed clinically and with morphological imaging. Targeted radiopeptide therapy using 213 Bi-DOTA-[Thi 8 , Met (O o ) 11 ]-Substanz P was very well tolerated by all patients. No additional neurological deficit was observed. Repetitive imaging is suggestive of progressive radiation-induced necrosis, which was validated by subsequent resection of the tumors. Time to progression was found to be 11 and 14 months respectively in patients with grade IV glioma. No progression is found after 18 to 23 months in patients with grade II or III glioma. We conclude that targeted loco-regional radiotherapy using 213 Bi-DOTA-[Thi 8 , Met (O o ) 11 ]-Substanz P represents an innovative and effective

  1. PEGylation, increasing specific activity and multiple dosing as strategies to improve the risk-benefit profile of targeted radionuclide therapy with 177Lu-DOTA-bombesin analogues

    Science.gov (United States)

    2012-01-01

    growth. The therapeutic efficacy was highest for the PEGylated derivative of high specific activity administered in two fractions (2 × 20 MBq = 40 MBq) at day 0 and day 7 (73% tumour growth inhibition, 3 weeks after therapy). Conclusions PEGylation and increasing the specific activity enhance the pharmacokinetic properties of a 177Lu-labelled BN-based radiopharmaceutical and provide a protocol for targeted radionuclide therapy with a beneficial anti-tumour effectiveness and a favourable risk-profile at the same time. PMID:22681935

  2. Model of metastatic growth valuable for radionuclide therapy

    International Nuclear Information System (INIS)

    Bernhardt, Peter; Ahlman, Haakan; Forssell-Aronsson, Eva

    2003-01-01

    The aim was to make a Monte Carlo simulation approach to estimate the distribution of tumor sizes and to study the curative potential of three candidate radionuclides for radionuclide therapy: the high-energy electron emitter 90 Y, the medium-energy electron emitter 177 Lu and the low-energy electron emitter 103m Rh. A patient with hepatocellular carcinoma with recently published serial CT data on tumor growth in the liver was used. From these data the growth of the primary tumor, and the metastatis formation rate, were estimated. Assuming the same tumor growth of the primary and all metastases and the same metastatis formation rate from both primary and metastases the metastatic size distribution was simulated for various time points. Tumor cure of the metastatic size distribution was simulated for uniform activity distribution of three radionuclides; the high-energy electron emitter 90 Y, the mean-energy electron emitter 177 Lu and the low-energy electron emitter 103m Rh. The simulation of a tumor cure was performed for various time points and tumor-to-normal tissue activity concentrations, TNC. It was demonstrated that it is important to start therapy as early as possible after diagnosis. It was of crucial importance to use an optimal radionuclide for therapy. These simulations demonstrated that 90 Y was not suitable for systemic radionuclide therapy, due to the low absorbed fraction of the emitted electrons in small tumors ( 103m Rh was slightly better than 177 Lu. For high TNC values low-energy electron emitters, e.g., 103m Rh was the best choice for tumor cure. However, the short half-life of 103m Rh (56 min) might not be optimal for therapy. Therefore, other low-energy electron emitters, or alpha emitters, should be considered for systemic targeted therapy

  3. WE-DE-201-06: Impact of Temporal Image Coregistration Methods On 3D Internal Dose Calculations in Targeted Radionuclide Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Besemer, A; Marsh, I; Bednarz, B [University of Wisconsin, Madison, WI (United States)

    2016-06-15

    Purpose: The calculation of 3D internal dose calculations in targeted radionuclide therapy requires the acquisition and temporal coregistration of a serial PET/CT or SPECT/CT images. This work investigates the dosimetric impact of different temporal coregistration methods commonly used for 3D internal dosimetry. Methods: PET/CT images of four mice were acquired at 1, 24, 48, 72, 96, 144 hrs post-injection of {sup 124}I-CLR1404. The therapeutic {sup 131}I-CLR1404 absorbed dose rate (ADR) was calculated at each time point using a Geant4-based MC dosimetry platform using three temporal image coregistration Methods: (1) no coregistration (NC), whole body sequential CT-CT affine coregistration (WBAC), and individual sequential ROI-ROI affine coregistration (IRAC). For NC, only the ROI mean ADR was integrated to obtain ROI mean doses. For WBAC, the CT at each time point was coregistered to a single reference CT. The CT transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the whole CT volume. For IRAC, each individual ROI was isolated and sequentially coregistered to a single reference ROI. The ROI transformations were applied to the corresponding ADR images and the dose was calculated on a voxel-basis within the ROI volumes. Results: The percent differences in the ROI mean doses were as large as 109%, 88%, and 32%, comparing the WBAC vs. IRAC, NC vs. IRAC, and NC vs. WBAC methods, respectively. The CoV in the mean dose between the all three methods ranged from 2–36%. The pronounced curvature of the spinal cord was not adequately coregistered using WBAC which resulted in large difference between the WBAC and IRAC. Conclusion: The method used for temporal image coregistration can result in large differences in 3D internal dosimetry calculations. Care must be taken to choose the most appropriate method depending on the imaging conditions, clinical site, and specific application. This work is partially funded by

  4. Potentiation of peptide receptor radionuclide therapy by the PARP inhibitor olaparib

    NARCIS (Netherlands)

    J. Nonnekens (Julie); M. van Kranenburg (Melissa); C.E.M.T. Beerens (Cecile); M. Suker (Mustafa); M. Doukas (Michael); C.H.J. van Eijck (Casper); M. de Jong (Marcel); D.C. van Gent (Dik)

    2016-01-01

    textabstractMetastases expressing tumor-specific receptors can be targeted and treated by binding of radiolabeled peptides (peptide receptor radionuclide therapy or PRRT). For example, patients with metastasized somatostatin receptor-positive neuroendocrine tumors (NETs) can be treated with

  5. Therapy with radionuclides. Radionuklid-Therapie

    Energy Technology Data Exchange (ETDEWEB)

    Biersack, H.J.; Hotze, A.L. (Bonn Univ. (Germany). Klinik fuer Nuklearmedizin)

    1992-12-01

    Radioiodine therapy of benign and malignant thyroid diseases is a well-established procedure in Nuclear Medicine. However, the therapeutic use of radioisotopes in other diseases is relatively unknown among our refering physicians. The therapeutic effects of intraarticular (rheumatoid arthritis) and intracavitary (pleural and peritoneal carcinosis) applications yields good results. The radiophosphorus therapy in polycythemia vera rubra has always to be considered as an alternative to chemotherapy. The use of analgetics may be reduced by pain therapy of bone metastasis by injection of bone-seeking beta emitters like Rh-186 HEDP. Other procedures like therapeutic application of meta-iodo-benzylguanidine in neuroblastoma and malignant pheochromocytoma resulted in at least remissions of the disease. Radioimmunotherapy needs further evaluation before it can be recommended as a routine procedure. (orig.).

  6. Targeted alpha therapy: Applications and current status

    International Nuclear Information System (INIS)

    Bruchertseifer, Frank

    2017-01-01

    Full text: The field of targeted alpha therapy has been developed rapidly in the last decade. Besides 223 Ra, 211 At and 212 Pb/ 212 Bi the alpha emitters 225 Ac and 213 Bi are promising therapeutic radionuclides for application in targeted alpha therapy of cancer and infectious diseases. The presentation will give a short overview about the current clinical treatments with alpha emitting radionuclides and will place an emphasis on the most promising clinical testing of peptides and antibodies labelled with 225 Ac and 213 Bi for treatment of metastatic castration-resistant prostate cancer patients with glioma and glioblastoma multiform, PSMA-positive tumor phenotype and bladder carcinoma in situ. (author)

  7. Quantitative single-particle digital autoradiography with α-particle emitters for targeted radionuclide therapy using the iQID camera

    Energy Technology Data Exchange (ETDEWEB)

    Miller, Brian W., E-mail: brian.miller@pnnl.gov [Pacific Northwest National Laboratory, Richland, Washington 99354 and College of Optical Sciences, The University of Arizona, Tucson, Arizona 85719 (United States); Frost, Sofia H. L.; Frayo, Shani L.; Kenoyer, Aimee L.; Santos, Erlinda; Jones, Jon C.; Orozco, Johnnie J. [Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 (United States); Green, Damian J.; Press, Oliver W.; Pagel, John M.; Sandmaier, Brenda M. [Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 and Department of Medicine, University of Washington, Seattle, Washington 98195 (United States); Hamlin, Donald K.; Wilbur, D. Scott [Department of Radiation Oncology, University of Washington, Seattle, Washington 98195 (United States); Fisher, Darrell R. [Dade Moeller Health Group, Richland, Washington 99354 (United States)

    2015-07-15

    Purpose: Alpha-emitting radionuclides exhibit a potential advantage for cancer treatments because they release large amounts of ionizing energy over a few cell diameters (50–80 μm), causing localized, irreparable double-strand DNA breaks that lead to cell death. Radioimmunotherapy (RIT) approaches using monoclonal antibodies labeled with α emitters may thus inactivate targeted cells with minimal radiation damage to surrounding tissues. Tools are needed to visualize and quantify the radioactivity distribution and absorbed doses to targeted and nontargeted cells for accurate dosimetry of all treatment regimens utilizing α particles, including RIT and others (e.g., Ra-223), especially for organs and tumors with heterogeneous radionuclide distributions. The aim of this study was to evaluate and characterize a novel single-particle digital autoradiography imager, the ionizing-radiation quantum imaging detector (iQID) camera, for use in α-RIT experiments. Methods: The iQID camera is a scintillator-based radiation detection system that images and identifies charged-particle and gamma-ray/x-ray emissions spatially and temporally on an event-by-event basis. It employs CCD-CMOS cameras and high-performance computing hardware for real-time imaging and activity quantification of tissue sections, approaching cellular resolutions. In this work, the authors evaluated its characteristics for α-particle imaging, including measurements of intrinsic detector spatial resolutions and background count rates at various detector configurations and quantification of activity distributions. The technique was assessed for quantitative imaging of astatine-211 ({sup 211}At) activity distributions in cryosections of murine and canine tissue samples. Results: The highest spatial resolution was measured at ∼20 μm full width at half maximum and the α-particle background was measured at a rate as low as (2.6 ± 0.5) × 10{sup −4} cpm/cm{sup 2} (40 mm diameter detector area

  8. Quantitative single-particle digital autoradiography with α-particle emitters for targeted radionuclide therapy using the iQID camera.

    Science.gov (United States)

    Miller, Brian W; Frost, Sofia H L; Frayo, Shani L; Kenoyer, Aimee L; Santos, Erlinda; Jones, Jon C; Green, Damian J; Hamlin, Donald K; Wilbur, D Scott; Fisher, Darrell R; Orozco, Johnnie J; Press, Oliver W; Pagel, John M; Sandmaier, Brenda M

    2015-07-01

    Alpha-emitting radionuclides exhibit a potential advantage for cancer treatments because they release large amounts of ionizing energy over a few cell diameters (50-80 μm), causing localized, irreparable double-strand DNA breaks that lead to cell death. Radioimmunotherapy (RIT) approaches using monoclonal antibodies labeled with α emitters may thus inactivate targeted cells with minimal radiation damage to surrounding tissues. Tools are needed to visualize and quantify the radioactivity distribution and absorbed doses to targeted and nontargeted cells for accurate dosimetry of all treatment regimens utilizing α particles, including RIT and others (e.g., Ra-223), especially for organs and tumors with heterogeneous radionuclide distributions. The aim of this study was to evaluate and characterize a novel single-particle digital autoradiography imager, the ionizing-radiation quantum imaging detector (iQID) camera, for use in α-RIT experiments. The iQID camera is a scintillator-based radiation detection system that images and identifies charged-particle and gamma-ray/x-ray emissions spatially and temporally on an event-by-event basis. It employs CCD-CMOS cameras and high-performance computing hardware for real-time imaging and activity quantification of tissue sections, approaching cellular resolutions. In this work, the authors evaluated its characteristics for α-particle imaging, including measurements of intrinsic detector spatial resolutions and background count rates at various detector configurations and quantification of activity distributions. The technique was assessed for quantitative imaging of astatine-211 ((211)At) activity distributions in cryosections of murine and canine tissue samples. The highest spatial resolution was measured at ∼20 μm full width at half maximum and the α-particle background was measured at a rate as low as (2.6 ± 0.5) × 10(-4) cpm/cm(2) (40 mm diameter detector area). Simultaneous imaging of multiple tissue sections was

  9. Radionuclide therapy: regional and systemic routes of administration

    International Nuclear Information System (INIS)

    Shapiro, B.

    1991-01-01

    The optimal sequencing and integration of radiopharmaceutical therapy with respect to the multiple and competing therapeutic modalities is examined. It is estimated that the central goal of therapeutic nuclear medicine is to increase radiopharmaceutical delivery to tumour targets while sparing sensitive normal tissues. Among the factors to be considered in the choice of therapeutic radionuclides are: the decay mode, gamma-ray yield, half-lives and chemical reactivity. Several routes of administration are discussed and a number of manipulations which may be used to further improve radioparmaceutical delivery are outlined. The difficulty to perform accurate radiation dosimetry is also briefly examined. 14 refs., 1 tab

  10. 21 CFR 892.5750 - Radionuclide radiation therapy system.

    Science.gov (United States)

    2010-04-01

    ... system. (a) Identification. A radionuclide radiation therapy system is a device intended to permit an... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Radionuclide radiation therapy system. 892.5750... patient's body. This generic type of device may include signal analysis and display equipment, patient and...

  11. Radionuclide targeting with particular emphasis on urinary bladder carcinoma

    International Nuclear Information System (INIS)

    Sjoestroem, A.

    2001-01-01

    The incidence of urinary bladder carcinoma is increasing and many patients die every year of this disease despite assumed radical therapy. Thus, there is a need for improved methods of diagnosis and therapy. Radionuclide targeting is based on achieving specific delivery of radioactive nuclides to tumour cells with minimal damage to surrounding normal tissues. Two possible target structures are the epidermal growth factor (EGF) receptor and the related receptor HER-2. Cellular binding and retention of 125 I-EGF-dextran conjugates was investigated in two bladder carcinoma cell lines. The conjugate bound specifically to the EGF receptor with delayed maximum binding, limited intracellular degradation and prolonged cellular retention compared to 125 I-EGF. EGF was labelled using different radionuclides and methods. All the labelled variants bound specifically to the tumour cells although the cellular binding patterns and retention varied considerably. 111 In-DTPA-EGF had highest cellular retention and in decreasing order 211 At-benzoyl-EGF and 125 I-labelled EGF. Bladder cancer spheroids bound both 125 I-EGF-dextran as well as 125 I-EGF. Conjugate binding increased during a 48 h incubation period and was most prominent in the outer cell layers. The length of the dextran chain appeared not to alter the binding pattern. The expression of EGF receptors and HER-2 in metastases and primary bladder carcinoma tumours was investigated. Both receptors were expressed in the majority of metastases and primary tumours. Targeting the EGF receptor and/or HER-2 in urinary bladder carcinoma is an exciting new concept

  12. Radionuclide-Based Cancer Imaging Targeting the Carcinoembryonic Antigen

    Directory of Open Access Journals (Sweden)

    Hao Hong

    2008-01-01

    Full Text Available Carcinoembryonic antigen (CEA, highly expressed in many cancer types, is an important target for cancer diagnosis and therapy. Radionuclide-based imaging techniques (gamma camera, single photon emission computed tomography [SPECT] and positron emission tomography [PET] have been extensively explored for CEA-targeted cancer imaging both preclinically and clinically. Briefly, these studies can be divided into three major categories: antibody-based, antibody fragment-based and pretargeted imaging. Radiolabeled anti-CEA antibodies, reported the earliest among the three categories, typically gave suboptimal tumor contrast due to the prolonged circulation life time of intact antibodies. Subsequently, a number of engineered anti-CEA antibody fragments (e.g. Fab’, scFv, minibody, diabody and scFv-Fc have been labeled with a variety of radioisotopes for CEA imaging, many of which have entered clinical investigation. CEA-Scan (a 99mTc-labeled anti-CEA Fab’ fragment has already been approved by the United States Food and Drug Administration for cancer imaging. Meanwhile, pretargeting strategies have also been developed for CEA imaging which can give much better tumor contrast than the other two methods, if the system is designed properly. In this review article, we will summarize the current state-of-the-art of radionuclide-based cancer imaging targeting CEA. Generally, isotopes with short half-lives (e.g. 18F and 99mTc are more suitable for labeling small engineered antibody fragments while the isotopes with longer half-lives (e.g. 123I and 111In are needed for antibody labeling to match its relatively long circulation half-life. With further improvement in tumor targeting efficacy and radiolabeling strategies, novel CEA-targeted agents may play an important role in cancer patient management, paving the way to “personalized medicine”.

  13. {sup 213}Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

    Energy Technology Data Exchange (ETDEWEB)

    Kratochwil, C.; Giesel, F.L.; Mier, W.; Haberkorn, U. [University Hospital Heidelberg, Department of Nuclear Medicine, Heidelberg (Germany); Bruchertseifer, F.; Apostolidis, C.; Morgenstern, A. [European Commission, Institute for Transuranium Elements, Karlsruhe (Germany); Boll, R.; Murphy, K. [Oak Ridge National Laboratory, Oak Ridge, TN (United States)

    2014-11-15

    Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as {sup 90}Y/{sup 177}Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with {sup 213}Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with {sup 90}Y/{sup 177}Lu-DOTATOC were treated with an intraarterial infusion of {sup 213}Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of {sup 213}Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and {sup 68}Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. The biodistribution of {sup 213}Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. (orig.)

  14. 213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

    International Nuclear Information System (INIS)

    Kratochwil, C.; Giesel, F.L.; Mier, W.; Haberkorn, U.; Bruchertseifer, F.; Apostolidis, C.; Morgenstern, A.; Boll, R.; Murphy, K.

    2014-01-01

    Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as 90 Y/ 177 Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with 213 Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with 90 Y/ 177 Lu-DOTATOC were treated with an intraarterial infusion of 213 Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of 213 Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and 68 Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. The biodistribution of 213 Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. (orig.)

  15. Targeted enzyme prodrug therapies.

    Science.gov (United States)

    Schellmann, N; Deckert, P M; Bachran, D; Fuchs, H; Bachran, C

    2010-09-01

    The cure of cancer is still a formidable challenge in medical science. Long-known modalities including surgery, chemotherapy and radiotherapy are successful in a number of cases; however, invasive, metastasized and inaccessible tumors still pose an unresolved and ongoing problem. Targeted therapies designed to locate, detect and specifically kill tumor cells have been developed in the past three decades as an alternative to treat troublesome cancers. Most of these therapies are either based on antibody-dependent cellular cytotoxicity, targeted delivery of cytotoxic drugs or tumor site-specific activation of prodrugs. The latter is a two-step procedure. In the first step, a selected enzyme is accumulated in the tumor by guiding the enzyme or its gene to the neoplastic cells. In the second step, a harmless prodrug is applied and specifically converted by this enzyme into a cytotoxic drug only at the tumor site. A number of targeting systems, enzymes and prodrugs were investigated and improved since the concept was first envisioned in 1974. This review presents a concise overview on the history and latest developments in targeted therapies for cancer treatment. We cover the relevant technologies such as antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT) as well as related therapies such as clostridial- (CDEPT) and polymer-directed enzyme prodrug therapy (PDEPT) with emphasis on prodrug-converting enzymes, prodrugs and drugs.

  16. Assessments for high dose radionuclide therapy treatment planning

    International Nuclear Information System (INIS)

    Fisher, D.R.

    2003-01-01

    Advances in the biotechnology of cell specific targeting of cancer and the increased number of clinical trials involving treatment of cancer patients with radiolabelled antibodies, peptides, and similar delivery vehicles have led to an increase in the number of high dose radionuclide therapy procedures. Optimised radionuclide therapy for cancer treatment is based on the concept of absorbed dose to the dose limiting normal organ or tissue. The limiting normal tissue is often the red marrow, but it may sometimes be the lungs, liver, intestinal tract, or kidneys. Appropriate treatment planning requires assessment of radiation dose to several internal organs and tissues, and usually involves biodistribution studies in the patient using a tracer amount of radionuclide bound to the targeting agent and imaged at sequential timepoints using a planar gamma camera. Time-activity curves are developed from the imaging data for the major organ tissues of concern, for the whole body and sometimes for selected tumours. Patient specific factors often require that dose estimates be customised for each patient. In the United States, the Food and Drug Administration regulates the experimental use of investigational new drugs and requires 'reasonable calculation of radiation absorbed dose to the whole body and to critical organs' using the methods prescribed by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine. Review of high dose studies shows that some are conducted with minimal dosimetry, that the marrow dose is difficult to establish and is subject to large uncertainties. Despite the general availability of software, internal dosimetry methods often seem to be inconsistent from one clinical centre to another. (author)

  17. Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues.

    NARCIS (Netherlands)

    Rolleman, E.J.; Melis, M.; Valkema, R.; Boerman, O.C.; Krenning, E.P.; Jong, M. de

    2010-01-01

    This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides

  18. Targeted alpha therapy: Applications and current status

    Energy Technology Data Exchange (ETDEWEB)

    Bruchertseifer, Frank, E-mail: frank.bruchertseifer@ec.europa.eu [European Commission, Joint Research Centre, Karlsruhe (Germany)

    2017-07-01

    Full text: The field of targeted alpha therapy has been developed rapidly in the last decade. Besides {sup 223}Ra, {sup 211}At and {sup 212}Pb/{sup 212}Bi the alpha emitters {sup 225}Ac and {sup 213}Bi are promising therapeutic radionuclides for application in targeted alpha therapy of cancer and infectious diseases. The presentation will give a short overview about the current clinical treatments with alpha emitting radionuclides and will place an emphasis on the most promising clinical testing of peptides and antibodies labelled with {sup 225}Ac and {sup 213}Bi for treatment of metastatic castration-resistant prostate cancer patients with glioma and glioblastoma multiform, PSMA-positive tumor phenotype and bladder carcinoma in situ. (author)

  19. Targeted Therapy for Melanoma

    International Nuclear Information System (INIS)

    Quinn, Thomas; Moore, Herbert

    2016-01-01

    The research project, entitled ''Targeted Therapy for Melanoma,'' was focused on investigating the use of kidney protection measures to lower the non-specific kidney uptake of the radiolabeled Pb-DOTA-ReCCMSH peptide. Previous published work demonstrated that the kidney exhibited the highest non-target tissue uptake of the "2"1"2"P"b"/"2"0"3Pb radiolabeled melanoma targeting peptide DOTA-ReCCMSH. The radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analog DOTA-Re(Arg"1"1)CCMSH, which binds the melanocortin-1 receptor over-expressed on melanoma tumor cells, has shown promise as a PRRT agent in pre-clinical studies. High tumor uptake of "2"1"2Pb labeled DOTA-Re(Arg"1"1)CCMSH resulted in tumor reduction or eradication in melanoma therapy studies. Of particular note was the 20-50% cure rate observed when melanoma mice were treated with alpha particle emitter "2"1"2Pb. However, as with most PRRT agents, high radiation doses to the kidneys where observed. To optimize tumor treatment efficacy and reduce nephrotoxicity, the tumor to kidney uptake ratio must be improved. Strategies to reduce kidney retention of the radiolabeled peptide, while not effecting tumor uptake and retention, can be broken into several categories including modification of the targeting peptide sequence and reducing proximal tubule reabsorption.

  20. Targeted Therapy for Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Quinn, Thomas [Alphamed, Jackson, TN (United States); Moore, Herbert [Alphamed, Jackson, TN (United States)

    2016-12-05

    The research project, entitled ”Targeted Therapy for Melanoma,” was focused on investigating the use of kidney protection measures to lower the non-specific kidney uptake of the radiolabeled Pb-DOTA-ReCCMSH peptide. Previous published work demonstrated that the kidney exhibited the highest non-target tissue uptake of the 212Pb/203Pb radiolabeled melanoma targeting peptide DOTA-ReCCMSH. The radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analog DOTA-Re(Arg11)CCMSH, which binds the melanocortin-1 receptor over-expressed on melanoma tumor cells, has shown promise as a PRRT agent in pre-clinical studies. High tumor uptake of 212Pb labeled DOTA-Re(Arg11)CCMSH resulted in tumor reduction or eradication in melanoma therapy studies. Of particular note was the 20-50% cure rate observed when melanoma mice were treated with alpha particle emitter 212Pb. However, as with most PRRT agents, high radiation doses to the kidneys where observed. To optimize tumor treatment efficacy and reduce nephrotoxicity, the tumor to kidney uptake ratio must be improved. Strategies to reduce kidney retention of the radiolabeled peptide, while not effecting tumor uptake and retention, can be broken into several categories including modification of the targeting peptide sequence and reducing proximal tubule reabsorption.

  1. Measured radionuclide production from copper, gold and lead spallation targets

    Energy Technology Data Exchange (ETDEWEB)

    Parish, T.A.; Belian, A.P. [Texas A & M Univ., College Station, TX (United States)

    1995-10-01

    Spallation target materials are chosen so as to produce large numbers of neutrons while at the same time avoiding the creation of long-lived radioactive wastes. While there has been considerable research to determine the number of neutrons produced per incident particle for various target materials, there has been less effort to precisely quantify the types and amounts of radionuclides produced. Accurate knowledge of the radioactive species produced by spallation reactions is important for specifying waste disposal criteria for targets. In order to verify the production rates calculated by LAHET, a study has been conducted using the Texas A&M University (TAMU) Cyclotron to measure radionuclide yields from copper, gold, and lead targets.

  2. Development of medical application methods using radiation. Radionuclide therapy

    International Nuclear Information System (INIS)

    Choi, Chang Woon; Lim, S. M.; Kim, E.H.; Woo, K. S.; Chung, W. S.; Lim, S. J.; Choi, T. H.; Hong, S. W.; Chung, H. Y.; No, W. C.; Oh, B. H.; Hong, H. J.

    1999-04-01

    In this project, we studied following subjects: 1. development of monoclonal antibodies and radiopharmaceuticals 2. clinical applications of radionuclide therapy 3. radioimmunoguided surgery 4. prevention of restenosis with intracoronary radiation. The results can be applied for the following objectives: 1) radionuclide therapy will be applied in clinical practice to treat the cancer patients or other diseases in multi-center trial. 2) The newly developed monoclonal antibodies and biomolecules can be used in biology, chemistry or other basic life science research. 3) The new methods for the analysis of therapeutic effects, such as dosimetry, and quantitative analysis methods of radioactivity, can be applied in basic research, such as radiation oncology and radiation biology

  3. Internal radiation dosimetry using nuclear medicine imaging in radionuclide therapy

    International Nuclear Information System (INIS)

    Kim, Kyeong Min; Byun, Byun Hyun; Cheon, Gi Jeong; Lim, Sang Moo

    2007-01-01

    Radionuclide therapy has been an important field in nuclear medicine. In radionuclide therapy, relevant evaluation of internally absorbed dose is essential for the achievement of efficient and sufficient treatment of incurable disease, and can be accomplished by means of accurate measurement of radioactivity in body and its changes with time. Recently, the advances of nuclear medicine imaging and multi modality imaging processing techniques can provide chance of more accurate and easier measurement of the measures commented above, in cooperation of conventional imaging based approaches. In this review, basic concept for internal dosimetry using nuclear medicine imaging is summarized with several check points which should be considered in real practice

  4. Development of medical application methods using radiation. Radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Chang Woon; Lim, S. M.; Kim, E.H.; Woo, K. S.; Chung, W. S.; Lim, S. J.; Choi, T. H.; Hong, S. W.; Chung, H. Y.; No, W. C. [Korea Atomic Energy Research Institute. Korea Cancer Center Hospital, Seoul, (Korea, Republic of); Oh, B. H. [Seoul National University. Hospital, Seoul (Korea, Republic of); Hong, H. J. [Antibody Engineering Research Unit, Taejon (Korea, Republic of)

    1999-04-01

    In this project, we studied following subjects: 1. development of monoclonal antibodies and radiopharmaceuticals 2. clinical applications of radionuclide therapy 3. radioimmunoguided surgery 4. prevention of restenosis with intracoronary radiation. The results can be applied for the following objectives: (1) radionuclide therapy will be applied in clinical practice to treat the cancer patients or other diseases in multi-center trial. (2) The newly developed monoclonal antibodies and biomolecules can be used in biology, chemistry or other basic life science research. (3) The new methods for the analysis of therapeutic effects, such as dosimetry, and quantitative analysis methods of radioactivity, can be applied in basic research, such as radiation oncology and radiation biology.

  5. Radionuclide therapy of endocrine-related cancer; Nuklearmedizinische Therapie endokriner Tumoren

    Energy Technology Data Exchange (ETDEWEB)

    Kratochwil, C.; Giesel, F.L. [Universitaetsklinikum Heidelberg, Abteilung Nuklearmedizin, Heidelberg (Germany)

    2014-10-15

    This article gives an overview of the established radionuclide therapies for endocrine-related cancer that already have market authorization or are currently under evaluation in clinical trials. Radioiodine therapy is still the gold standard for differentiated iodine-avid thyroid cancer. In patients with bone and lung metastases (near) total remission is seen in approximately 50 % and the 15-year survival rate for these patients is approximately 90 %. In contrast to the USA, meta-iodobenzylguanidine (MIBG) therapy has market approval in Europe. According to the current literature, in the setting of advanced stage neuroblastoma and malignant pheochromocytoma or paraganglioma, radiological remission can be achieved in > 30 % and symptom control in almost 80 % of the treated patients. Somatostatin receptor targeted radionuclide therapies (e.g. with DOTATATE or DOTATOC) demonstrated promising results in phase 2 trials, reporting progression-free survival in the range of 24-36 months. A first phase 3 pivotal trial for intestinal carcinoids is currently recruiting and another trial for pancreatic neuroendocrine tumors is planned. Radiopharmaceuticals based on glucagon-like peptide 1 (GLP1) or minigastrins are in the early evaluation stage for application in the treatment of insulinomas and medullary thyroid cancer. In general, radiopharmaceutical therapy belongs to the group of so-called theranostics which means that therapy is tailored for individual patients based on molecular imaging diagnostics to stratify target positive or target negative tumor phenotypes. (orig.) [German] Dieser Artikel gibt einen Ueberblick ueber die etablierten sowie weitere vielversprechende, aktuell im Rahmen von Studien eingesetzte nuklearmedizinische Therapiemoeglichkeiten diverser endokrinologischer Neoplasien. Die Radiojodtherapie ist unveraendert die Therapie der Wahl beim differenzierten, jodspeichernden Schilddruesenkarzinom. Im metastasierten Stadium sind in ca. 50 % der Faelle noch

  6. New aspects of radionuclide therapy of bone and joint diseases

    International Nuclear Information System (INIS)

    Fischer, M.

    2001-01-01

    Whereas in developing countries P-32 is widely used for radionuclide therapy of painful bone metastases, in Europe three radionuclides or radiopharmaceutical agents are available for pain palliation: Sr-89, Sm-153-EDTMP, and Re-186-HEDP. Radionuclide therapy for pain palliation is indicated for bone pain due to metastatic malignancy that has involved multiple skeletal sites and has evoked an osteoblastic response on bone scintigraphy. Response rates of about 70-80% in patients with breast or prostate cancer is reported in the literature, less in metastatic lesions of other primary malignancies. Sm-153-EDTMP may also be used for curative treatment of primary bone tumours or their metastases. Radiosynovectomy as therapeutic procedure or rheumatoid arthritis, other inflammatory joint diseases, persistent synovial perfusion, and other joint diseases is widely used. Using Y-90 for the knee joint, Re-186 for middle sized joints, and Er-169 for small joints an improvement of symptoms may be observed in about 70-80%. (author)

  7. Radionuclide therapy in Russia: Experience, problems, and perspectives

    International Nuclear Information System (INIS)

    Tsyb, A.F.; Drozdovsky, B. Ya.; Garbuzov, P.I.

    2004-01-01

    Full text: Radionuclide therapy in Russia has more than 50-years history. Radioiodine has been successfully used for the treatment of differentiated thyroid cancer and toxic goiter. Au-198 colloidal solution was used in the therapy of synovitis as well as mesothelioma. P-32 was used for polycythemia vera and metastatic bone pain palliation. The treatment was routinely performed in various radiological clinics. However, after the Chernobyl accident and due to more stringent radiation safety measures, it is now exclusively performed in the clinic of Medical Radiological Research Center RAMS, Obninsk. For the last 20 years, more than 10000 patients have been treated in the clinic including 200 children, mainly from the contaminated regions of Chernobyl accident. The palliative treatment of bone metastases is performed with home-produced 89Sr chloride in outpatient clinics and 153Sm-oxabifore in the clinic of MRRC. Nowadays majority of the 160 radionuclides of 80 chemical elements are produced in Russia and exported. Of these, only three are commonly used for therapy purposes, most common being the 131I for treatment of toxic goiter and thyroid differentiated cancer (about 2000 GBq annually). In Russia more than 50 thousand patients suffer from thyroid diseases. Other therapies include bone metastases with marked pain syndrome and hard bone and joint diseases. Radionuclide therapy in Russia is being expanded with the creation of radionuclide therapy departments in each region including Center of Nuclear Medicine and Radiopharmaceutics (CNMAR) in Obninsk. This city has many research and medical institutes, nuclear-physical and radiochemical departments with highly skilled personnel and industrial production of medical radionuclides and radiopharmaceuticals. Obninsk has a convenient geographical location for easy transportation of radiopharmaceuticals and patients. Under the aegis of CNMAR, many research works are being carried out to make radionuclide therapy more

  8. New radiopharmaecuticals for receptor scintigraphy and radionuclide therapy

    International Nuclear Information System (INIS)

    Virgolini, I.; Traub, T.; Leimer, M.; Novotny, C.; Pangerl, T.; Ofluoglu, S.; Halvadjieva, E.; Smith-Jones, P.; Flores, J.; Li, S.R.; Angelberger, P.; Havlik, E.; Andreae, F.; Raderer, M.; Kurtaran, A.; Niederle, B.; Dudczak, R.

    2000-01-01

    In vitro data have demonstrated a high amount of receptors for various hormones and peptides on malignant cells of neuroendocrine origin. Among these, binding sites for member of the SST-family (hSSTR1-5) are frequently found, and their expression has led to therapeutic and diagnostic attempts to specifically target these receptors. Receptor scintigraphy using radiolabeled peptide ligands has proved its effectiveness in clinical practice. In addition, initial results have indicated a clinical potential for receptor-targeted radiotherapy. Based on somatostatin (SST) receptor (R) recognition, the novel radiopharmaceuticals 111 In/ 9 0Y-DOTA-lanreotide developed at the University of Vienna as well as 111 In/ 9 0Y-DOTA-DPhe 1 -Tyr 3 -octreotide (NOVARTIS) both have provided promising data for diagnosis and treatment of hSSTR-positive tumors. SSTR scintigraphy using 111 In-DTPA-DPhe 1 -octreotide has a high positive predictive value for the vast majority of neuroendocrine tumors and has gained its place in the diagnostic work-up as well as follow-up of patients. Here it was used 111 In-DOTA-lanreotide scintigraphy in 166 patients since 1997 and have seen positive results in 93% of patients. In 42 patients with neuroendocrine tumors comparative data were obtained. As opposed to 111 In-DTPA-DPhe 1 -octreotide and 111 In-DOTA-DPhe 1 -Tyr 3 -octreotide, discrepancies in the scintigraphic results were seen in about one third of patients concerning both the tumor uptake as well as tumor lesion detection. Initial results both with 9 0Y-DOTA-lanreotide as well as 9 0Y-DOTA-DPhe 1 -Tyr 3 -octreotide has pointed out the clinical potential of radionuclide receptor-targeted radiotherapy. This new therapy could offer palliation and disease control at a reduced cost. The final peptide therapy strategy is most probably cheaper than conventional radio therapies or prolonged chemo therapies. Overall, receptor-mediated radiotherapy with 9 0Y-DOTA-lanreotide/ 9 0Y-DOTA-DPhe 1 -Tyr 3

  9. New radiopharmaceuticals for receptor scintigraphy and radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Virgolini, I.; Traub, T.; Leimer, M.; Novotny, C.; Pangerl, T.; Ofluoglu, S.; Halvadjieva, E.; Smith-Jones, P.; Flores, J.; Li, S.R.; Angelberger, P.; Havlik, E.; Andreae, F.; Raderer, M.; Kurtaran, A.; Niederle, B.; Dudczak, R. [Vienna Univ., Vienna (Austria). Dept. of Nuclear Medicine

    2000-03-01

    In vitro data have demonstrated a high amount of receptors for various hormones and peptides on malignant cells of neuroendocrine origin. Among these, binding sites for member of the SST-family (hSSTR1-5) are frequently found, and their expression has led to therapeutic and diagnostic attempts to specifically target these receptors. Receptor scintigraphy using radiolabeled peptide ligands has proved its effectiveness in clinical practice. In addition, initial results have indicated a clinical potential for receptor-targeted radiotherapy. Based on somatostatin (SST) receptor (R) recognition, the novel radiopharmaceuticals {sup 111}In/{sup 9}0Y-DOTA-lanreotide developed at the University of Vienna as well as {sup 111}In/{sup 9}0Y-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide (NOVARTIS) both have provided promising data for diagnosis and treatment of hSSTR-positive tumors. SSTR scintigraphy using {sup 111}In-DTPA-DPhe{sup 1}-octreotide has a high positive predictive value for the vast majority of neuroendocrine tumors and has gained its place in the diagnostic work-up as well as follow-up of patients. Here it was used {sup 111}In-DOTA-lanreotide scintigraphy in 166 patients since 1997 and have seen positive results in 93% of patients. In 42 patients with neuroendocrine tumors comparative data were obtained. As opposed to {sup 111}In-DTPA-DPhe{sup 1}-octreotide and {sup 111}In-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide, discrepancies in the scintigraphic results were seen in about one third of patients concerning both the tumor uptake as well as tumor lesion detection. Initial results both with {sup 9}0Y-DOTA-lanreotide as well as {sup 9}0Y-DOTA-DPhe{sup 1}-Tyr{sup 3}-octreotide has pointed out the clinical potential of radionuclide receptor-targeted radiotherapy. This new therapy could offer palliation and disease control at a reduced cost. The final peptide therapy strategy is most probably cheaper than conventional radio therapies or prolonged chemo therapies. Overall

  10. TH-AB-206-01: Advances in Radionuclide Therapy - From Radioiodine to Nanoparticles

    International Nuclear Information System (INIS)

    Humm, J.

    2016-01-01

    In the past few decades, the field of nuclear medicine has made long strides with the continued advancement of related sciences and engineering and the availability of diagnostic and therapeutic radionuclides. Leveraging these advancements while combining the advantages of therapeutic and diagnostic radionuclides into one radiopharmaceutical has also created a new subfield “theranostics” in nuclear medicine that has the potential to further propel the field into the future. This session is composed of two talks; one focused on the physics principles of theranostics from properties of beta and alpha emitting radionuclides to dosimetric models and quantification; while the second describes preclinical and clinical applications of theranostics and discusses the challenges and opportunities of bringing them to the clinic. At the end of the session the listener should be able to identify: The different properties of beta and alpha emitting radionuclides Which radionuclides are selected for which nuclear medicine therapies and why How PET can be used to accurately quantify the uptake of tumor targeting molecules How individualized dosimetry can be performed from the management of thyroid cancer to novel radiolabeled antibody therapies Promising pre-clinical radiopharmaceutical pairs in prostate cancer and melanoma. Promising clinical Theranostics in neuroendocrine cancers. Challenges of bringing Theranostics to the clinic. E. Delpassand, RITA Foundation -Houston; SBIR Grant; CEO and share holder of RadioMedix.

  11. TH-AB-206-01: Advances in Radionuclide Therapy - From Radioiodine to Nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Humm, J. [Memorial Sloan-Kettering Cancer Center (United States)

    2016-06-15

    In the past few decades, the field of nuclear medicine has made long strides with the continued advancement of related sciences and engineering and the availability of diagnostic and therapeutic radionuclides. Leveraging these advancements while combining the advantages of therapeutic and diagnostic radionuclides into one radiopharmaceutical has also created a new subfield “theranostics” in nuclear medicine that has the potential to further propel the field into the future. This session is composed of two talks; one focused on the physics principles of theranostics from properties of beta and alpha emitting radionuclides to dosimetric models and quantification; while the second describes preclinical and clinical applications of theranostics and discusses the challenges and opportunities of bringing them to the clinic. At the end of the session the listener should be able to identify: The different properties of beta and alpha emitting radionuclides Which radionuclides are selected for which nuclear medicine therapies and why How PET can be used to accurately quantify the uptake of tumor targeting molecules How individualized dosimetry can be performed from the management of thyroid cancer to novel radiolabeled antibody therapies Promising pre-clinical radiopharmaceutical pairs in prostate cancer and melanoma. Promising clinical Theranostics in neuroendocrine cancers. Challenges of bringing Theranostics to the clinic. E. Delpassand, RITA Foundation -Houston; SBIR Grant; CEO and share holder of RadioMedix.

  12. Radiation-Induced Second Cancer Risk Estimates From Radionuclide Therapy

    Science.gov (United States)

    Bednarz, Bryan; Besemer, Abigail

    2017-09-01

    The use of radionuclide therapy in the clinical setting is expected to increase significantly over the next decade. There is an important need to understand the radiation-induced second cancer risk associated with these procedures. In this study the radiation-induced cancer risk in five radionuclide therapy patients was investigated. These patients underwent serial SPECT imaging scans following injection as part of a clinical trial testing the efficacy of a 131Iodine-labeled radiopharmaceutical. Using these datasets the committed absorbed doses to multiple sensitive structures were calculated using RAPID, which is a novel Monte Carlo-based 3D dosimetry platform developed for personalized dosimetry. The excess relative risk (ERR) for radiation-induced cancer in these structures was then derived from these dose estimates following the recommendations set forth in the BEIR VII report. The radiation-induced leukemia ERR was highest among all sites considered reaching a maximum value of approximately 4.5. The radiation-induced cancer risk in the kidneys, liver and spleen ranged between 0.3 and 1.3. The lifetime attributable risks (LARs) were also calculated, which ranged from 30 to 1700 cancers per 100,000 persons and were highest for leukemia and the liver for both males and females followed by radiation-induced spleen and kidney cancer. The risks associated with radionuclide therapy are similar to the risk associated with external beam radiation therapy.

  13. Tumor targeted gene therapy

    International Nuclear Information System (INIS)

    Kang, Joo Hyun

    2006-01-01

    Knowledge of molecular mechanisms governing malignant transformation brings new opportunities for therapeutic intervention against cancer using novel approaches. One of them is gene therapy based on the transfer of genetic material to an organism with the aim of correcting a disease. The application of gene therapy to the cancer treatment had led to the development of new experimental approaches such as suicidal gene therapy, inhibition of oncogenes and restoration of tumor-suppressor genes. Suicidal gene therapy is based on the expression in tumor cells of a gene encoding an enzyme that converts a prodrug into a toxic product. Representative suicidal genes are Herpes simplex virus type 1 thymidine kinase (HSV1-tk) and cytosine deaminase (CD). Especially, physicians and scientists of nuclear medicine field take an interest in suicidal gene therapy because they can monitor the location and magnitude, and duration of expression of HSV1-tk and CD by PET scanner

  14. Radionuclide reporter gene imaging for cardiac gene therapy

    International Nuclear Information System (INIS)

    Inubushi, Masayuki; Tamaki, Nagara

    2007-01-01

    In the field of cardiac gene therapy, angiogenic gene therapy has been most extensively investigated. The first clinical trial of cardiac angiogenic gene therapy was reported in 1998, and at the peak, more than 20 clinical trial protocols were under evaluation. However, most trials have ceased owing to the lack of decisive proof of therapeutic effects and the potential risks of viral vectors. In order to further advance cardiac angiogenic gene therapy, remaining open issues need to be resolved: there needs to be improvement of gene transfer methods, regulation of gene expression, development of much safer vectors and optimisation of therapeutic genes. For these purposes, imaging of gene expression in living organisms is of great importance. In radionuclide reporter gene imaging, ''reporter genes'' transferred into cell nuclei encode for a protein that retains a complementary ''reporter probe'' of a positron or single-photon emitter; thus expression of the reporter genes can be imaged with positron emission tomography or single-photon emission computed tomography. Accordingly, in the setting of gene therapy, the location, magnitude and duration of the therapeutic gene co-expression with the reporter genes can be monitored non-invasively. In the near future, gene therapy may evolve into combination therapy with stem/progenitor cell transplantation, so-called cell-based gene therapy or gene-modified cell therapy. Radionuclide reporter gene imaging is now expected to contribute in providing evidence on the usefulness of this novel therapeutic approach, as well as in investigating the molecular mechanisms underlying neovascularisation and safety issues relevant to further progress in conventional gene therapy. (orig.)

  15. Electroplating targets for production of unique PET radionuclides

    International Nuclear Information System (INIS)

    Bui, V.; Sheh, Y.; Finn, R.

    1994-01-01

    The past decade has witnessed the applications of Positron Emission Tomography (PET) evolving from a purely research endeavour to a procedure which has specific clinical applications in the areas of cardiology, neurology and oncology. The growth of PET has been facilitated by developments in medical instrumentation and radiopharmaceutical chemistry efforts. Included in this latter effort has been the low energy accelerator production and processing of unique PET radionuclides appropriate for the radiolabeling of biomolecules i.e. monoclonal antibodies and pepetides. The development and application of electroplated targets of antimony and copper for the production of iodine-124 and gallium-66 respectively, utilizing the Memorial Sloan-Kettering Cancer Center cyclotron are examples of target design and development applicable to many medical accelerators

  16. Targeted Cancer Therapies

    Science.gov (United States)

    ... are sometimes referred to as the product of "rational" drug design.) One approach to identify potential targets ... molecules that stimulate new blood vessel growth. Immunotherapies trigger the immune system to destroy cancer cells. Some ...

  17. Translational Applications of Molecular Imaging and Radionuclide Therapy

    International Nuclear Information System (INIS)

    Welch, Michael J.; Eckelman, William C.; Vera, David

    2005-01-01

    Molecular imaging is becoming a larger part of imaging research and practice. The Office of Biological and Environmental Research of the Department of Energy funds a significant number of researchers in this area. The proposal is to partially fund a workshop to inform scientists working in nuclear medicine and nuclear medicine practitioners of the recent advances of molecular imaging in nuclear medicine as well as other imaging modalities. A limited number of topics related to radionuclide therapy will also be discussed. The proposal is to request partial funds for the workshop entitled ''Translational Applications of Molecular Imaging and Radionuclide Therapy'' to be held prior to the Society of Nuclear Medicine Annual Meeting in Toronto, Canada in June 2005. The meeting will be held on June 17-18. This will allow scientists interested in all aspects of nuclear medicine imaging to attend. The chair of the organizing group is Dr. Michael J. Welch. The organizing committee consists of Dr. Welch, Dr. William C. Eckelman and Dr. David Vera. The goal is to invite speakers to discuss the most recent advances of modern molecular imaging and therapy. Speakers will present advances made in in vivo tagging imaging assays, technical aspects of small animal imaging, in vivo imaging and bench to bedside translational study; and the role of a diagnostic scan on therapy selection. This latter topic will include discussions on therapy and new approaches to dosimetry. Several of these topics are those funded by the Department of Energy Office of Biological and Environmental Research

  18. What is the role of the bystander response in radionuclide therapies?

    Directory of Open Access Journals (Sweden)

    Darren eBrady

    2013-08-01

    Full Text Available Radionuclide therapy for cancer is undergoing a renaissance, with a wide range of radionuclide and clinical delivery systems currently under investigation. Dosimetry at the cellular and subcellular level is complex with inhomogeneity and incomplete targeting of all cells such that some tumour cells will receive little or no direct radiation energy. There is now sufficient preclinical evidence of a bystander response which can modulate the biology of these unirradiated cells with current research demonstrating both protective and inhibitory responses. Dependence upon fraction of irradiated cells has also been found has and the presence of functional gap junctions appears to be import for several bystander responses. The selection of either high or low LET radionuclides may be critical. While low LET radionuclides appear to have a bystander response proportional to dose, the dose-response from high LET radionuclides are more complex. In media transfer experiments a U shaped response curve has been demonstrated for high LET treatments. However this U shaped response has not been seen with co-culture experiments and its relevance remains uncertain. For high LET treatments there is a suggestion that dose rate effects may also be important with inhibitory effects noted with 125I labelling study and a stimulatory seen with 123I labelling in one study.

  19. Targeted therapy for sarcomas

    Directory of Open Access Journals (Sweden)

    Forscher C

    2014-03-01

    Full Text Available Charles Forscher,1 Monica Mita,2 Robert Figlin3 1Sarcoma Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Academic Development Program, Samuel Oschin Comprehensive Cancer Institute, and Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Abstract: Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones described with ever-increasing frequency. One way to look at sarcomas is to divide them into categories on the basis of their genetic make-up. One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing's sarcoma. These specific abnormalities often lead to the presence of fusion proteins, such as EWS-FLI1 in Ewing's sarcoma, which are helpful as diagnostic tools and may become therapeutic targets in the future. Another group of sarcomas is characterized by complex genetic abnormalities as seen in leiomyosarcoma, osteosarcoma, and undifferentiated sarcoma. It is important to keep these distinctions in mind when contemplating the development of targeted agents for sarcomas. Different abnormalities in sarcoma could be divided by tumor subtype or by the molecular or pathway abnormality. However, some existing drugs or drugs in development may interfere with or alter more than one of the presented pathways. Keywords: sarcoma, targeted agents, tyrosine kinase inhibitors, mTor inhibition

  20. Report of a Technical Meeting on ''Alpha emitting radionuclides and radiopharmaceuticals for therapy''

    International Nuclear Information System (INIS)

    2013-01-01

    Considering the high potential of α-emitters for future development of radionuclide therapy, the International Atomic Energy Agency (IAEA) organized a Technical Meeting on ‘Alpha Emitting Radionuclides and Radiopharmaceuticals for Therapy’, from June 24 to 28, 2013, at IAEA Headquarters in Vienna with the purpose of gathering eminent Experts in the field and discuss with them the status and future perspectives of the field. Sixteen Experts and two External Observers from ten different countries, and four IAEA Technical Officers attended this meeting. Outstanding lectures have been presented covering all relevant aspects of α-therapy, which were followed by extensive discussions and analysis. Selected arguments encompassed production methods and availability of alpha-emitting radionuclides, labelling chemistry of alpha-emittting radioelements, design and development of target-specific radiopharmaceuticals, physical principles of alpha-particle dosimetry and advanced dosimetric models, biological effects of alpha radiation at the cellular level, on-going preclinical and clinical studies with new radiopharmaceuticals, results of clinical trials on the use of radium-223 chloride solutions for the treatment of metastatic bone cancer. The broad scientific background of invited components of the Experts’ panel conferred a strong interdisciplinary trait to the overall discussion and stimulated a critical analysis of this emerging unexplored field. Results of this comprehensive overview on alpha therapy, including recommendations to the Agency on suitable initiatives that may help to promote and spread the knowledge to Members States on this emerging therapeutic modality, are summarized in the present Report

  1. Thin-target excitation functions: a powerful tool for optimizing yield, radionuclidic purity and specific activity of cyclotron produced radionuclides

    International Nuclear Information System (INIS)

    Bonardi, M.L.

    2002-01-01

    In accelerator production of radionuclides, thin-target yield, y(E), is defined as a function of the projectile energy E, at the End Of an Instantaneous Bombardment (EOIB), as the slope at the origin of the growing curve of the activity per unit beam current (A/I) of a specific radionuclide vs. irradiation time, for a target in which the energy loss is negligible with respect to the projectile energy itself. In practice, y(E) is defined as the second derivative of A/I with respect to particle energy and irradiation time, calculated when the irradiation time tends to zero (EOIB). The thin-target yields of different radionuclides, produced by direct and side reactions, are numerically fitted, taking into account the overall statistical errors as weights. The 'effective' cross-section σ ± (E) as a function of projectile energy is proportional to thin-target yield, but the physical meaning of this parameter is poor, being only a raw summation of the several cross sections of the reaction channels concerned, weighted on target isotopic composition. Conversely, Thick-Target Yield, Y(E,ΔE), is defined as a two parameter function of the incident particle energy E(MeV) onto the target and the energy loss ΔE (MeV), in the target itself, obtained by integration of thin-target excitation function, y(E). This approach holds in the strict approximation of a monochromatic beam of energy E, not affected by either intrinsic energy spread or straggling. The energy straggling is computed by Monte Carlo computer codes, like TRIM 2001. In case of total particle energy absorption in the target, for a nuclear reaction of energy threshold E th , the function Y(E,ΔE) reaches a value Y(E,E- E th ), for ΔE=E- E th , that represents mathematically the envelope of the Y(E,ΔE) family of curves. This envelope is a monotonically increasing curve, never reaching either a maximum or a saturation value, even if its slope becomes negligible for high particle energies and energy losses. Some

  2. Target development for 67Cu, 82Sr radionuclide production at the RIC-80 facility

    Science.gov (United States)

    Panteleev, V. N.; Barzakh, A. E.; Batist, L. Kh.; Fedorov, D. V.; Ivanov, V. S.; Krotov, S. A.; Molkanov, P. L.; Moroz, F. V.; Orlov, S. Yu.; Volkov, Yu. M.

    2018-01-01

    A high-current cyclotron C-80 capable of producing 40-80 MeV proton beams with a current of up to 200 μA has been constructed and commissioned at PNPI (Petersburg Nuclear Physics Institute). One of the main goals of cyclotron C-80 is the production of a wide spectrum of medical radionuclides for diagnostics and therapy. To date, the project development of a radioisotope facility RIC-80 (radioisotopes at cyclotron C-80) has been completed. The feature of the project is the use of a mass-separator combined with the ion-target device for obtaining ion beams of radioisotopes with a high purity of separation that is especially important for medical applications. The first results of a new high-temperature method for extracting 82Sr and 67Cu radioisotopes from irradiated targets have been presented.

  3. Accelerator based Production of Auger-Electron-emitting Isotopes for Radionuclide Therapy

    DEFF Research Database (Denmark)

    Thisgaard, Helge

    Sb from the enriched 119Sn target material with high radionuclidic- and chemical purity. A method that also allows efficient recovery of the 119Sn for recycling. To demonstrate the ability of producing therapeutic quantities of 119Sb and other radioisotopes for therapy with a low-energy cyclotron...... isotopes (e.g. 119Sb or 64Cu) using the PETtrace cyclotron commonly found at the larger PET-centers in the hospitals. Finally, research in a new method to measure the radiotoxicity of Auger-emitters invitro using cellular microinjection has been carried out. The purpose of this method is to be able...

  4. Dosimetry in radionuclide therapies with 90Y-conjugates. The IEO experience

    International Nuclear Information System (INIS)

    Cremonesi, M.; Ferrari, M.; Chinol, M.; Bartolomei, M.; Sacco, E.; Fiorenza, M.; Tosi, G.; Paganelli, G.; Stabin, M. G.

    2000-01-01

    The basis for successful radionuclide therapy is a high and stable uptake of the radiopharmaceutical in the target tissue along with low activity concentration in other normal organs. The contribution of dosimetry in radionuclide therapy is to predict before the treatment the absorbed doses in tumor and normal organs, to identify the critical organs, to minimize any possible toxicity and to evaluate the maximum tolerated dose. In this article is reported the experience concerning pharmacokinetics and dosimetry of two 90 Y-therapeutic protocols: 3-step pretargeting radioimmunotherapy (RIT) according to the biotin-avidin system and receptor mediated radionuclide therapy with the somatostatin analogue (DOTA-D-Phe 1 -Tyr 3 ) octreotide named DOTATOC. For the dosimetric analysis, analogous approaches for the two radiolabeled compounds due to the similar pharmacokinetic characteristics were adopted; the MIRD formalism was applied, taking into account both the physical and the biological characteristics of the radio conjugate and patients' metabolism. In order to determine biological clearance, serial blood samples and complete urine collection were obtained up to 48 hours after injection; to evaluate biodistribution, several whole body scans were acquired. Both therapies showed the advantageous characteristics of a fast blood clearance and a predominantly renal excretion of the radiopharmaceuticals thus lowering the irradiation of the total body. Although pharmacokinetic characteristics were similar, different critical organs were found for the two therapies: in particular, some considerations regarding red marrow, spleen and kidneys were required. The results of the studies indicate that high activities of 90 Y-biotin (3-step RIT) and 90 Y-DOTATOC can be administered with acceptable radiation doses to normal organs

  5. Targeted therapies for bone sarcomas

    International Nuclear Information System (INIS)

    Mudry, P.

    2011-01-01

    Therapy success in bone sarcoma is significantly better compared to history cohorts with 60 - 70 % overall survival to date. Unfortunately, there is yet no shift and movement in better survival of patients with relapsed and refractory bone sarcomas during last twenty years. This article reviews targeted therapeutics for bone sarcomas which are under investigation and which could give chance to patients suffering from relapsed and chemo resistant bone sarcomas. Majority of the targeted drugs are given as part of phase 1 or 2 studies. (author)

  6. Standardized high current solid targets for cyclotron production of radionuclides

    International Nuclear Information System (INIS)

    Al-Jammaz, Ibrahim

    2000-01-01

    The Cyclotron and Radiopharmaceuticals Department (CRP) is an advanced and modern facility that encompasses two essential components: radioisotope research, and radiopharmaceuticals manufacturing. Radiopharmaceuticals manufacturing program is not only quite unique, but also an essential component of King Faisal Specialist Hospital and Research Center (KFSH and RC) in providing quality patient care for the population of the Kingdom. Accurate diagnosis and therapy with medical imaging equipment requires quality radiopharmaceuticals that are available readily and with reliability. The CRP Department provides that quality and reliability. Research activities of the CRP Department are focused on developing new radiotracers with potential usefulness in biomedical research and clinical applications. Research projects consist of: developing cyclotron targetry for radioisotope production; developing synthesis methods for radiolabeling biomolecules; and developing analytical methods for quality control. The CRP Department operates a semi-commercial radiopharmaceuticals manufacturing program that supplies the diagnostic radioactive products to several hospitals in the Kingdom and neighboring countries. These products for clinical applications are produced according to the international standards of Good Manufacturing Practices of quality and efficacy. At the heart of the radioisotope program is a medium energy cyclotron capable of accelerating a number of particles for transformation of non-radioactive atoms into radionuclides that are the primary sources for research and development activities, and for preparing radiopharmaceuticals. In addition to having the only cyclotron facility in the region, KFSH and RC also has the only Positron Emission Tomography Center (PET) in this part of the world. This combination of cyclotron and the ultra modern PET facility translates into advanced and specialized care for the patients at KFSH and RC

  7. Accumulation of the radionuclides in a target irradiated in the reactor of tajoura nuclear research center

    International Nuclear Information System (INIS)

    Abdunnobi, A.R.; Arebi, B.

    1998-01-01

    One of the main stages of radionuclides production in reactor is the distinguishing of a regime on target irradiation in order to acquire the sufficient activity and the purity of radioisotope required. The authors have derived formula for calculating radionuclidic accumulation on a target irradiated in the reactor operating 10 hours per day, 4 days a week during 4 weeks. The results of I-131 and other radionuclide accumulation are illustrated by a tellurium target irradiation in the reactor operating continuously or with interruptions

  8. THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy - The Bad Berka Experience.

    Science.gov (United States)

    Baum, Richard P; Kulkarni, Harshad R

    2012-01-01

    The acronym THERANOSTICS epitomizes the inseparability of diagnosis and therapy, the pillars of medicine and takes into account personalized management of disease for a specific patient. Molecular phenotypes of neoplasms can be determined by molecular imaging with specific probes using positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), or optical methods, so that the treatment is specifically targeted against the tumor and its environment. To meet these demands, we need to define the targets, ligands, coupling and labeling chemistry, the most appropriate radionuclides, biodistribution modifiers, and finally select the right patients for the personalized treatment. THERANOSTICS of neuroendocrine tumors (NETs) using Ga-68 labeled tracers for diagnostics with positron emission tomography/ computed tomography (PET/CT), and using Lu-177 or other metallic radionuclides for radionuclide therapy by applying the same peptide proves that personalized radionuclide therapy today is already a fact and not a fiction.

  9. THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy - The Bad Berka Experience

    Directory of Open Access Journals (Sweden)

    Richard P. Baum, Harshad R. Kulkarni

    2012-01-01

    Full Text Available The acronym THERANOSTICS epitomizes the inseparability of diagnosis and therapy, the pillars of medicine and takes into account personalized management of disease for a specific patient. Molecular phenotypes of neoplasms can be determined by molecular imaging with specific probes using positron emission tomography (PET, single photon emission computed tomography (SPECT, magnetic resonance imaging (MRI, or optical methods, so that the treatment is specifically targeted against the tumor and its environment. To meet these demands, we need to define the targets, ligands, coupling and labeling chemistry, the most appropriate radionuclides, biodistribution modifiers, and finally select the right patients for the personalized treatment. THERANOSTICS of neuroendocrine tumors (NETs using Ga-68 labeled tracers for diagnostics with positron emission tomography/ computed tomography (PET/CT, and using Lu-177 or other metallic radionuclides for radionuclide therapy by applying the same peptide proves that personalized radionuclide therapy today is already a fact and not a fiction.

  10. Targeted Therapies for Lung Cancer.

    Science.gov (United States)

    Stinchcombe, Thomas E

    Targeted therapies have become standard therapies for patients with non-small cell lung cancer (NSCLC). A phase III trial of carboplatin and paclitaxel with and without bevacizumab in patients with advanced NSCLC with non-squamous histology demonstrated a statistically significant improvement in efficacy. In patients with NSCLC with an activating epidermal growth factor receptor (EGFR) mutation (defined as exon 19 deletion and exon 21 L858R point mutation), phase III trials of EGFR tyrosine kinase inhibitors (TKI) compared to platinum-based chemotherapy have demonstrated superior efficacy in the first-line setting. In patients with NSCLC with anaplastic lymphoma kinase (ALK) rearrangements, phase III trials of crizotinib have demonstrated superior efficacy compared to platinum-pemetrexed in the first-line setting and standard chemotherapy in the second-line setting. A second-generation ALK inhibitor, ceritinib, is available for patients who have progressed after or were intolerant of crizotinib. Crizotinib has also demonstrated activity on patients with ROS1 rearrangements, and BRAF inhibitors (dabrafenib, vemurafenib) have demonstrated activity in patients with NSCLC with BRAF V600E mutation. The oncogenic mutations that are susceptible to targeted therapy are mainly found in non-squamous NSCLC. The development of targeted therapy in patients with squamous NSCLC has been more challenging due to the genomic complexity observed in the squamous histology and the low prevalence of EGFR, ALK, and ROS1 molecular alterations. A phase III trial of cisplatin and gemcitabine with and without necitumumab in patients with advanced NSCLC with squamous histology demonstrated a statistically significant improvement in progression-free and overall survival.

  11. Preparation and characterization of radionuclide 64Cu for positron emission tomographic diagnosis and therapy

    International Nuclear Information System (INIS)

    Ometakova, J.

    2013-01-01

    We occupy ourselves with preparation of 64 Cu using cyclotron IBA 18/9. 64 Cu is a starting product for production of radiopharmaceuticals for positron emission tomographic diagnostics and therapy and metrological characterization as well. The use of non-traditional PET radionuclides has been spread in the world recently. Due to the physical properties (T 1/2 =12.7 h, β- 37.1 %, β + 17.9 %), 64 Cu is suitable for therapy (β - ) and diagnosing as well (β+). 64 Cu is suitable radionuclide for labeling of radiopharmaceuticals on the basis of bis-thiosemicarbazone for study of hypoxic tumors. The number and orientation of articles and papers at conferences show a great demand for 64 Cu in the world. It is caused by specific physical properties and possibility of preparation in small biomedical cyclotrons as well. An electrolytic preparation of a target lies in a galvanostatic plating of 64 Ni on a gold target. The target is irradiated by a cyclotron IBA Cyclone 18/9. COSTIS station (Compact Solid Target Irradiation System) is installed at the end of external proton beam. 64 Cu is separated from the target material by ionex Bio-Rad AG1-X8 as [ 64 Cu]CuCl 2 . The target material is recycled by a simple method. A process of 64 Cu preparation is completely automated and runs in a separation module with Plc Simatin S-1200 developed by Biont a.s. The product was measured by an ionization chamber (Curiementor), HPGe detector and LSC method (TDCR). (author)

  12. Preparation and characterization of radionuclide 64Cu for positron emission tomographic diagnosis and therapy

    International Nuclear Information System (INIS)

    Ometakova, J.

    2013-01-01

    We occupy ourselves with preparation of 64 Cu using cyclotron IBA 18/9. 64 Cu is a starting product for production of radiopharmaceuticals for positron emission tomographic diagnostics and therapy and metrological characterization as well. The use of non-traditional PET radionuclides has been spread in the world recently. Due to the physical properties (T 1/2 =12.7 h, β- 37.1 %, β + 17.9 %), 64 Cu is suitable for therapy (β - ) and diagnosing as well (β+). 64 Cu is suitable radionuclide for labeling of radiopharmaceuticals on the basis of bis-thiosemicarbazone for study of hypoxic tumors. The number and orientation of articles and papers at conferences show a great demand for 64 Cu in the world. It is caused by specific physical properties and possibility of preparation in small biomedical cyclotrons as well. An electrolytic preparation of a target lies in a galvanostatic plating of 64 Ni on a gold target. The target is irradiated by a cyclotron IBA Cyclone 18/9. COSTIS station (Compact Solid Target Irradiation System) is installed at the end of external proton beam. 64 Cu is separated from the target material by ionex Bio-Rad AG1-X8 as [ 64 Cu]CuCl 2 . The target material is recycled by a simple method. A process of 64 Cu preparation is completely automated and runs in a separation module with PLC SIMATIC S7-1200 developed by Biont a.s. The product was measured by an ionization chamber (Curiementor), HPGe detector and LSC method (TDCR). (author)

  13. Report of the consultants' meeting on target and processing technologies for cyclotron production of radionuclides

    International Nuclear Information System (INIS)

    1999-11-01

    Cyclotron produced radionuclides are used routinely for the diagnosis of a wide variety of diseases. Recently a number of radionuclides available from cyclotrons have been proposed for use in radiotherapy. In fact Pd-103 has become routinely available in some parts of the world for incorporation into brachytherapy seeds for treating prostate cancer. The consultants meeting reviewed the status of target and processing technologies associated with cyclotron production of radionuclides. The main topics of discussion included the basic nuclear data that is crucial to the production of the desired radionuclides, gas and solid target systems, the automated chemical processing units, the Good Manufacturing Practices (GMP) required in order to use these radionuclides in human patients in a safe and efficacious manner and a review of possible candidate nuclides that show promise for use in Nuclear Medicine in the near future. Advances in the preparation of solid targets using electroplating technology has created the possibility of preparing targets capable of operating at very high beam currents which would make the production of large quantities of SPECT agents possible at cyclotron facilities throughout the world. Recognising the needs of the developing countries which have established cyclotron facilities, the consultants focussed on how to provide the technology for preparing solid targets that could be used in the existing facilities. While solid target technology can be used for many radionuclides the report concentrated on several key radionuclides, which are of current importance or show potential for use in the near future. Tl-201 is currently used for cardiac profusion studies throughout the world. New target preparation techniques could potentially make many of the member states self sufficient in the production of this nuclide. I-123 has tremendous potential because of the near ideal photon energy for SPECT cameras and its well-understood chemistry. However, it

  14. Gene Therapy Targeting HIV Entry

    Directory of Open Access Journals (Sweden)

    Chuka Didigu

    2014-03-01

    Full Text Available Despite the unquestionable success of antiretroviral therapy (ART in the treatment of HIV infection, the cost, need for daily adherence, and HIV-associated morbidities that persist despite ART all underscore the need to develop a cure for HIV. The cure achieved following an allogeneic hematopoietic stem cell transplant (HSCT using HIV-resistant cells, and more recently, the report of short-term but sustained, ART-free control of HIV replication following allogeneic HSCT, using HIV susceptible cells, have served to both reignite interest in HIV cure research, and suggest potential mechanisms for a cure. In this review, we highlight some of the obstacles facing HIV cure research today, and explore the roles of gene therapy targeting HIV entry, and allogeneic stem cell transplantation in the development of strategies to cure HIV infection.

  15. The potential of 211Astatine for NIS-mediated radionuclide therapy in prostate cancer

    International Nuclear Information System (INIS)

    Willhauck, Michael J.; Sharif Samani, Bibi-Rana; Goeke, Burkhard; Wolf, Ingo; Senekowitsch-Schmidtke, Reingard; Stark, Hans-Juergen; Meyer, Geerd J.; Knapp, Wolfram H.; Morris, John C.; Spitzweg, Christine

    2008-01-01

    We reported recently the induction of selective iodide uptake in prostate cancer cells (LNCaP) by prostate-specific antigen (PSA) promoter-directed sodium iodide symporter (NIS) expression that allowed a significant therapeutic effect of 131 I. In the current study, we studied the potential of the high-energy alpha-emitter 211 At, also transported by NIS, as an alternative radionuclide after NIS gene transfer in tumors with limited therapeutic efficacy of 131 I due to rapid iodide efflux. We investigated uptake and therapeutic efficacy of 211 At in LNCaP cells stably expressing NIS under the control of the PSA promoter (NP-1) in vitro and in vivo. NP-1 cells concentrated 211 At in a perchlorate-sensitive manner, which allowed a dramatic therapeutic effect in vitro. After intrapertoneal injection of 211 At (1 MBq), NP-1 tumors accumulated approximately 16% ID/g 211 At (effective half-life 4.6 h), which resulted in a tumor-absorbed dose of 1,580 ± 345 mGy/MBq and a significant tumor volume reduction of up to 82 ± 19%, while control tumors continued their growth exponentially. A significant therapeutic effect of 211 At has been demonstrated in prostate cancer after PSA promoter-directed NIS gene transfer in vitro and in vivo suggesting a potential role for 211 At as an attractive alternative radioisotope for NIS-targeted radionuclide therapy, in particular in smaller tumors with limited radionuclide retention time. (orig.)

  16. From molecular imaging to personalized radionuclide therapy of cancer

    International Nuclear Information System (INIS)

    Baum, R.P.

    2015-01-01

    Full text of publication follows. 68 Gallium is a positron emitter (t 1/2 68 min) which can be produced from a generator in a convenient, 'in-house' preparation and used for labeling of peptides, e.g. somatostatin analogues (SA) like DOTATOC or DOTATATE for molecular imaging of SSTR expressing tumors. Since 2004, we have performed over 7700 68 Ga PET/CT studies in patients with neuroendocrine tumors (NET) and have established SSTR PET/CT as the new gold standard for imaging G1 and G2 NET (staging, re-staging, therapy response evaluation and detection of unknown primary NET). The same peptides can be labeled with 177 Lutetium or 90 Yttrium for radionuclide therapy, a form of personalized treatment (THERANOSTICS approach). PRRNT is based on the receptor-mediated internalization of SA. Several clinical trials indicate that PRRNT can deliver effective radiation doses to tumors. A German multi-institutional registry study with prospective follow up in 450 patients indicates that PRRT is an effective therapy for patients with G1-2 neuroendocrine tumors, irrespective of previous therapies, with a survival advantage of several years compared to other therapies and only minor side effects. Median overall survival (OS) of all patients from the start of treatment was 59 months. Median progression-free survival (PFS) measured from last cycle of therapy accounted to 41 mo. Median PFS of pancreatic NET was 39 mo. Similar results were obtained for NET of unknown primary (median PFS: 38 mo) whereas NET of small bowel had a median PFS of 51 months. Side effects like 3-4 NEThro- or hemato-toxicity were observed in only 0.2% and 2% of patients respectively. PRRNT is highly effective in the management of NET, even in advanced cases. In patients with progressive neuroendocrine tumors, fractionated, personalized PRRNT with lower doses of radioactivity given over a longer period of time (Bad Berka Concept using sequential (DUO) PRRNT) results in excellent therapeutic responses

  17. Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy

    International Nuclear Information System (INIS)

    Ogawa, Kazuma; Mizuno, Yoshiaki; Washiyama, Kohshin; Shiba, Kazuhiro; Takahashi, Naruto; Kozaka, Takashi; Watanabe, Shigeki; Shinohara, Atsushi; Odani, Akira

    2015-01-01

    Introduction: Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated 131 I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[ 131 I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[ 131 I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[ 211 At]pAtV, an 211 At-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy. Methods: The radiolabeled sigma receptor ligand (+)-[ 211 At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[ 211 At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[ 211 At]pAtV and (+)-[ 125 I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice. Results: The lipophilicity of (+)-[ 211 At]pAtV was similar to that of (+)-[ 125 I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1 h post-injection were also similar between (+)-[ 211 At]pAtV and (+)-[ 125 I]pIV. Namely, (+)-[ 211 At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors. Conclusion: These results indicate that (+)-[ 211 At]pAtV could function as an new agent for alpha-radionuclide receptor therapy.

  18. Preparation and evaluation of an astatine-211-labeled sigma receptor ligand for alpha radionuclide therapy.

    Science.gov (United States)

    Ogawa, Kazuma; Mizuno, Yoshiaki; Washiyama, Kohshin; Shiba, Kazuhiro; Takahashi, Naruto; Kozaka, Takashi; Watanabe, Shigeki; Shinohara, Atsushi; Odani, Akira

    2015-11-01

    Sigma receptors are overexpressed in a variety of human tumors, making them potential targets for radionuclide receptor therapy. We have previously synthesized and evaluated (131)I-labeled (+)-2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[(131)I]pIV], which has a high affinity for sigma receptors. Therefore, (+)-[(131)I]pIV significantly inhibited tumor cell proliferation in tumor-bearing mice. In the present study, we report the synthesis and the in vitro and in vivo characterization of (+)-[(211)At]pAtV, an (211)At-labeled sigma receptor ligand, that has potential use in alpha-radionuclide receptor therapy. The radiolabeled sigma receptor ligand (+)-[(211)At]pAtV was prepared using a standard halogenation reaction generating a 91% radiochemical yield with 98% purity after HPLC purification. The partition coefficient of (+)-[(211)At]pAtV was measured. Cellular uptake experiments and in vivo biodistribution experiments were performed using a mixed solution of (+)-[(211)At]pAtV and (+)-[(125)I]pIV; the human prostate cancer cell line DU-145, which expresses high levels of the sigma receptors, and DU-145 tumor-bearing mice. The lipophilicity of (+)-[(211)At]pAtV was similar to that of (+)-[(125)I]pIV. DU-145 cellular uptake and the biodistribution patterns in DU-145 tumor-bearing mice at 1h post-injection were also similar between (+)-[(211)At]pAtV and (+)-[(125)I]pIV. Namely, (+)-[(211)At]pAtV demonstrated high uptake and retention in tumor via binding to sigma receptors. These results indicate that (+)-[(211)At]pAtV could function as an new agent for alpha-radionuclide receptor therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Targeted drugs in radiation therapy

    International Nuclear Information System (INIS)

    Favaudon, V.; Hennequin, C.; Hennequin, C.

    2004-01-01

    New drugs aiming at the development of targeted therapies have been assayed in combination with ionizing radiation over the past few years. The rationale of this concept comes from the fact that the cytotoxic potential of targeted drugs is limited, thus requiring concomitant association with a cytotoxic agent for the eradication of tumor cells. Conversely a low level of cumulative toxicity is expected from targeted drugs. Most targeted drugs act through inhibition of post-translational modifications of proteins, such as dimerization of growth factor receptors, prenylation reactions, or phosphorylation of tyrosine or serine-threonine residues. Many systems involving the proteasome, neo-angiogenesis promoters, TGF-β, cyclooxygenase or the transcription factor NF-κB, are currently under investigation in hopes they will allow a control of cell proliferation, apoptosis, cell cycle progression, tumor angiogenesis and inflammation. A few drugs have demonstrated an antitumor potential in particular phenotypes. In most instances, however, radiation-drug interactions proved to be strictly additive in terms of cell growth inhibition or induced cell death. Strong potentiation of the response to radiotherapy is expected to require interaction with DNA repair mechanisms. (authors)

  20. Cyclotron Produced Radionuclides for Diagnosis and Therapy of Human Neoplasms

    Energy Technology Data Exchange (ETDEWEB)

    Steven Larson MD

    2009-09-21

    This project funded since 1986 serves as a core project for cancer research throughout MSKCC, producing key radiotracers as well as basic knowledge about thel physics of radiation decay and imaging, for nuclear medicine applications to cancer diagnosis and therapy. In recent years this research application has broadened to include experiments intended to lead to an improved understanding of cancer biology and into the discovery and testing of new cancer drugs. Advances in immune based radiotargeting form the basis for this project. Both antibody and cellular based immune targeting methods have been explored. The multi-step targeting methodologies (MST) developed by NeoRex (Seattle,Washington), have been adapted for use with positron emitting isotopes and PET allowing the quantification and optimization of targeted delivery. In addition, novel methods for radiolabeling immune T-cells with PET tracers have advanced our ability to track these cells of prolonged period of time.

  1. Targeted therapy of multiple myeloma.

    Science.gov (United States)

    Dolloff, Nathan G; Talamo, Giampaolo

    2013-01-01

    Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematologic cancer. MM is characterized by the accumulation of malignant plasma cells within the bone marrow, and presents clinically with a broad range of symptoms, including hypercalcemia, renal insufficiency, anemia, and lytic bone lesions. MM is a heterogeneous disease associated with genomic instability, where patients may express multiple genetic abnormalities that affect several oncogenic pathways. Commonly detected genetic aberrations are translocations involving immunoglobulin heavy chain (IgH) switch regions (chromosome 14q32) and oncogenes such as c-maf [t(14:16)], cyclin D1 [t(11:14)], and FGFR3/MMSET [t(4:14)]. Advances in the basic understanding of MM and the development of novel agents, such as the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor bortezomib, have increased therapeutic response rates and prolonged patient survival. Despite these advances MM remains incurable in the majority of patients, and it is therefore critical to identify additional therapeutic strategies and targets for its treatment. In this chapter, we review the underlying genetic components of MM and discuss the results of recent clinical trials that demonstrate the effectiveness of targeted agents in the management of MM. In addition, we discuss experimental therapies that are currently in clinical development along with their molecular rationale in the treatment of MM.

  2. Bounding Radionuclide Inventory and Accident Consequence Calculation for the 1L Target

    International Nuclear Information System (INIS)

    Kelsey, Charles T. IV

    2011-01-01

    A bounding radionuclide inventory for the tungsten of the Los Alamos Neutron Science Center (LANSCE) IL Target is calculated. Based on the bounding inventory, the dose resulting from the maximum credible incident (MCI) is calculated for the maximally exposed offsite individual (MEOl). The design basis accident involves tungsten target oxidation following a loss of cooling accident. Also calculated for the bounding radionuclide inventory is the ratio to the LANSCE inventory threshold for purposes of inventory control as described in the target inventory control policy. A bounding radionuclide inventory calculation for the lL Target was completed using the MCNPX and CINDER'90 codes. Continuous beam delivery at 200 (micro)A to 2500 mA·h was assumed. The total calculated activity following this irradiation period is 205,000 Ci. The dose to the MEOI from the MCI is 213 mrem for the bounding inventory. The LANSCE inventory control threshold ratio is 132.

  3. Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

    Energy Technology Data Exchange (ETDEWEB)

    Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, V 220, Rotterdam (Netherlands); Boerman, Otto C. [Radboud University Hospital, Department of Nuclear Medicine, Nijmegen (Netherlands)

    2010-05-15

    This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

  4. Kidney protection during peptide receptor radionuclide therapy with somatostatin analogues

    International Nuclear Information System (INIS)

    Rolleman, Edgar J.; Melis, Marleen; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de; Boerman, Otto C.

    2010-01-01

    This review focuses on the present status of kidney protection during peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues. This treatment modality for somatostatin receptor-positive tumours is limited by renal reabsorption and retention of radiolabelled peptides resulting in dose-limiting high kidney radiation doses. Radiation nephropathy has been described in several patients. Studies on the mechanism and localization demonstrate that renal uptake of radiolabelled somatostatin analogues largely depends on the megalin/cubulin system in the proximal tubule cells. Thus methods are needed that interfere with this reabsorption pathway to achieve kidney protection. Such methods include coadministration of basic amino acids, the bovine gelatin-containing solution Gelofusine or albumin fragments. Amino acids are already commonly used in the clinical setting during PRRT. Other compounds that interfere with renal reabsorption capacity (maleic acid and colchicine) are not suitable for clinical use because of potential toxicity. The safe limit for the renal radiation dose during PRRT is not exactly known. Dosimetry studies applying the principle of the biological equivalent dose (correcting for the effect of dose fractionation) suggest that a dose of about 37 Gy is the threshold for development of kidney toxicity. This threshold is lower when risk factors for development of renal damage exist: age over 60 years, hypertension, diabetes mellitus and previous chemotherapy. A still experimental pathway for kidney protection is mitigation of radiation effects, possibly achievable by cotreatment with amifostine (Ethylol), a radiation protector, or with blockers of the renin-angiotensin-aldosterone system. Future perspectives on improving kidney protection during PRRT include combinations of agents to reduce renal retention of radiolabelled peptides, eventually together with mitigating medicines. Moreover, new somatostatin analogues with lower

  5. Radionuclide imaging in diagnosis and therapy of the diabetic foot

    International Nuclear Information System (INIS)

    Zhu Cansheng

    2000-01-01

    Early and accurate diagnosis of angiopathy or infection of the diabetic foot is the key to the successful management. Radionuclide imaging is very useful in detecting diabetic microangiopathy, assessing the prognosis of foot ulcers, and diagnosing the osteomyelitis

  6. Anti-tumor effects of Egr-IFN γ gene therapy combined with 125I-UdR radionuclide therapy

    International Nuclear Information System (INIS)

    Zhao Jingguo; Ni Yanjun; Song Xiangfu; Li Yanyi; Yang Wei; Sun Ting; Ma Qingjie; Gao Fengtong

    2008-01-01

    Objective: To explore the anti-tumor effects of Egr-IFNγ gene therapy combined with 125 I-UdR radionuclide therapy in mice bearing H22 hepatocarcinoma and its mechanism. Methods: The recombinant plasmid pcDNAEgr-IFNγ mixed with liposome was injected into tumor. 48 h later, 370 kBq 125 I-UdR was injected into tumor. The tumor growth rates at different times were observed. After 3 d gene-radionuclide therapy, the concentration of IFNγ in cytoplasm of H22 cells and cytotoxic activities of splenic CTL of the mice in different groups were examined. Results: The tumor growth rates of pcDNAEgr-IFNγ + 125 I-UdR group were obviously lower than those of control group, 125 I-UdR group and pcDNAEgr-1 + 125 I-UdR group 6-15 d after gene-radionuclide therapy. IFNγ protein was found in cytoplasm of H22 cells in pcDNAEgr-IFNγ + 125 I-UdR group after 3 d gene-radionuclide therapy. Cytotoxic activity of splenic CTL in pcDNAEgr-IFNγ + 125 I-UdR group was significantly higher than that in the other groups (P 125 I-UdR radionuclide therapy are better than those of 125 I-UdR therapy. (authors)

  7. Accelerator based production of auger-electron-emitting isotopes for radionuclide therapy

    International Nuclear Information System (INIS)

    Thisgaard, H.

    2008-08-01

    In this research project the focus has been on the identification and production of new, unconventional Auger-electron-emitting isotopes for targeted radionuclide therapy of cancer. Based on 1st principles dosimetry calculations on the subcellular level, the Auger-emitter 119Sb has been identified as a potent candidate for therapy. The corresponding imaging analogue 117Sb has been shown from planar scintigraphy and single-photon emission computed tomography (SPECT) to be suitable for SPECT-based dosimetry of a future Sb-labeled radiopharmaceutical. The production method of these radioisotopes has been developed using a low-energy cyclotron via the nuclear reactions 119Sn(p,n)119Sb and 117Sn(p,n)117Sb including measurements of the excitation function for the former reaction. Moreover, a new high-yield radiochemical separation method has been developed to allow the subsequent separation of the produced 119Sb from the enriched 119Sn target material with high radionuclidic- and chemical purity. A method that also allows efficient recovery of the 119Sn for recycling. To demonstrate the ability of producing therapeutic quantities of 119Sb and other radioisotopes for therapy with a low-energy cyclotron, two new 'High Power' cyclotron targets were developed in this study. The target development was primarily based on theoretical thermal modeling calculations using finite-element-analysis software. With these targets, I have shown that it will be possible to produce several tens of GBq of therapeutics isotopes (e.g. 119Sb or 64Cu) using the PETtrace cyclotron commonly found at the larger PET-centers in the hospitals. Finally, research in a new method to measure the radiotoxicity of Auger-emitters invitro using cellular microinjection has been carried out. The purpose of this method is to be able to experimentally evaluate and compare the potency of the new and unconventional Auger-emitters (e.g. 119Sb). However, due to experimental complications, the development of this

  8. Accelerator based production of auger-electron-emitting isotopes for radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Thisgaard, H.

    2008-08-15

    In this research project the focus has been on the identification and production of new, unconventional Auger-electron-emitting isotopes for targeted radionuclide therapy of cancer. Based on 1st principles dosimetry calculations on the subcellular level, the Auger-emitter 119Sb has been identified as a potent candidate for therapy. The corresponding imaging analogue 117Sb has been shown from planar scintigraphy and single-photon emission computed tomography (SPECT) to be suitable for SPECT-based dosimetry of a future Sb-labeled radiopharmaceutical. The production method of these radioisotopes has been developed using a low-energy cyclotron via the nuclear reactions 119Sn(p,n)119Sb and 117Sn(p,n)117Sb including measurements of the excitation function for the former reaction. Moreover, a new high-yield radiochemical separation method has been developed to allow the subsequent separation of the produced 119Sb from the enriched 119Sn target material with high radionuclidic- and chemical purity. A method that also allows efficient recovery of the 119Sn for recycling. To demonstrate the ability of producing therapeutic quantities of 119Sb and other radioisotopes for therapy with a low-energy cyclotron, two new 'High Power' cyclotron targets were developed in this study. The target development was primarily based on theoretical thermal modeling calculations using finite-element-analysis software. With these targets, I have shown that it will be possible to produce several tens of GBq of therapeutics isotopes (e.g. 119Sb or 64Cu) using the PETtrace cyclotron commonly found at the larger PET-centers in the hospitals. Finally, research in a new method to measure the radiotoxicity of Auger-emitters invitro using cellular microinjection has been carried out. The purpose of this method is to be able to experimentally evaluate and compare the potency of the new and unconventional Auger-emitters (e.g. 119Sb). However, due to experimental complications, the development

  9. Separation of protactinum, actinium, and other radionuclides from proton irradiated thorium target

    Science.gov (United States)

    Fassbender, Michael E.; Radchenko, Valery

    2018-04-24

    Protactinium, actinium, radium, radiolanthanides and other radionuclide fission products were separated and recovered from a proton-irradiated thorium target. The target was dissolved in concentrated HCl, which formed anionic complexes of protactinium but not with thorium, actinium, radium, or radiolanthanides. Protactinium was separated from soluble thorium by loading a concentrated HCl solution of the target onto a column of strongly basic anion exchanger resin and eluting with concentrated HCl. Actinium, radium and radiolanthanides elute with thorium. The protactinium that is retained on the column, along with other radionuclides, is eluted may subsequently treated to remove radionuclide impurities to afford a fraction of substantially pure protactinium. The eluate with the soluble thorium, actinium, radium and radiolanthanides may be subjected to treatment with citric acid to form anionic thorium, loaded onto a cationic exchanger resin, and eluted. Actinium, radium and radiolanthanides that are retained can be subjected to extraction chromatography to separate the actinium from the radium and from the radio lanthanides.

  10. Targeted Therapy of Ewing's Sarcoma

    Directory of Open Access Journals (Sweden)

    Vivek Subbiah

    2011-01-01

    Full Text Available Refractory and/or recurrent Ewing's sarcoma (EWS remains a clinical challenge because the disease's resistance to therapy makes it difficult to achieve durable results with standard treatments that include chemotherapy, radiation, and surgery. Recently, insulin-like-growth-factor-1-receptor (IGF1R antibodies have been shown to have a modest single-agent activity in EWS. Patient selection using biomarkers and understanding response and resistance mechanisms in relation to IGF1R and mammalian target of rapamycin pathways are areas of active research. Since EWS has a unique tumor-specific EWS-FLI1 t(11;22 translocation and oncogenic fusion protein, inhibition of EWS-FLI1 transcription, translation, and/or protein function may be key to eradicating EWS at the stem-cell level. Recently, a small molecule that blocks the protein-protein interaction of EWS-FLI1 with RNA helicase A has been shown in preclinical models to inhibit EWS growth. The successful application of this first-in-class protein-protein inhibitor in the clinic could become a model system for translocation-associated cancers such as EWS.

  11. Functionalized NaA nanozeolites labeled with 224,225Ra for targeted alpha therapy.

    Science.gov (United States)

    Piotrowska, Agata; Leszczuk, Edyta; Bruchertseifer, Frank; Morgenstern, Alfred; Bilewicz, Aleksander

    2013-01-01

    The 223 Ra, 224 Ra, and 225 Ra radioisotopes exhibit very attractive nuclear properties for application in radionuclide therapy. Unfortunately the lack of appropriate bifunctional ligand for radium is the reason why these radionuclides have not found application in receptor-targeted therapy. In the present work, the potential usefulness of the NaA nanozeolite as a carrier for radium radionuclides has been studied. 224 Ra and 225 Ra, α-particle emitting radionuclides, have been absorbed in the nanometer-sized NaA zeolite (30-70 nm) through simple ion exchange. 224,225 Ra-nanozeolites exhibited very high stability in solutions containing physiological salt, EDTA, amino acids, and human serum. To make NaA nanozeolite particles dispersed in water their surface was modified with a silane coupling agent containing poly(ethylene glycol) molecules. This functionalization approach let us covalently attach a biomolecule to the NaA nanozeolite surface.

  12. E1B-attenuated onco lytic adenovirus enhances antitumor effect of radionuclide therapy by P53-independent way: cellular basic for radionuclide-viral therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zhenwei, Zhang [Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai (China); Hua, Wu; Xuemei, Zhang [Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Xinyuan, Liu [Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai (China)

    2004-07-01

    Purpose: Chemotherapy or external radiation therapy can potentiate the therapeutic effect of E1 B-attenuated oncolytic adenovirus. In this study, the antitumor efficacy of oncolytic adenovirus combined with internal radionuclide therapy was evaluated. Methods: Firstly, viral replication was examined by plaque assay and Southern blotting, after oncolytic adenovirus, ZD55, was exposed to iodine-131. Cell viability was evaluated qualitatively by crystal violet staining and quantitatively by MTT assay. FACS analysis was performed to determine the synergic proapoptotic effect of iodine-131 combined with ZD55. Results: Irradiation of iodine-131 does not influence ZD55 viral DNA replication. In combination with ZD55, iodine-131 can efficiently kill tumor cells in a p53-independent model. ZD55 augments the proapoptotic effect of iodine-131. Conclusion: Radionuclide-viral therapy might be a novel tool for treatment of hepatocarcinoma. (authors)

  13. Activity determination of radionuclides for diagnostic and therapy

    International Nuclear Information System (INIS)

    Kossert, Karsten

    2013-01-01

    The application of radionuclides plays in medicine an important role and requires reliable activity determination. The PTB provides for this activity normals and determines the activity of the presented sources. The article describes, how activity determinations in the PTB occur, and by which ways this can be used for nuclear medicine. Research and development works in the PTB are just so illuminated as the determination of nuclide data of some isotopes relevant for medicine.

  14. Magnetically responsive microparticles for targeted drug and radionuclide delivery

    International Nuclear Information System (INIS)

    Kaminski, M. D.; Ghebremeskel, A. N.; Nunez, L.; Kasza, K. E.; Chang, F.; Chien, T.-H.; Fisher, P. F.; Eastman, J. A.; Rosengart, A. J.; McDonald, L.; Xie, Y.; Johns, L.; Pytel, P.; Hafeli, U. O.

    2004-01-01

    We are currently investigating the use of magnetic particles--polymeric-based spheres containing dispersed magnetic nanocrystalline phases--for the precise delivery of drugs via the human vasculature. According to this review, meticulously prepared magnetic drug targeting holds promise as a safe and effective method of delivering drugs to specific organ, tissue or cellular targets. We have critically examined the wide range of approaches in the design and implementation of magnetic-particle-based drug delivery systems to date, including magnetic particle preparation, drug encapsulation, biostability, biocompatibility, toxicity, magnetic field designs, and clinical trials. However, we strongly believe that there are several limitations with past developments that need to be addressed to enable significant strides in the field. First, particle size has to be carefully chosen. Micrometer-sized magnetic particles are better attracted over a distance than nanometer sized magnetic particles by a constant magnetic field gradient, and particle sizes up to 1 (micro)m show a much better accumulation with no apparent side effects in small animal models, since the smallest blood vessels have an inner diameter of 5-7 (micro)m. Nanometer-sized particles <70 nm will accumulate in organ fenestrations despite an effective surface stabilizer. To be suitable for future human applications, our experimental approach synthesizes the magnetic drug carrier according to specific predefined outcome metrics: monodisperse population in a size range of 100 nm to 1.0 (micro)m, non-toxic, with appropriate magnetic properties, and demonstrating successful in vitro and in vivo tests. Another important variable offering possible improvement is surface polarity, which is expected to prolong particle half-life in circulation and modify biodistribution and stability of drugs in the body. The molecules in the blood that are responsible for enhancing the uptake of particles by the reticuloendothelial

  15. Novel Targeted Therapies for Inflammatory Breast Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0461 TITLE: Novel Targeted Therapies for Inflammatory Breast Cancer PRINCIPAL INVESTIGATOR: Jose Silva CONTRACTING...CONTRACT NUMBER Novel Targeted Therapies for Inflammatory Breast Cancer 5b. GRANT NUMBER W81XWH-16-1-0461 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) l 5d...NOTES 14. ABSTRACT Inflammatory breast cancer (IBC, ~5% of all breast cancers ) is the most lethal form of breast cancer , presenting a 5- year

  16. Radionuclide esophageal transit: an evaluation of therapy in achalasia

    Energy Technology Data Exchange (ETDEWEB)

    McKinney, M.K.; Brady, C.E.; Weiland, F.L.

    1983-09-01

    We measured quantitative esophageal transit, expressed as percentage of esophageal retention, before and after pneumatic dilatation in two patients with achalasia. In the sitting position they ingested a 500 ml liquid meal containing 500 muCi technetium Tc 99m sulfur colloid. Radioactivity counts of the entire esophagus were plotted at five-minute intervals for 30 minutes. In five normal control subjects the esophagus essentially cleared in less than one minute. Both patients with achalasia had definite retention 30 minutes before dilatation and had quantitative improvement after dilatation. Radionuclide scintigraphic esophageal transit probably correlates better than other parameters with the physiologic degree of obstruction in achalasia.

  17. Targeted Therapy for Medullary Thyroid Cancer: A Review

    Directory of Open Access Journals (Sweden)

    S. R. Priya

    2017-10-01

    Full Text Available Medullary thyroid cancers (MTCs constitute between 2 and 5% of all thyroid cancers. The 10-year overall survival (OS rate of patients with localized disease is around 95% while that of patients with regional stage disease is about 75%. Only 20% of patients with distant metastases at diagnosis survive 10 years which is significantly lower than for differentiated thyroid cancers. Cases with regional metastases at presentation have high recurrence rates. Adjuvant external radiation confers local control but not improved OS. The management of residual, recurrent, or metastatic disease till a few years ago was re-surgery with local measures such as radiation. Chemotherapy was used with marginal benefit. The development of targeted therapy has brought in a major advantage in management of such patients. Two drugs—vandetanib and cabozantinib—have been approved for use in progressive or metastatic MTC. In addition, several drugs acting on other steps of the molecular pathway are being investigated with promising results. Targeted radionuclide therapy also provides an effective treatment option with good quality of life. This review covers the rationale of targeted therapy for MTC, present treatment options, drugs and methods under investigation, as well as an outline of the adverse effects and their management.

  18. The study of the radiation protection problem in the radionuclide interstitial implantation therapy

    International Nuclear Information System (INIS)

    Zhang Jimian

    2006-01-01

    Objective: To analyze and study the radiation protection problem in the radionuclide interstitial permanent implantation therapy. Methods: Based on test data from radioactive measurement department, calculating results and national standards, the radiation dose of the exposed radioactive particles, the operator who has participated in the radionuclide interstitial permanent implantation therapy operation and the relatives who have accompanied the patient during the whole course, the reference time of being discharged from hospital for the patients who have been cured by different activity of radioactive particles are studied. Results: The maximal radiation dose of operating doctor who has participated in a single radionuclide interstitial permanent implantation therapy operation and the relatives who has accompanied the patient during the whole course are 0.315 mSv/a and 0.70 mSv. Based on actual contact frequencies, their radiation dose is proved to be smaller than the restricted dose prescribed by national standards. The reference time of leaving hospital for the patients who have been cured by different activity of radioactive particles is 0 to 44 days. Conclusion: The radiation dose of radiation workers and surrounding publics in the radionuclide interstitial permanent implantation therapy operation can be acceptable under certain shields. But the risk of potential exposure should be guarded. The authors should Lay down operation indications and avoid performing operation blindly. If one must be operated, the authors should plan the quantity and the part of the painting radioactive particles accurately in order to avoid some passible complications. (authors)

  19. Evaluation of radioiodinated vesamicol analogs for sigma receptor imaging in tumor and radionuclide receptor therapy.

    Science.gov (United States)

    Ogawa, Kazuma; Shiba, Kazuhiro; Akhter, Nasima; Yoshimoto, Mitsuyoshi; Washiyama, Kohshin; Kinuya, Seigo; Kawai, Keiichi; Mori, Hirofumi

    2009-11-01

    It has been reported that sigma receptors are highly expressed in a variety of human tumors. In this study, we selected (+)-2-[4-(4-iodophenyl)piperidino] cyclohexanol [(+)-pIV] as a sigma receptor ligand and evaluated the potential of radioiodinated (+)-pIV for tumor imaging and therapy. (+)-[(125/131)I]pIV was prepared by an iododestannylation reaction under no-carrier-added conditions with radiochemical purity over 99% after HPLC purification. Biodistribution experiments were performed by the intravenous injection of (+)-[(125)I]pIV into mice bearing human prostate tumors (DU-145). Blocking studies were performed by intravenous injection of (+)-[(125)I]pIV mixed with an excess amount of unlabeled sigma ligand into DU-145 tumor-bearing mice. For therapeutic study, (+)-[(131)I]pIV was injected at a dose of 7.4 MBq followed by measurement of the tumor size. In biodistribution experiments, (+)-[(125)I]pIV showed high uptake and long residence in the tumor. High tumor to blood and muscle ratios were achieved because the radioactivity levels of blood and muscle were low. However, the accumulations of radioactivity in non-target tissues, such as liver and kidney, were high. The radioactivity in the non-target tissues slowly decreased over time. Co-injection of (+)-[(125)I]pIV with an excess amount of unlabeled sigma ligand resulted in a significant decrease in the tumor/blood ratio, indicating sigma receptor-mediated tumor uptake. In therapeutic study, tumor growth in mice treated with (+)-[(131)I]pIV was significantly inhibited compared to that of an untreated group. These results indicate that radioiodinated (+)-pIV has a high potential for sigma receptor imaging in tumor and radionuclide receptor therapy.

  20. 188Re(V) Nitrido Radiopharmaceuticals for Radionuclide Therapy.

    Science.gov (United States)

    Boschi, Alessandra; Martini, Petra; Uccelli, Licia

    2017-01-19

    The favorable nuclear properties of rhenium-188 for therapeutic application are described, together with new methods for the preparation of high yield and stable 188 Re radiopharmaceuticals characterized by the presence of the nitride rhenium core in their final chemical structure. 188 Re is readily available from an 188 W/ 188 Re generator system and a parallelism between the general synthetic procedures applied for the preparation of nitride technetium-99m and rhenium-188 theranostics radiopharmaceuticals is reported. Although some differences between the chemical characteristics of the two metallic nitrido fragments are highlighted, it is apparent that the same general procedures developed for the labelling of biologically active molecules with technetium-99m can be applied to rhenium-188 with minor modification. The availability of these chemical strategies, that allow the obtainment, in very high yield and in physiological condition, of 188 Re radiopharmaceuticals, gives a new attractive prospective to employ this radionuclide for therapeutic applications.

  1. 188Re(V) Nitrido Radiopharmaceuticals for Radionuclide Therapy

    Science.gov (United States)

    Boschi, Alessandra; Martini, Petra; Uccelli, Licia

    2017-01-01

    The favorable nuclear properties of rhenium-188 for therapeutic application are described, together with new methods for the preparation of high yield and stable 188Re radiopharmaceuticals characterized by the presence of the nitride rhenium core in their final chemical structure. 188Re is readily available from an 188W/188Re generator system and a parallelism between the general synthetic procedures applied for the preparation of nitride technetium-99m and rhenium-188 theranostics radiopharmaceuticals is reported. Although some differences between the chemical characteristics of the two metallic nitrido fragments are highlighted, it is apparent that the same general procedures developed for the labelling of biologically active molecules with technetium-99m can be applied to rhenium-188 with minor modification. The availability of these chemical strategies, that allow the obtainment, in very high yield and in physiological condition, of 188Re radiopharmaceuticals, gives a new attractive prospective to employ this radionuclide for therapeutic applications. PMID:28106830

  2. Chemotherapy and molecular target therapy combined with radiation therapy

    International Nuclear Information System (INIS)

    Akimoto, Tetsuo

    2012-01-01

    Combined chemotherapy and radiation therapy has been established as standard treatment approach for locally advanced head and neck cancer, esophageal cancer and so on through randomized clinical trials. However, radiation-related morbidity such as acute toxicity also increased as treatment intensity has increased. In underlining mechanism for enhancement of normal tissue reaction in chemo-radiation therapy, chemotherapy enhanced radiosensitivity of normal tissues in addition to cancer cells. Molecular target-based drugs combined with radiation therapy have been expected as promising approach that makes it possible to achieve cancer-specific enhancement of radiosensitivity, and clinical trials using combined modalities have been performed to evaluate the feasibility and efficacy of this approach. In order to obtain maximum radiotherapeutic gain, a detailed understanding of the mechanism underlying the interaction between radiation and Molecular target-based drugs is indispensable. Among molecular target-based drugs, inhibitors targeting epidermal growth factor receptor (EGFR) and its signal transduction pathways have been vigorously investigated, and mechanisms regarding the radiosensitizing effect have been getting clear. In addition, the results of randomized clinical trials demonstrated that radiation therapy combined with cetuximab resulted in improvement of overall and disease-specific survival rate compared with radiation therapy in locally advanced head and neck cancer. In this review, clinical usefulness of chemo-radiation therapy and potential molecular targets for potentiation of radiation-induced cell killing are summarized. (author)

  3. Modeling the effects of repeated systemic administrations of small activity amounts In radionuclide therapy with beta emitters

    International Nuclear Information System (INIS)

    Calderon, Carlos; Gonzalez, Joaquin; Cepero, Janet; Colom, Camila; Rodriguez, Juan C.

    2008-01-01

    Full text: Good results for radionuclide therapy treatments where repeated short time spaced systemic injection of small activity amounts are given have been reported. Bone marrow and kidneys are usually considered as dose-limiting organs in radionuclide therapy. The treatments in radionuclide therapy with repeated administration could be optimized if irradiation effects in those one might be estimated. Xeno-grafted mice is the often biological model used during the evaluation of candidates for radionuclide therapy. A mathematical model of tumor cell kinetics was combined with another one reported for marrow cell kinetics which allows the calculation of marrow cell survival and proliferation in response to different irradiation schemes. Radionuclide therapy treatment with repeated administrations with radiopharmaceuticals labeled with beta emitters were simulated. The effects on fast-growing and slow-growing tumors were evaluated, as well as radiosensitive and radioresistant tumors. For more realistic estimation of absorbed dose in mice organs the cross-irradiation due to high energy beta particles was included into the MIRD's formula. Tumor and kidneys responses to the irradiation were estimated on the linear-quadratic model framework which was adapted for a multi-exponential dose rate function describing radionuclide therapy treatments with repeated administrations. Published values for murine tumors kinetics, marrows cellular turnover rates and radiosensitivities were used during the calculations. Iso-effective schemes were also determined varying the interval between fractions and the number of administration. For a given tolerated level of thrombocytopenia and absorbed dose in kidneys an optimal regime of radionuclide therapy with repeated administration could be found. The mathematical model presented here allows the prediction of the nadir and duration of thrombocytopenia, the effects on kidneys and the tumor cell response to various treatment schemes

  4. Targeted Therapies in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Jurjees Hasan

    2010-02-01

    Full Text Available Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.

  5. Targeted Therapies in Epithelial Ovarian Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Dean, Emma; El-Helw, Loaie; Hasan, Jurjees, E-mail: jurjees.hasan@christie.nhs.uk [Christie Hospital NHS Foundation Trust / Wilmslow Road, Manchester, M20 4BX (United Kingdom)

    2010-02-23

    Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer.

  6. Metastasis Targeted Therapies in Renal Cell Cancer

    OpenAIRE

    K. Fehmi Narter; Bora Özveren

    2018-01-01

    Metastatic renal cell cancer is a malignant disease and its treatment has been not been described clearly yet. These patients are generally symptomatic and resistant to current treatment modalities. Radiotherapy, chemotherapy, and hormonal therapy are not curative in many of these patients. A multimodal approach consisting of cytoreductive nephrectomy, systemic therapy (immunotherapy or targeted molecules), and metastasectomy has been shown to be hopeful in prolonging the survival and improvi...

  7. Targeted Radiation Therapy for Cancer Initiative

    Science.gov (United States)

    2017-11-01

    AWARD NUMBER: W81XWH-08-2-0174 TITLE: Targeted Radiation Therapy for Cancer Initiative PRINCIPAL INVESTIGATOR: Dusten Macdonald, MD...for Cancer Initiative 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Dusten Macdonald, MD 5d. PROJECT NUMBER...Cancer Initiative Final Report INTRODUCTION: The full potential of radiation therapy has not been realized due to the inability to locate and

  8. Neuroendocrine Tumours : From Radiomolecular Imaging to Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    GEORGIOS eLIMOURIS

    2012-02-01

    Full Text Available Transhepatic radionuclide infusion (THRI has been introduced as a new treatment approach for unresectable liver neuroendocrine metastatic lesions with the prerequisite of a positive In-111 Pentetreotide (Octreoscan. Patients with multiple liver neuroendocrine metastases can be locally treated after selective hepatic artery catheterization and infusion of radiolabelled somatostatin analogues, and in case of extra-hepatic secondary spread, after simple i.v. application. According to the world wide references, the average dose per session to each patient is 6.3±0.3 GBq (~ 160-180 mCi of In-111-DTPA-Phe1- Pentetreotide, 10-12 fold in total, administered monthly or of 4.1± 0.2 GBq (~105-116 mCi of Y-90 DOTA TOC, 3 fold in total or of 7.0 ± 0.4 GBq (~178-200 mCi of Lu-177 DOTA TATE, 4-6 fold in total (the choice of which being based on the tumor size, assessed by CT or MRI . Follow-up at monthly intervals has to be performed by means of ultrasonography (US. Treat- ment response has to be assessed according to the WHO criteria (RECIST or SWOG.

  9. Extension of the biological effective dose to the MIRD schema and possible implications in radionuclide therapy dosimetry

    International Nuclear Information System (INIS)

    Baechler, Sebastien; Hobbs, Robert F.; Prideaux, Andrew R.; Wahl, Richard L.; Sgouros, George

    2008-01-01

    In dosimetry-based treatment planning protocols, patients with rapid clearance of the radiopharmaceutical require a larger amount of initial activity than those with slow clearance to match the absorbed dose to the critical organ. As a result, the dose-rate to the critical organ is higher in patients with rapid clearance and may cause unexpected toxicity compared to patients with slow clearance. In order to account for the biological impact of different dose-rates, radiobiological modeling is beginning to be applied to the analysis of radionuclide therapy patient data. To date, the formalism used for these analyses is based on kinetics derived from activity in a single organ, the target. This does not include the influence of other source organs to the dose and dose-rate to the target organ. As a result, only self-dose irradiation in the target organ contributes to the dose-rate. In this work, the biological effective dose (BED) formalism has been extended to include the effect of multiple source organ contributions to the net dose-rate in a target organ. The generalized BED derivation has been based on the Medical Internal Radionuclide Dose Committee (MIRD) schema assuming multiple source organs following exponential effective clearance of the radionuclide. A BED-based approach to determine the largest safe dose to critical organs has also been developed. The extended BED formalism is applied to red marrow dosimetry, as well as kidney dosimetry considering the cortex and the medulla separately, since both those organs are commonly dose limiting in radionuclide therapy. The analysis shows that because the red marrow is an early responding tissue (high α/β), it is less susceptible to unexpected toxicity arising from rapid clearance of high levels of administered activity in the marrow or in the remainder of the body. In kidney dosimetry, the study demonstrates a complex interplay between clearance of activity in the cortex and the medulla, as well as the initial

  10. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Fulda, Simone, E-mail: simone.fulda@kgu.de [Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt (Germany)

    2011-08-29

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  11. Targeting Apoptosis Signaling Pathways for Anticancer Therapy

    International Nuclear Information System (INIS)

    Fulda, Simone

    2011-01-01

    Treatment approaches for cancer, for example chemotherapy, radiotherapy, or immunotherapy, primarily act by inducing cell death in cancer cells. Consequently, the inability to trigger cell death pathways or alternatively, evasion of cancer cells to the induction of cell death pathways can result in resistance of cancers to current treatment protocols. Therefore, in order to overcome treatment resistance a better understanding of the underlying mechanisms that regulate cell death and survival pathways in cancers and in response to cancer therapy is necessary to develop molecular-targeted therapies. This strategy should lead to more effective and individualized treatment strategies that selectively target deregulated signaling pathways in a tumor type- and patient-specific manner.

  12. Target marketing strategies for occupational therapy entrepreneurs.

    Science.gov (United States)

    Kautzmann, L N; Kautzmann, F N; Navarro, F H

    1989-01-01

    Understanding marketing techniques is one of the skills needed by successful entre renews. Target marketing is an effective method for occupational therapy entrepreneurs to use in determining when and where to enter the marketplace. The two components of target marketing, market segmentation and the development of marketing mix strategies for each identified market segment, are described. The Profife of Attitudes Toward Health Care (PATH) method of psychographic market segmentation of health care consumers is presented. Occupational therapy marketing mix strategies for each PATH consumer group are delineated and compatible groupings of market segments are suggested.

  13. Enhancing the effect of radionuclide tumor targeting, using lysosomotropic weak bases

    International Nuclear Information System (INIS)

    Sundberg, Asa Liljegren; Steffen, Ann-Charlott

    2007-01-01

    Purpose: The aim of the present study was to investigate if treatment with lysosomotropic weak bases could increase the intracellular retention of radiohalogens and thereby increase the therapeutic effect of radionuclide tumor targeting. Methods and Materials: Four different lysosomotropic bases, chloroquine, ammonium chloride, amantadine, and thioridazine, were investigated for their ability to increase radiohalogen retention in vitro. The two most promising substances, chloroquine and ammonium chloride, were studied in several cell lines (A431, U343MGaCl2:6, SKOV-3, and SKBR-3) in combination with radiolabeled epidermal growth factor (EGF) or the HER2 binding affibody (Z HER2:4 ) 2 . Results: The uptake and retention of radionuclides was found to be substantially increased by simultaneous treatment with the lysosomotropic bases. The effect was, however, more pronounced in the epidermal growth factor:epidermal growth factor receptor (EGF:EGFR) system than in the (Z HER2:4 ) 2 :HER2 system. The therapeutic effect of ammonium chloride treatment combined with 211 At-EGF was also studied. The effect obtained after combined treatment was found to be much better than after 211 At-EGF treatment alone. Conclusions: The encouraging results from the present study indicate that the use of lysosomotropic weak bases is a promising approach for increasing the therapeutic effect of radionuclide targeting with radiohalogens

  14. Targeting Herpetic Keratitis by Gene Therapy

    Directory of Open Access Journals (Sweden)

    Hossein Mostafa Elbadawy

    2012-01-01

    Full Text Available Ocular gene therapy is rapidly becoming a reality. By November 2012, approximately 28 clinical trials were approved to assess novel gene therapy agents. Viral infections such as herpetic keratitis caused by herpes simplex virus 1 (HSV-1 can cause serious complications that may lead to blindness. Recurrence of the disease is likely and cornea transplantation, therefore, might not be the ideal therapeutic solution. This paper will focus on the current situation of ocular gene therapy research against herpetic keratitis, including the use of viral and nonviral vectors, routes of delivery of therapeutic genes, new techniques, and key research strategies. Whereas the correction of inherited diseases was the initial goal of the field of gene therapy, here we discuss transgene expression, gene replacement, silencing, or clipping. Gene therapy of herpetic keratitis previously reported in the literature is screened emphasizing candidate gene therapy targets. Commonly adopted strategies are discussed to assess the relative advantages of the protective therapy using antiviral drugs and the common gene therapy against long-term HSV-1 ocular infections signs, inflammation and neovascularization. Successful gene therapy can provide innovative physiological and pharmaceutical solutions against herpetic keratitis.

  15. Report on the 1. research coordination meeting on 'Development of therapeutic radiopharmaceuticals based on {sup 177}Lu for radionuclide therapy'

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2006-07-01

    Radionuclide therapy (RNT) employing radiopharmaceuticals labelled with emitting radionuclides is fast emerging as an important part of nuclear medicine. Radionuclide therapy is effectively utilized for bone pain palliation, thus providing significant improvement in quality of life of patients suffering from pain resulting from bone metastasis. Targeting primary diseases by using specific carrier molecules labelled with radionuclides is also widely investigated and efficacious products have been emerging for the treatment of Lymphoma and Neuroendocrine tumours. In order to ensure the wider use of radiopharmaceuticals, it is essential to carefully consider the choice of radionuclides that together with the carrier molecules will give suitable pharmacokinetic properties and therapeutic efficacy. The criteria for the selection of a radionuclide for radiotherapy are suitable decay characteristics and amenable chemistry. However, the practical considerations in selecting a radionuclide for targeted therapy are availability in high radionuclidic purity as well as high specific activity and low production cost and comfortable delivery logistics. {sup 177}Lu is one of the isotopes emerging as a clear choice for therapy. Worldwide, the isotope is under investigation for approximately 30 different clinical applications, including treatment of colon cancer, metastatic bone cancer, non-Hodgkin's lymphoma, and lung cancer. {sup 177}Lu decays with a half-life of 6.71 d by emission of particles with E{sub max} of 497 keV (78.6%), 384 keV (9.1%) and 176 keV (12.2%). It also emits photons of 113 keV (6.4%) and 208 keV (11%), that are ideally suited for imaging the in-vivo localization and dosimetric calculations applying a gamma camera. The physical half-life of {sup 177}Lu is comparable to that of {sup 131}I, the most widely used therapeutic radionuclide. The long halflife of {sup 177}Lu provides logistic advantage for production, QA/QC of the products as well as feasibility to

  16. Report on the 1. research coordination meeting on 'Development of therapeutic radiopharmaceuticals based on 177Lu for radionuclide therapy'

    International Nuclear Information System (INIS)

    2006-01-01

    Radionuclide therapy (RNT) employing radiopharmaceuticals labelled with emitting radionuclides is fast emerging as an important part of nuclear medicine. Radionuclide therapy is effectively utilized for bone pain palliation, thus providing significant improvement in quality of life of patients suffering from pain resulting from bone metastasis. Targeting primary diseases by using specific carrier molecules labelled with radionuclides is also widely investigated and efficacious products have been emerging for the treatment of Lymphoma and Neuroendocrine tumours. In order to ensure the wider use of radiopharmaceuticals, it is essential to carefully consider the choice of radionuclides that together with the carrier molecules will give suitable pharmacokinetic properties and therapeutic efficacy. The criteria for the selection of a radionuclide for radiotherapy are suitable decay characteristics and amenable chemistry. However, the practical considerations in selecting a radionuclide for targeted therapy are availability in high radionuclidic purity as well as high specific activity and low production cost and comfortable delivery logistics. 177 Lu is one of the isotopes emerging as a clear choice for therapy. Worldwide, the isotope is under investigation for approximately 30 different clinical applications, including treatment of colon cancer, metastatic bone cancer, non-Hodgkin's lymphoma, and lung cancer. 177 Lu decays with a half-life of 6.71 d by emission of particles with E max of 497 keV (78.6%), 384 keV (9.1%) and 176 keV (12.2%). It also emits photons of 113 keV (6.4%) and 208 keV (11%), that are ideally suited for imaging the in-vivo localization and dosimetric calculations applying a gamma camera. The physical half-life of 177 Lu is comparable to that of 131 I, the most widely used therapeutic radionuclide. The long halflife of 177 Lu provides logistic advantage for production, QA/QC of the products as well as feasibility to supply the products to places

  17. PET SUV correlates with radionuclide uptake in peptide receptor therapy in meningioma

    Energy Technology Data Exchange (ETDEWEB)

    Haenscheid, Heribert; Buck, Andreas K.; Samnick, Samuel; Kreissl, Michael [University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Sweeney, Reinhart A.; Flentje, Michael [University Hospital Wuerzburg, Department of Radiation Oncology, Wuerzburg (Germany); Loehr, Mario [University Hospital Wuerzburg, Department of Neurosurgery, Wuerzburg (Germany); Verburg, Frederik A. [University Hospital Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); RWTH University Hospital Aachen, Department of Nuclear Medicine, Aachen (Germany)

    2012-08-15

    To investigate whether the tumour uptake of radionuclide in peptide receptor radionuclide therapy (PRRT) of meningioma can be predicted by a PET scan with {sup 68}Ga-labelled somatostatin analogue. In this pilot trial, 11 meningioma patients with a PET scan indicating somatostatin receptor expression received PRRT with 7.4 GBq {sup 177}Lu-DOTATOC or {sup 177}Lu-DOTATATE, followed by external beam radiotherapy. A second PET scan was scheduled for 3 months after therapy. During PRRT, multiple whole-body scans and a SPECT/CT scan of the head and neck region were acquired and used to determine the kinetics and dose in the voxel with the highest radionuclide uptake within the tumour. Maximum voxel dose and retention of activity 1 h after administration in PRRT were compared to the maximum standardized uptake values (SUV{sub max}) in the meningiomas from the PET scans before and after therapy. The median SUV{sub max} in the meningiomas was 13.7 (range 4.3 to 68.7), and the maximum fractional radionuclide uptake in voxels of size 0.11 cm{sup 3} was a median of 23.4 x 10{sup -6} (range 0.4 x 10{sup -6} to 68.3 x 10{sup -6}). A strong correlation was observed between SUV{sub max} and the PRRT radionuclide tumour retention in the voxels with the highest uptake (Spearman's rank test, P < 0.01). Excluding one patient who showed large differences in biokinetics between PET and PRRT and another patient with incomplete data, linear regression analysis indicated significant correlations between SUV{sub max} and the therapeutic uptake (r = 0.95) and between SUV{sub max} and the maximum voxel dose from PRRT (r = 0.76). Observed absolute deviations from the values expected from regression were a median of 5.6 x 10{sup -6} (maximum 9.3 x 10{sup -6}) for the voxel fractional radionuclide uptake and 0.40 Gy per GBq (maximum 0.85 Gy per GBq) {sup 177}Lu for the voxel dose from PRRT. PET with {sup 68}Ga-labelled somatostatin analogues allows the pretherapeutic assessment of tumour

  18. PET SUV correlates with radionuclide uptake in peptide receptor therapy in meningioma

    International Nuclear Information System (INIS)

    Haenscheid, Heribert; Buck, Andreas K.; Samnick, Samuel; Kreissl, Michael; Sweeney, Reinhart A.; Flentje, Michael; Loehr, Mario; Verburg, Frederik A.

    2012-01-01

    To investigate whether the tumour uptake of radionuclide in peptide receptor radionuclide therapy (PRRT) of meningioma can be predicted by a PET scan with 68 Ga-labelled somatostatin analogue. In this pilot trial, 11 meningioma patients with a PET scan indicating somatostatin receptor expression received PRRT with 7.4 GBq 177 Lu-DOTATOC or 177 Lu-DOTATATE, followed by external beam radiotherapy. A second PET scan was scheduled for 3 months after therapy. During PRRT, multiple whole-body scans and a SPECT/CT scan of the head and neck region were acquired and used to determine the kinetics and dose in the voxel with the highest radionuclide uptake within the tumour. Maximum voxel dose and retention of activity 1 h after administration in PRRT were compared to the maximum standardized uptake values (SUV max ) in the meningiomas from the PET scans before and after therapy. The median SUV max in the meningiomas was 13.7 (range 4.3 to 68.7), and the maximum fractional radionuclide uptake in voxels of size 0.11 cm 3 was a median of 23.4 x 10 -6 (range 0.4 x 10 -6 to 68.3 x 10 -6 ). A strong correlation was observed between SUV max and the PRRT radionuclide tumour retention in the voxels with the highest uptake (Spearman's rank test, P max and the therapeutic uptake (r = 0.95) and between SUV max and the maximum voxel dose from PRRT (r = 0.76). Observed absolute deviations from the values expected from regression were a median of 5.6 x 10 -6 (maximum 9.3 x 10 -6 ) for the voxel fractional radionuclide uptake and 0.40 Gy per GBq (maximum 0.85 Gy per GBq) 177 Lu for the voxel dose from PRRT. PET with 68 Ga-labelled somatostatin analogues allows the pretherapeutic assessment of tumour radionuclide uptake in PRRT of meningioma and an estimate of the achievable dose. (orig.)

  19. Human Anti-Oxidation Protein A1M—A Potential Kidney Protection Agent in Peptide Receptor Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    Jonas Ahlstedt

    2015-12-01

    Full Text Available Peptide receptor radionuclide therapy (PRRT has been in clinical use for 15 years to treat metastatic neuroendocrine tumors. PRRT is limited by reabsorption and retention of the administered radiolabeled somatostatin analogues in the proximal tubule. Consequently, it is essential to develop and employ methods to protect the kidneys during PRRT. Today, infusion of positively charged amino acids is the standard method of kidney protection. Other methods, such as administration of amifostine, are still under evaluation and show promising results. α1-microglobulin (A1M is a reductase and radical scavenging protein ubiquitously present in plasma and extravascular tissue. Human A1M has antioxidation properties and has been shown to prevent radiation-induced in vitro cell damage and protect non-irradiated surrounding cells. It has recently been shown in mice that exogenously infused A1M and the somatostatin analogue octreotide are co-localized in proximal tubules of the kidney after intravenous infusion. In this review we describe the current situation of kidney protection during PRRT, discuss the necessity and implications of more precise dosimetry and present A1M as a new, potential candidate for renal protection during PRRT and related targeted radionuclide therapies.

  20. Targeted Alpha Therapy: From Alpha to Omega

    International Nuclear Information System (INIS)

    Allen, Barry J; Clarke, Raymond; Huang Chenyu

    2013-01-01

    This review covers the broad spectrum of Targeted Alpha Therapy (TAT) research in Australia; from in vitro and in vivo studies to clinical trials. The principle of tumour anti-vascular alpha therapy (TAVAT) is discussed in terms of its validation by Monte Carlo calculations of vascular models and the potential role of biological dosimetry is examined. Summmary of this review is as follows: 1. The essence of TAT 2. Therapeutic objectives 3. TAVAT and Monte Carlo microdosimetry 4. Biological dosimetry 5. Preclinical studies 6. Clinical trials 7. What next? 8. Obstacles. (author)

  1. Dosimetric characterization of radionuclides for systemic tumor therapy: Influence of particle range, photon emission, and subcellular distribution

    International Nuclear Information System (INIS)

    Uusijaervi, Helena; Bernhardt, Peter; Ericsson, Thomas; Forssell-Aronsson, Eva

    2006-01-01

    Various radionuclides have been proposed for systemic tumor therapy. However, in most dosimetric analysis of proposed radionuclides the charged particles are taken into consideration while the potential photons are ignored. The photons will cause undesirable irradiation of normal tissue, and increase the probability of toxicity in, e.g., the bone marrow. The aim of this study was to investigate the dosimetric properties according to particle range, photon emission, and subcellular radionuclide distribution, of a selection of radionuclides used or proposed for radionuclide therapy, and to investigate the possibility of dividing radionuclides into groups according to their dosimetric properties. The absorbed dose rate to the tumors divided by the absorbed dose rate to the normal tissue (TND) was estimated for different tumor sizes in a mathematical model of the human body. The body was simulated as a 70-kg ellipsoid and the tumors as spheres of different sizes (1 ng-100 g). The radionuclides were either assumed to be uniformly distributed throughout the entire tumor and normal tissue, or located in the nucleus or the cytoplasm of the tumor cells and on the cell membrane of the normal cells. Fifty-nine radionuclides were studied together with monoenergetic electrons, positrons, and alpha particles. The tumor and normal tissue were assumed to be of water density. The activity concentration ratio between the tumor and normal tissue was assumed to be 25. The radionuclides emitting low-energy electrons combined with a low photon contribution, and the alpha emitters showed high TND values for most tumor sizes. Electrons with higher energy gave reduced TND values for small tumors, while a higher photon contribution reduced the TND values for large tumors. Radionuclides with high photon contributions showed low TND value for all tumor sizes studied. The radionuclides studied could be divided into four main groups according to their TND values: beta emitters, Auger electron

  2. Peptide receptor radionuclide therapy for neuroendocrine tumors in Germany: first results of a multi-institutional cancer registry.

    Science.gov (United States)

    Hörsch, Dieter; Ezziddin, Samer; Haug, Alexander; Gratz, Klaus Friedrich; Dunkelmann, Simone; Krause, Bernd Joachim; Schümichen, Carl; Bengel, Frank M; Knapp, Wolfram H; Bartenstein, Peter; Biersack, Hans-Jürgen; Plöckinger, Ursula; Schwartz-Fuchs, Sabine; Baum, R P

    2013-01-01

    Peptide receptor radionuclide therapy is an effective treatment option for patients with well-differentiated somatostatin receptor-expressing neuroendocrine tumors. However, published data result mainly from retrospective monocentric studies. We initiated a multi-institutional, prospective, board-reviewed registry for patients treated with peptide receptor radionuclide therapy in Germany in 2009. In five centers, 297 patients were registered. Primary tumors were mainly derived from pancreas (117/297) and small intestine (80/297), whereas 56 were of unknown primary. Most tumors were well differentiated with median Ki67 proliferation rate of 5% (range 0.9-70%). Peptide receptor radionuclide therapy was performed using mainly yttrium-90 and/or lutetium-177 as radionuclides in 1-8 cycles. Mean overall survival was estimated at 213 months with follow-up between 1 and 230 months after initial diagnosis, and 87 months with follow-up between 1 and 92 months after start of peptide receptor radionuclide therapy. Median overall survival was not yet reached. Subgroup analysis demonstrated that best results were obtained in neuroendocrine tumors with proliferation rate below 20%. Our results indicate that peptide receptor radionuclide therapy is an effective treatment for well- and moderately differentiated neuroendocrine tumors irrespective of previous therapies and should be regarded as one of the primary treatment options for patients with somatostatin receptor-expressing neuroendocrine tumors.

  3. Targeted therapy using nanotechnology: focus on cancer.

    Science.gov (United States)

    Sanna, Vanna; Pala, Nicolino; Sechi, Mario

    2014-01-01

    Recent advances in nanotechnology and biotechnology have contributed to the development of engineered nanoscale materials as innovative prototypes to be used for biomedical applications and optimized therapy. Due to their unique features, including a large surface area, structural properties, and a long circulation time in blood compared with small molecules, a plethora of nanomaterials has been developed, with the potential to revolutionize the diagnosis and treatment of several diseases, in particular by improving the sensitivity and recognition ability of imaging contrast agents and by selectively directing bioactive agents to biological targets. Focusing on cancer, promising nanoprototypes have been designed to overcome the lack of specificity of conventional chemotherapeutic agents, as well as for early detection of precancerous and malignant lesions. However, several obstacles, including difficulty in achieving the optimal combination of physicochemical parameters for tumor targeting, evading particle clearance mechanisms, and controlling drug release, prevent the translation of nanomedicines into therapy. In spite of this, recent efforts have been focused on developing functionalized nanoparticles for delivery of therapeutic agents to specific molecular targets overexpressed on different cancer cells. In particular, the combination of targeted and controlled-release polymer nanotechnologies has resulted in a new programmable nanotherapeutic formulation of docetaxel, namely BIND-014, which recently entered Phase II clinical testing for patients with solid tumors. BIND-014 has been developed to overcome the limitations facing delivery of nanoparticles to many neoplasms, and represents a validated example of targeted nanosystems with the optimal biophysicochemical properties needed for successful tumor eradication.

  4. Monte Carlo verification of polymer gel dosimetry applied to radionuclide therapy: a phantom study

    International Nuclear Information System (INIS)

    Gear, J I; Partridge, M; Flux, G D; Charles-Edwards, E

    2011-01-01

    This study evaluates the dosimetric performance of the polymer gel dosimeter 'Methacrylic and Ascorbic acid in Gelatin, initiated by Copper' and its suitability for quality assurance and analysis of I-131-targeted radionuclide therapy dosimetry. Four batches of gel were manufactured in-house and sets of calibration vials and phantoms were created containing different concentrations of I-131-doped gel. Multiple dose measurements were made up to 700 h post preparation and compared to equivalent Monte Carlo simulations. In addition to uniformly filled phantoms the cross-dose distribution from a hot insert to a surrounding phantom was measured. In this example comparisons were made with both Monte Carlo and a clinical scintigraphic dosimetry method. Dose-response curves generated from the calibration data followed a sigmoid function. The gels appeared to be stable over many weeks of internal irradiation with a delay in gel response observed at 29 h post preparation. This was attributed to chemical inhibitors and slow reaction rates of long-chain radical species. For this reason, phantom measurements were only made after 190 h of irradiation. For uniformly filled phantoms of I-131 the accuracy of dose measurements agreed to within 10% when compared to Monte Carlo simulations. A radial cross-dose distribution measured using the gel dosimeter compared well to that calculated with Monte Carlo. Small inhomogeneities were observed in the dosimeter attributed to non-uniform mixing of monomer during preparation. However, they were not detrimental to this study where the quantitative accuracy and spatial resolution of polymer gel dosimetry were far superior to that calculated using scintigraphy. The difference between Monte Carlo and gel measurements was of the order of a few cGy, whilst with the scintigraphic method differences of up to 8 Gy were observed. A manipulation technique is also presented which allows 3D scintigraphic dosimetry measurements to be compared to polymer

  5. Cardiotoxicity of novel HER2-targeted therapies.

    Science.gov (United States)

    Sendur, Mehmet A N; Aksoy, Sercan; Altundag, Kadri

    2013-08-01

    Trastuzumab, an anti-HER2 humanized monoclonal antibody, is the standard treatment for both early and metastatic HER2-positive breast cancer. In addition to other chemotherapeutic agents, trastuzumab significantly improves response rate and survival in HER2-positive early and metastatic breast cancer. Although it is well known that trastuzumab therapy is closely associated with both symptomatic and asymptomatic cardiotoxicity, less is known about novel HER2-targeted therapies. The aim of this review is to discuss the cardiac safety data from recent studies of novel anti-HER2 drugs other than trastuzumab. Novel HER2-targeted therapies showed favorable results in HER2 positive metastatic breast cancer patients. Pubmed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched until January 2013 using the following search keywords; 'trastuzumab, trastuzumab cardiotoxicity, HER-2 targeted therapies, lapatinib, pertuzumab, trastuzumab emtansine, afatinib and neratinib'; papers which were considered relevant for the aim of this review were selected by the authors. Lapatinib, pertuzumab, T-DM1, neratinib and afatinib molecules are evaluated in the study. In a comprehensive analysis, 3689 lapatinib treated patients enrolled in 49 trials; asymptomatic cardiac events were reported in 53 patients (1.4%) and symptomatic grade III and IV systolic dysfunction was observed only in 7 patients (0.2%) treated with lapatinib. In phase I-III trials of pertuzumab, cardiac dysfunction was seen in 4.5-14.5% of patients with pertuzumab treatment and cardiac dysfunction was usually grade I and II. Cardiotoxicity of pertuzumab was usually reported with the trastuzumab combination and no additive cardiotoxicity was reported with addition of pertuzumab to trastuzumab. T-DM1 had a better safety profile compared to trastuzumab, no significant cardiotoxicity was observed with T-DM1 in heavily pre-treated patients. In the EMILIA study, only in 1.7% of patients in the T

  6. Targeted Therapy in Nonmelanoma Skin Cancers

    Directory of Open Access Journals (Sweden)

    Giulia Spallone

    2011-05-01

    Full Text Available Nonmelanoma skin cancer (NMSC is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC, representing around 75% of NMSC and Squamous Cell Carcinomas (SCC. The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC.

  7. Targeted Therapy in Nonmelanoma Skin Cancers

    International Nuclear Information System (INIS)

    Spallone, Giulia; Botti, Elisabetta; Costanzo, Antonio

    2011-01-01

    Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC

  8. [Resistance to target-based therapy and its circumvention].

    Science.gov (United States)

    Nishio, Kazuto

    2004-07-01

    Intrinsic and acquired resistance to molecular target therapy critically limits the outcome of cancer treatments. Target levels including quantitative and gene alteration should be determinants for the resistance. Downstream of the target molecules, drug metabolism, and drug transport influences the tumor sensitivity to molecular target therapy. The mechanisms of resistance to antibody therapy have not been fully clarified. Correlative clinical studies using these biomarkers of resistance are extremely important for circumvention of clinical resistance to target based therapy.

  9. External tandem target system for efficient production of short-lived positron emitting radionuclides

    International Nuclear Information System (INIS)

    Koh, K.; Dwyer, J.; Finn, R.; Sheh, Y.; Sinnreich, J.; Wooten, T.

    1983-01-01

    Recent developments in radiopharmaceutical chemistry allow the incorporation of short-lived, positron-emitting radionuclides into a variety of compounds which when used with a positron emission tomograph provide a means of monitoring physiological disorders by a standard technique. To effectively meet the increased ''in-house'' clinical demands while maintaining a production schedule, a tandem target was designed and has been installed for the simultaneous ''on-line'' preparation of oxygen-15 labelled compounds such as CO 2 15 , H 2 O 15 ; and nitrogen-13 labelled compounds such as 13 NH 3 , 13 N 2 O, and 13 N 2 . The processing time required for the synthesis of the nitrogen-13 products as compared to the essentially instantaneous formation of oxygen-15 labelled compounds has provided the necessary time delay for clinical utilization. The characterisitcs of this external tandem target system as well as the automation for the dual processing are presented

  10. Nuclear medicine in Uzbekistan and current status of radionuclide therapy in the country

    International Nuclear Information System (INIS)

    Rasulova, N.; Khodjibekova, M.

    2005-01-01

    Full text: The population of Uzbekistan is 26 million and to cater to this population we have only two nuclear medicine departments; one at the Clinical Centre for Surgery and the other at the Institute of Endocrinology, both situated in Tashkent, the capital city of Uzbekistan. Over the years through its own initiatives and through the support provided by several International Organizations including the IAEA, Uzbekistan has been able to marginally improve its nuclear medicine services. SPECT imaging was introduced through generous support from IAEA in the year 2001. As a result of this, the country is now able to provide modern in vivo nuclear medicine service to the population in a limited scale. At the Clinical Centre for Surgery we are able to provide gamma camera and SPECT imaging services to patients suffering from various nephro-urological, cardiac, neuro and oncological disorders. The other nuclear medicine centre at the Institute of Endocrinology does not have any modern imaging system. However it has been engaged in providing radionuclide therapy service for thyroid diseases like thyroid cancer and hyperthyroidism. From the year 1983 to 1999 the country has reported a total number of 6374 cases of Thyroid Cancer. This number is growing each year, for example the incidence of thyroid cancer in 1989 was 1.95 per 100,000, which has grown to 2.39 per 100,000 in 1999. While the Institute of Endocrinology provides therapeutic service to thyroid diseases, the main role of the Nuclear Medicine Department of Republic Specialized Center of Surgery is in following-up of patients after therapy by performing large dose I-131 whole body imaging, screening for metastases and for assessment of results of radioactive iodine therapy. Besides treating thyroid diseases with I-131 limited services are also available for treatment of polycythemia vera rubra with P-32 and radionuclide therapy for metastatic bone pain. Radionuclide therapy is growing rapidly around the world

  11. Radiation therapy following targeted therapy in oligometastatic renal cell carcinoma.

    Science.gov (United States)

    Gravis, Gwenaelle; Faure, Marjorie; Rybikowski, Stanislas; Dermeche, Slimane; Tyran, Marguerite; Calderon, Benoit; Thomassin, Jeanne; Walz, Jochen; Salem, Naji

    2015-11-01

    Up to 40% of patients with renal cell carcinoma (RCC) with initially localized disease eventually develop metastasis following nephrectomy. The current standard of care for metastatic RCC (mRCC) is targeted therapy. However, complete response remains rare. A state of oligometastatic disease may exist, in which metastases are present in a limited number of locations; such cases may benefit from metastasis-directed local therapy, based on the evidence supporting resection of limited-volume metastases, allowing for improved disease control. We retrospectively analyzed 7 cases of response of RCC metastases, in patients treated with targeted therapies followed by radiation therapy (RT) of residual metastatic lesions in Paoli-Calmettes Institute (Marseille, France). We analyzed disease response rates, response to sequential strategy, relapse at the irradiated locations and disease evolution. The median follow-up was 34.1 months (range, 19.2-54.5 months). No progression at the irradiated sites was observed. A total of 5 patients had stable disease at the irradiated locations at the last follow-up; 3 remained in complete remission at the assessment, and 2 were stable. Excellent local response and clinical benefit may be achieved without added toxicity. In conclusion, sequential therapeutic strategies with RT following systemic treatment using sunitinib appear to be highly effective in patients with progressive mRCC and prompt the conduction of further confirmatory trials.

  12. Methodology for quantification of radionuclides used in therapy by bioanalysis 'in vitro'

    International Nuclear Information System (INIS)

    Juliao, Ligia M.Q.C.; Sousa, Wanderson O.; Mesquita, Sueli A.; Santos, Maristela S.; Oliveira, S.M. Velasques de

    2008-01-01

    In Brazil, the radionuclides used for therapy are 131 ; 153 Sm, 90 Y and 177 Lu, under routine or experimentally. The quantification of the radiopharmaceutical activity excreted by the patient through the bioassay method, can be an important tool for individualized dosimetry, aiming the planning of subsequent therapies. The Bioanalysis In Vitro Laboratory (LBIOVT) of the Service of Individual monitoring (SEMIN) of the Institute for Radiation Protection and Dosimetry (IRD/CNEN-RJ), Brazil, has equipment and procedures for gamma and beta spectrometry. These detection systems are calibrated in energy and efficiency, and used standard reference sources provided by the National Laboratory of Metrology of Ionizing Radiation (LMNRI/IRD/CNEN-RJ). The LBIOVT Quality System follows the guidelines of the ISO-ABNT-17025 standard and annually, the laboratory participates in national (PNI) and international (PROCORAD). With respect to the excreta samples from patients, these are collected immediately after administration of the radiopharmaceutical. During the first 24 hours, they are collected with the patient hospitalized, and depending upon the physical half-life of the radionuclide can also be collected in the patient's home. Both in hospital and at home, the excreta is handled, stored and transported in accordance with standards for clinical research, radiation protection and transport of radioactive and biological materials. The specific activity radionuclide is referenced to the date and time of collection, allowing further evaluation of biological individual half-life. The care with the registration of excreted volumes as well as possible loss of excreta during collection, may interfere with the interpretation of the measures, since the results are provided in specific activity (Bq / L). Regarding the bioassay laboratory, these results are reliable when the laboratory is certified and participates in intercomparison programs of measures and methods. The laboratory

  13. Cyclotron production of radionuclides in aqueous target matrices as alternative to solid state targetry. Production of Y-86 as example

    Energy Technology Data Exchange (ETDEWEB)

    Vogg, A.T.J.; Lang, R.; Meier-Boeke, P.; Scheel, W.; Reske, S.N.; Neumaier, B. [Universitaetsklinikum Ulm (Germany). Abt. Nuklearmedizin

    2004-07-01

    Commonly used ''organic'' positron emitting radionuclides {sup 18}F, {sup 11}C, {sup 13}N, and {sup 15}O are simply obtained from gaseous or aqueous targets, which enable an automated handling of target, i.e. both, filling and radionuclide delivery to a hot cell containing a chemistry processing and/or labelling module. In the recent years other - mostly metallic - radionuclides for PET gained more and more interest, since they can be used as surrogates for therapeutic nuclides attached to biomolecules like peptides or antibodies. The implication for surrogate nuclides results from the circumstance that an optimum dosimetric regime in endo radiotherapy relies on quantitative pharmacokinetic data obtained only by non invasive in vivo PET scans. However, for production of these alternative positron emitters the vast majority of them affords solid targets in form of metal foils, oxide or salt pellets which can not be operated by an automated processing. Those solid target systems have to be mounted and dismounted after irradiation by man, leading to two major disadvantages. First, manual cyclotron intervention is practically unsuited for daily routine radionuclide production and second the operating staff receives high radiation doses from the activated target. An alternative could be the irradiation of aqueous salts of target isotopes, allowing automated target operation. The major requirements are firstly a thermal stability of the dissolved compound, secondly the avoidance of counter ions containing nuclides which produce long-lived radionuclides under irradiation and thirdly a high solubility of the salt in the aqueous matrix. Here we report the proof of principle of the new radionuclide production concept by irradiation of strontium nitrate dissolved in water in order to produce {sup 86}Y (cf.). (orig.)

  14. EGFR-expression in primary urinary bladder cancer and corresponding metastases and the relation to HER2-expression. On the possibility to target these receptors with radionuclides

    International Nuclear Information System (INIS)

    Carlsson, Jörgen; Wester, Kenneth; De La Torre, Manuel; Malmström, Per-Uno; Gårdmark, Truls

    2015-01-01

    There is limited effect of tyrosine kinase inhibitors or “naked” antibodies binding EGFR or HER2 for therapy of metastasized urinary bladder cancer and these methods are therefore not routinely used. Targeting radio-nuclides to the extracellular domain of the receptors is potentially a better possibility. EGFR- and HER2-expression was analyzed for primary tumors and corresponding metastases from 72 patients using immunohistochemistry and the internationally recommended HercepTest. Intracellular mutations were not analyzed since only the receptors were considered as targets and intracellular abnormalities should have minor effect on radiation dose. EGFR was positive in 71% of the primary tumors and 69% of corresponding metastases. Local and distant metastases were EGFR-positive in 75% and 66% of the cases, respectively. The expression frequency of HER2 in related lesions was slightly higher (data from previous study). The EGFR-positive tumors expressed EGFR in metastases in 86% of the cases. The co-expression of EGFR and HER2 was 57% for tumors and 53% for metastases. Only 3% and 10% of the lesions were negative for both receptors in tumors and metastases, respectively. Thus, targeting these receptors with radionuclides might be applied for most patients. At least one of the EGFR- or HER2-receptors was present in most cases and co-expressed in more than half the cases. It is therefore interesting to deliver radionuclides for whole-body receptor-analysis, dosimetry and therapy. This can hopefully compensate for resistance to other therapies and more patients can hopefully be treated with curative instead of palliative intention

  15. Investigation of the radionuclide inventory and the production yields of the target stacks at the PEFP radioisotope production facility

    International Nuclear Information System (INIS)

    Yoon, Sang-Pil; Hong, In-Seok; Cho, Yong-Sub

    2010-01-01

    The Proton Engineering Frontier Project (PEFP) will construct a radioisotope production facility by using the nuclear reaction between the 100-MeV proton beam and the solid target. For investigating the radionuclide inventory and the production yield of the radioisotope production facility, we have optimized the thickness of the prototype target stacks by using a SRIM calculation. The target stacks consist of RbCl encapsulated in inconel alloy, Zn metal, and Ga metal encapsulated in niobium. Typical beam parameters were 300 μA and 95 hours. An inventory of all generated radionuclide activities is mandatory in order to prepare the operation scenario and design the hot cell. The Monte Carlo code MCNPX was used to investigate what radionuclide is generated. The obtained radionuclide inventory indicated that about 100 radionuclides were generated and that the total radioactivity of the irradiated target stacks was 1324.1 Ci at the end of the bombardment. The production yields of Sr-82, Cu-67, and Ge-68 were 3.79 Ci, 2.74 Ci, and 1.23 Ci at the end of the bombardment.

  16. Anti-tumor effects of Egr-IFN gamma gene therapy combined with {sup 125}I-UdR radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Jingguo, Zhao [No.403 Hospital of PLA, Dalian (China); Yanjun, Ni; Xiangfu, Song; Yanyi, Li; Wei, Yang; Ting, Sun; Qingjie, Ma; Fengtong, Gao

    2008-12-15

    Objective: To explore the anti-tumor effects of Egr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy in mice bearing H22 hepatocarcinoma and its mechanism. Methods: The recombinant plasmid pcDNAEgr-IFNgamma mixed with liposome was injected into tumor. 48 h later, 370 kBq {sup 125}I-UdR was injected into tumor. The tumor growth rates at different times were observed. After 3 d gene-radionuclide therapy, the concentration of IFNgamma in cytoplasm of H22 cells and cytotoxic activities of splenic CTL of the mice in different groups were examined. Results: The tumor growth rates of pcDNAEgr-IFNgamma + {sup 125}I-UdR group were obviously lower than those of control group, {sup 125}I-UdR group and pcDNAEgr-1 + {sup 125}I-UdR group 6-15 d after gene-radionuclide therapy. IFNgamma protein was found in cytoplasm of H22 cells in pcDNAEgr-IFNgamma + {sup 125}I-UdR group after 3 d gene-radionuclide therapy. Cytotoxic activity of splenic CTL in pcDNAEgr-IFNgamma + {sup 125}I-UdR group was significantly higher than that in the other groups (P<0.01). Conclusions: The anti-tumor effects in vivo of pcDNAEgr-IFNgamma gene therapy combined with {sup 125}I-UdR radionuclide therapy are better than those of {sup 125}I-UdR therapy. (authors)

  17. Engineering liposomal nanoparticles for targeted gene therapy.

    Science.gov (United States)

    Zylberberg, C; Gaskill, K; Pasley, S; Matosevic, S

    2017-08-01

    Recent mechanistic studies have attempted to deepen our understanding of the process by which liposome-mediated delivery of genetic material occurs. Understanding the interactions between lipid nanoparticles and cells is still largely elusive. Liposome-mediated delivery of genetic material faces systemic obstacles alongside entry into the cell, endosomal escape, lysosomal degradation and nuclear uptake. Rational design approaches for targeted delivery have been developed to reduce off-target effects and enhance transfection. These strategies, which have included the modification of lipid nanoparticles with target-specific ligands to enhance intracellular uptake, have shown significant promise at the proof-of-concept stage. Control of physical and chemical specifications of liposome composition, which includes lipid-to-DNA charge, size, presence of ester bonds, chain length and nature of ligand complexation, is integral to the performance of targeted liposomes as genetic delivery agents. Clinical advances are expected to rely on such systems in the therapeutic application of liposome nanoparticle-based gene therapy. Here, we discuss the latest breakthroughs in the development of targeted liposome-based agents for the delivery of genetic material, paying particular attention to new ligand and cationic lipid design as well as recent in vivo advances.

  18. [Preparation, quality control and thyroid molecule imaging of solid-target based radionuclide ioine-124].

    Science.gov (United States)

    Zhu, H; Wang, F; Guo, X Y; Li, L Q; Duan, D B; Liu, Z B; Yang, Z

    2018-04-18

    To provide useful information for the further production and application of this novel radio-nuclide for potential clinical application. 124 Te (p,n) 124 I nuclide reaction was used for the 124 I production. Firstly, the target material, 124 TeO 2 (200 mg) and Al2O3 (30 mg) mixture, were compressed into the round platinum based solid target by tablet device. HM-20 medical cyclotron was applied to irradiate the solid target slice for 6-10 h with helium and water cooling. Then, the radiated solid target was placed for 12 h (overnight) to decay the radioactive impurity; finally, 124 I was be purified by dry distillation using 1 mL/min nitrogen for about 6 hours and radiochemical separation methods. Micro-PET imaging studies were performed to investigate the metabolism properties and thyroid imaging ability of 124 I.After 740 kBq 124 I was injected intravenously into the tail vein of the normal mice, the animals were imaged with micro-PET and infused with CT. The micro-PET/CT infusion imaging revealed actual state 124 I's metabolism in the mice. It was been successfully applied for 200 mg 124 TeO 2 plating by the tablet device on the surface of platinum. It showed smooth, dense surface and without obviously pits and cracks. The enriched 124 Te target was irradiated for 6 to 10 hours at about 12.0 MeV with 20 μA current on HM-20 cyclotron. Then 370-1 110 MBq 124 I could be produced on the solid target after irradiation and 370-740 MBq high specific activity could be collected afterdry distillation separation and radio-chemical purification. 124 I product was finally dissolved in 0.01 mol/L NaOH for the future distribution. The gamma spectrum of the produced 124 I-solution showed that radionuclide purity was over 80.0%. The micro-PET imaging of 124 I in the normal mice exhibited the thyroid and stomach accumulations and kidney metabolism, the bladder could also be clearly visible, which was in accordance with what was previously reported. To the best of our knowledge

  19. Combined anti-tumor therapeutic effect of targeted gene, hyperthermia, radionuclide brachytherapy in breast carcinoma

    International Nuclear Information System (INIS)

    Chen Daozhen; Tang Qiusha; Xiang Jingying; Xu Fei; Zhang Li; Wang Junfeng

    2011-01-01

    Objective: To investigate the antitumor therapeutic effect of combined therapy of magnetic induction heating by nano-magnetic particles, herpes simplex virus thymidine kinase gene (HSV-tk suicide gene) and internal radiation in mice bearing MCF-7 breast carcinoma. Methods: The transfection reagents, plasmids heat shock protein-HSV-tk (pHSP-HSV-tk), ferroso-ferric oxide nano-magnetic fluid flow and 188 Re-ganciclovir-bovine serum albumin-nanopaticles (GCV-BSA-NP) were prepared. The heating experiments in vivo were carried out using ferroso-ferric oxide nano-magnetic fluid flow. Sixty mice tumor models bearing MCF-7 breast carcinoma were established and randomly divided into six groups. Group A was the control group, B was gene transfection therapy group, C was hyperthermia group, D was gene transfection therapy combined with radionuclide brachytherapy group, E was gene therapy combined with hyperthermia group, and F was gene therapy, hyperthermia combined with radionuclide brachytherapy group. The tumor growth, tumor mass and histopathological changes were evaluated. The expression of HSV-tk in the groups of B, D, E and F was detected by RT-PCR. Poisson distribution and one-way analysis of variance (ANOVA) were used for statistical analysis by SPSS 10.0 software. Results: In the animal heating experiments, the temperature of tumor increased up to 39.6 degree C, 43.2 degree C, and 48.1 degree C quickly with different injected doses (2, 4 and 6 mg respectively) of nano-magnetic particles and maintained for 40 min. The temperature of tumor tissue reduced to 36.8 degree C, 37.5 degree C and 37.8 degree C in 10 min when alternating magnetic field (AMF) stopped. The tumor mass in Groups C ((452.50±30.29) mg), D ((240.98±35.32)mg), E((231.87±27.41) mg) and F ((141.55±23.78) mg) were much lower than that in Group A ((719.12±22.65) mg) (F=800.07, P<0.01), with the most significant treatment effect in Group F.The tumor mass in Group B((684.05±24.02) mg) was higher than

  20. MAIN MOLECULAR TARGETS FOR PROSTATE CANCER THERAPY

    Directory of Open Access Journals (Sweden)

    G. S. Krasnov

    2014-01-01

    Full Text Available Androgenic pathway plays a pivotal role in the development of benign and malignant prostate tumors. Most of the prostate neoplasms are hormone-dependent at the time of diagnosis. Therapeutic interventions aimed at reducing the level of testosterone in the blood allow to stop progression of the disease. But over time, the tumor almost inevitably starts to progress, moving in the castration-resistant state (CRPC, representing a serious problem of oncourology. In recent years, the possibility of CRRPC therapy increased significantly – there was developed a number of new drugs that effectively inhibit the development of castration-resistant tumors and significantly push back the start of chemotherapy. This review describes the major drug targets and mechanisms of action of abiraterone, enzalutamide, galeterone, VT-464 and other approved and promising CRPC therapies.

  1. Cancer gene therapy with targeted adenoviruses.

    Science.gov (United States)

    Bachtarzi, Houria; Stevenson, Mark; Fisher, Kerry

    2008-11-01

    Clinical experience with adenovirus vectors has highlighted the need for improved delivery and targeting. This manuscript aims to provide an overview of the techniques currently under development for improving adenovirus delivery to malignant cells in vivo. Primary research articles reporting improvements in adenoviral gene delivery are described. Strategies include genetic modification of viral coat proteins, non-genetic modifications including polymer encapsulation approaches and pharmacological interventions. Reprogramming adenovirus tropism in vitro has been convincingly demonstrated using a range of genetic and physical strategies. These studies have provided new insights into our understanding of virology and the field is progressing. However, there are still some limitations that need special consideration before adenovirus-targeted cancer gene therapy emerges as a routine treatment in the clinical setting.

  2. Oncolytic viral therapy: targeting cancer stem cells

    Directory of Open Access Journals (Sweden)

    Smith TT

    2014-02-01

    Full Text Available Tyrel T Smith,1 Justin C Roth,1 Gregory K Friedman,1 G Yancey Gillespie2 1Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Neurosurgery, The University of Alabama at Birmingham, Birmingham, AL, USA Abstract: Cancer stem cells (CSCs are defined as rare populations of tumor-initiating cancer cells that are capable of both self-renewal and differentiation. Extensive research is currently underway to develop therapeutics that target CSCs for cancer therapy, due to their critical role in tumorigenesis, as well as their resistance to chemotherapy and radiotherapy. To this end, oncolytic viruses targeting unique CSC markers, signaling pathways, or the pro-tumor CSC niche offer promising potential as CSCs-destroying agents/therapeutics. We provide a summary of existing knowledge on the biology of CSCs, including their markers and their niche thought to comprise the tumor microenvironment, and then we provide a critical analysis of the potential for targeting CSCs with oncolytic viruses, including herpes simplex virus-1, adenovirus, measles virus, reovirus, and vaccinia virus. Specifically, we review current literature regarding first-generation oncolytic viruses with their innate ability to replicate in CSCs, as well as second-generation viruses engineered to enhance the oncolytic effect and CSC-targeting through transgene expression. Keywords: oncolytic virotherapy, cancer stem cell niche

  3. Targeting embryonic signaling pathways in cancer therapy.

    Science.gov (United States)

    Harris, Pamela Jo; Speranza, Giovanna; Dansky Ullmann, Claudio

    2012-01-01

    The embryonic signaling pathways (ESP), Hedgehog, Notch and Wnt, are critical for the regulation of normal stem cells and cellular development processes. They are also activated in the majority of cancers. ESP are operational in putative cancer stem cells (CSC), which drive initial tumorigenesis and sustain cancer progression and recurrence in non-CSC bulk subpopulations. ESP represent novel therapeutic targets. A variety of inhibitors and targeting strategies are being developed. This review discusses the rationale for targeting ESP for cancer treatment, as well as specific inhibitors under development; mainly focusing on those approaching clinical use and the challenges that lie ahead. The data sources utilized are several database search engines (PubMed, Google, Clinicaltrials.gov), and the authors' involvement in the field. CSC research is rapidly evolving. Expectations regarding their therapeutic targeting are rising quickly. Further definition of what constitutes a true CSC, proper validation of CSC markers, a better understanding of cross-talk among ESP and other pathways, and interactions with tumor non-CSC and the tumor microenvironment are needed. The appropriate patient population, the right clinical setting and combination strategies to test these therapies, as well as the proper pharmacodynamic markers to measure, need to be further established.

  4. Advances in the targeted therapy of liposarcoma

    Directory of Open Access Journals (Sweden)

    Guan Z

    2015-01-01

    Full Text Available Zhonghai Guan,1 Xiongfei Yu,1 Haohao Wang,1 Haiyong Wang,1 Jing Zhang,1 Guangliang Li,2 Jiang Cao,3 Lisong Teng1 1Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, 2Department of Medicine Oncology, Zhejiang Cancer Hospital, 3Clinical Research Center, The 2nd Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China Abstract: Liposarcoma (LPS is the most common type of soft-tissue sarcoma. Complete surgical resection is the only curative means for localized disease; however, both radiation and conventional cytotoxic chemotherapy remain controversial for metastatic or unresectable disease. An increasing number of trials with novel targeted therapy of LPS have provided encouraging data during recent years. This review will provide an overview of the advances in our understanding of LPS and summarize the results of recent trials with novel therapies targeting different genetic and molecular aberrations for different subtypes of LPS. Keywords: well-/dedifferentiated, myxoid/round cell, pleomorphic, soft-tissue sarcoma

  5. New design targets and new automated technology for the production of radionuclides with high specificity radioactivity in nuclear research reactors

    International Nuclear Information System (INIS)

    Gerasimov, A.S.; Kiselev, G.V.

    1997-01-01

    Current demands of industry require the application of radionuclides with high specific radioactivity under low consumption of neutrons. To provide this aim staff of ITEP Reactor Department investigated the different type AEs of start targets for the production of the main radionuclides; Co-60, Ir-192 and others. In first turn the targets of Co and Ir without the block-effect of neutron flux (with low absorption of neutrons) were investigated. The following principal results were received for example for Ir-192: block effect is equal 0.086 for diameter of Ir target mm and is equal 0.615 for diameter Ir target 0.5mm. It means average neutron flux for Ir target diameter 0.5mm and therefore the production of Ir-192 will be at 10 times more than for diameter 6.0mm. To provide the automated technology of the manufacture of radioactive sources with radionuclides with high specific radioactivity it was proposed that the compound targets for the irradiation of ones and for the management with the irradiated targets. Different types of compound targets were analyzed. (authors)

  6. Antibody-Hapten Recognition at the Surface of Functionalized Liposomes Studied by SPR: Steric Hindrance of Pegylated Phospholipids in Stealth Liposomes Prepared for Targeted Radionuclide Delivery

    Directory of Open Access Journals (Sweden)

    Eliot. P. Botosoa

    2011-01-01

    Full Text Available Targeted PEGylated liposomes could increase the amount of drugs or radionuclides delivered to tumor cells. They show favorable stability and pharmacokinetics, but steric hindrance of the PEG chains can block the binding of the targeting moiety. Here, specific interactions between an antihapten antibody (clone 734, specific for the DTPA-indium complex and DTPA-indium-tagged liposomes were characterized by surface plasmon resonance (SPR. Non-PEGylated liposomes fused on CM5 chips whereas PEGylated liposomes did not. By contrast, both PEGylated and non-PEGylated liposomes attached to L1 chips without fusion. SPR binding kinetics showed that, in the absence of PEG, the antibody binds the hapten at the surface of lipid bilayers with the affinity of the soluble hapten. The incorporation of PEGylated lipids hinders antibody binding to extents depending on PEGylated lipid fraction and PEG molecular weight. SPR on immobilized liposomes thus appears as a useful technique to optimize formulations of liposomes for targeted therapy.

  7. Targeting DNA Replication Stress for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2016-08-01

    Full Text Available The human cellular genome is under constant stress from extrinsic and intrinsic factors, which can lead to DNA damage and defective replication. In normal cells, DNA damage response (DDR mediated by various checkpoints will either activate the DNA repair system or induce cellular apoptosis/senescence, therefore maintaining overall genomic integrity. Cancer cells, however, due to constitutive growth signaling and defective DDR, may exhibit “replication stress” —a phenomenon unique to cancer cells that is described as the perturbation of error-free DNA replication and slow-down of DNA synthesis. Although replication stress has been proven to induce genomic instability and tumorigenesis, recent studies have counterintuitively shown that enhancing replicative stress through further loosening of the remaining checkpoints in cancer cells to induce their catastrophic failure of proliferation may provide an alternative therapeutic approach. In this review, we discuss the rationale to enhance replicative stress in cancer cells, past approaches using traditional radiation and chemotherapy, and emerging approaches targeting the signaling cascades induced by DNA damage. We also summarize current clinical trials exploring these strategies and propose future research directions including the use of combination therapies, and the identification of potential new targets and biomarkers to track and predict treatment responses to targeting DNA replication stress.

  8. Targeted Therapy for Biliary Tract Cancer

    International Nuclear Information System (INIS)

    Furuse, Junji; Okusaka, Takuji

    2011-01-01

    It is necessary to establish effective chemotherapy to improve the survival of patients with biliary tract cancer, because most of these patients are unsuitable candidates for surgery, and even patients undergoing curative surgery often have recurrence. Recently, the combination of cisplatin plus gemcitabine was reported to show survival benefits over gemcitabine alone in randomized clinical trials conducted in the United Kingdom and Japan. Thus, the combination of cisplatin plus gemcitabine is now recognized as the standard therapy for unresectable biliary tract cancer. One of the next issues that need to be addressed is whether molecular targeted agents might also be effective against biliary tract cancer. Although some targeted agents have been investigated as monotherapy for first-line chemotherapy, none were found to exert satisfactory efficacy. On the other hand, monoclonal antibodies such as bevacizumab and cetuximab have also been investigated in combination with a gemcitabine-based regimen and have been demonstrated to show promising activity. Furthermore, clinical trials using new targeted agents for biliary tract cancer are also proposed. This cancer is a relatively rare and heterogeneous tumor consisting of cholangiocarcinoma and gallbladder carcinoma. Therefore, a large randomized clinical trial is necessary to confirm the efficacy of chemotherapy, and international collaboration is important

  9. Molecular targeted therapy for advanced gastric cancer.

    Science.gov (United States)

    Kim, Jong Gwang

    2013-03-01

    Although medical treatment has been shown to improve quality of life and prolong survival, no significant progress has been made in the treatment of advanced gastric cancer (AGC) within the last two decades. Thus, the optimum standard first-line chemotherapy regimen for AGC remains debatable, and most responses to chemotherapy are partial and of short duration; the median survival is approximately 7 to 11 months, and survival at 2 years is exceptionally > 10%. Recently, remarkable progress in tumor biology has led to the development of new agents that target critical aspects of oncogenic pathways. For AGC, many molecular targeting agents have been evaluated in international randomized studies, and trastuzumab, an anti-HER-2 monoclonal antibody, has shown antitumor activity against HER-2-positive AGC. However, this benefit is limited to only ~20% of patients with AGC (patients with HER-2-positive AGC). Therefore, there remains a critical need for both the development of more effective agents and the identification of molecular predictive and prognostic markers to select those patients who will benefit most from specific chemotherapeutic regimens and targeted therapies.

  10. Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up.

    Science.gov (United States)

    Hörsch, Dieter; Ezziddin, Samer; Haug, Alexander; Gratz, Klaus Friedrich; Dunkelmann, Simone; Miederer, Matthias; Schreckenberger, Mathias; Krause, Bernd Joachim; Bengel, Frank M; Bartenstein, Peter; Biersack, Hans-Jürgen; Pöpperl, Gabriele; Baum, R P

    2016-05-01

    Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany. A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan-Meier curves and uni-variate log rank test Cox models. Median overall survival of all patients was 59 (95% confidence interval [CI] 49-68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83-5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79-5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41-12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18-0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9-46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71-4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow

  11. Targeted Therapy for Breast Cancer Prevention

    Science.gov (United States)

    den Hollander, Petra; Savage, Michelle I.; Brown, Powel H.

    2013-01-01

    With a better understanding of the etiology of breast cancer, molecularly targeted drugs have been developed and are being testing for the treatment and prevention of breast cancer. Targeted drugs that inhibit the estrogen receptor (ER) or estrogen-activated pathways include the selective ER modulators (tamoxifen, raloxifene, and lasofoxifene) and aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) have been tested in preclinical and clinical studies. Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer and promising results of AIs in breast cancer trials, suggest that AIs might be even more effective in the prevention of ER-positive breast cancer. However, these agents only prevent ER-positive breast cancer. Therefore, current research is focused on identifying preventive therapies for other forms of breast cancer such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC, breast cancer that does express ER, progesterone receptor, or HER2). HER2-positive breast cancers are currently treated with anti-HER2 therapies including trastuzumab and lapatinib, and preclinical and clinical studies are now being conducted to test these drugs for the prevention of HER2-positive breast cancers. Several promising agents currently being tested in cancer prevention trials for the prevention of TNBC include poly(ADP-ribose) polymerase inhibitors, vitamin D, and rexinoids, both of which activate nuclear hormone receptors (the vitamin D and retinoid X receptors). This review discusses currently used breast cancer preventive drugs, and describes the progress of research striving to identify and develop more effective preventive agents for all forms of breast cancer. PMID:24069582

  12. Gene transfer technology and genetic radioisotope targeting therapy

    International Nuclear Information System (INIS)

    Wang Jiaqiong; Wang Zizheng

    2004-01-01

    With deeper cognition about mechanisms of disease at the cellular and molecular level, gene therapy has become one of the most important research fields in medical molecular biology at present. Gene transfer technology plays an important role during the course of gene therapy, and further improvement should be made about vectors carrying target gene sequences. Also, gene survey is needed during gene therapy, and gene imaging is the most effective method. The combination of gene therapy and targeted radiotherapy, that is, 'Genetic Radioisotope Targeting Therapy', will be a novel approach to tumor gene therapy

  13. TARGETED NANOPARTICLES FOR PEDIATRIC LEUKEMIA THERAPY

    Directory of Open Access Journals (Sweden)

    Riyaz eBasha

    2014-05-01

    Full Text Available The two major forms of leukemia, acute lymphoblastic leukemia (ALL and acute myeloid leukemia (AML account for about one third of the malignancies diagnosed in children. Despite the marked successes in ALL and AML treatment, concerns remain regarding the occurrence of resistant disease in subsets of patients the residual effects of therapy that often persist for decades beyond the cessation of treatment. Therefore, new approaches are needed to reduce or to avoid off target toxicities, associated with chemotherapy and their long term residual effects. Recently, nanotechnology has been employed to enhance cancer therapy, via improving the bioavailability and therapeutic efficacy of anti-cancer agents. While in the last several years, numerous review articles appeared detailing the size, composition, assembly and performance evaluation of different types of drug carrying nanoparticles, the description and evaluation of lipoprotein based drug carriers have been conspicuously absent from most of these major reviews. The current review focuses on such information regarding nanoparticles with an emphasis on high density lipoprotein (HDL-based drug delivery systems to examine their potential role(s in the enhanced treatment of children with leukemia.

  14. Radioactive Indium(114mIn) complexes derived thiosemicarbazones for development of glioma radionuclide therapy tools

    International Nuclear Information System (INIS)

    Ribeiro, Thais S.; Menezes, Maria Ângela B.C.; Belo, Luiz Cláudio M.; Santos, Raquel G. dos; Franco, Lucas L.; Oliveira, Alexandre A.; Beraldo, Heloisa O.

    2017-01-01

    Chemotherapy is widely used as the main course of treatment for various types of cancer. However, the side effects derived from the prolonged use of highly cytotoxic drugs in association with chemotherapy induced resistance are important challenges for effective therapy. In this context, radionuclide therapy (RNT) can be an alternative way to decrease the toxicity and improve the specificity of anti tumoral drugs. Our group has recently demonstrated that Indium (III) coordination to N(4)-Tolyl-2-acetylpyridine-derived thiosemicarbazones improves cytotoxic effects on leukemia cell lines. Once 114m In is a prolific Auger electron emitter, in this study In (III) complexes and their radioactive analogs were produced by neutron activation and their potential for RNT was further studied. Native and radioactive complexes were tested in different concentrations in U87 and T98 glioblastoma multiform (GBM) cell lines, as well as in MRC5 fibroblast cell line. All drugs presented a dose dependent cytotoxicity against cancer cells at submicromolar concentrations. The treatment with 1 μM of the radioactive analogs containing 114m In proved to be at least 1.5 times more potent than non-radioactive complexes in GBM cell lines. Due to the innate resistance of glioblastomas to chemotherapy and radiotherapy, the potentiation factor showed by the test radioactive complexes may be interesting in the course of treatment against these tumors. Therefore, the presented data suggests a synergistic effect of the radionuclide therapy conducted in this study, which might be due to the combinations of pharmacological and radiotherapeutic activities of the 114m In - thiosemicarbazone compounds. (author)

  15. Therapies targeting inflammation after stent implantation.

    Science.gov (United States)

    Okura, Hiroyuki; Takagi, Tsutomu; Yoshida, Kiyoshi

    2013-07-01

    Since the introduction of coronary vessel scaffold by metallic stent, percutaneous coronary intervention has become widely performed all over the world. Although drug-eluting stent technology has further decrease the incidence of in-stent restenosis, there still remaining issues related to stent implantation. Vessel inflammation is one of the causes that may be related to stent restenosis as well as stent thrombosis. Therefore, systemic therapies targeting inflammation emerged as adjunctive pharmacological intervention to improve outcome. Statins, corticosteroids, antiplatelets, and immunosuppresive or anti-cancer drugs are reported to favorably impact outcome after bare-metal stent implantation. In type 2 diabetic patients, pioglitazone may be the most promising drug that can lower neointimal proliferation and, as a result, lower incidence of restenosis and target lesion revascularization. On the other hand, several new stent platforms that might decrease inflammatory response after drug-eluting stent implantation have been introduced. Because durable polymer used in the first generation drug-eluting stents are recognized to be responsible for unfavorable vessel response, biocompatible or bioabsorbable polymer has been introduce and already used clinically. Furthermore, polymer-free drug-eluting stent and bioresorbable scaffold are under investigation. Although vessel inflammation may be reduced by using these new drug-eluting stents or scaffold, long-term impact needs to be investigated further.

  16. RLIP76 Targeted Therapy for Kidney Cancer.

    Science.gov (United States)

    Singhal, Sharad S; Singhal, Jyotsana; Figarola, James; Horne, David; Awasthi, Sanjay

    2015-10-01

    Despite recent improvements in chemotherapeutic approaches to treating kidney cancer, this malignancy remains deadly if not found and removed at an early stage of the disease. Kidney cancer is highly drug-resistant, which may at least partially result from high expression of transporter proteins in the cell membranes of kidney cells. Although these transporter proteins can contribute to drug-resistance, targeting proteins from the ATP-binding cassette transporter family has not been effective in reversing drug-resistance in kidney cancer. Recent studies have identified RLIP76 as a key stress-defense protein that protects normal cells from damage caused by stress conditions, including heat, ultra-violet light, X-irradiation, and oxidant/electrophilic toxic chemicals, and is crucial for protecting cancer cells from apoptosis. RLIP76 is the predominant glutathione-electrophile-conjugate (GS-E) transporter in cells, and inhibiting it with antibodies or through siRNA or antisense causes apoptosis in many cancer cell types. To date, blocking of RLIP76, either alone or in combination with chemotherapeutic drugs, as a therapeutic strategy for kidney cancer has not yet been evaluated in human clinical trials, although there is considerable potential for RLIP76 to be developed as a therapeutic agent for kidney cancer. In the present review, we discuss the mechanisms underlying apoptosis caused by RLIP76 depletion, the role of RLIP76 in clathrin-dependent endocytosis deficiency, and the feasibility of RLIP76-targeted therapy for kidney cancer.

  17. DNA damage in blood lymphocytes in patients after {sup 177}Lu peptide receptor radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Eberlein, Uta; Bluemel, Christina; Buck, Andreas Konrad; Werner, Rudolf Alexander; Lassmann, Michael [University of Wuerzburg, Department of Nuclear Medicine, Wuerzburg (Germany); Nowak, Carina; Scherthan, Harry [Bundeswehr Institute of Radiobiology affiliated to the University of Ulm, Munich (Germany)

    2015-10-15

    The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with {sup 177}Lu-labelled DOTATATE/DOTATOC. The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time-activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing γ-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with {sup 131}I and {sup 177}Lu. The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair. Measurements of RIF and the absorbed dose to the blood after systemic administration of {sup 177}Lu may be used to obtain data on the individual dose-response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair. (orig.)

  18. Practical Guidance on Peptide Receptor Radionuclide Therapy (PRRNT) for Neuroendocrine Tumours

    International Nuclear Information System (INIS)

    2013-01-01

    Peptide receptor radionuclide therapy (PRRNT) using 90 Y-DOTATOC was first administered in 1996 in Basel, Switzerland, to a 40 year old patient with a gastroenteropancreatic neuroendocrine tumour (NET). The objective was to stabilize the progression of the tumour, which had proven refractory to conventional chemotherapy. The excellent subjective and objective responses after several treatment cycles prompted exhaustive pre-clinical and clinical research to explore the therapeutic potential of PRRNT for the treatment of NETs. Since then, PRRNT using 90 Y- or 177 Lu-DOTATOC has acquired wide acceptance and is now used in many medical centres in Europe and other parts of the world. NET is a unique subclass of cancer in which a good percentage of affected patients may experience disease control following several cycles of PRRNT, with improvement of symptoms and quality of life in the majority of cases. This book is a practical reference for specialists in clinical oncology and nuclear medicine embarking on deploying and executing a comprehensive programme for treating patients with NETs. It is part of a larger endeavour of the IAEA to enable medical centres in Member States to introduce therapeutic applications of unsealed radioisotopes in clinical routine practice. This publication provides comprehensive, multidisciplinary guidance on the use of PRRNT in order to enhance the effective, safe and standardized implementation of best practice for treating patients with NETs and gastroenteropancreatic cancers, with due regard to the recent international classifications of NETs. It provides comprehensive protocols for employing either 90 Y or 177 Lu tagged somatostatin receptor targeting peptides, as well as clinically assessed protocols for renal protection. It is a comprehensive compilation of clinically based evidence with input from experienced and renowned medical professionals in this field. The various sections cover clinical presentations, patient eligibility

  19. Practical Guidance on Peptide Receptor Radionuclide Therapy (PRRNT) for Neuroendocrine Tumours

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2013-03-15

    Peptide receptor radionuclide therapy (PRRNT) using {sup 90}Y-DOTATOC was first administered in 1996 in Basel, Switzerland, to a 40 year old patient with a gastroenteropancreatic neuroendocrine tumour (NET). The objective was to stabilize the progression of the tumour, which had proven refractory to conventional chemotherapy. The excellent subjective and objective responses after several treatment cycles prompted exhaustive pre-clinical and clinical research to explore the therapeutic potential of PRRNT for the treatment of NETs. Since then, PRRNT using {sup 90}Y- or {sup 177}Lu-DOTATOC has acquired wide acceptance and is now used in many medical centres in Europe and other parts of the world. NET is a unique subclass of cancer in which a good percentage of affected patients may experience disease control following several cycles of PRRNT, with improvement of symptoms and quality of life in the majority of cases. This book is a practical reference for specialists in clinical oncology and nuclear medicine embarking on deploying and executing a comprehensive programme for treating patients with NETs. It is part of a larger endeavour of the IAEA to enable medical centres in Member States to introduce therapeutic applications of unsealed radioisotopes in clinical routine practice. This publication provides comprehensive, multidisciplinary guidance on the use of PRRNT in order to enhance the effective, safe and standardized implementation of best practice for treating patients with NETs and gastroenteropancreatic cancers, with due regard to the recent international classifications of NETs. It provides comprehensive protocols for employing either {sup 90}Y or {sup 177}Lu tagged somatostatin receptor targeting peptides, as well as clinically assessed protocols for renal protection. It is a comprehensive compilation of clinically based evidence with input from experienced and renowned medical professionals in this field. The various sections cover clinical presentations

  20. Targeted Gene Therapy of Cancer: Second Amendment toward Holistic Therapy.

    Science.gov (United States)

    Barar, Jaleh; Omidi, Yadollah

    2013-01-01

    It seems solid tumors are developing smart organs with specialized cells creating specified bio-territory, the so called "tumor microenvironment (TME)", in which there is reciprocal crosstalk among cancer cells, immune system cells and stromal cells. TME as an intricate milieu also consists of cancer stem cells (CSCs) that can resist against chemotherapies. In solid tumors, metabolism and vascularization appears to be aberrant and tumor interstitial fluid (TIF) functions as physiologic barrier. Thus, chemotherapy, immunotherapy and gene therapy often fail to provide cogent clinical outcomes. It looms that it is the time to accept the fact that initiation of cancer could be generation of another form of life that involves a cluster of thousands of genes, while we have failed to observe all aspects of it. Hence, the current treatment modalities need to be re-visited to cover all key aspects of disease using combination therapy based on the condition of patients. Perhaps personalized cluster of genes need to be simultaneously targeted.

  1. Targeted Gene Therapy of Cancer: Second Amendment toward Holistic Therapy

    Directory of Open Access Journals (Sweden)

    Jaleh Barar

    2013-02-01

    Full Text Available It seems solid tumors are developing smart organs with specialized cells creating specified bio-territory, the so called “tumor microenvironment (TME”, in which there is reciprocal crosstalk among cancer cells, immune system cells and stromal cells. TME as an intricate milieu also consists of cancer stem cells (CSCs that can resist against chemotherapies. In solid tumors, metabolism and vascularization appears to be aberrant and tumor interstitial fluid (TIF functions as physiologic barrier. Thus, chemotherapy, immunotherapy and gene therapy often fail to provide cogent clinical outcomes. It looms that it is the time to accept the fact that initiation of cancer could be generation of another form of life that involves a cluster of thousands of genes, while we have failed to observe all aspects of it. Hence, the current treatment modalities need to be re-visited to cover all key aspects of disease using combination therapy based on the condition of patients. Perhaps personalized cluster of genes need to be simultaneously targeted.

  2. Referent 3D tumor model at cellular level in radionuclide therapy

    International Nuclear Information System (INIS)

    Spaic, R.; Ilic, R.D.; Petrovic, B.J.

    2002-01-01

    Aim Conventional internal dosimetry has a lot of limitations because of tumor dose nonuniformity. The best approach for absorbed dose at cellular level for different tumors in radionuclide therapy calculation is Monte Carlo method. The purpose of this study is to introduce referent tumor 3D model at cellular level for Monte Carlo simulation study in radionuclide therapy. Material and Methods The moment when tumor is detectable and when same therapy can start is time period in which referent 3D tumor model at cellular level was defined. In accordance with tumor growth rate at that moment he was a sphere with same radius (10 000 μm). In that tumor there are cells or cluster of cells, which are randomly distributed spheres. Distribution of cells/cluster of cells can be calculated from histology data but it was assumed that this distribution is normal with the same mean value and standard deviation (100±50 mm). Second parameter, which was selected to define referent tumor, is volume density of cells (30%). In this referent tumor there are no necroses. Stroma is defined as space between spheres with same concentration of materials as in spheres. Results: Referent tumor defined on this way have about 2,2 10 5 cells or cluster of cells random distributed. Using this referent 3D tumor model and for same concentration of radionuclides (1:100) and energy of beta emitters (1000 keV) which are homogeneously distributed in labeled cells absorbed dose for all cells was calculated. Simulations are done using FOTELP Monte Carlo code, which is modified for this purposes. Results of absorbed dose in cells are given in numerical values (1D distribution) and as the images (2D or 3D distributions). Conclusion Geometrical module for Monte Carlo simulation study can be standardized by introducing referent 3D tumor model at cellular level. This referent 3D tumor model gives most realistic presentation of different tumors at the moment of their detectability. Referent 3D tumor model at

  3. First meeting on the CRP 'standardized high current solid targets for cyclotron production of diagnostic and therapeutic radionuclides'

    International Nuclear Information System (INIS)

    Winkel, P. van den

    2000-01-01

    The Cyclotron Department of the VUB has three groups performing research in the field of target development, production of radionuclides and their application in nuclear medicine. 1. The Physics Group is busy on the optimization of beam parameters, on the determination of cross sections and on neutron spectrometry. 2. The Inorganic Radiochemistry Group performs research on solid target electroplating (Tl, Zn, Cd, Rh ... ), on optimisation of target carrier geometry and cooling and on automated PC-controlled radiochemistry (Tl-201, Ga-67, In-111) and recovery systems and the associated software written in Modula-2 and Visual Basic. 3. The Organic Radiochemistry Group develops new techniques for radiolabelling of organic molecules (fatty acids, neuroleptics, synthetic polypeptides...) useful in diagnostic and therapeutic nuclear medicine. All three groups take part in bulk productions of radionuclides

  4. Clinical targeting recombinant immunotoxins for cancer therapy

    Directory of Open Access Journals (Sweden)

    Li M

    2017-07-01

    Full Text Available Meng Li,1,* Zeng-Shan Liu,1,* Xi-Lin Liu,1,* Qi Hui,2,* Shi-Ying Lu,1 Lin-Lin Qu,1 Yan-Song Li,1 Yu Zhou,1 Hong-Lin Ren,1 Pan Hu1 1Key Laboratory of Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, China-Japan Union Hospital, The First Hospital, Jilin University, Changchun, 2School of Pharmacy, Wenzhou Medical University, Wenzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Recombinant immunotoxins (RITs are proteins that contain a toxin fused to an antibody or small molecules and are constructed by the genetic engineering technique. RITs can bind to and be internalized by cells and kill cancerous or non-cancerous cells by inhibiting protein synthesis. A wide variety of RITs have been tested against different cancers in cell culture, xenograft models, and human patients during the past several decades. RITs have shown activity in therapy of several kinds of cancers, but different levels of side effects, mainly related to vascular leak syndrome, were also observed in the treated patients. High immunogenicity of RITs limited their long-term or repeat applications in clinical cases. Recent advances in the design of immunotoxins, such as humanization of antibody fragment, PEGylation, and modification of human B- and T-cell epitopes, are overcoming the above mentioned problems, which predict the use of these immunotoxins as a potential therapeutic method to treat cancer patients. Keywords: targeted therapy, hematologic malignancies, solid tumors, vascular leak syndrome, immunogenicity 

  5. Diagnostic radionuclide imaging of amyloid: biological targeting by circulating human serum amyloid P component

    Energy Technology Data Exchange (ETDEWEB)

    Hawkins, P.N.; Lavender, J.P.; Myers, M.J.; Pepys, M.B.

    1988-06-25

    The specific molecular affinity of the normal plasma protein, serum amyloid P component (SAP), for all known types of amyloid fibrils was used to develop a new general diagnostic method for in-vivo radionuclide imaging of amyloid deposits. After intravenous injection of /sup 123/I-labelled purified human SAP there was specific uptake into amyloid deposits in all affected patients, 7 with systematic AL amyloid, 5 with AA amyloid, and 2 with ..beta../sub 2/M amyloid, in contrast to the complete absence of any tissue localisation in 5 control subjects. Distinctive high-resolution scintigraphic images, even of minor deposits in the carpal regions, bone marrow, or adrenals, were obtained. This procedure should yield much information on the natural history and the management of amyloidosis, the presence of which has hitherto been confirmed only by biopsy. Clearance and metabolic studies indicated that, in the presence of extensive amyloidosis, the rate of synthesis of SAP was greatly increased despite maintenance of normal plasma levels. Futhermore, once localised to amyloid deposits the /sup 123/I-SAP persisted for long periods and was apparently protected from its normal rapid degradation. These findings shed new light on the pathophysiology of amyloid and may have implications for therapeutic strategies based upon specific molecular targeting with SAP.

  6. Influence of androgen deprivation therapy on the uptake of PSMA-targeted agents: Emerging opportunities challenges

    Energy Technology Data Exchange (ETDEWEB)

    Bakht, Martin K.; Oh, So Won; Youn, Hye Won; Cheon, Gi Jeong; Kwak, Cheol; Kang, Keon Wook [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2017-09-15

    Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgen-deprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer.

  7. Influence of androgen deprivation therapy on the uptake of PSMA-targeted agents: Emerging opportunities challenges

    International Nuclear Information System (INIS)

    Bakht, Martin K.; Oh, So Won; Youn, Hye Won; Cheon, Gi Jeong; Kwak, Cheol; Kang, Keon Wook

    2017-01-01

    Prostate-specific membrane antigen (PSMA) is an attractive target for both diagnosis and therapy because of its high expression in the vast majority of prostate cancers. Development of small molecules for targeting PSMA is important for molecular imaging and radionuclide therapy of prostate cancer. Recent evidence implies that androgen-deprivation therapy increase PSMA-ligand uptake in some cases. The reported upregulations in PSMA-ligand uptake after exposure to second-generation antiandrogens such as enzalutamide and abiraterone might disturb PSMA-targeted imaging for staging and response monitoring of patients undergoing treatment with antiandrogen-based drugs. On the other hand, second-generation antiandrogens are emerging as potential endoradio-/chemosensitizers. Therefore, the enhancement of the therapeutic efficiency of PSMA-targeted theranostic methods can be listed as a new capability of antiandrogens. In this manuscript, we will present what is currently known about the mechanism of increasing PSMA uptake following exposure to antiandrogens. In addition, we will discuss whether these above-mentioned antiandrogens could play the role of endoradio-/chemosensitizers in combination with the well-established PSMA-targeted methods for pre-targeting of prostate cancer

  8. Proceedings of Soil Decon `93: Technology targeting radionuclides and heavy metals

    Energy Technology Data Exchange (ETDEWEB)

    1993-09-01

    The principal objective for convening this workshop was to exchange ideas and discuss with scientists and engineers methods for removing radionuclides and/or toxic metals from soils. Over the years there have been numerous symposia, conferences, and workshops directed at soil remediation. However, this may be the first where the scope was narrowed to the removal of radionuclides and toxic metals from soils. The intent was to focus on the separation processes controlling the removal of the radionuclide and/or metal from soil. Its purpose was not intended to be a soil washing/leaching workshop, but rather to identify a variety or combination of processes (chemical, physical, and biological) that can be used in concert with the applicable engineering approaches to decontaminate soils of radionuclides and toxic metals. Abstracts and visual aids used by the speakers of the workshop are presented in this document.

  9. Proceedings of Soil Decon '93: Technology targeting radionuclides and heavy metals

    International Nuclear Information System (INIS)

    1993-09-01

    The principal objective for convening this workshop was to exchange ideas and discuss with scientists and engineers methods for removing radionuclides and/or toxic metals from soils. Over the years there have been numerous symposia, conferences, and workshops directed at soil remediation. However, this may be the first where the scope was narrowed to the removal of radionuclides and toxic metals from soils. The intent was to focus on the separation processes controlling the removal of the radionuclide and/or metal from soil. Its purpose was not intended to be a soil washing/leaching workshop, but rather to identify a variety or combination of processes (chemical, physical, and biological) that can be used in concert with the applicable engineering approaches to decontaminate soils of radionuclides and toxic metals. Abstracts and visual aids used by the speakers of the workshop are presented in this document

  10. Experimental peptide receptor radionuclide therapy in radioiodine negative somatostatin receptor positive thyroid cancer

    International Nuclear Information System (INIS)

    Nilica, B.; Kroiss, A.; Putzer, D.; Uprimmy, C.; Warwitz, B.; Kendler, D.; Waitz, D.; Virgolini, I.

    2015-01-01

    Full text of publication follows. Purpose: This retrospective analysis evaluated the time to progression (TTP), progression free survival (PFS) and overall survival (OS) in patients with radioiodine negative thyroid cancer who had undergone peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTA-TATE, 177 Lu-DOTA-LAN, 90 Y-DOTA-TOC or 90 Y-DOTA-LAN after tumor progression. Methods: Data derived from twenty patients with either differentiated (n=15), anaplastic (n=1) or medullary (n=4) somatostatin receptor positive thyroid cancer who had received treatment with PRRT after tumor progression. TTP, PFS and OS were defined according to the clinical trial endpoints suggested by the FDA (Food and Drug Administration). Progressive disease was defined by sonography, FDG-PET, Ga-DOTA-TOC-PET, or CT (RECIST Criteria). Results: In 17 patients the median overall survival time after the first PRRT was 17.3 (range: 0.1 - 109.7) months. Three patients still alive are actually showing stable disease. The median of PFS in 20 Patients (6 with more than one PRRT-cycle or PRRT-substance) has been 10.9 (range: 0.1 - 44.0) months. The median TTP was 15.6 (range 4.4 to 29.2) months. Conclusion: PRRT appears to be useful in patients with somatostatin receptor positive but radioiodine negative thyroid cancer as a complementary palliative cytotoxic therapy. (authors)

  11. The study of parotid function with radionuclide imaging after radiation therapy in nasopharyngeal cancer

    International Nuclear Information System (INIS)

    Li Huanbin; Zhang Qi; Wang Ling; Wu Shixiu; Xie Congying

    2006-01-01

    Objective: To study the uptake and excretion function of parotid by radionuclide imaging after simultaneous modulated accelerated radiation therapy (SMART) in nasopharyngeal cancer. Methods: Forty-eight nasopharyngeal cancer cases, 38 of them were treated by SMART with 2.5 Gy/fraction at tumor and enlarged lymph node to a total dose of 70 Gy, and 2.0 Gy/fraction at subclinical foci and prophy laxtic area volume to a total dose of 56 Gy in 38 d. The other 10 cases were treated by traditional radiation therapy (RT). After treatment, all patients performed parotid imaging and both uptake index (UI) and excretion index (EI) after acid stimulation were calculated. Clinical manifestation such as grade of mouth dryness was also analyzed. Results: Average UI and EI in SMART group decreased 21.9% and 37.3% respectively, with 12 cases moderate and severe mouth dryness, whereas in traditional RT group, mean UI and El decreased 56.1% and 96.1% respectively, with 9 cases moderate and severe mouth dryness. There was significant difference between them (P<0.05). Conclusion: Parotid imaging is sensitive for monitoring parotid function, and it is also reliable to evaluate the safety of SMART to parotid.. (authors)

  12. Peptide receptor radionuclide therapy with {sup 90}Y-DOTATOC in recurrent meningioma

    Energy Technology Data Exchange (ETDEWEB)

    Bartolomei, Mirco; Bodei, Lisa; De Cicco, Concetta; Grana, Chiara Maria; Baio, Silvia Melania; Arico, Demetrio; Paganelli, Giovanni [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Cremonesi, Marta [European Institute of Oncology, Division of Medical Physics, Milan (Italy); Botteri, Edoardo [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Sansovini, Maddalena [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Radiometabolic Medicine Division, Meldola (Italy)

    2009-09-15

    Meningiomas are generally benign and in most cases surgery is curative. However, for high-grade histotypes or partially resected tumours, recurrence is fairly common. External beam radiation therapy (EBRT) is usually given in such cases but is not always effective. We assessed peptide receptor radionuclide therapy (PRRT) using {sup 90}Y-DOTATOC in a group of patients with meningioma recurring after standard treatments in all of whom somatostatin receptors were strongly expressed on meningioma cell surfaces. Twenty-nine patients with scintigraphically proven somatostatin subtype 2 receptor-positive meningiomas were enrolled: 14 had benign (grade I), 9 had atypical (grade II) and 6 had malignant (grade III) disease. Patients received intravenous {sup 90}Y-DOTATOC for 2-6 cycles for a cumulative dose in the range of 5-15 GBq. Clinical and neuroradiological evaluations were performed at baseline, during and after PRRT. The treatment was well tolerated in all patients. MRI 3 months after treatment completion showed disease stabilization in 19 of 29 patients (66%) and progressive disease in the remaining 10 (34%). Better results were obtained in patients with grade I meningioma than in those with grade II-III, with median time to progression (from beginning PRRT) of 61 months in the low-grade group and 13 months in the high-grade group. PRRT with {sup 90}Y-DOTATOC can interfere with the growth of meningiomas. The adjuvant role of this treatment, soon after surgery, especially in atypical and malignant histotypes, deserves further investigation. (orig.)

  13. Studies on the preparation of 109Pd and 111Ag by (n,γ) reactions on natural palladium for possible applications in radionuclide therapy

    International Nuclear Information System (INIS)

    Vimalnath, K.V.; Chirayil, Viju; Saha, Sujata

    2007-01-01

    Natural palladium on neutron activation provided two radionuclides viz 111 Ag and 109 Pd with attractive nuclear properties for use in radionuclide therapy applications in nuclear medicine. 109 Pd (t 1/2 13.7h, E βmax 1.03MeV) was produced by neutron activation of 108 Pd, while in the same target 111 Ag (t 1/2 7.45d, E βmax 1.04MeV) is formed by the beta decay of co-produced radioactive 111 Pd. Measured samples of palladium foils were neutron irradiated in Dhruva reactor for 7d at a flux of 9 x 10 13 n.cm -2 .s -1 . Radioactive palladium and silver were separated by ion-exchange chromatography over Dowex 1x8, 200-400 mesh size anion exchanger column. Radiochemical mixture of palladium and silver loaded in 10M HCl acid medium showed retention of palladium, while silver eluted out freely. The separated radionuclidically pure fractions of 109 Pd and 111 Ag activity were reconstituted as chloride and nitrate solutions respectively. About 133 GBq 109 Pd and 930 MBq of 111 Ag activity were produced from 100mg palladium. (author)

  14. Radionuclide therapy (radiation synovectomy) in rheumatology and orthopaedics; Nuklearmedizinische Therapie (Radiosynoviorthese) in Rheumatologie und Orthopaedie

    Energy Technology Data Exchange (ETDEWEB)

    Moedder, G. [Praxis fuer Nuklearmedizin, Koeln (Germany)

    1995-02-01

    An overview is given over those diseases being an indication for radiosynovectomy, especially inflammatory rheumatoid diseases and the activated arthrosis. In the diagnostic field of nuclear medicine arthrosonography and soft tissue scintigraphy of joints is absolutely therapy-relevant. Hints are offered, technique, results and problems are presented. Baker`s cyst and progressive state of rheumatoid arthritis are no contraindication against radiosynovectomy. (orig./VHE) [Deutsch] Es wird ein Ueberblick ueber die Erkrankungen, die eine Indikation zur Radiosynoviorthese darstellen, insbesondere entzuendlich-rheumatische Erkrankungen und die aktivierte Arthrose gegeben. An diagnostischen Verfahren sind fuer den Nuklearmediziner die Arthrosonographie und die Weichteilszintigraphie der Gelenke absolut therapierelevant. Hinweise werden hierzu gegeben, Technik, Ergebnisse, Probleme werden abgehandelt. So sind die Bakerzyste und ein fortgeschrittenes Stadium der chronischen Polyarthritis keineswegs eine Kontraindikation zur Radiosynoviorthese. (orig./VHE)

  15. Utility of γH2AX as a molecular marker of DNA double-strand breaks in nuclear medicine: applications to radionuclide therapy employing auger electron-emitting isotopes.

    Science.gov (United States)

    Mah, Li-Jeen; Orlowski, Christian; Ververis, Katherine; El-Osta, Assam; Karagiannis, Tom C

    2011-01-01

    There is an intense interest in the development of radiopharmaceuticals for cancer therapy. In particular, radiopharmaceuticals which involve targeting radionuclides specifically to cancer cells with the use of monoclonal antibodies (radioimmunotherapy) or peptides (targeted radiotherapy) are being widely investigated. For example, the ultra-short range Auger electron-emitting isotopes, which are discussed in this review, are being considered in the context of DNAtargeted radiotherapy. The efficient quantitative evaluation of the levels of damage caused by such potential radiopharmaceuticals is required for assessment of therapeutic efficacy and determination of relevant doses for successful treatment. The DNA double-strand break surrogate marker, γH2AX, has emerged as a useful biomonitor of damage and thus effectiveness of treatment, offering a highly specific and sensitive means of assessment. This review will cover the potential applications of γH2AX in nuclear medicine, in particular radionuclide therapy.

  16. DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours

    International Nuclear Information System (INIS)

    Zhang, Hanwen; Maecke, Helmut R.; Schuhmacher, Jochen; Eisenhut, Michael; Waser, Beatrice; Reubi, Jean Claude; Wild, Damian

    2007-01-01

    We aimed at designing and developing a novel bombesin analogue, DOTA-PEG 4 -BN(7-14) (DOTA-PESIN), with the goal of labelling it with 67/68 Ga and 177 Lu for diagnosis and radionuclide therapy of prostate and other human cancers overexpressing bombesin receptors. The 8-amino acid peptide bombesin (7-14) was coupled to the macrocyclic chelator DOTA via the spacer 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG 4 ). The conjugate was complexed with Ga(III) and Lu(III) salts. The GRP receptor affinity and the bombesin receptor subtype profile were determined in human tumour specimens expressing the three bombesin receptor subtypes. Internalisation and efflux studies were performed with the human GRP receptor cell line PC-3. Xenografted nude mice were used for biodistribution. [Ga III /Lu III ]-DOTA-PESIN showed good affinity to GRP and neuromedin B receptors but no affinity to BB3. [ 67 Ga/ 177 Lu]-DOTA-PESIN internalised rapidly into PC-3 cells whereas the efflux from PC-3 cells was relatively slow. In vivo experiments showed a high and specific tumour uptake and good retention of [ 67 Ga/ 177 Lu]-DOTA-PESIN. [ 67 Ga/ 177 Lu]-DOTA-PESIN highly accumulated in GRP receptor-expressing mouse pancreas. The uptake specificity was demonstrated by blocking tumour uptake and pancreas uptake. Fast clearance was found from blood and all non-target organs except the kidneys. High tumour-to-normal tissue ratios were achieved, which increased with time. PET imaging with [ 68 Ga]-DOTA-PESIN was successful in visualising the tumour at 1 h post injection. Planar scintigraphic imaging showed that the 177 Lu-labelled peptide remained in the tumour even 3 days post injection. The newly designed ligands have high potential with regard to PET and SPECT imaging with 68/67 Ga and targeted radionuclide therapy with 177 Lu. (orig.)

  17. Molecular targeting of gene therapy and radiotherapy

    International Nuclear Information System (INIS)

    Weichselbaum, R.R.; Kufe, D.W.; Advani, S.J.; Roizman, B.

    2001-01-01

    The full promise of gene therapy has been limited by the lack of specificity of vectors for tumor tissue as well as the lack of antitumor efficacy of transgenes encoded by gene delivery systems. In this paper we review our studies investigating two modifications of gene therapy combined with radiotherapy. The first investigations described include studies of radiation inducible gene therapy. In this paradigm, radio-inducible DNA sequences from the CarG elements of the Egr-1 promoter are cloned upstream of a cDNA encoding TNFa. The therapeutic gene (TNFa) is induced by radiation within the tumor microenvironment. In the second paradigm, genetically engineered herpes simplex virus (HSV-1) is induced by ionizing radiation to proliferate within the tumor volume. These modifications of radiotherapy and gene therapy may enhance the efficacy of both treatments

  18. Radiopharmacy requirements in the context of advances in radionuclide therapy (RNT)

    International Nuclear Information System (INIS)

    Ramamoorthy, N.

    2004-01-01

    Full text: The advances in the use of radiopharmaceutical products for radionuclide therapy (RNT) are accompanied by additional demands on the facilities and practices in hospital based and centralized radiopharmacies. In general, therapeutic radiopharmaceuticals meant for systemic administration should be preferably availed as ready-to-use products from a licensed source. Amongst the radionuclides for therapy being evaluated extensively, a few such as the generator produced 188 Re (T 1/2 17 h), would warrant additional formulation processing steps at the hospital end and it is required to institute appropriate validated protocols. 188 Re is eluted from a 188 W- 188 Re generator and is often used after post-elution concentration involving use of ion exchanger columns in tandem. The radiochemical purity of the final formulation e.g. 188 Re-HEDP, 188 Re-lipiodol, etc. and the breakthrough of the long-lived parent nuclide 188 W in 188 Re have to be reliably ascertained and certified for compliance with the stipulated standards. The equipment and other facilities required would depend on the nature and range of products handled. In the event of use of another important therapeutic radionuclide, 90 Y (T 1/2 64 h) (sourced from 90 Sr- 90 Y generator), a pure beta emitter, the assay of activity and the breakthrough of 90Sr in 90Y would involve using special techniques. Also, in view of the long half-life of the parent nuclides, 188 W (T 1/2 70 d) and 90 Sr (T 1/2 28.3 y), in turn, the shelf-life of the generators, greater care in aseptic practices in the operation and maintenance of the generators is essential to assure pharmaceutical safety. Reliable validated practices need to be evolved leading to establishing SOP for formulation, QC testing and certification, as well as institution of necessary calibration protocols. There can be differences in mandatory regulations depending on the national authorities/systems. Wherever, the licensing of the radiopharmacist and

  19. Release of patients after radionuclide therapy. With contributions from the [International Commission on Radiological Protection] ICRP

    International Nuclear Information System (INIS)

    2009-01-01

    The use of unsealed radiopharmaceuticals for treatment of disease is common practice worldwide. This approach was widely employed some years ago and, following a decline, there has recently been a resurgence of interest in it. The combination of newly accessible radionuclides, improved labelling technology and developments in biotechnology has resulted in more enthusiasm and a wider range of applications for this form of therapy. Radionuclide treatments are performed with either the patient admitted to hospital or as an outpatient only. The criteria to determine which approach is best vary considerably, and are not always closely linked with the well established standards of radiation protection practice. Safety issues for the patient, their family, associated carers, staff and the general public arise with either approach. The potential risks are from both external irradiation and contamination. The International Basic Safety Standards for Protection against Ionizing Radiation and for the Safety of Radiation Sources (BSS) specify the dose constraints and limits for all of these groups, and their more general provisions with respect to the as low as reasonably achievable principle and justification also apply. One way of managing exposures of the various groups is to control when patients are released from hospital. While they are in hospital, it is relatively easy to control exposure. Once they have returned to their family in the community, they must be advised on how to restrict the exposure of those people that they will come into contact with. Until recently, the International Commission on Radiological Protection (ICRP) did not provide specific advice in this area, and relied on the application of dose limits and constraints. However, regulators in some countries took a prescriptive approach, often using estimates of retained activity as a release criterion. These only loosely relate to dose limits. This publication attempts to bring newly available advice

  20. Successful neoadjuvant peptide receptor radionuclide therapy for an inoperable pancreatic neuroendocrine tumour

    Directory of Open Access Journals (Sweden)

    Tiago Nunes da Silva

    2018-04-01

    Full Text Available Non-functional pancreatic neuroendocrine tumours (NETs can present with advanced local or distant (metastatic disease limiting the possibility of surgical cure. Several treatment options have been used in experimental neoadjuvant settings to improve the outcomes in such cases. Peptide receptor radionuclide therapy (PPRT using beta emitting radiolabelled somatostatin analogues has been used in progressive pancreatic NETs. We report a 55-year-old female patient with a 12.8 cm pancreatic NET with significant local stomach and superior mesenteric vein compression and liver metastases. The patient underwent treatment with [177Lutetium-DOTA0,Tyr3]octreotate (177Lu-octreotate for the treatment of local and metastatic symptomatic disease. Six months after 4 cycles of 177lutetium-octreotate, resolution of the abdominal complaints was associated with a significant reduction in tumour size and the tumour was rendered operable. Histology of the tumour showed a 90% necrotic tumour with abundant hyalinized fibrosis and haemorrhage compatible with PPRT-induced radiation effects on tumour cells. This report supports that PPRT has a role in unresectable and metastatic pancreatic NET.

  1. Patient-specific dosimetry in peptide receptor radionuclide therapy: a clinical review

    International Nuclear Information System (INIS)

    Chalkia, M.T.; Stefanoyiannis, A.P.; Chatziioannou, S.N.; Efstathopoulos, E.P.; Round, W.H.; Nikiforidis, G.C.

    2015-01-01

    Neuroendocrine tumours (NETs) belong to a relatively rare class of neoplasms. Nonetheless, their prevalence has increased significantly during the last decades. Peptide receptor radionuclide therapy (PRRT) is a relatively new treatment approach for inoperable or metastasised NETs. The therapeutic effect is based on the binding of radiolabelled somatostatin analogue peptides with NETs’ somatostatin receptors, resulting in internal irradiation of tumours. Pre-therapeutic patient-specific dosimetry is essential to ensure that a treatment course has high levels of safety and efficacy. This paper reviews the methods applied for PRRT dosimetry, as well as the dosimetric results presented in the literature. Focus is given on data concerning the therapeutic somatostatin analogue radiopeptides 111 In-[DTPA o , D -Phe 1 ]-octreotide ( 111 In-DTPA-octreotide), 90 Y-[DOTA o ,Tyr 3 ]-octreotide ( 90 Y-DOTATOC) and 177 Lu-[DOTA o ,Tyr 3 ,Thr 8 ]-octreotide ( 177 Lu-DOTATATE). Following the Medical Internal Radiation Dose (MIRD) Committee formalism, dosimetric analysis demonstrates large interpatient variability in tumour and organ uptake, with kidneys and bone marrow being the critical organs. The results are dependent on the image acquisition and processing protocol, as well as the dosimetric imaging radiopharmaceutical.

  2. Targeted Radionuclide and Fluorescence Dual-modality Imaging of Cancer : Preclinical Advances and Clinical Translation

    NARCIS (Netherlands)

    Lutje, S.; Rijpkema, M.; Helfrich, W.; Oyen, W. J. G.; Boerman, O. C.

    2014-01-01

    In oncology, sensitive and reliable detection tumor tissue is crucial to prevent recurrences and to improve surgical outcome. Currently, extensive research is focused on the use of radionuclides as well as fluorophores to provide real-time guidance during surgery to aid the surgeon in the

  3. Peptide Receptor Radionuclide Therapy with (90)Y-DOTATOC and (177)Lu-DOTATOC in Advanced Neuroendocrine Tumors: Results from a Danish Cohort Treated in Switzerland

    DEFF Research Database (Denmark)

    Pfeifer, Andreas Klaus; Gregersen, Tine; Grønbæk, Henning

    2011-01-01

    Limited therapeutic options have highlighted the demand for new treatment modalities for patients with advanced neuroendocrine tumors (NET). Promising results of initial studies have warranted the implementation of peptide receptor radionuclide therapy (PRRT) in clinical practice. However, this t...

  4. Peptide receptor radionuclide therapy with Y-DOTATOC and (177)Lu-DOTATOC in advanced neuroendocrine tumors: results from a Danish cohort treated in Switzerland

    DEFF Research Database (Denmark)

    Pfeifer, Andreas Klaus; Gregersen, Tine; Grønbæk, Henning

    2011-01-01

    Limited therapeutic options have highlighted the demand for new treatment modalities for patients with advanced neuroendocrine tumors (NET). Promising results of initial studies have warranted the implementation of peptide receptor radionuclide therapy (PRRT) in clinical practice. However, this t...

  5. Inflammation as target in cancer therapy.

    Czech Academy of Sciences Publication Activity Database

    Marelli, G.; Sica, A.; Vannucci, Luca; Allavena, P.

    2017-01-01

    Roč. 35, August 2017 (2017), s. 57-65 ISSN 1471-4892 Institutional support: RVO:61388971 Keywords : cancer therapy * cancer-promoting inflammation * Tumour-Associated Macrophages Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 5.363, year: 2016

  6. Hitting the target with antithrombotic therapy.

    Science.gov (United States)

    Fritsma, Margaret G; Rodak, Bernadette F

    2007-05-01

    Thrombus treatment and prevention can be regulated by a number of intravenous or subcutaneous drugs, as well as oral warfarin. Many therapies require laboratory monitoring for efficacy and for detection of dangerous sequelae, such as bleeding, thrombosis, or heparin induced thrombocytopenia.

  7. Monte Carlo simulation of age-dependent radiation dose from alpha- and beta-emitting radionuclides to critical trabecular bone and bone marrow targets

    Science.gov (United States)

    Dant, James T.; Richardson, Richard B.; Nie, Linda H.

    2013-05-01

    Alpha (α) particles and low-energy beta (β) particles present minimal risk for external exposure. While these particles can induce leukemia and bone cancer due to internal exposure, they can also be beneficial for targeted radiation therapies. In this paper, a trabecular bone model is presented to investigate the radiation dose from bone- and marrow-seeking α and β emitters to different critical compartments (targets) of trabecular bone for different age groups. Two main issues are addressed with Monte Carlo simulations. The first is the absorption fractions (AFs) from bone and marrow to critical targets within the bone for different age groups. The other issue is the application of 223Ra for the radiotherapy treatment of bone metastases. Both a static model and a simulated bone remodeling process are established for trabecular bone. The results show significantly lower AFs from radionuclide sources in the bone volume to the peripheral marrow and the haematopoietic marrow for adults than for newborns and children. The AFs from sources on the bone surface and in the bone marrow to peripheral marrow and haematopoietic marrow also varies for adults and children depending on the energy of the particles. Regarding the use of 223Ra as a radionuclide for the radiotherapy of bone metastases, the simulations show a significantly higher dose from 223Ra and its progeny in forming bone to the target compartment of bone metastases than that from two other more commonly used β-emitting radiopharmaceuticals, 153Sm and 89Sr. There is also a slightly lower dose from 223Ra in forming bone to haematopoietic marrow than that from 153Sm and 89Sr. These results indicate a higher therapy efficiency and lower marrow toxicity from 223Ra and its progeny. In conclusion, age-related changes in bone dimension and cellularity seem to significantly affect the internal dose from α and β emitters in the bone and marrow to critical targets, and 223Ra may be a more efficient

  8. Quality of life assessment in radionuclide therapy: a feasibility study of the EORTC QLQ-C30 questionnaire in palliative 131I-lipiodol therapy

    International Nuclear Information System (INIS)

    Brans, B.; Lambert, B.; De Beule, E.; De Winter, F.; Dierckx, R.A.; Van Belle, S.; Van Vlierberghe, H.; De Hemptinne, B.

    2002-01-01

    The good tolerance of radionuclide therapy has frequently been proposed as a major advantage. This study explored the feasibility of using the EORTC QLQ-C30 questionnaire in palliative iodine-131 lipiodol therapy for hepatocellular carcinoma. Questionnaires were completed during interviews in which all symptoms, co-morbidity and medication were assessed at baseline within 1 week before 131 I-lipiodol therapy, and subsequently after 1 and 3 months, in 20 patients treated with locoregional, intra-arterial 131 I-lipiodol therapy with or without cisplatin. Principal observations were that (1) a number of important scales, i.e. overall quality of life, physical functioning and pain, worsened between 0 and 3 months after 131 I-lipiodol therapy, irrespective of tumour response, and (2) the occurrence of clinical side-effects was associated with a negative impact on quality of life and physical functioning 1 and 3 months after 131 I-lipiodol. The QLQ-C30 can be regarded as a feasible method for quality of life assessment in 131 I-lipiodol therapy for hepatocellular carcinoma and possibly in other radionuclide therapies. These observations should be related to the impact of other treatment modalities on quality of life. (orig.)

  9. Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2017-12-01

    deprivation therapy (ADT) or androgen receptor (AR) pathway inhibition (ARPI) but eventually develops into lethal castration resistance prostate cancer ...AWARD NUMBER: W81XWH-14-1-0553 TITLE: Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer PRINCIPAL INVESTIGATOR: Martin Gleave...Siah2 as Novel Therapy for Metastatic Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0553 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Martin Gleave 5d

  10. Targeting the Thioredoxin System for Cancer Therapy.

    Science.gov (United States)

    Zhang, Junmin; Li, Xinming; Han, Xiao; Liu, Ruijuan; Fang, Jianguo

    2017-09-01

    Thioredoxin (Trx) and thioredoxin reductase (TrxR) are essential components of the Trx system which plays pivotal roles in regulating multiple cellular redox signaling pathways. In recent years TrxR/Trx have been increasingly recognized as an important modulator of tumor development, and hence targeting TrxR/Trx is a promising strategy for cancer treatment. In this review we first discuss the structural details of TrxR, the functions of the Trx system, and the rational of targeting TrxR/Trx for cancer treatment. We also highlight small-molecule TrxR/Trx inhibitors that have potential anticancer activity and review their mechanisms of action. Finally, we examine the challenges of developing TrxR/Trx inhibitors as anticancer agents and perspectives for selectively targeting TrxR/Trx. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Immunological targeting of cytomegalovirus for glioblastoma therapy

    OpenAIRE

    Nair, Smita K; Sampson, John H; Mitchell, Duane A

    2014-01-01

    Human cytomegalovirus (CMV) is purportedly present in glioblastoma (GBM) while absent from the normal brain, making CMV antigens potentially ideal immunological anti-GBM targets. We recently demonstrated that patient-derived CMV pp65-specific T cells are capable of recognizing and killing autologous GBM tumor cells. This data supports CMV antigen-directed immunotherapies against GBM.

  12. Bacterial proteases: targets for diagnostics and therapy

    NARCIS (Netherlands)

    Kaman, W.E.; Hays, J.P.; Endtz, H.P.; Bikker, F.J.

    2014-01-01

    Proteases are essential for the proliferation and growth of bacteria, and are also known to contribute to bacterial virulence. This makes them interesting candidates as diagnostic and therapeutic targets for infectious diseases. In this review, the authors discuss the most recent developments and

  13. Intravenous streptokinase therapy in acute myocardial infarction: Assessment of therapy effects by quantitative 201Tl myocardial imaging (including SPECT) and radionuclide ventriculography

    International Nuclear Information System (INIS)

    Koehn, H.; Bialonczyk, C.; Mostbeck, A.; Frohner, K.; Unger, G.; Steinbach, K.

    1984-01-01

    To evaluate a potential beneficial effect of systemic streptokinase therapy in acute myocardial infarction, 36 patients treated with streptokinase intravenously were assessed by radionuclide ventriculography and quantitative 201 Tl myocardial imaging (including SPECT) in comparison with 18 conventionally treated patients. Patients after thrombolysis had significantly higher EF, PFR, and PER as well as fewer wall motion abnormalities compared with controls. These differences were also observed in the subset of patients with anterior wall infarction (AMI), but not in patients with inferior wall infarction (IMI). Quantitative 201 Tl imaging demonstrated significantly smaller percent myocardial defects and fewer pathological stress segments in patients with thrombolysis compared with controls. The same differences were also found in both AMI and IMI patients. Our data suggest a favorable effect of intravenous streptokinase on recovery of left ventricular function and myocardial salvage. Radionuclide ventriculography and quantitative 201 Tl myocardial imaging seem to be reliable tools for objective assessment of therapy effects. (orig.)

  14. Release criteria for patients having undergone radionuclide therapy and criteria for their crossing the state border of the Russian Federation

    International Nuclear Information System (INIS)

    Zvonova, I.; Balonov, M.; Golikov, V.

    2011-01-01

    By means of a conservative dosimetry model, the values of operational radiological criteria for patients released from hospital-residual activity in a body and dose rate near the patient's body-are substantiated based on the effective dose limit of 5 mSv for persons helping the patient or living with him and 1 mSv for other adults and children. Two sets of operative criteria for radionuclides 125 I, 131 I, 153 Sm and 188 Re used in Russia for radionuclide therapy were derived. Release criteria for 125 I well differ from such values in other countries because in this work absorption of 125 I low-energy photon radiation in the patient was taken into account. When a patient having undergone radionuclide therapy crosses the frontier of Russia, high-sensitivity devices for radiation control at the custom can detect the patient. A simplified radiological assessment of the patient was suggested aimed at provision of radiation safety for patient companions in transport. (authors)

  15. Hepatocarcinoma: from pathogenic mechanisms to target therapy

    Directory of Open Access Journals (Sweden)

    Luigi Manzione

    2011-12-01

    Full Text Available Hepatocellular carcinoma (HCC is among the most prevalent and lethal cancers worldwide. It is currently estimated that there are 14,000–18,000 new cases of hepatocellular carcinoma in the United States each year. It is often difficult to identify individuals at risk for HCC. The main associated diseases are chronic hepatitis B and chronic hepatitis C viral infections. While a significant number of potential mutations have been generated including p53 and Insulin-like Growth Factor, our understanding of the molecular mechanisms driving the genesis and progression of HCC remain limited. HCC screening is recommended in high-risk patients. High-risk patients include virtually all patients with cirrhosis and some HBV-infected patients irrespective of cirrhosis (>40 years in men and >50 years in women. A diagnostic approach to HCC has been developed incorporating serology, cytohistology, and radiological characteristics. A precise staging of the disease may help decide on prognosis as well as choice of therapy with the greatest survival potential. Liver transplantation, in theory, is the optimal therapeutic option for HCC; it simultaneously removes the tumor and underlying cirrhosis thus minimizing the risk of HCC recurrence. When it is impossible for this to be performed, percutaneous ablation, chemoembolization, chemotherapy and the newer molecular therapies can be used. Sorafenib is the only drug registered today for the treatment of advanced HCC.

  16. Somatostatin receptor gene therapy combined with targeted therapy with radiolabeled octreotide: a new treatment for liver metastases.

    NARCIS (Netherlands)

    A. Mearadji (Amir); W.A.P. Breeman (Wouter); L.J. Hofland (Leo); R.L. Marquet (Richard); J. Jeekel (Hans); E.P. Krenning (Eric); C.H.J. van Eijck (Casper); P.M. van Koetsveld (Peter)

    2002-01-01

    textabstractOBJECTIVE: To evaluate the effect of peptide receptor radionuclide therapy (PRRT) on somatostatin receptor (SSR)-transfected colon carcinoma cells in a rat liver metastases model.SUMMARY BACKGROUND DATA: Previously the authors have shown highly effective therapy with

  17. Design of a cryogenic deuterium gas target for neutron therapy

    International Nuclear Information System (INIS)

    Kuchnir, F.T.; Waterman, F.M.; Forsthoff, H.; Skaggs, L.S.; Vander Arend, P.C.; Stoy, S.

    1976-01-01

    A cryogenic deuterium gas target operating at 80 0 K and 10 atm pressure has been designed for use with a small cyclotron; the D(d,n) reaction is used to produce a neutron beam suitable for radiation therapy. The target is cooled by circulation of the gas in a closed loop between the target and an external heat exchanger immersed in liquid nitrogen

  18. Targeted therapy in lung and breast cancer: a big deal

    OpenAIRE

    Caffarra, Cristina

    2015-01-01

    Great strides have been done in treating cancer. For decades, the hallmark of medical treatment for cancer has been intravenous cytotoxic chemotherapy which targets all dividing cells. In the last ten years the identification of different driver oncogenic mutations has allowed the development of targeted drugs. Targeted cancer therapies are based on the use of drugs that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. The ...

  19. Tumour control probability (TCP) for non-uniform activity distribution in radionuclide therapy

    International Nuclear Information System (INIS)

    Uusijaervi, Helena; Bernhardt, Peter; Forssell-Aronsson, Eva

    2008-01-01

    Non-uniform radionuclide distribution in tumours will lead to a non-uniform absorbed dose. The aim of this study was to investigate how tumour control probability (TCP) depends on the radionuclide distribution in the tumour, both macroscopically and at the subcellular level. The absorbed dose in the cell nuclei of tumours was calculated for 90 Y, 177 Lu, 103m Rh and 211 At. The radionuclides were uniformly distributed within the subcellular compartment and they were uniformly, normally or log-normally distributed among the cells in the tumour. When all cells contain the same amount of activity, the cumulated activities required for TCP = 0.99 (A-tilde TCP=0.99 ) were 1.5-2 and 2-3 times higher when the activity was distributed on the cell membrane compared to in the cell nucleus for 103m Rh and 211 At, respectively. TCP for 90 Y was not affected by different radionuclide distributions, whereas for 177 Lu, it was slightly affected when the radionuclide was in the nucleus. TCP for 103m Rh and 211 At were affected by different radionuclide distributions to a great extent when the radionuclides were in the cell nucleus and to lesser extents when the radionuclides were distributed on the cell membrane or in the cytoplasm. When the activity was distributed in the nucleus, A-tilde TCP=0.99 increased when the activity distribution became more heterogeneous for 103m Rh and 211 At, and the increase was large when the activity was normally distributed compared to log-normally distributed. When the activity was distributed on the cell membrane, A-tilde TCP=0.99 was not affected for 103m Rh and 211 At when the activity distribution became more heterogeneous. A-tilde TCP=0.99 for 90 Y and 177 Lu were not affected by different activity distributions, neither macroscopic nor subcellular

  20. Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy

    Directory of Open Access Journals (Sweden)

    Wiebke Sihver

    2014-03-01

    Full Text Available The epidermal growth factor receptor (EGFR has evolved over years into a main molecular target for the treatment of different cancer entities. In this regard, the anti-EGFR antibody cetuximab has been approved alone or in combination with: (a chemotherapy for treatment of colorectal and head and neck squamous cell carcinoma and (b with external radiotherapy for treatment of head and neck squamous cell carcinoma. The conjugation of radionuclides to cetuximab in combination with the specific targeting properties of this antibody might increase its therapeutic efficiency. This review article gives an overview of the preclinical studies that have been performed with radiolabeled cetuximab for imaging and/or treatment of different tumor models. A particularly promising approach seems to be the treatment with therapeutic radionuclide-labeled cetuximab in combination with external radiotherapy. Present data support an important impact of the tumor micromilieu on treatment response that needs to be further validated in patients. Another important challenge is the reduction of nonspecific uptake of the radioactive substance in metabolic organs like liver and radiosensitive organs like bone marrow and kidneys. Overall, the integration of diagnosis, treatment and monitoring as a theranostic approach appears to be a promising strategy for improvement of individualized cancer treatment.

  1. Country report: Brazil. Development of Radiopharmaceuticals Based on {sup 188}Re and {sup 90}Y for Radionuclide Therapy at IPEN-CNEN/SP

    Energy Technology Data Exchange (ETDEWEB)

    Osso, Jr., J. A.; Barrio, G.; Dias, C. R.B.R.; Brambilla, T. P.; Dantas, D. M.; Suzuki, K. N.; Barboza, M. F.S.; Bortoleti, E.; Fukumori, N. T.; Mengatti, J. [Radiopharmacy Center – Institute of Energetic and Nuclear Research – IPE N-CNEN/SP, São Paulo – Brazil (Brazil)

    2010-07-01

    The overall objective of this CRP is to develop radiopharmaceuticals for targeted therapy using {sup 188}Re and {sup 90}Y and to study the performance of generators with long lived parent radionuclides as well as to validate the QC control procedures for estimating the purity of generator eluents. The CRP is expected to enhance the capability in production of {sup 90}Y and {sup 188}Re radiopharmaceuticals to meet the increasing demand of therapeutic products for clinical applications, in particular in Brazil. In this period efforts were made towards the assembling of {sup 90}Sr-{sup 90}Y generators, quality control of {sup 90}Y, the labelling of DMSA(V) and anti-CD20 with {sup 188}Re and the labelling of Hydroxiapatite(HA) with {sup 90}Y. (author)

  2. Novel targeted therapies for cancer cachexia.

    Science.gov (United States)

    Argilés, Josep M; López-Soriano, Francisco Javier; Stemmler, Britta; Busquets, Sílvia

    2017-07-27

    Anorexia and metabolic alterations are the main components of the cachectic syndrome. Glucose intolerance, fat depletion, muscle protein catabolism and other alterations are involved in the development of cancer cachexia, a multi-organ syndrome. Nutritional approach strategies are not satisfactory in reversing the cachectic syndrome. The aim of the present review is to deal with the recent therapeutic targeted approaches that have been designed to fight and counteract wasting in cancer patients. Indeed, some promising targeted therapeutic approaches include ghrelin agonists, selective androgen receptor agonists, β-blockers and antimyostatin peptides. However, a multi-targeted approach seems absolutely essential to treat patients affected by cancer cachexia. This approach should not only involve combinations of drugs but also nutrition and an adequate program of physical exercise, factors that may lead to a synergy, essential to overcome the syndrome. This may efficiently reverse the metabolic changes described above and, at the same time, ameliorate the anorexia. Defining this therapeutic combination of drugs/nutrients/exercise is an exciting project that will stimulate many scientific efforts. Other aspects that will, no doubt, be very important for successful treatment of cancer wasting will be an optimized design of future clinical trials, together with a protocol for staging cancer patients in relation to their degree of cachexia. This will permit that nutritional/metabolic/pharmacological support can be started early in the course of the disease, before severe weight loss occurs. Indeed, timing is crucial and has to be taken very seriously when applying the therapeutic approach. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

  3. Radiolabelled peptides: New radiopharmaceuticals for targeted therapy

    International Nuclear Information System (INIS)

    Chinol, M.

    2001-01-01

    Radiolabelled peptides have been the focus of an increasing interest by the nuclear medicine community within the last few years. This has mainly been due to successful development of one of these peptides, somatostatin, as a tool to visualise various pathologic conditions known to express a high number of somatostatin receptors. Somatostatin receptors have been identified in different tumours such as neuroendocrine tumours, tumours of the central nervous system, breast, lung and lymphatic tissue. These observations served as the biomolecular basis for the clinical use of radiolabelled somatostatin analogs, which are at present of great interest for diagnostic and therapeutic applications. A promising somatostatin analogue, DOTA-D-Phe 1 -Ty 3 -octreotide, named DOTATOC, has shown favourable biodistribution and high affinity binding to SSTR2 and SSTR5, high hydrophilicity and ease of labelling and stability with 111 In and 90 Y. A clinical trial aimed at evaluating the biodistribution and dosimetry of DOTATOC radiolabelled with 111 In, in anticipation of therapy trials with 90 Y-DOTATOC in patients was undertaken. 111 In-DOTATOC showed favourable pharmacokinetics (fast blood clearance and urinary excretion) and biodistribution, and high affinity to tumours expressing somatostatin receptors (thus, a high residence time in tumour). These results are promising for therapy trials with 90 Y-DOTAOC, for which radiation dosimetry appears acceptable for normal organs (including the red marrow). Moreover, labelling conditions of DOTATOC with 90 Y has been optimised in order to achieve labelling yields of more than 98% and specific activities of greater than 60 GBq (1.6 Ci)/μmol. (author)

  4. Molecular targeted therapies of aggressive thyroid cancer

    Directory of Open Access Journals (Sweden)

    Silvia Martina eFerrari

    2015-11-01

    Full Text Available Differentiated thyroid carcinomas (DTC that arise from follicular cells account > 90% of thyroid cancer (TC [papillary thyroid cancer (PTC 90%, follicular thyroid cancer (FTC 10%], while medullary thyroid cancer (MTC accounts < 5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts towards the development of new drugs.Several genetic alterations in different molecular pathways in TC have been shown in the last decades, associated with TC development and progression. Rearranged during transfection (RET/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the above-mentioned molecular pathways involved in growth, angiogenesis, local and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC and anaplastic thyroid cancer (ATC, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds, and to personalize

  5. Biomarkers and Targeted Therapy in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Fataneh Karandish

    2016-01-01

    Full Text Available Pancreatic ductal adenocarcinoma (PDAC constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%–3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

  6. Biomarkers and Targeted Therapy in Pancreatic Cancer.

    Science.gov (United States)

    Karandish, Fataneh; Mallik, Sanku

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of pancreatic cancers. PDAC is a complex and devastating disease with only 1%-3% survival rate in five years after the second stage. Treatment of PDAC is complicated due to the tumor microenvironment, changing cell behaviors to the mesenchymal type, altered drug delivery, and drug resistance. Considering that pancreatic cancer shows early invasion and metastasis, critical research is needed to explore different aspects of the disease, such as elaboration of biomarkers, specific signaling pathways, and gene aberration. In this review, we highlight the biomarkers, the fundamental signaling pathways, and their importance in targeted drug delivery for pancreatic cancers.

  7. Comparison on the production of radionuclides in 1.4 GeV proton irradiated LBE targets of different thickness

    CERN Document Server

    Maiti, Moumita; Mendonça, Tania M; Stora, Thierry; Lahiri, Susanta

    2014-01-01

    This is the first report on the inventory of radionuclides produced in 1.4 GeV proton induced reaction on Lead-Bismuth Eutectic (LBE) targets. LBE targets of 6 mm diameter and 1 to 8 mm lengths were irradiated with 1.4 GeV protons. The radionuclides ranging from Be-7 (53.12 days) to Po-207 (5.8 h) were identified in the samples with the help of time resolved gamma-ray spectroscopy. However, there is no signature of formation of At radioisotopes, which can be produced by the interaction of secondary particles, typical for thick targets.

  8. Apoptosis and Molecular Targeting Therapy in Cancer

    Science.gov (United States)

    Hassan, Mohamed; Watari, Hidemichi; AbuAlmaaty, Ali; Ohba, Yusuke; Sakuragi, Noriaki

    2014-01-01

    Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction. PMID:25013758

  9. Targeted therapy for esophagogastric cancers: a review

    Directory of Open Access Journals (Sweden)

    Khattak MA

    2012-05-01

    Full Text Available Muhammad A Khattak,1 Hilary L Martin,2 Christos S Karapetis1,31Flinders Medical Centre, Adelaide, South Australia; 2Calvary Hospital, Adelaide, SA, Australia; 3Flinders University, Adelaide, SA, AustraliaAbstract: The incidence of esophagogastric cancers is increasing rapidly in the Western population. Despite better understanding of the biology and intense research in the treatment of these cancers, the long-term survival remains poor both in the locally advanced and metastatic settings. The addition of combined modality strategies has resulted in modest improvement in 5-year survival rates. A number of biologic agents targeting epidermal-derived growth factor receptor, vascular endothelial derived growth factor and its receptor, and mammalian target of rapamycin (mTOR are being currently evaluated in Phase II and III clinical trials. Some of these, like trastuzumab, cetuximab, and bevacizumab, have shown promising results. This review provides a brief overview of the recent developments in biologic agents for the treatment of esophagogastric cancers.Keywords: adenocarcinoma, squamous cell carcinoma, VEGF, trastuzumab, Her2- positive EGC

  10. Neoadjuvant targeted therapy in patients with renal cell carcinoma

    Directory of Open Access Journals (Sweden)

    B. Ya. Alekseev

    2015-01-01

    Full Text Available Cytoreductive nephrectomy as an independent option in patients with metastatic renal cell carcinoma (mRCC cannot be considered as the only effective method, with rare exception, of a few patients with solitary metastases. Cytoreductive nephrectomy is now part of a multimodal approach encompassing surgical treatment and systemic drug therapy. Many retrospective and two prospective studies have demonstrated that it is expedient to perform cytoreductive nephrectomy. Immunotherapy should not be used as preoperatively in the era of cytokine therapy for mRCC due to that fact that it has no impact on primary tumor. In the current targeted therapy era, many investigators have concentrated attentionon the role of neoadjuvant targeted therapy for the treatment of patients with both localized and locally advanced mRCC. The potential benefits of neoadjuvant therapy for localized and locally advanced RCC include to make surgery easier and to increase the possibility of organsparing treatment, by decreasing the stage of primary tumor and the size of tumors. The possible potential advantages of neoadjuvant targeted therapy in patients with mRCC include prompt initiation of necessary systemic therapy; identification of patients with primary refractory tumors; and a preoperative reduction in the stage of primary tumor. Numerous retrospective and some prospective phase II studies have shown that neoadjuvant targeted therapy in patients with localized and locally advanced RCC is possible and tolerable and surgical treatment after neoadjuvant targeted therapy is safe and executable with a low incidence of complications. If neoadjuvant therapy is to be performed, it should be done within 2–4 months before surgery. Sorafenib and sunitinib are now most tested and suitable for neoadjuvant targeted therapy. Sorafenib is a more preferred drug due to its shorter half-life and accordingly to the possibility of discontinuing the drug immediately prior to

  11. A Monte Carlo study on {sup 223}Ra imaging for unsealed radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Akihiko, E-mail: takahsr@hs.med.kyushu-u.ac.jp; Miwa, Kenta; Sasaki, Masayuki [Faculty of Medical Sciences, Department of Health Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Baba, Shingo [Department of Clinical Radiology, Kyushu University Hospital, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

    2016-06-15

    Purpose: Radium-223 ({sup 223}Ra), an α-emitting radionuclide, is used in unsealed radionuclide therapy for metastatic bone tumors. The demand for qualitative {sup 223}Ra imaging is growing to optimize dosimetry. The authors simulated {sup 223}Ra imaging using an in-house Monte Carlo simulation code and investigated the feasibility and utility of {sup 223}Ra imaging. Methods: The Monte Carlo code comprises two modules, HEXAGON and NAI. The HEXAGON code simulates the photon and electron interactions in the tissues and collimator, and the NAI code simulates the response of the NaI detector system. A 3D numeric phantom created using computed tomography images of a chest phantom was installed in the HEXAGON code. {sup 223}Ra accumulated in a part of the spine, and three x-rays and 19 γ rays between 80 and 450 keV were selected as the emitted photons. To evaluate the quality of the {sup 223}Ra imaging, the authors also simulated technetium-99m ({sup 99m}Tc) imaging under the same conditions and compared the results. Results: The sensitivities of the three photopeaks were 147 counts per unit of source activity (cps MBq{sup −1}; photopeak: 84 keV, full width of energy window: 20%), 166 cps MBq{sup −1} (154 keV, 15%), and 158 cps MBq{sup −1} (270 keV, 10%) for a low-energy general-purpose (LEGP) collimator, and those for the medium-energy general-purpose (MEGP) collimator were 33, 13, and 8.0 cps MBq{sup −1}, respectively. In the case of {sup 99m}Tc, the sensitivity was 55 cps MBq{sup −1} (141 keV, 20%) for LEGP and 52 cps MBq{sup −1} for MEGP. The fractions of unscattered photons of the total photons reflecting the image quality were 0.09 (84 keV), 0.03 (154 keV), and 0.02 (270 keV) for the LEGP collimator and 0.41, 0.25, and 0.50 for the MEGP collimator, respectively. Conversely, this fraction was approximately 0.65 for the simulated {sup 99m}Tc imaging. The sensitivity with the LEGP collimator appeared very high. However, almost all of the counts were

  12. Inflammation as target in cancer therapy.

    Science.gov (United States)

    Marelli, Giulia; Sica, Antonio; Vannucci, Luca; Allavena, Paola

    2017-08-01

    Cells of the innate immunity infiltrating tumour tissues promote, rather than halt, cancer cell proliferation and distant spreading. Tumour-Associated Macrophages (TAMs) are abundantly present in the tumour milieu and here trigger and perpetrate a state of chronic inflammation which ultimately supports disease development and contributes to an immune-suppressive environment. Therapeutic strategies to limit inflammatory cells and their products have been successful in pre-clinical tumour models. Early clinical trials with specific cytokine and chemokine inhibitors, or with strategies designed to target TAMs, are on their way in different solid malignancies. Partial clinical responses and stabilization of diseases were observed in some patients, in the absence of significant toxicity. These encouraging results open new perspectives of combination treatments aimed at reducing cancer-promoting inflammation to maximize the anti-tumour efficacy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Production and separation of terbium-149 and terbium-152 for targeted cancer therapy

    International Nuclear Information System (INIS)

    Sarkar, S.; Leigh, J.

    1997-01-01

    This work reports the production and separation of useful quantities of 149 , 152 Tb from natural neodymium ( nat Nd) and 141 Pr for in vitro studies by bombarding the targets with 12 C projectiles. The physical, chemical and nuclear properties of radionuclides determine their efficacy in therapy and diagnosis. Tb-149 is an alpha-emitter with a half-life of 4.1h and 152 Tb is a positron emitter with a half-life of 17.5 h. Both of the isotopes have suitable gamma emission with good branching ratio suggesting their application to diagnosis apart from therapy. Alpha-emitters are effective in controlling cancer because of their short range and high Relative Biological Effectiveness. Long-lived positron emitters are effective in studying physiological function in positron emission tomography other than therapy. The aim of this work is to optimise the production and carrier free separation of terbium. Because of the presence of other stable isotopes in nat Nd, a number of other lanthanides are produced by secondary reactions during the production of terbium. In order to remove the secondary products, α-hydroxyisobutyric acid of pH 5 was used as eluent. satisfactory separation of terbium was achieved and demonstrate that useful quantities of 144,152 Tb can be produced by Tandem accelerator from 141 Pr and nat Nd targets

  14. Targeted therapy in the treatment of malignant gliomas

    Directory of Open Access Journals (Sweden)

    Rimas V Lukas

    2009-05-01

    Full Text Available Rimas V Lukas1, Adrienne Boire2, M Kelly Nicholas1,2 1Department of Neurology; 2Department of Medicine, University of Chicago, Chicago, IL, USAAbstract: Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In addition, we will discuss strategies that target the extracellular matrix in which these cells reside as well as angiogenesis, a process emerging as central to tumor development and growth. Finally, we will briefly touch on the role of neural stem cells as both potential targets as well as delivery vectors for other therapies. Interdependence between these varied pathways, both in maintaining health and in causing disease, is clear. Thus, attempts to easily classify some targeted therapies are problematic.Keywords: glioma, EGFR, mTOR, HDAC, Ras, angiogenesis

  15. Familial breast cancer - targeted therapy in secondary and tertiary prevention.

    Science.gov (United States)

    Kast, Karin; Rhiem, Kerstin

    2015-02-01

    The introduction of an increasing number of individualized molecular targeted therapies into clinical routine mirrors their importance in modern cancer prevention and treatment. Well-known examples for targeted agents are the monoclonal antibody trastuzumab and the selective estrogen receptor modulator tamoxifen. The identification of an unaltered gene in tumor tissue in colon cancer (KRAS) is a predictor for the patient's response to targeted therapy with a monoclonal antibody (cetuximab). Targeted therapy for hereditary breast and ovarian cancer has become a reality with the approval of olaparib for platin-sensitive late relapsed BRCA-associated ovarian cancer in December 2014. This manuscript reviews the status quo of poly-ADP-ribose polymerase inhibitors (PARPi) in the therapy of breast and ovarian cancer as well as the struggle for carboplatin as a potential standard of care for triple-negative and, in particular, BRCA-associated breast cancer. Details of the mechanism of action with information on tumor development are provided, and an outlook for further relevant research is given. The efficacy of agents against molecular targets together with the identification of an increasing number of cancer-associated genes will open the floodgates to a new era of treatment decision-making based on molecular tumor profiles. Current clinical trials involving patients with BRCA-associated cancer explore the efficacy of the molecular targeted therapeutics platinum and PARPi.

  16. Recent advances in targeted drug therapy for hepatocellular carcinoma

    Directory of Open Access Journals (Sweden)

    FAN Yongqiang

    2018-02-01

    Full Text Available More and more clinical trials have proved the efficacy of targeted drugs in the treatment of hepatocellular carcinoma (HCC. With the development of science and technology, more and more targeted drugs have appeared. In recent years, targeted drugs such as regorafenib and ramucirumab have shown great potential in related clinical trials. In addition, there are ongoing clinical trials for second-line candidate drugs, such as c-Met inhibitors tivantinib and cabozantinib and a VEGFR-2 inhibitor ramucirumab. This article summarizes the advances in targeted drug therapy for HCC and related trial data, which provides a reference for further clinical trials and treatment.

  17. Target volumes in gastric cancer radiation therapy

    International Nuclear Information System (INIS)

    Caudry, M.; Maire, J.P.; Ratoanina, J.L.; Escarmant, P.

    2001-01-01

    The spread of gastric adenocarcinoma may follow three main patterns: hemato-genic, lymphatic and intraperitoneal. A GTV should be considered in preoperative or exclusive radiation therapy. After non-radical surgery, a 'residual GTV' will be defined with the help of the surgeon. The CTV encompasses three intricated volumes. a) A 'tumor bed' volume. After radical surgery, local recurrences appear as frequent as distant metastases. The risk depends upon the depth of parietal invasion and the nodal status. Parietal infiltration may extend beyond macroscopic limits of the tumor, especially in dinitis plastica. Therefore this volume will include: the tumor and the remaining stomach or their 'bed of resection', a part of the transverse colon, the duodenum, the pancreas and the troncus of the portal vein. In postoperative RT, this CTV also includes the jejuno-gastric or jejuno-esophageal anastomosis. b) A peritoneal volume. For practical purposes, two degrees of spread must be considered: (1) contiguous microscopic extension from deeply invasive T3 and T4 tumors, that remain amenable to local sterilization with doses of 45-50 Gy, delivered in a CTV including the peritoneal cavity at the level of the gastric bed, and under the parietal incision; (2) true 'peritoneal carcinomatosis', with widespread seeds, where chemotherapy (systemic or intraperitoneal) is more appropriate. c) A lymphatic volume including the lymph node groups 1 to 16 of the Japanese classification. This volume must encompass the hepatic pedicle and the splenic hilum. In proximal tumors, it is possible to restrict the lover part of the CTV to the lymphatic volume, and therefore to avoid irradiation of large intestinal and renal volumes. In distal and proximal tumors, involvement of resection margins is of poor prognosis -a radiation boost must be delivered at this level. The CTV in tumors of the cardia should encompass the lover part of the thoracic esophagus and the corresponding posterior mediastinum. In

  18. The folate receptor as a molecular target for tumor-selective radionuclide delivery

    International Nuclear Information System (INIS)

    Ke, C.-Y.; Mathias, Carla J.; Green, Mark A.

    2003-01-01

    The cell-membrane folate receptor is a potential molecular target for tumor-selective drug delivery, including radiolabeled folate-chelate conjugates for diagnostic imaging. We review here some background on the folate receptor as tumor-associated molecular target for drug delivery, and briefly survey the literature on tumor-targeting with radiolabeled folate-chelate conjugates

  19. Personalized {sup 177}Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: a simulation study

    Energy Technology Data Exchange (ETDEWEB)

    Del Prete, Michela; Buteau, Francois-Alexandre; Beauregard, Jean-Mathieu [Laval Univ., QC (Canada). Dept. of Radiology and Nuclear Medicine, and Cancer Research Center; CHU de Quebec - Laval Univ., QC (Canada). Dept. of Medical Imaging, and Oncology Branch of Research Center

    2017-08-15

    Peptide receptor radionuclide therapy (PRRT) with {sup 177}Lu-octreotate is commonly administered at empiric, fixed amounts of injected radioactivity (IA). This results in highly variable absorbed doses to critical organs and suboptimal treatment of most patients. The primary aims of this study were to design a personalized PRRT (P-PRRT) protocol based on dosimetry, and to perform a simulation of this protocol in a retrospective cohort of patients with neuroendocrine tumours, in order to assess the potential of P-PRRT to safely increase the absorbed dose to the tumour during a four-cycle induction course. Thirty-six patients underwent 122 fixed-IA {sup 177}Lu-octreotate PRRT cycles with quantitative SPECT/CT-based dosimetry. Twenty-two patients completed a four-cycle induction course (29.6 ± 2.4 GBq cumulative IA), with kidney, bone marrow and maximum tumour absorbed doses of 16.2 ± 5.5, 1.3 ± 0.8, and 114 ± 66 Gy, respectively. We simulated a P-PRRT regime in which the renal absorbed dose per IA was predicted by the body surface area and glomerular filtration rate for the first cycle, and by renal dosimetry of the previous cycle(s) for the following cycles. Personalized IA was adjusted at each cycle in order to reach the prescribed renal absorbed dose of 23 Gy over four cycles (with a 25-50% reduction when renal or bone marrow function was impaired). Simulated IA and absorbed doses were based on actual patient characteristics, laboratory values and absorbed doses per IA delivered at each cycle. In the P-PRRT regime, cumulative IA could have been increased to 43.7 ± 16.5 GBq over four induction cycles (10.9 ± 5.0 GBq per cycle), yielding cumulative kidney, bone marrow and maximum tumour absorbed doses of 21.5 ± 2.5, 1.63 ± 0.61, and 163.4 ± 85.9 Gy, respectively. This resulted in an average 1.48-fold increase in cumulative maximum tumour absorbed dose over empiric PRRT (range, 0.68-2.64-fold; P = 0.0013). By standardizing the renal absorbed dose delivered

  20. Targeted alpha therapy using Radium-223: From physics to biological effects.

    Science.gov (United States)

    Marques, I A; Neves, A R; Abrantes, A M; Pires, A S; Tavares-da-Silva, E; Figueiredo, A; Botelho, M F

    2018-05-25

    With the advance of the use of ionizing radiation in therapy, targeted alpha therapy (TAT) has assumed an important role around the world. This kind of therapy can potentially reduce side effects caused by radiation in normal tissues and increased destructive radiobiological effects in tumor cells. However, in many countries, the use of this therapy is still in a pioneering phase. Radium-223 ( 223 Ra), an alpha-emitting radionuclide, has been the first of its kind to be approved for the treatment of bone metastasis in metastatic castration-resistant prostate cancer. Nevertheless, the interaction mechanism and the direct effects of this radiopharmaceutical in tumor cells are not fully understood neither characterized at a molecular level. In fact, the ways how TAT is linked to radiobiological effects in cancer is not yet revised. Therefore, this review introduces some physical properties of TAT that leads to biological effects and links this information to the hallmarks of cancer. The authors also collected the studies developed with 223 Ra to correlate with the three categories reviewed - properties of TAT, 5 R's of radiobiology and hallmarks of cancer- and with the promising future to this radiopharmaceutical. Copyright © 2018 Elsevier Ltd. All rights reserved.

  1. New perspectives on biological HDL-targeted therapies

    OpenAIRE

    Muthuramu, Ilayaraja; Amin, Md Ruhul; De Geest, Bart

    2017-01-01

    According to a modified high-density lipoprotein (HDL) hypothesis, improving HDL function will lead to a decrease of coronary events. The stringent requirement for proving or refuting this hypothesis is that the causal pathway between the therapeutic intervention and a clinically meaningful endpoint obligatory passes through HDL. Infusion therapy of reconstituted HDL particles and human apolipoprotein A-I gene transfer are biological HDL-targeted therapies that are distinguished by HDL specif...

  2. Oligonucleotide Aptamers: New Tools for Targeted Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Hongguang Sun

    2014-01-01

    Full Text Available Aptamers are a class of small nucleic acid ligands that are composed of RNA or single-stranded DNA oligonucleotides and have high specificity and affinity for their targets. Similar to antibodies, aptamers interact with their targets by recognizing a specific three-dimensional structure and are thus termed “chemical antibodies.” In contrast to protein antibodies, aptamers offer unique chemical and biological characteristics based on their oligonucleotide properties. Hence, they are more suitable for the development of novel clinical applications. Aptamer technology has been widely investigated in various biomedical fields for biomarker discovery, in vitro diagnosis, in vivo imaging, and targeted therapy. This review will discuss the potential applications of aptamer technology as a new tool for targeted cancer therapy with emphasis on the development of aptamers that are able to specifically target cell surface biomarkers. Additionally, we will describe several approaches for the use of aptamers in targeted therapeutics, including aptamer-drug conjugation, aptamer-nanoparticle conjugation, aptamer-mediated targeted gene therapy, aptamer-mediated immunotherapy, and aptamer-mediated biotherapy.

  3. SFACTOR: a computer code for calculating dose equivalent to a target organ per microcurie-day residence of a radionuclide in a source organ

    International Nuclear Information System (INIS)

    Dunning, D.E. Jr.; Pleasant, J.C.; Killough, G.G.

    1977-11-01

    A computer code SFACTOR was developed to estimate the average dose equivalent S (rem/μCi-day) to each of a specified list of target organs per microcurie-day residence of a radionuclide in source organs in man. Source and target organs of interest are specified in the input data stream, along with the nuclear decay information. The SFACTOR code computes components of the dose equivalent rate from each type of decay present for a particular radionuclide, including alpha, electron, and gamma radiation. For those transuranic isotopes which also decay by spontaneous fission, components of S from the resulting fission fragments, neutrons, betas, and gammas are included in the tabulation. Tabulations of all components of S are provided for an array of 22 source organs and 24 target organs for 52 radionuclides in an adult

  4. SFACTOR: a computer code for calculating dose equivalent to a target organ per microcurie-day residence of a radionuclide in a source organ

    Energy Technology Data Exchange (ETDEWEB)

    Dunning, D.E. Jr.; Pleasant, J.C.; Killough, G.G.

    1977-11-01

    A computer code SFACTOR was developed to estimate the average dose equivalent S (rem/..mu..Ci-day) to each of a specified list of target organs per microcurie-day residence of a radionuclide in source organs in man. Source and target organs of interest are specified in the input data stream, along with the nuclear decay information. The SFACTOR code computes components of the dose equivalent rate from each type of decay present for a particular radionuclide, including alpha, electron, and gamma radiation. For those transuranic isotopes which also decay by spontaneous fission, components of S from the resulting fission fragments, neutrons, betas, and gammas are included in the tabulation. Tabulations of all components of S are provided for an array of 22 source organs and 24 target organs for 52 radionuclides in an adult.

  5. Targeting therapy-resistant cancer stem cells by hyperthermia

    DEFF Research Database (Denmark)

    Oei, A L; Vriend, L E M; Krawczyk, P M

    2017-01-01

    Eradication of all malignant cells is the ultimate but challenging goal of anti-cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy-resistant. A subpopulation of cancer cells, the cancer stem cells...... are limited. Here, we argue that hyperthermia - a therapeutic approach based on local heating of a tumour - is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising...

  6. Individualized therapies in colorectal cancer: KRAS as a marker for response to EGFR-targeted therapy

    Directory of Open Access Journals (Sweden)

    Li Kuiyuan

    2009-04-01

    Full Text Available Abstract Individualized therapies that are tailored to a patient's genetic composition will be of tremendous value for treatment of cancer. Recently, Kirsten ras (KRAS status has emerged as a predictor of response to epidermal growth factor receptor (EGFR targeted therapies. In this article, we will discuss targeted therapies for colorectal cancers (CRC based on EGFR signaling pathway and review published data about the potential usefulness of KRAS as a biological marker for response to these therapies. Results from relevant studies published since 2005 and unpublished results presented at national meetings were retrieved and summarized. These studies reflected response (or lack of response to EGFR-targeted therapies in patients with metastatic CRC as a function of KRAS status. It has become clear that patients with colorectal cancer whose tumor has an activating mutation in KRAS do not respond to monoclonal antibody therapies targeting EGFR. It should now become a standard practice that any patients being considered for EGFR targeted therapies have their tumors tested for KRAS status and only those with wild-type KRAS being offered such therapies.

  7. Palliative nephrectomy until targeted therapy of disseminated kidney cancer patients

    Directory of Open Access Journals (Sweden)

    A. V. Klimov

    2015-01-01

    Full Text Available Objective: to assess the role of palliative nephrectomy in disseminated kidney cancer patients planned to undergo targeted antiangiogenic treatment.Subjects and methods. The investigation included data on 83 patients with T1-4N0 / +M1 disseminated renal cell carcinoma (RCC who had received at least 2 targeted therapy cycles in 2009 to 2011. In 48 (57.8 % patients, the treatment was preceded by palliative nephrectomy that was not carried out in 35 (42.2 %. Before starting targeted therapy, all the cases were confirmed to be diagnosed with clear cell RCC, with a sarcomatoid component being in 7 (8.4 % patients. The median follow-up of all the patients was 21 (12–36 months.Results. The unremoved affected kidney in disseminated kidney cancer patients receiving targeted antiangiogenic therapy is an independent factor for the poor prognosis of progression-free (odds ratio (OR, 2.4; 95 % confidence interval (CI, 1.2–4.7 and overall (OR, 2.8; 95 % CI, 1.3–6.3 survival. Palliative nephrectomy does not improve the prognosis in patients with a low somatic status, the N+ category, and metastases into the bones and nonregional lymph nodes.Conclusion. Palliative nephrectomy in the selected patients with disseminated kidney cancer on targeted antiangiogenic therapy increases progression-free and overall survival.

  8. Metastatic gastric cancer – focus on targeted therapies

    Directory of Open Access Journals (Sweden)

    Meza-Junco J

    2012-06-01

    Full Text Available Judith Meza-Junco, Michael B SawyerDepartment of Oncology, Cross Cancer Institute, Edmonton, Alberta, CanadaAbstract: Gastric cancer (GC is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.Keywords: gastric cancer, targeted therapy, antiangiogenesis drugs, anti-EGFR drugs

  9. Heart failure—potential new targets for therapy

    Science.gov (United States)

    Nabeebaccus, Adam; Zheng, Sean; Shah, Ajay M.

    2016-01-01

    Abstract Introduction/background Heart failure is a major cause of cardiovascular morbidity and mortality. This review covers current heart failure treatment guidelines, emerging therapies that are undergoing clinical trial, and potential new therapeutic targets arising from basic science advances. Sources of data A non-systematic search of MEDLINE was carried out. International guidelines and relevant reviews were searched for additional articles. Areas of agreement Angiotensin-converting enzyme inhibitors and beta-blockers are first line treatments for chronic heart failure with reduced left ventricular function. Areas of controversy Treatment strategies to improve mortality in heart failure with preserved left ventricular function are unclear. Growing points Many novel therapies are being tested for clinical efficacy in heart failure, including those that target natriuretic peptides and myosin activators. A large number of completely novel targets are also emerging from laboratory-based research. Better understanding of pathophysiological mechanisms driving heart failure in different settings (e.g. hypertension, post-myocardial infarction, metabolic dysfunction) may allow for targeted therapies. Areas timely for developing research Therapeutic targets directed towards modifying the extracellular environment, angiogenesis, cell viability, contractile function and microRNA-based therapies. PMID:27365454

  10. Targeted therapies for diarrhea-predominant irritable bowel syndrome

    OpenAIRE

    Olden, Kevin W

    2012-01-01

    Kevin W OldenDepartment of Medicine, St Joseph's Hospital and Medical Center, Phoenix, AZ, USAAbstract: Irritable bowel syndrome (IBS) causes gastrointestinal symptoms such as abdominal pain, bloating, and bowel pattern abnormalities, which compromise patients' daily functioning. Common therapies address one or two IBS symptoms, while others offer wider symptom control, presumably by targeting pathophysiologic mechanisms of IBS. The aim of this targeted literature review was t...

  11. Targeted Therapies for Myeloma and Metastatic Bone Cancers

    Science.gov (United States)

    2010-09-01

    Cancer J Clin 2003; 53:5. Kasugai S, Fujisawa R, Waki Y, Miyamoto K, Ohya K 2000 Selective drug delivery system to bone: small peptide (Asp)6...page. Bone targeted nanoparticles , bone cancer myeloma, mice studies, PLGA , Biodegradable materials. Targeted Therapies for Myeloma and Metastatic Bone...present results from this program at talk at the Particles 2006 –Medical/Biochemical Diagnostic , Pharmaceutical, and Drug Delivery . 3

  12. DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Hanwen; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Department of Radiology, Basel (Switzerland); Schuhmacher, Jochen; Eisenhut, Michael [German Cancer Research Centre, Department of Radiopharmaceutical Chemistry, Heidelberg (Germany); Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, P.O. Box 62, Berne (Switzerland); Wild, Damian [University Hospital, Clinic and Institute of Nuclear Medicine, Department of Radiology, Basel (Switzerland)

    2007-08-15

    We aimed at designing and developing a novel bombesin analogue, DOTA-PEG{sub 4}-BN(7-14) (DOTA-PESIN), with the goal of labelling it with {sup 67/68}Ga and {sup 177}Lu for diagnosis and radionuclide therapy of prostate and other human cancers overexpressing bombesin receptors. The 8-amino acid peptide bombesin (7-14) was coupled to the macrocyclic chelator DOTA via the spacer 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG{sub 4}). The conjugate was complexed with Ga(III) and Lu(III) salts. The GRP receptor affinity and the bombesin receptor subtype profile were determined in human tumour specimens expressing the three bombesin receptor subtypes. Internalisation and efflux studies were performed with the human GRP receptor cell line PC-3. Xenografted nude mice were used for biodistribution. [Ga{sup III}/Lu{sup III}]-DOTA-PESIN showed good affinity to GRP and neuromedin B receptors but no affinity to BB3. [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN internalised rapidly into PC-3 cells whereas the efflux from PC-3 cells was relatively slow. In vivo experiments showed a high and specific tumour uptake and good retention of [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN. [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN highly accumulated in GRP receptor-expressing mouse pancreas. The uptake specificity was demonstrated by blocking tumour uptake and pancreas uptake. Fast clearance was found from blood and all non-target organs except the kidneys. High tumour-to-normal tissue ratios were achieved, which increased with time. PET imaging with [{sup 68}Ga]-DOTA-PESIN was successful in visualising the tumour at 1 h post injection. Planar scintigraphic imaging showed that the {sup 177}Lu-labelled peptide remained in the tumour even 3 days post injection. The newly designed ligands have high potential with regard to PET and SPECT imaging with {sup 68/67}Ga and targeted radionuclide therapy with {sup 177}Lu. (orig.)

  13. New Molecular Targets of Anticancer Therapy - Current Status and Perspectives.

    Science.gov (United States)

    Zajac, Marianna; Muszalska, Izabela; Jelinska, Anna

    2016-01-01

    Molecularly targeted anticancer therapy involves the use of drugs or other substances affecting specific molecular targets that play a part in the development, progression and spread of a given neoplasm. By contrast, the majority of classical chemotherapeutics act on all rapidly proliferating cells, both healthy and cancerous ones. Target anticancer drugs are designed to achieve a particular aim and they usually act cytostatically, not cytotoxically like classical chemotherapeutics. At present, more than 300 biological molecular targets have been identified. The proteins involved in cellular metabolism include (among others) receptor proteins, signal transduction proteins, mRNA thread matrix synthesis proteins participating in neoplastic transformation, cell cycle control proteins, functional and structural proteins. The receptor proteins that are targeted by currently used anticancer drugs comprise the epithelial growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor(VEGFR). Target anticancer drugs may affect extracellular receptor domains (antibodies) or intracellular receptor domains (tyrosine kinase inhibitors). The blocking of the mRNA thread containing information about the structure of oncogenes (signal transduction proteins) is another molecular target of anticancer drugs. That type of treatment, referred to as antisense therapy, is in clinical trials. When the synthesis of genetic material is disturbed, in most cases the passage to the next cycle phase is blocked. The key proteins responsible for the blockage are cyclines and cycline- dependent kinases (CDK). Clinical trials are focused on natural and synthetic substances capable of blocking various CDKs. The paper discusses the molecular targets and chemical structure of target anticancer drugs that have been approved for and currently applied in antineoplastic therapy together with indications and contraindications for their

  14. Nanobody-photosensitizer conjugates for targeted photodynamic therapy

    NARCIS (Netherlands)

    Heukers, Raimond; van Bergen en Henegouwen, P; Oliveira, Sabrina

    2014-01-01

    Photodynamic therapy (PDT) induces cell death through light activation of a photosensitizer (PS). Targeted delivery of PS via monoclonal antibodies has improved tumor selectivity. However, these conjugates have long half-lives, leading to relatively long photosensitivity in patients. In an attempt

  15. Auger radiation targeted into DNA: a therapy perspective

    International Nuclear Information System (INIS)

    Buchegger, Franz; Perillo-Adamer, Florence; Bischof Delaloye, Angelika; Dupertuis, Yves M.

    2006-01-01

    Auger electron emitters that can be targeted into DNA of tumour cells represent an attractive systemic radiation therapy goal. In the situation of DNA-associated decay, the high linear energy transfer (LET) of Auger electrons gives a high relative biological efficacy similar to that of α particles. In contrast to α radiation, however, Auger radiation is of low toxicity when decaying outside the cell nucleus, as in cytoplasm or outside cells during blood transport. The challenge for such therapies is the requirement to target a high percentage of all cancer cells. An overview of Auger radiation therapy approaches of the past decade shows several research directions and various targeting vehicles. The latter include hormones, peptides, halogenated nucleotides, oligonucleotides and internalising antibodies. Here, we will discuss the basic principles of Auger electron therapy as compared with vector-guided α and β radiation. We also review some radioprotection issues and briefly present the main advantages and disadvantages of the different targeting modalities that are under investigation. (orig.)

  16. Auger radiation targeted into DNA: a therapy perspective

    Energy Technology Data Exchange (ETDEWEB)

    Buchegger, Franz [University Hospital of Lausanne CHUV, Service of Nuclear Medicine, Lausanne (Switzerland); University Hospital of Lausanne, Service of Nuclear Medicine, Lausanne (Switzerland); Perillo-Adamer, Florence; Bischof Delaloye, Angelika [University Hospital of Lausanne CHUV, Service of Nuclear Medicine, Lausanne (Switzerland); Dupertuis, Yves M. [University Hospital of Geneva, Service of Nutrition, Geneva (Switzerland)

    2006-11-15

    Auger electron emitters that can be targeted into DNA of tumour cells represent an attractive systemic radiation therapy goal. In the situation of DNA-associated decay, the high linear energy transfer (LET) of Auger electrons gives a high relative biological efficacy similar to that of {alpha} particles. In contrast to {alpha} radiation, however, Auger radiation is of low toxicity when decaying outside the cell nucleus, as in cytoplasm or outside cells during blood transport. The challenge for such therapies is the requirement to target a high percentage of all cancer cells. An overview of Auger radiation therapy approaches of the past decade shows several research directions and various targeting vehicles. The latter include hormones, peptides, halogenated nucleotides, oligonucleotides and internalising antibodies. Here, we will discuss the basic principles of Auger electron therapy as compared with vector-guided {alpha} and {beta} radiation. We also review some radioprotection issues and briefly present the main advantages and disadvantages of the different targeting modalities that are under investigation. (orig.)

  17. Preclinical Evaluation of a Novel 177Lu- Radiopharmaceutical Based on Bombesin Structure for Prostate Tumor Diagnosis and Radionuclide Therapy

    International Nuclear Information System (INIS)

    Pujatti, P.B.; Santos, J.S.; Mengatti, J.; Araujo, E.B. de; Suzuki, M.F.; Soares, C.R.J.

    2009-01-01

    Prostate cancer is the most frequently diagnosed cancer in men in Brazil. Treatment options have varied, but once the tumor has metastasized, treatment become less effective and the cancer can progresses to a hormone refractory state characterized by high morbidity and mortality. Bombesin (BBN) receptors - in particular, the gastrin-releasing peptide (GRP) receptor - have been shown to be massively overexpressed in several human tumors types, including prostate cancer, and could be an alternative as target for its treatment by radionuclide therapy (RNT). A large number of BBN analogs had already been synthesized for this purpose and have shown to reduce tumor growth in mice. Nevertheless, most of the studied analogs exhibit high abdominal accumulation, especially in pancreas. This abdominal accumulation may represent a problem in clinical use of radiolabeled bombesin analogs probably due to serious side effects to patients. The goal of the present work was to radiolabel a novel peptide based on bombesin structure - DOTA-X-BBN(6-14), where X is a spacer of six aminoacids. - with lutetium-177, a β- emitter with optimal physical characteristics for RNT of small tumors and metastases, and to evaluate its in vitro and in vivo properties in Balb-c and Nude mice bearing prostate tumor (PC-3) xenografts. Preliminary studies were done to determine the best labeling conditions of BBNp6 and both ITLC and HPLC were applied to evaluate the radiochemical purity of the preparations. The stability of the radiolabeled peptide was assayed either after storing at 4 o C or incubation in human plasma at 37 deg. C. Biodistribution, pharmacokinetics, whole body and scintigraphic studies were performed in both healthy Balb-c and xenografted Nude mice, in order to characterize the biological properties of labeled peptide. In addition, the specificity of labeled bombesin derivative targeting to PC-3 tumor cells was analysed by in vivo competition assays. In vitro studies involved the

  18. Targeted therapies in the treatment of urothelial cancers.

    Science.gov (United States)

    Aragon-Ching, Jeanny B; Trump, Donald L

    2017-07-01

    Progress has been slow in systemic management of locally advanced and metastatic bladder cancer over the past 20 years. However, the recent approval of immunotherapy with atezolizumab and nivolumab for second-line salvage therapy may usher in an era of more rapid improvement. Systemic treatment is suboptimal and is an area of substantial unmet medical need. The recent findings from The Cancer Genome Atlas project revealed promising pathways that may be amenable to targeted therapies. Promising results with treatment using vascular endothelial growth factor inhibitors such as ramucirumab, sunitinib or bevacizumab, and human epidermal growth factor receptor 2 targeted therapies, epidermal growth factor receptor inhibitors, and fibroblast growth factor receptor inhibitors, are undergoing clinical trials and are discussed later. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Pancreatic Cancer Gene Therapy: From Molecular Targets to Delivery Systems

    Energy Technology Data Exchange (ETDEWEB)

    Fillat, Cristina, E-mail: cristina.fillat@crg.es; Jose, Anabel; Ros, Xavier Bofill-De; Mato-Berciano, Ana; Maliandi, Maria Victoria; Sobrevals, Luciano [Programa Gens i Malaltia, Centre de Regulació Genòmica-CRG, UPF, Parc de Recerca Biomedica de Barcelona-PRBB and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona (Spain)

    2011-01-18

    The continuous identification of molecular changes deregulating critical pathways in pancreatic tumor cells provides us with a large number of novel candidates to engineer gene-targeted approaches for pancreatic cancer treatment. Targets—both protein coding and non-coding—are being exploited in gene therapy to influence the deregulated pathways to facilitate cytotoxicity, enhance the immune response or sensitize to current treatments. Delivery vehicles based on viral or non-viral systems as well as cellular vectors with tumor homing characteristics are a critical part of the design of gene therapy strategies. The different behavior of tumoral versus non-tumoral cells inspires vector engineering with the generation of tumor selective products that can prevent potential toxic-associated effects. In the current review, a detailed analysis of the different targets, the delivery vectors, the preclinical approaches and a descriptive update on the conducted clinical trials are presented. Moreover, future possibilities in pancreatic cancer treatment by gene therapy strategies are discussed.

  20. Why Targeted Therapies are Necessary for Systemic Lupus Erythematosus

    Science.gov (United States)

    Durcan, Laura; Petri, Michelle

    2016-01-01

    Systemic lupus erythematosus (SLE) continues to have important morbidity and accelerated mortality despite therapeutic advances. Targeted therapies offer the possibility of improved efficacy with fewer side-effects. Current management strategies rely heavily on non-specific immunosuppressive agents. Prednisone, in particular, is responsible for a considerable burden of later organ damage. There are a multitude of diverse mechanisms of disease activity, immunogenic abnormalities and clinical manifestations to take into consideration in SLE. Many targeted agents with robust mechanistic pre-clinical data and promising early phase studies have ultimately been disappointing in phase III randomized controlled studies. Recent efforts have focused on B cell therapies, in particular given the success of belimumab in clinical trials, with limited success. We remain optimistic regarding other specific therapies being evaluated including interferon alpha blockade. It is likely that in SLE, given the heterogeneity of the population involved, precision medicine is needed, rather than expecting that any single biologic will be universally effective. PMID:27497251

  1. RAPID AUTOMATED RADIOCHEMICAL ANALYZER FOR DETERMINATION OF TARGETED RADIONUCLIDES IN NUCLEAR PROCESS STREAMS

    International Nuclear Information System (INIS)

    O'Hara, Matthew J.; Durst, Philip C.; Grate, Jay W.; Egorov, Oleg; Devol, Timothy A.

    2008-01-01

    Some industrial process-scale plants require the monitoring of specific radionuclides as an indication of the composition of their feed streams or as indicators of plant performance. In this process environment, radiochemical measurements must be fast, accurate, and reliable. Manual sampling, sample preparation, and analysis of process fluids are highly precise and accurate, but tend to be expensive and slow. Scientists at Pacific Northwest National Laboratory (PNNL) have assembled and characterized a fully automated prototype Process Monitor instrument which was originally designed to rapidly measure Tc-99 in the effluent streams of the Waste Treatment Plant at Hanford, WA. The system is capable of a variety of tasks: extraction of a precise volume of sample, sample digestion/analyte redox adjustment, column-based chemical separations, flow-through radiochemical detection and data analysis/reporting. The system is compact, its components are fluidically inter-linked, and analytical results can be immediately calculated and electronically reported. It is capable of performing a complete analytical cycle in less than 15 minutes. The system is highly modular and can be adapted to a variety of sample types and analytical requirements. It exemplifies how automation could be integrated into reprocessing facilities to support international nuclear safeguards needs

  2. Chromatin-regulating proteins as targets for cancer therapy

    International Nuclear Information System (INIS)

    Oike, Takahiro; Ogiwara, Hideaki; Kohno, Takashi; Amornwichet, Napapat; Nakano, Takashi

    2014-01-01

    Chromatin-regulating proteins represent a large class of novel targets for cancer therapy. In the context of radiotherapy, acetylation and deacetylation of histones by histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in the repair of DNA double-strand breaks generated by ionizing irradiation, and are therefore attractive targets for radiosensitization. Small-molecule inhibitors of HATs (garcinol, anacardic acid and curcumin) and HDACs (vorinostat, sodium butyrate and valproic acid) have been shown to sensitize cancer cells to ionizing irradiation in preclinical models, and some of these molecules are being tested in clinical trials, either alone or in combination with radiotherapy. Meanwhile, recent large-scale genome analyses have identified frequent mutations in genes encoding chromatin-regulating proteins, especially in those encoding subunits of the SWI/SNF chromatin-remodeling complex, in various human cancers. These observations have driven researchers toward development of targeted therapies against cancers carrying these mutations. DOT1L inhibition in MLL-rearranged leukemia, EZH2 inhibition in EZH2-mutant or MLL-rearranged hematologic malignancies and SNF5-deficient tumors, BRD4 inhibition in various hematologic malignancies, and BRM inhibition in BRG1-deficient tumors have demonstrated promising anti-tumor effects in preclinical models, and these strategies are currently awaiting clinical application. Overall, the data collected so far suggest that targeting chromatin-regulating proteins is a promising strategy for tomorrow's cancer therapy, including radiotherapy and molecularly targeted chemotherapy. (author)

  3. Therapeutic radionuclides: Making the right choice

    International Nuclear Information System (INIS)

    Srivastava, S.C.

    1996-01-01

    Recently, there has been a resurgence of interest in nuclear medicine therapeutic procedures. Using unsealed sources for therapy is not a new concept; it has been around since the beginnings of nuclear medicine. Treatment of thyroid disorders with radioiodine is a classic example. The availability of radionuclides with suitable therapeutic properties for specific applications, as well as methods for their selective targeting to diseased tissue have, however, remained the main obstacles for therapy to assume a more widespread role in nuclear medicine. Nonetheless, a number of new techniques that have recently emerged, (e.g., tumor therapy with radiolabeled monoclonal antibodies, treatment of metastatic bone pain, etc.) appear to have provided a substantial impetus to research on production of new therapeutic radionuclides. Although there are a number of new therapeutic approaches requiring specific radionuclides, only selected broad areas will be used as examples in this article

  4. Validation of an amino-acid-based radionuclide therapy plus external beam radiotherapy in heterotopic glioblastoma models

    Energy Technology Data Exchange (ETDEWEB)

    Israel, Ina [Department of Nuclear Medicine, University of Wuerzburg, D-97080 Wuerzburg (Germany); Blass, Georg [Department of Radiotherapy and Radiooncology, Saarland University Medical Center, Homburg (Germany); Reiners, Christoph [Department of Nuclear Medicine, University of Wuerzburg, D-97080 Wuerzburg (Germany); Samnick, Samuel, E-mail: samnick_s@klinik.uni-wuerzburg.d [Department of Nuclear Medicine, University of Wuerzburg, D-97080 Wuerzburg (Germany)

    2011-05-15

    Background and purpose: Malignant gliomas represent a major therapeutic challenge because no efficient treatment is currently available. p-[{sup 131}I]iodo-L-phenylalanine ([{sup 131}I]IPA) is a glioma avid radiopharmaceutical that demonstrated antiproliferative and tumoricidal effects in gliomas. The present study validated the therapeutic efficiency of [{sup 131}I]IPA combined with external beam radiotherapy in experimental gliomas. Materials and methods: Glioma cells derived from the primary human A1207, T5135, Tx3868 and M059K glioblastoma cell lines or rat F98 glioma cell line were treated with various doses of [{sup 131}I]IPA, external photon irradiation (RT) or combined [{sup 131}I]IPA/RT treatment. Responsiveness of glioma cells to the different therapy modalities was investigated at 24, 48 and 72 h after treatments by trypan blue, WST-1 assay, propidium iodide and bisbenzimide staining as well as by clonogenic assay. In addition, the therapy-induced DNA damage and repair were evaluated using phosphorylated histone H2AX ({gamma}-H2AX). In vivo, the effectiveness of the combination treatment was validated in human Tx3868 and A1207 glioblastoma xenografts in CD1 nu/nu mice and RNU rats. Results: In vitro, the combination treatment resulted in a greater than additive increase in cytotoxic effect in glioma cell lines. Cell survival rate following a treatment with 1.0 {mu}Ci (37 kBq) of [{sup 131}I]IPA amounted to 70%{+-}15% and 60%{+-}10% after 48 and 72 h, respectively, and decreased under 20% after additional RT with 5 Gy. At higher RT doses, cell survival rate decreased below 5%. As a measure of DNA double-strand break, nuclear {gamma}-H2AX foci were determined as a function of time. Within 24 h, the number of {gamma}-H2AX foci per cell was significantly greater after combined modality compared with the individual treatments. In vivo, when combined with RT, the radionuclide therapy with [{sup 131}I]IPA resulted in an extended tumor growth delay, a reduction

  5. Design criteria for a high energy Compton Camera and possible application to targeted cancer therapy

    Science.gov (United States)

    Conka Nurdan, T.; Nurdan, K.; Brill, A. B.; Walenta, A. H.

    2015-07-01

    The proposed research focuses on the design criteria for a Compton Camera with high spatial resolution and sensitivity, operating at high gamma energies and its possible application for molecular imaging. This application is mainly on the detection and visualization of the pharmacokinetics of tumor targeting substances specific for particular cancer sites. Expected high resolution (animals with a human tumor xenograft which is one of the first steps in evaluating the potential utility of a candidate gene. The additional benefit of high sensitivity detection will be improved cancer treatment strategies in patients based on the use of specific molecules binding to cancer sites for early detection of tumors and identifying metastasis, monitoring drug delivery and radionuclide therapy for optimum cell killing at the tumor site. This new technology can provide high resolution, high sensitivity imaging of a wide range of gamma energies and will significantly extend the range of radiotracers that can be investigated and used clinically. The small and compact construction of the proposed camera system allows flexible application which will be particularly useful for monitoring residual tumor around the resection site during surgery. It is also envisaged as able to test the performance of new drug/gene-based therapies in vitro and in vivo for tumor targeting efficacy using automatic large scale screening methods.

  6. DNA repair in cancer: emerging targets for personalized therapy

    International Nuclear Information System (INIS)

    Abbotts, Rachel; Thompson, Nicola; Madhusudan, Srinivasan

    2014-01-01

    Genomic deoxyribonucleic acid (DNA) is under constant threat from endogenous and exogenous DNA damaging agents. Mammalian cells have evolved highly conserved DNA repair machinery to process DNA damage and maintain genomic integrity. Impaired DNA repair is a major driver for carcinogenesis and could promote aggressive cancer biology. Interestingly, in established tumors, DNA repair activity is required to counteract oxidative DNA damage that is prevalent in the tumor microenvironment. Emerging clinical data provide compelling evidence that overexpression of DNA repair factors may have prognostic and predictive significance in patients. More recently, DNA repair inhibition has emerged as a promising target for anticancer therapy. Synthetic lethality exploits intergene relationships where the loss of function of either of two related genes is nonlethal, but loss of both causes cell death. Exploiting this approach by targeting DNA repair has emerged as a promising strategy for personalized cancer therapy. In the current review, we focus on recent advances with a particular focus on synthetic lethality targeting in cancer

  7. Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy

    Science.gov (United States)

    Yu, Mi Kyung; Park, Jinho; Jon, Sangyong

    2012-01-01

    Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications. PMID:22272217

  8. Lu-177 DOTA-TATE for peptide receptor radionuclide therapy (PRRT): organ-, tumor- and blood kinetics

    International Nuclear Information System (INIS)

    Wehrmann, C.; Senftleben, S.; Baum, R.P.

    2007-01-01

    Full text: Aim: Peptide Receptor Radionuclide Therapy (PRRT) with Lu-177 DOTA-TATE is used for the treatment of patients with neuroendocrine tumors. The aim of our study was to determine the organ and tumor kinetics for dosimetric calculations. Material and Methods: 130 patients (aged 60+/-11 years; 57m, 73f) with metastasized neuroendocrine tumors (somatostatin expression verified before by Ga-68 DOTA-NOC PET/CT) were treated with activities of 2.5- 7.4 GBq Lu-177 DOTA-TATE (1-5 cycles). On the basis of conjugated planar whole-body scintigraphies 0.5h, 3h, 24h, 48h and 72h p.i. the time-dependent whole-body, organ and tumor activities were determined and dosimetric calculations were performed according to the MIRD scheme using OLINDA software. Blood samples were drawn from 23 patients to estimate the absorbed dose to the red marrow. To describe the kinetics we used the following parameters: mean half-life and uptake (fraction of injected activity/dose, ID) which were calculated using the fit of the time-dependent activity curve to a mono- or bi-exponential function. Results: The renal uptake decreased for the first 3- 5 hours p.i. with a mean half-life of 1.0+/-0.5h, followed by a second phase with a longer half-life of 65+/-17h. The maximum kidney uptake was 4+/-1%. The uptake in the spleen was with 2+/-1.8% ID stable until 24 hours p.i. and then showed a decline with a half-life of 72+/-19h. The tumor uptake showed an increase until 24h p.i. to a maximum of 0.1+/-0.1% ID per unit mass and then slowly decreased with a half-life of 77+/-25h. Liver metastases showed a higher maximal uptake (0.1+/-0.1%) as compared to lymph node metastases (0.08+/-0.07%). The blood kinetics were fitted to a tri-exponential function with large variation: half-life 1: 0.2+/-0.2h; half-life 2: 2+/-1.8h and half-life 3: 21+/-10h. The following organ absorbed doses were calculated: kidneys: 5+/-2 Sv; spleen: 7+/-4 Sv; metastases: 47+/-66 Sv (44+/-38 Sv for lymph node, and 60+/-86 Sv for

  9. The role of patient-based treatment planning in peptide receptor radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hardiansyah, Deni; Attarwala, Ali Asgar [Heidelberg University, Medical Radiation Physics/Radiation Protection, Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Mannheim (Germany); Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Department of Radiation Oncology, Mannheim (Germany); Maass, Christian; Glatting, Gerhard [Heidelberg University, Medical Radiation Physics/Radiation Protection, Universitaetsmedizin Mannheim, Medical Faculty Mannheim, Mannheim (Germany); Mueller, Berthold [University Hospital, RWTH Aachen University, Klinik fuer Nuklearmedizin, Aachen (Germany); Kletting, Peter [Universitaet Ulm, Klinik fuer Nuklearmedizin, Ulm (Germany); Mottaghy, Felix M. [University Hospital, RWTH Aachen University, Klinik fuer Nuklearmedizin, Aachen (Germany); Maastricht University Medical Center (MUMC+), Department of Nuclear Medicine, Maastricht (Netherlands)

    2016-05-15

    Accurate treatment planning is recommended in peptide-receptor radionuclide therapy (PRRT) to minimize the toxicity to organs at risk while maximizing tumor cell sterilization. The aim of this study was to quantify the effect of different degrees of individualization on the prediction accuracy of individual therapeutic biodistributions in patients with neuroendocrine tumors (NETs). A recently developed physiologically based pharmacokinetic (PBPK) model was fitted to the biokinetic data of 15 patients with NETs after pre-therapeutic injection of {sup 111}In-DTPAOC. Mathematical phantom patients (MPP) were defined using the assumed true (true MPP), mean (MPP 1A) and median (MPP 1B) parameter values of the patient group. Alterations of the degree of individualization were introduced to both mean and median patients by including patient-specific information as a priori knowledge: physical parameters and hematocrit (MPP 2A/2B). Successively, measurable individual biokinetic parameters were added: tumor volume V{sub tu} (MPP 3A/3B), glomerular filtration rate GFR (MPP 4A/4B), and tumor perfusion f{sub tu} (MPP 5A/5B). Furthermore, parameters of MPP 5A/5B and a simulated {sup 68}Ga-DOTATATE PET measurement 60 min p.i. were used together with the population values used as Bayesian parameters (MPP 6A/6B). Therapeutic biodistributions were simulated assuming an infusion of {sup 90}Y-DOTATATE (3.3 GBq) over 30 min to all MPPs. Time-integrated activity coefficients were predicted for all MPPs and compared to the true MPPs for each patient in tumor, kidneys, spleen, liver, remainder, and whole body to obtain the relative differences RD. The large RD values of MPP 1A [RD{sub tumor} = (625 ± 1266)%, RD{sub kidneys} = (11 ± 38)% ], and MPP 1B [RD{sub tumor} = (197 ± 505)%, RD{sub kidneys} = (11 ± 39)% ] demonstrate that individual treatment planning is needed due to large physiological differences between patients. Although addition of individual patient parameters reduced the

  10. RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis

    Directory of Open Access Journals (Sweden)

    Stéphane Mathis

    2018-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

  11. RNA-Targeted Therapies and Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Mathis, Stéphane; Le Masson, Gwendal

    2018-01-15

    Amyotrophic lateral sclerosis (ALS) is a fatal motor disease in adults. Its pathophysiology remains mysterious, but tremendous advances have been made with the discovery of the most frequent mutations of its more common familial form linked to the C9ORF72 gene. Although most cases are still considered sporadic, these genetic mutations have revealed the role of RNA production, processing and transport in ALS, and may be important players in all ALS forms. There are no disease-modifying treatments for adult human neurodegenerative diseases, including ALS. As in spinal muscular atrophy, RNA-targeted therapies have been proposed as potential strategies for treating this neurodegenerative disorder. Successes achieved in various animal models of ALS have proven that RNA therapies are both safe and effective. With careful consideration of the applicability of such therapies in humans, it is possible to anticipate ongoing in vivo research and clinical trial development of RNA therapies for treating ALS.

  12. Nuclear medicine - factors influencing the choice and use of radionuclides in diagnosis and therapy

    International Nuclear Information System (INIS)

    Anon.

    1983-01-01

    This report addresses the many factors which influence the choice of the proper radiopharmaceutical drug product for the diagnosis or treatment of a specific disease or condition in a human subject. The Report examines the historical factors that influence the choice of radionuclides, the factors that influence the localization of radionuclides in tissues, the factors that influence the choice of instruments, and include an evaluation of the nuclear medicine procedures that could be selected and their clinical usefulness. In examining these factors the desirable characteristics of the radiopharmaceutical drug products of the measurement systems are identified. The methods of dose determination and the assumptions used in determination of dose are developed. There is also a section on radiation effects. A chapter on guidelines for procedures in nuclear medicine and some general and specific recommendations for protection of patients conclude the body of the text

  13. Radiation protection of staff in 111In radionuclide therapy--is the lead apron shielding effective?

    Science.gov (United States)

    Lyra, M; Charalambatou, P; Sotiropoulos, M; Diamantopoulos, S

    2011-09-01

    (111)In (Eγ = 171-245 keV, t1/2 = 2.83 d) is used for targeted therapies of endocrine tumours. An average activity of 6.3 GBq is injected into the liver by catheterisation of the hepatic artery. This procedure is time-consuming (4-5 min) and as a result, both the physicians and the technical staff involved are subjected to radiation exposure. In this research, the efficiency of the use of lead apron has been studied as far as the radiation protection of the working staff is concerned. A solution of (111)In in a cylindrical scattering phantom was used as a source. Close to the scattering phantom, an anthropomorphic male Alderson RANDO phantom was positioned. Thermoluminescent dosemeters were located in triplets on the front surface, in the exit and in various depths in the 26th slice of the RANDO phantom. The experiment was repeated by covering the RANDO phantom by a lead apron 0.25 mm Pb equivalent. The unshielded dose rates and the shielded photon dose rates were measured. Calculations of dose rates by Monte Carlo N-particle transport code were compared with this study's measurements. A significant reduction of 65 % on surface dose was observed when using lead apron. A decrease of 30 % in the mean absorbed dose among the different depths of the 26th slice of the RANDO phantom has also been noticed. An accurate correlation of the experimental results with Monte Carlo simulation has been achieved.

  14. Radiation protection of staff in 111In radionuclide therapy-Is the lead apron shielding effective?

    International Nuclear Information System (INIS)

    Lyra, M.; Charalambatou, P.; Sotiropoulos, M.; Diamantopoulos, S.

    2011-01-01

    111 In (Eγ=171-245 keV, t1/2=2.83 d) is used for targeted therapies of endocrine tumours. An average activity of 6.3 GBq is injected into the liver by catheterisation of the hepatic artery. This procedure is time-consuming (4-5 min) and as a result, both the physicians and the technical staff involved are subjected to radiation exposure. In this research, the efficiency of the use of lead apron has been studied as far as the radiation protection of the working staff is concerned. A solution of 111 In in a cylindrical scattering phantom was used as a source. Close to the scattering phantom, an anthropomorphic male Alderson RANDO phantom was positioned. Thermoluminescent dosemeters were located in triplets on the front surface, in the exit and in various depths in the 26. slice of the RANDO phantom. The experiment was repeated by covering the RANDO phantom by a lead apron 0.25 mm Pb equivalent. The unshielded dose rates and the shielded photon dose rates were measured. Calculations of dose rates by Monte Carlo N-particle transport code were compared with this study's measurements. A significant reduction of 65 % on surface dose was observed when using lead apron. A decrease of 30 % in the mean absorbed dose among the different depths of the 26. slice of the RANDO phantom has also been noticed. An accurate correlation of the experimental results with Monte Carlo simulation has been achieved. (authors)

  15. Financial relationships in economic analyses of targeted therapies in oncology.

    Science.gov (United States)

    Valachis, Antonis; Polyzos, Nikolaos P; Nearchou, Andreas; Lind, Pehr; Mauri, Davide

    2012-04-20

    A potential financial relationship between investigators and pharmaceutical manufacturers has been associated with an increased likelihood of reporting favorable conclusions about a sponsor's proprietary agent in pharmacoeconomic studies. The purpose of this study is to investigate whether there is an association between financial relationships and outcome in economic analyses of new targeted therapies in oncology. We searched PubMed (last update June 2011) for economic analyses of targeted therapies (including monoclonal antibodies, tyrosine-kinase inhibitors, and mammalian target of rapamycin inhibitors) in oncology. The trials were qualitatively rated regarding the cost assessment as favorable, neutral, or unfavorable on the basis of prespecified criteria. Overall, 81 eligible studies were identified. Economic analyses that were funded by pharmaceutical companies were more likely to report favorable qualitative cost estimates (28 [82%] of 34 v 21 [45%] of 47; P = .003). The presence of an author affiliated with manufacturer was not associated with study outcome. Furthermore, if only studies including a conflict of interest statement were included (66 of 81), studies that reported any financial relationship with manufacturers (author affiliation and/or funding and/or other financial relationship) were more likely to report favorable results of targeted therapies compared with studies without financial relationship (32 [71%] of 45 v nine [43%] of 21; P = .025). Our study reveals a potential threat for industry-related bias in economic analyses of targeted therapies in oncology in favor of analyses with financial relationships between authors and manufacturers. A more balanced funding of economic analyses from other sources may allow greater confidence in the interpretation of their results.

  16. Cancer gene therapy targeting angiogenesis: An updated Review

    Science.gov (United States)

    Liu, Ching-Chiu; Shen, Zan; Kung, Hsiang-Fu; Lin, Marie CM

    2006-01-01

    Since the relationship between angiogenesis and tumor growth was established by Folkman in 1971, scientists have made efforts exploring the possibilities in treating cancer by targeting angiogenesis. Inhibition of angiogenesis growth factors and administration of angiogenesis inhibitors are the basics of anti-angiogenesis therapy. Transfer of anti-angiogenesis genes has received attention recently not only because of the advancement of recombinant vectors, but also because of the localized and sustained expression of therapeutic gene product inside the tumor after gene transfer. This review provides the up-to-date information about the strategies and the vectors studied in the field of anti-angiogenesis cancer gene therapy. PMID:17109514

  17. Radioactive Indium({sup 114m}In) complexes derived thiosemicarbazones for development of glioma radionuclide therapy tools

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro, Thais S.; Menezes, Maria Ângela B.C.; Belo, Luiz Cláudio M.; Santos, Raquel G. dos, E-mail: thaissribeiro01@gmail.com, E-mail: lcmb@cdtn.br, E-mail: menezes@cdtn.br, E-mail: gouvears@gmail.com [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Franco, Lucas L.; Oliveira, Alexandre A.; Beraldo, Heloisa O., E-mail: lucas_lopardi@yahoo.com.br, E-mail: a13xandr31@hotmail.com, E-mail: heloisaberaldoufmg@gmail.com [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Departamento de Química

    2017-07-01

    Chemotherapy is widely used as the main course of treatment for various types of cancer. However, the side effects derived from the prolonged use of highly cytotoxic drugs in association with chemotherapy induced resistance are important challenges for effective therapy. In this context, radionuclide therapy (RNT) can be an alternative way to decrease the toxicity and improve the specificity of anti tumoral drugs. Our group has recently demonstrated that Indium (III) coordination to N(4)-Tolyl-2-acetylpyridine-derived thiosemicarbazones improves cytotoxic effects on leukemia cell lines. Once {sup 114m}In is a prolific Auger electron emitter, in this study In (III) complexes and their radioactive analogs were produced by neutron activation and their potential for RNT was further studied. Native and radioactive complexes were tested in different concentrations in U87 and T98 glioblastoma multiform (GBM) cell lines, as well as in MRC5 fibroblast cell line. All drugs presented a dose dependent cytotoxicity against cancer cells at submicromolar concentrations. The treatment with 1 μM of the radioactive analogs containing {sup 114m}In proved to be at least 1.5 times more potent than non-radioactive complexes in GBM cell lines. Due to the innate resistance of glioblastomas to chemotherapy and radiotherapy, the potentiation factor showed by the test radioactive complexes may be interesting in the course of treatment against these tumors. Therefore, the presented data suggests a synergistic effect of the radionuclide therapy conducted in this study, which might be due to the combinations of pharmacological and radiotherapeutic activities of the {sup 114m}In - thiosemicarbazone compounds. (author)

  18. Development of lithium target for accelerator based neutron capture therapy

    International Nuclear Information System (INIS)

    Taskaev, Sergey; Bayanov, Boris; Belov, Victor; Zhoorov, Eugene

    2006-01-01

    Pilot innovative accelerator based neutron source for neutron capture therapy of cancer is now of the threshold of its operation at the BINP, Russia. One of the main elements of the facility is lithium target producing neutrons via threshold 7 Li(p,n) 7 Be reaction at 25 kW proton beam with energies 1.915 MeV or 2.5 MeV. The main problems of lithium target were determined to be: 7 Be radioactive isotope activation keeping lithium layer solid, presence of photons due to proton inelastic scattering on lithium nuclei, and radiation blistering. The results of thermal test of target prototype were presented as previous NCT Congress. It becomes clear that water is preferable for cooling the target, and that lithium target 10 cm in diameter is able to run before melting. In the present report, the conception of optimal target is proposed: thin metal disk 10 cm in diameter easy for detaching, with evaporated thin layer of pure lithium from the side of proton beam exposure, its back being intensively cooled with turbulent water flow to maintain lithium layer solid. Design of the target for the neutron source constructed at BINP is shown. The results of investigation of radiation blistering and lithium layer are presented. Target unit of facility is under construction now, and obtaining neutrons is expected in nearest future. (author)

  19. Targeted Alpha Therapy Approach to the Management of Pancreatic Cancer

    International Nuclear Information System (INIS)

    Allen, Barry J.; Abbas Rizvi, Syed M.; Qu, Chang F.; Smith, Ross C.

    2011-01-01

    Evidence for the efficacy of targeted alpha therapy for the control of pancreatic cancer in preclinical models is reviewed. Results are given for in vitro pancreatic cancer cells and clusters and micro-metastatic cancer lesions in vivo. Two complementary targeting vectors are examined. These are the C595 monoclonal antibody that targets the MUC1 antigen and the PAI2 ligand that targets the uPA receptor. The expression of the tumor-associated antigen MUC-1 and the uPA receptor on three pancreatic cancer cell lines is reported for cell clusters, human mouse xenografts and lymph node metastases, as well as for human pancreatic cancer tissues, using immuno-histochemistry, confocal microscopy and flow cytometry. The targeting vectors C595 and PAI2 were labeled with the alpha emitting radioisotope 213 Bi using the chelators cDTPA and CHX-A″ to form the alpha-conjugates (AC). Cell clusters were incubated with the AC and examined at 48 hours. Apoptosis was documented using the TUNEL assay. In vivo, the anti-proliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AC by local or systemic administration. Changes in tumor progression were assessed by tumor size. MUC-1 and uPA are strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The ACs can target pancreatic cells and regress cell clusters (∼100 μm diameter), causing apoptosis in some 70–90 % of cells. At two days post-cell inoculation in mice, a single local injection of 74 MBq/kg of AC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of alpha-conjugate caused significant tumor growth delay in a dose dependent manner after 16 weeks, compared with the non-specific control at 333 MBq/kg. Cytotoxicity was assessed by the MTS and TUNEL assays. The C595 and PAI2-alpha conjugates are indicated for the treatment of micro

  20. Choice of radionuclides for radioimmunotherapy

    International Nuclear Information System (INIS)

    DeNardo, S.J.; Jungerman, J.A.; DeNardo, G.L.; Lagunas-Solar, M.C.; Cole, W.C.; Meares, C.F.

    1985-01-01

    Innumerable questions need to be answered and obstacles overcome before radioimmunotherapy can be generally successful in cancer patients. Major developments have greatly enhanced the likelihood of success. The important development of appropriate radionuclides and radiochemistry for this therapy must be intimately linked with the biological and biochemical realities. All aspects must be considered, such as the specific nature of the antigenic target, the pharmacokinetics of the antibody fragment carrier, the capability of in vivo quantitation of tumor uptake and turnover time, as well as total body kinetics. With this knowledge, then, practical radiochemistry methods can be integrated with the suitable radionuclide choices, and production methods can be developed which will deliver effective and dependable products for patient therapy

  1. Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies.

    Science.gov (United States)

    Ransohoff, Julia D; Kwong, Bernice Y

    2017-12-01

    The identification of oncogenic drivers of liquid tumors has led to the rapid development of targeted agents with distinct cutaneous adverse event (AE) profiles. The diagnosis and management of these skin toxicities has motivated a novel partnership between dermatologists and oncologists in developing supportive oncodermatology clinics. In this article we review the current state of knowledge of clinical presentation, mechanisms, and management of the most common and significant cutaneous AEs observed during treatment with targeted therapies for hematologic and lymphoid malignancies. We systematically review according to drug-targeting pathway the cutaneous AE profiles of these drugs, and offer insight when possible into whether pharmacologic target versus immunologic modulation primarily underlie presentation. We include discussion of tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, bosutinib, ponatinib), blinatumomab, ibrutinib, idelalisib, anti-B cell antibodies (rituximab, ibritumomab, obinutuzumab, ofatumumab, tositumomab), immune checkpoint inhibitors (nivolumab, pembrolizumab), alemtuzumab, brentuximab, and proteasome inhibitors (bortezomib, carfilzomib, ixazomib). We highlight skin reactions seen with antiliquid but not solid tumor agents, draw attention to serious cutaneous AEs that might require therapy modification or cessation, and offer management strategies to permit treatment tolerability. We emphasize the importance of early diagnosis and treatment to minimize disruptions to care, optimize prognosis and quality of life, and promptly address life-threatening skin or infectious events. This evolving partnership between oncologists and dermatologists in the iterative characterization and management of skin toxicities will contribute to a better understanding of these drugs' cutaneous targets and improved patient care. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Epithelioid Sarcoma: Opportunities for Biology-driven Targeted Therapy

    Directory of Open Access Journals (Sweden)

    Jonathan eNoujaim

    2015-08-01

    Full Text Available Epithelioid sarcoma is a soft tissue sarcoma of children and young adults for which the preferred treatment for localised disease is wide surgical resection. Medical management is to a great extent undefined, and therefore for patients with regional and distal metastases, the development of targeted therapies is greatly desired. In this review we will summarize clinically-relevant biomarkers (e.g., SMARCB1, CA125, dysadherin and others with respect to targeted therapeutic opportunities. We will also examine the role of EGFR, mTOR and polykinase inhibitors (e.g., sunitinib in the management of local and disseminated disease. Towards building a consortium of pharmaceutical, academic and non-profit collaborators, we will discuss the state of resources for investigating epithelioid sarcoma with respect to cell line resources, tissue banks, and registries so that a roadmap can be developed towards effective biology-driven therapies.

  3. Epithelioid Sarcoma: Opportunities for Biology-Driven Targeted Therapy.

    Science.gov (United States)

    Noujaim, Jonathan; Thway, Khin; Bajwa, Zia; Bajwa, Ayeza; Maki, Robert G; Jones, Robin L; Keller, Charles

    2015-01-01

    Epithelioid sarcoma (ES) is a soft tissue sarcoma of children and young adults for which the preferred treatment for localized disease is wide surgical resection. Medical management is to a great extent undefined, and therefore for patients with regional and distal metastases, the development of targeted therapies is greatly desired. In this review, we will summarize clinically relevant biomarkers (e.g., SMARCB1, CA125, dysadherin, and others) with respect to targeted therapeutic opportunities. We will also examine the role of EGFR, mTOR, and polykinase inhibitors (e.g., sunitinib) in the management of local and disseminated disease. Toward building a consortium of pharmaceutical, academic, and non-profit collaborators, we will discuss the state of resources for investigating ES with respect to cell line resources, tissue banks, and registries so that a roadmap can be developed toward effective biology-driven therapies.

  4. Cancer Nanomedicine: From Targeted Delivery to Combination Therapy

    Science.gov (United States)

    Xu, Xiaoyang; Ho, William; Zhang, Xueqing; Bertrand, Nicolas; Farokhzad, Omid

    2015-01-01

    The advent of nanomedicine marks an unparalleled opportunity to advance the treatment of a variety of diseases, including cancer. The unique properties of nanoparticles, such as large surface-to volume ratio, small size, the ability to encapsulate a variety of drugs, and tunable surface chemistry, gives them many advantages over their bulk counterparts. This includes multivalent surface modification with targeting ligands, efficient navigation of the complex in vivo environment, increased intracellular trafficking, and sustained release of drug payload. These advantages make nanoparticles a mode of treatment potentially superior to conventional cancer therapies. This article highlights the most recent developments in cancer treatment using nanoparticles as drug-delivery vehicles, including promising opportunities in targeted and combination therapy. PMID:25656384

  5. Adoptive T cell therapy targeting CD1 and MR1

    Directory of Open Access Journals (Sweden)

    Tingxi eGuo

    2015-05-01

    Full Text Available Adoptive T cell immunotherapy has demonstrated clinically relevant efficacy in treating malignant and infectious diseases. However, much of these therapies have been focused on enhancing, or generating de novo, effector functions of conventional T cells recognizing HLA molecules. Given the heterogeneity of HLA alleles, mismatched patients are ineligible for current HLA-restricted adoptive T cell therapies. CD1 and MR1 are class I-like monomorphic molecules and their restricted T cells possess unique T cell receptor specificity against entirely different classes of antigens. CD1 and MR1 molecules present lipid and vitamin B metabolite antigens, respectively, and offer a new front of targets for T cell therapies. This review will cover the recent progress in the basic research of CD1, MR1, and their restricted T cells that possess translational potential.

  6. Targeted therapies for diarrhea-predominant irritable bowel syndrome

    Directory of Open Access Journals (Sweden)

    Olden KW

    2012-05-01

    Full Text Available Kevin W OldenDepartment of Medicine, St Joseph's Hospital and Medical Center, Phoenix, AZ, USAAbstract: Irritable bowel syndrome (IBS causes gastrointestinal symptoms such as abdominal pain, bloating, and bowel pattern abnormalities, which compromise patients' daily functioning. Common therapies address one or two IBS symptoms, while others offer wider symptom control, presumably by targeting pathophysiologic mechanisms of IBS. The aim of this targeted literature review was to capture clinical trial reports of agents receiving the highest recommendation (Grade 1 for treatment of IBS from the 2009 American College of Gastroenterology IBS Task Force, with an emphasis on diarrhea-predominant IBS. Literature searches in PubMed captured articles detailing randomized placebo-controlled trials in IBS/diarrhea-predominant IBS for agents receiving Grade I (strong 2009 American College of Gastroenterology IBS Task Force recommendations: tricyclic antidepressants, nonabsorbable antibiotics, and the 5-HT3 receptor antagonist alosetron. Studies specific for constipation-predominant IBS were excluded. Tricyclic antidepressants appear to improve global IBS symptoms but have variable effects on abdominal pain and uncertain tolerability; effects on stool consistency, frequency, and urgency were not adequately assessed. Nonabsorbable antibiotics show positive effects on global symptoms, abdominal pain, bloating, and stool consistency but may be most efficacious in patients with altered intestinal microbiota. Alosetron improves global symptoms and abdominal pain and normalizes bowel irregularities, including stool frequency, consistency, and fecal urgency. Both the nonabsorbable antibiotic rifaximin and the 5-HT3 receptor antagonist alosetron improve quality of life. Targeted therapies provide more complete relief of IBS symptoms than conventional agents. Familiarization with the quantity and quality of evidence of effectiveness can facilitate more individualized

  7. Targeting Signaling to YAP for the Therapy of NF2

    Science.gov (United States)

    2015-10-01

    which encodes the FERM domain-containing protein Merlin. Children and young adults, who inherit an NF2 mutation, develop Schwannomas, usually of the...targeted therapy in the same way Chronic Myelogenous Leukemia is cured by Gleevec. The prospect of resistance is minimal, as Schwannoma cells do not seem to... treatment with Verteporfin, suggesting that this reporter system is not sensitive enough in physiopathologically relevant cell types. In parallel, it

  8. Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives

    Directory of Open Access Journals (Sweden)

    Salvatore Giovanni Vitale

    2017-05-01

    Full Text Available Carcinosarcomas (CS in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%. Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms “uterine carcinosarcoma”, “uterine Malignant Mixed Müllerian Tumors”, “target therapies”, “angiogenesis therapy”, “cancer stem cell therapy”, “prognostic biomarker”, and “novel antibody-drug”. Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2 open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes.

  9. New perspectives on targeted therapy in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Coward JIG

    2015-02-01

    Full Text Available Jermaine IG Coward,1–3 Kathryn Middleton,1 Felicity Murphy1 1Mater Health Services, Raymond Terrace, South Brisbane, QLD, Australia; 2Inflammtion and Cancer Therapeutics Group, Mater Research, University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, QLD, Australia; 3School of Medicine, University of Queensland, Brisbane, QLD, Australia Abstract: Epithelial ovarian cancer remains the most lethal gynecologic malignancy. During the last 15 years, there has been only marginal improvement in 5 year overall survival. These daunting statistics are compounded by the fact that despite all subtypes exhibiting striking heterogeneity, their systemic management remains identical. Although changes to the scheduling and administration of chemotherapy have improved outcomes to a degree, a therapeutic ceiling is being reached with this approach, resulting in a number of trials investigating the efficacy of targeted therapies alongside standard treatment algorithms. Furthermore, there is an urge to develop subtype-specific studies in an attempt to improve outcomes, which currently remain poor. This review summarizes the key studies with antiangiogenic agents, poly(adenosine diphosphate [ADP]-ribose inhibitors, and epidermal growth factor receptor/human epidermal growth factor receptor family targeting, in addition to folate receptor antagonists and insulin growth factor receptor inhibitors. The efficacy of treatment paradigms used in non-ovarian malignancies for type I tumors is also highlighted, in addition to recent advances in appropriate patient stratification for targeted therapies in epithelial ovarian cancer. Keywords: antiangiogenic therapy, high-grade serous, low grade ovarian cancer, PARP inhibition, cancer-related inflammation

  10. [50 years of hepatology - from therapeutic nihilism to targeted therapies].

    Science.gov (United States)

    Manns, Michael P

    2013-04-01

    Over the past 50 years significant progress has been made in the whole field of hepatology. Part of this is translation of basic research (biochemistry, immunology, virology, molecular biology and others) into clinical hepatology. This enabled us to understand more about the pathogenesis of liver diseases and led to the discovery of the five major hepatotropic viruses, the identification of hepatocellular autoantigens, and to the development of specific therapies for chronic hepatitis B, C and D. In addition, the molecular basis of most genetic liver diseases has been identified. Significant progress was made in the development of medical therapies for various liver diseases with different underlying etiologies. Surgery significantly contributed to the progress in the management of liver diseases; examples are laparoscopic cholecystectomy and the development of liver transplantation. A multimodal therapeutic algorithm has been established for the therapy of hepatocelluar carcinoma (HCC); with Sorafenib "targeted therapy" has entered the area of HCC. The progress made over the last 50 years not only led to an aetiological differentiation of acute and chronic liver diseases but also to specific therapies based on the identification and understanding of the underlying etiology. © Georg Thieme Verlag KG Stuttgart · New York.

  11. Current Molecular Targeted Therapies for Bone and Soft Tissue Sarcomas

    Directory of Open Access Journals (Sweden)

    Kenji Nakano

    2018-03-01

    Full Text Available Systemic treatment options for bone and soft tissue sarcomas remained unchanged until the 2000s. These cancers presented challenges in new drug development partly because of their rarity and heterogeneity. Many new molecular targeting drugs have been tried in the 2010s, and some were approved for bone and soft tissue sarcoma. As one of the first molecular targeted drugs approved for solid malignant tumors, imatinib’s approval as a treatment for gastrointestinal stromal tumors (GISTs has been a great achievement. Following imatinib, other tyrosine kinase inhibitors (TKIs have been approved for GISTs such as sunitinib and regorafenib, and pazopanib was approved for non-GIST soft tissue sarcomas. Olaratumab, the monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR-α, was shown to extend the overall survival of soft tissue sarcoma patients and was approved in 2016 in the U.S. as a breakthrough therapy. For bone tumors, new drugs are limited to denosumab, a receptor activator of nuclear factor κB ligand (RANKL inhibitor, for treating giant cell tumors of bone. In this review, we explain and summarize the current molecular targeting therapies approved and in development for bone and soft tissue sarcomas.

  12. Folate-targeted nanoparticles for rheumatoid arthritis therapy.

    Science.gov (United States)

    Nogueira, Eugénia; Gomes, Andreia C; Preto, Ana; Cavaco-Paulo, Artur

    2016-05-01

    Rheumatoid arthritis (RA) is the most common inflammatory rheumatic disease, affecting almost 1% of the world population. Although the cause of RA remains unknown, the complex interaction between immune mediators (cytokines and effector cells) is responsible for the joint damage that begins at the synovial membrane. Activated macrophages are critical in the pathogenesis of RA and showed specifically express a receptor for the vitamin folic acid (FA), folate receptor β (FRβ). This particular receptor allows internalization of FA-coupled cargo. In this review we will address the potential of nanoparticles as an effective drug delivery system for therapies that will directly target activated macrophages. Special attention will be given to stealth degree of the nanoparticles as a strategy to avoid clearance by macrophages of the mononuclear phagocytic system (MPS). This review summarizes the application of FA-target nanoparticles as drug delivery systems for RA and proposes prospective future directions. Rheumatoid arthritis is a debilitating autoimmune disease of the joints which affects many people worldwide. Up till now, there is a lack of optimal therapy against this disease. In this review article, the authors outlined in depth the current mechanism of disease for rheumatoid arthritis and described the latest research in using folic acid-targeted nanoparticles to target synovial macrophages in the fight against rheumatoid arthritis. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Dynamic and static small-animal SPECT in rats for monitoring renal function after 177Lu-labeled Tyr3-octreotate radionuclide therapy.

    NARCIS (Netherlands)

    Melis, M.; Swart, J.; Visser, M. de; Berndsen, S.C.; Koelewijn, S.; Valkema, R.; Boerman, O.C.; Krenning, E.P.; Jong, M. de

    2010-01-01

    High kidney radiation doses during clinical peptide receptor radionuclide therapy (PRRT) with beta-particle-emitting radiolabeled somatostatin analogs will lead to renal failure several months after treatment, urging the coinfusion of the cationic amino acids lysine and arginine to reduce the renal

  14. Radiation protection measures for reduction of incorporations of iodine-131 by the staff of a radionuclide therapy ward

    International Nuclear Information System (INIS)

    Petzold, J.; Meyer, K.; Lincke, T.; Sabri, O.; Alborzi, H.; Lorenz, J.; Schoenmuth, T.; Keller, A.

    2009-01-01

    The air in patient's rooms with thyroid therapies is loaded with iodine 131, which is to be seen as a cause for the incorporation of iodine 131 by the staff. The patients exhale a part of the iodine applied for their intended radionuclide therapy. The activity is concentrated in the saliva and, thereby, the breath air is moistened and iodine reaches the exhaled and compartment air. The detection of iodine in the form of contaminations and/or incorporations with the staff succeeds only after a longer stay in the patient's room. With this, a clear relation between the particular type of work performed in the room and therapy of malignant thyroid disease with high amounts of radioactivity can be found. The measured values of incorporations, obtained with an whole-body counter, are in the range of up to 400Bq. The activity concentration in the compartment air some hours after application of the therapeutic activity reaches a maximum and then decreases with a half-life of about 15 hours. As a protection measure we asked the patients wearing a mask up to 30 hours after application to (orig.)

  15. Targeting SR-BI for cancer diagnostics, imaging and therapy

    Directory of Open Access Journals (Sweden)

    Maneesha Amrita Rajora

    2016-09-01

    Full Text Available Scavenger receptor class B type I (SR-BI plays an important role in trafficking cholesteryl esters between the core of high density lipoprotein and the liver. Interestingly, this integral membrane protein receptor is also implicated in the metabolism of cholesterol by cancer cells, whereby overexpression of SR-BI has been observed in a number of tumours and cancer cell lines, including breast and prostate cancers. Consequently, SR-BI has recently gained attention as a cancer biomarker and exciting target for the direct cytosolic delivery of therapeutic agents. This brief review highlights these key developments in SR-BI-targeted cancer therapies and imaging probes. Special attention is given to the exploration of high density lipoprotein nanomimetic platforms that take advantage of upregulated SR-BI expression to facilitate targeted drug-delivery and cancer diagnostics, and promising future directions in the development of these agents.

  16. Excitation functions of radionuclides produced by proton induced reactions on gadolinium targets

    International Nuclear Information System (INIS)

    Challana, M.B.; Comsana, M.N.H.; Moawadb, G.S.; Abou-Zeid, M.A.

    2008-01-01

    Cross section study for proton induced reaction on natural Gadolinium targets were performed. Excitation functions for the reactions n atGd(p,x) 152m+g , 154m,154g Tb from threshold up to E p = 18 MeV have been measured employing the stacked foil activation technique, and using high resolution HPGe gamma spectrometry. Utilizing the simultaneous measurement of the excitation function of n atCu(p,x) 62 Zn, n atCu(p,x) 63 Zn, and n atCu(p,x) 65 Zn as monitor reactions. The theoretical analysis of the excitation functions has been done employing both ALICE-91 and EMPIRE-II codes. In general, theoretical calculations agree well with the experimental data. A significant contribution of pre-equilibrium component has been observed at these energies

  17. Solid targets and irradiation facilities for production of diagnostic and therapeutic radionuclides at the Debrecen cyclotron

    International Nuclear Information System (INIS)

    Tarkanyi, F.; Ando, L.; Szucs, Z.; Mahunka, I.; Kovacs, Z.

    2000-01-01

    The MGC-20E (NIIEFA, Leningrad, USSR) variable energy compact cyclotron (k=20) was installed in ATOMKI (Debrecen, Hungary) in 1985. Protons, deuterons, 3 He- and α-particles can be accelerated with currents up to 300 μA for internal irradiation and up to 50 μA for external beams. The establishment of the Cyclotron Laboratory was partly supported by the International Atomic Energy Agency. The application of the cyclotron is multipurpose: basic nuclear research, application of activation technique for analytical and wear studies, application of intense fast neutron source for agro-biological, bio-medical application and for radiation damage test of electronic components, and finally radioisotope production for medical diagnostics and for other scientific and applied fields. The cyclotron laboratory has six target rooms, a radiochemistry laboratory and a medical unit equipped with PET

  18. A Surgical Perspective on Targeted Therapy of Hepatocellular Carcinoma

    Science.gov (United States)

    Faltermeier, Claire; Busuttil, Ronald W.; Zarrinpar, Ali

    2015-01-01

    Hepatocellular carcinoma (HCC), the second leading cause of cancer deaths worldwide, is difficult to treat and highly lethal. Since HCC is predominantly diagnosed in patients with cirrhosis, treatment planning must consider both the severity of liver disease and tumor burden. To minimize the impact to the patient while treating the tumor, techniques have been developed to target HCC. Anatomical targeting by surgical resection or locoregional therapies is generally reserved for patients with preserved liver function and minimal to moderate tumor burden. Patients with decompensated cirrhosis and small tumors are optimal candidates for liver transplantation, which offers the best chance of long-term survival. Yet, only 20%–30% of patients have disease amenable to anatomical targeting. For the majority of patients with advanced HCC, chemotherapy is used to target the tumor biology. Despite these treatment options, the five-year survival of patients in the United States with HCC is only 16%. In this review we provide a comprehensive overview of current approaches to target HCC. We also discuss emerging diagnostic and prognostic biomarkers, novel therapeutic targets identified by recent genomic profiling studies, and potential applications of immunotherapy in the treatment of HCC. PMID:28943622

  19. A Surgical Perspective on Targeted Therapy of Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Claire Faltermeier

    2015-09-01

    Full Text Available Hepatocellular carcinoma (HCC, the second leading cause of cancer deaths worldwide, is difficult to treat and highly lethal. Since HCC is predominantly diagnosed in patients with cirrhosis, treatment planning must consider both the severity of liver disease and tumor burden. To minimize the impact to the patient while treating the tumor, techniques have been developed to target HCC. Anatomical targeting by surgical resection or locoregional therapies is generally reserved for patients with preserved liver function and minimal to moderate tumor burden. Patients with decompensated cirrhosis and small tumors are optimal candidates for liver transplantation, which offers the best chance of long-term survival. Yet, only 20%–30% of patients have disease amenable to anatomical targeting. For the majority of patients with advanced HCC, chemotherapy is used to target the tumor biology. Despite these treatment options, the five-year survival of patients in the United States with HCC is only 16%. In this review we provide a comprehensive overview of current approaches to target HCC. We also discuss emerging diagnostic and prognostic biomarkers, novel therapeutic targets identified by recent genomic profiling studies, and potential applications of immunotherapy in the treatment of HCC.

  20. Modified inorganic nanoparticles as vehicles for alpha emitters in radionuclide therapy

    International Nuclear Information System (INIS)

    Piotrowska, A.; Leszczuk, E.; Koźmiński, P.; Bilewicz, A.; Morgenstern, A.; Bruchertseifer, F.

    2014-01-01

    The TiO 2 nanoparticles have unique properties like: high specific surface, high affinity for multivalent cations and simple way of synthesis, which are useful in the process of labelling. Commercially available (e.g. P-25 Degussa) and synthesised in our laboratory nanoparticles were used in experiments. The nanoparticles were characterized by TEM, SEM, DLS and NanoSight techniques. In the experiments, two different methods of labeling are tested. The first one was based on the possibility of formation strong bonds with certain cations on the surface of the nanoparticles. In the 65 second one, TiO 2 nanoparticles were doped with 225 Ac during the process of synthesis. In both cases, high yields of labelling (>99%) was obtained. Afterwards, the stability of labelled nanoparticles was examined in 0.9 % NaCl, 10 -3 M EDTA, solutions of biologically active substances (cysteine, glutathione) and human serum. In case of TiO 2 nanoparticles labelled with 225 Ac, which was built in the crystalline structure, the leakage of 225 Ac and its daughter radionuclides was not significant in any of solutions, even when the incubation time was extended to 10 days. In the case of nanoparticles with adsorbed 225 Ac on surface the leakage in serum was slightly higher, but still insignificant. Also the NaA nanozeolite as a carrier for radium radionuclides has been studied. 224 Ra and 225 Ra, the α-particle emitting radionuclides, have been absorbed in the nanometer-sized NaA zeolite through simple ion-exchange. 224,225 Ra-nanozeolites have shown very good stability in solutions containing: physiological salt, EDTA, amino acid and human serum. To make NaA nanozeolite particles dispersed in water their surface has been modified with silane coupling agent containing poly (ethylene glycol) (PEG) molecules. To obtain conjugates specific for receptors on glioma cancer cells short peptide substance P were covalently attached to the PEG-TiO 2 and PEG-nanozeolite surface. The obtained

  1. Proposal on ''standardized high current solid targets for cyclotron production of diagnostic and therapeutic radionuclides''

    International Nuclear Information System (INIS)

    Suparman, Ibon

    2000-01-01

    The Center for the Development of Radioisotopes and Radiopharmaceuticals - National Nuclear Energy Agency (P2RR-BATAN) has one Cyclotron type CS-30 with maximum 30 MeV proton energy. It is used since 1990 for 201 Tl production. The main use of 201 Tl in Indonesia is for diagnosis and assessment of myocardial ischaemia, especially diagnosis of coronary artery disease, viability of the heart muscle and forecasting the outcome for patients with coronary disease. The Cyclotron facility is supported with a solid target station, two hot cells and the chemical equipment for electroplating. The yield of 201 Tl production currently achieved around 40-50%. The irradiation technique and chemical separation should be improved. We are also very interested in the development of the production of 103 Pd via 103 Rh (p,n) 103 Pd reaction. The objective of this proposal will support the main program of the National Nuclear Energy Agency (BATAN) in enhancement of health care and in providing Cyclotron produced radiopharmaceuticals for hospitals

  2. Engineering of magnetic DNA nanoparticles for tumor-targeted therapy

    International Nuclear Information System (INIS)

    Hosseinkhani, Hossein; Chen Yiru; He Wenjie; Hong Poda; Yu, Dah-Shyong; Domb, Abraham J.

    2013-01-01

    This study aims to engineer novel targeted delivery system composed of magnetic DNA nanoparticles to be effective as an efficient targeted gene therapy vehicle for tumor therapy. A polysaccharide, dextran, was chosen as the vector of plasmid DNA-encoded NK4 that acts as an HGF-antagonist and anti-angiogenic regulator for inhibitions of tumor growth, invasion, and metastasis. Spermine (Sm) was chemically introduced to the hydroxyl groups of dextran to obtain dextran-Sm. When Fe 2+ solution was added to the mixture of dextran-Sm and a plasmid DNA, homogenous DNA nanoparticles were formed via chemical metal coordination bonding with average size of 230 nm. Characterization of DNA nanoparticles was performed via dynamic light scattering measurement, electrophoretic light scattering measurement, as well as transmission electron microscope. DNA nanoparticles effectively condensed plasmid DNA into nanoparticles and enhanced the stability of DNA, while significantly improved transfection efficiency in vitro and tumor accumulation in vivo. In addition, magnetic DNA nanoparticles exhibited high efficiency in antitumor therapy with regards to tumor growth as well as survival of animals evaluated in the presence of external magnetic field. We conclude that the magnetic properties of these DNA nanoparticles would enhance the tracking of non-viral gene delivery systems when administrated in vivo in a test model. These findings suggest that DNA nanoparticles effectively deliver DNA to tumor and thereby inhibiting tumor growth.

  3. Engineering of magnetic DNA nanoparticles for tumor-targeted therapy

    Energy Technology Data Exchange (ETDEWEB)

    Hosseinkhani, Hossein, E-mail: hosseinkhani@yahoo.com [Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology (Taiwan Tech) (China); Chen Yiru [National Yang-Ming University, Department of Biomedical Engineering (China); He Wenjie; Hong Poda [Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology (Taiwan Tech) (China); Yu, Dah-Shyong [Nanomedicine Research Center, National Defense Medical Center (China); Domb, Abraham J. [Institute of Drug Research, The Center for Nanoscience and Nanotechnology, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem (Israel)

    2013-01-15

    This study aims to engineer novel targeted delivery system composed of magnetic DNA nanoparticles to be effective as an efficient targeted gene therapy vehicle for tumor therapy. A polysaccharide, dextran, was chosen as the vector of plasmid DNA-encoded NK4 that acts as an HGF-antagonist and anti-angiogenic regulator for inhibitions of tumor growth, invasion, and metastasis. Spermine (Sm) was chemically introduced to the hydroxyl groups of dextran to obtain dextran-Sm. When Fe{sup 2+} solution was added to the mixture of dextran-Sm and a plasmid DNA, homogenous DNA nanoparticles were formed via chemical metal coordination bonding with average size of 230 nm. Characterization of DNA nanoparticles was performed via dynamic light scattering measurement, electrophoretic light scattering measurement, as well as transmission electron microscope. DNA nanoparticles effectively condensed plasmid DNA into nanoparticles and enhanced the stability of DNA, while significantly improved transfection efficiency in vitro and tumor accumulation in vivo. In addition, magnetic DNA nanoparticles exhibited high efficiency in antitumor therapy with regards to tumor growth as well as survival of animals evaluated in the presence of external magnetic field. We conclude that the magnetic properties of these DNA nanoparticles would enhance the tracking of non-viral gene delivery systems when administrated in vivo in a test model. These findings suggest that DNA nanoparticles effectively deliver DNA to tumor and thereby inhibiting tumor growth.

  4. IGF1 Receptor Targeted Theranostic Nanoparticles for Targeted and Image-Guided Therapy of Pancreatic Cancer.

    Science.gov (United States)

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M; Wang, Liya; Wang, Y Andrew; Chen, Hongyu; Kooby, David; Yu, Qian; Lipowska, Malgorzata; Staley, Charles A; Mao, Hui; Yang, Lily

    2015-08-25

    Overcoming resistance to chemotherapy is a major and unmet medical challenge in the treatment of pancreatic cancer. Poor drug delivery due to stromal barriers in the tumor microenvironment and aggressive tumor biology are additional impediments toward a more successful treatment of pancreatic cancer. In attempts to address these challenges, we developed IGF1 receptor (IGF1R)-directed, multifunctional theranostic nanoparticles for targeted delivery of therapeutic agents into IGF1R-expressing drug-resistant tumor cells and tumor-associated stromal cells. These nanoparticles were prepared by conjugating recombinant human IGF1 to magnetic iron oxide nanoparticles (IONPs) carrying the anthracycline doxorubicin (Dox) as the chemotherapeutic payload. Intravenously administered IGF1-IONPs exhibited excellent tumor targeting and penetration in an orthotopic patient-derived xenograft (PDX) model of pancreatic cancer featuring enriched tumor stroma and heterogeneous cancer cells. IGF1R-targeted therapy using the theranostic IGF1-IONP-Dox significantly inhibited the growth of pancreatic PDX tumors. The effects of the intratumoral nanoparticle delivery and therapeutic responses in the orthotopic pancreatic PDX tumors could be detected by magnetic resonance imaging (MRI) with IONP-induced contrasts. Histological analysis showed that IGF1R-targeted delivery of Dox significantly inhibited cell proliferation and induced apoptotic cell death of pancreatic cancer cells. Therefore, further development of IGF1R-targeted theranostic IONPs and MRI-guided cancer therapy as a precision nanomedicine may provide the basis for more effective treatment of pancreatic cancer.

  5. Radiotherapy in combination with vascular-targeted therapies

    International Nuclear Information System (INIS)

    Ciric, Eva; Sersa, Gregor

    2010-01-01

    Given the critical role of tumor vasculature in tumor development, considerable efforts have been spent on developing therapeutic strategies targeting the tumor vascular network. A variety of agents have been developed, with two general approaches being pursued. Antiangiogenic agents (AAs) aim to interfere with the process of angiogenesis, preventing new tumor blood vessel formation. Vascular-disrupting agents (VDAs) target existing tumor vessels causing tumor ischemia and necrosis. Despite their great therapeutic potential, it has become clear that their greatest clinical utility may lie in combination with conventional anticancer therapies. Radiotherapy is a widely used treatment modality for cancer with its distinct therapeutic challenges. Thus, combining the two approaches seems reasonable. Strong biological rationale exist for combining vascular-targeted therapies with radiation. AAs and VDAs were shown to alter the tumor microenvironment in such a way as to enhance responses to radiation. The results of preclinical and early clinical studies have confirmed the therapeutic potential of this new treatment strategy in the clinical setting. However, concerns about increased normal tissue toxicity, have been raised

  6. HER3 signaling and targeted therapy in cancer

    Directory of Open Access Journals (Sweden)

    Rosalin Mishra

    2018-05-01

    Full Text Available ERBB family members including epidermal growth factor receptor (EGFR also known as HER1, ERBB2/HER2/Neu, ERBB3/HER3 and ERBB4/HER4 are aberrantly activated in multiple cancers and hence serve as drug targets and biomarkers in modern precision therapy. The therapeutic potential of HER3 has long been underappreciated, due to impaired kinase activity and relatively low expression in tumors. However, HER3 has received attention in recent years as it is a crucial heterodimeric partner for other EGFR family members and has the potential to regulate EGFR/HER2-mediated resistance. Upregulation of HER3 is associated with several malignancies where it fosters tumor progression via interaction with different receptor tyrosine kinases (RTKs. Studies also implicate HER3 contributing significantly to treatment failure, mostly through the activation of PI3K/AKT, MAPK/ERK and JAK/STAT pathways. Moreover, activating mutations in HER3 have highlighted the role of HER3 as a direct therapeutic target. Therapeutic targeting of HER3 includes abrogating its dimerization partners’ kinase activity using small molecule inhibitors (lapatinib, erlotinib, gefitinib, afatinib, neratinib or direct targeting of its extracellular domain. In this review, we focus on HER3-mediated signaling, its role in drug resistance and discuss the latest advances to overcome resistance by targeting HER3 using mono- and bispecific antibodies and small molecule inhibitors.

  7. Denosumab for bone diseases: translating bone biology into targeted therapy.

    Science.gov (United States)

    Tsourdi, Elena; Rachner, Tilman D; Rauner, Martina; Hamann, Christine; Hofbauer, Lorenz C

    2011-12-01

    Signalling of receptor activator of nuclear factor-κB (RANK) ligand (RANKL) through RANK is a critical pathway to regulate the differentiation and activity of osteoclasts and, hence, a master regulator of bone resorption. Increased RANKL activity has been demonstrated in diseases characterised by excessive bone loss such as osteoporosis, rheumatoid arthritis and osteolytic bone metastases. The development and approval of denosumab, a fully MAB against RANKL, has heralded a new era in the treatment of bone diseases by providing a potent, targeted and reversible inhibitor of bone resorption. This article summarises the molecular and cellular biology of the RANKL/RANK system and critically reviews preclinical and clinical studies that have established denosumab as a promising novel therapy for metabolic and malignant bone diseases. We will discuss the potential indications for denosumab along with a critical review of safety and analyse its potential within the concert of established therapies.

  8. Cell-targeted sup 114 In sup m and drug (BCNU) combination therapy in a rat acute lymphoblastic leukaemia. [Bischloroethylnitrosourea

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, N.C.; Jackson, H.; Bock, M.; Sharma, H.L. (Manchester Univ. (United Kingdom). Dept. of Medical Biophysics); Ramsden, C. (Manchester Univ. (United Kingdom). Dept. of Immunology)

    1992-08-01

    A proportion of syngeneic female rats inoculated intramuscularly with a lethal T-cell lymphoblastic (Roser) leukaemia are cured by a single intraperitoneal injection of bischloroethylnitrosourea (BCNU) (Carmustine)(10 mg kg{sup -1}) given towards the end of the preleukaemic phase (day 7). Additional therapy on day 4, using intravenous leukaemia cells lethally labelled with the radionuclide {sup 114}In{sup m}, enhanced the overall cure rate by 30%. The spleen is a major site of indium concentration from the targeting cells so that the continuous local radiation field appears to result in a substantial reduction of the body load of leukaemia cells in the enlarged spleen particularly, thus enhancing the curative potential of the drug. The results demonstrate in principle that in patients in remission a single dose of targeted radiotherapy in the spleen combined sequentially with an appropriate drug might provide considerable aid in eliminating a residual population of leukaemia cells. (author).

  9. Neutrophils, a candidate biomarker and target for radiation therapy?

    Science.gov (United States)

    Schernberg, Antoine; Blanchard, Pierre; Chargari, Cyrus; Deutsch, Eric

    2017-11-01

    Neutrophils are the most abundant blood-circulating white blood cells, continuously generated in the bone marrow. Growing evidence suggests they regulate the innate and adaptive immune system during tumor evolution. This review will first summarize the recent findings on neutrophils as a key player in cancer evolution, then as a potential biomarker, and finally as therapeutic targets, with respective focuses on the interplay with radiation therapy. A complex interplay: Neutrophils have been associated with tumor progression through multiple pathways. Ionizing radiation has cytotoxic effects on cancer cells, but the sensitivity to radiation therapy in vivo differ from isolated cancer cells in vitro, partially due to the tumor microenvironment. Different microenvironmental states, whether baseline or induced, can modulate or even attenuate the effects of radiation, with consequences for therapeutic efficacy. Inflammatory biomarkers: Inflammation-based scores have been widely studied as prognostic biomarkers in cancer patients. We have performed a large retrospective cohort of patients undergoing radiation therapy (1233 patients), with robust relationship between baseline blood neutrophil count and 3-year's patient's overall survival in patients with different cancer histologies. (Pearson's correlation test: p = .001, r = -.93). Therapeutic approaches: Neutrophil-targeting agents are being developed for the treatment of inflammatory and autoimmune diseases. Neutrophils either can exert antitumoral (N1 phenotype) or protumoral (N2 phenotype) activity, depending on the Tumor Micro Environment. Tumor associated N2 neutrophils are characterized by high expression of CXCR4, VEGF, and gelatinase B/MMP9. TGF-β within the tumor microenvironment induces a population of TAN with a protumor N2 phenotype. TGF-β blockade slows tumor growth through activation of CD8 + T cells, macrophages, and tumor associated neutrophils with an antitumor N1 phenotype. This supports

  10. Nanoparticle targeted therapy against childhood acute lymphoblastic leukemia

    Science.gov (United States)

    Satake, Noriko; Lee, Joyce; Xiao, Kai; Luo, Juntao; Sarangi, Susmita; Chang, Astra; McLaughlin, Bridget; Zhou, Ping; Kenney, Elaina; Kraynov, Liliya; Arnott, Sarah; McGee, Jeannine; Nolta, Jan; Lam, Kit

    2011-06-01

    The goal of our project is to develop a unique ligand-conjugated nanoparticle (NP) therapy against childhood acute lymphoblastic leukemia (ALL). LLP2A, discovered by Dr. Kit Lam, is a high-affinity and high-specificity peptidomimetic ligand against an activated α4β1 integrin. Our study using 11 fresh primary ALL samples (10 precursor B ALL and 1 T ALL) showed that childhood ALL cells expressed activated α4β1 integrin and bound to LLP2A. Normal hematopoietic cells such as activated lymphocytes and monocytes expressed activated α4β1 integrin; however, normal hematopoietic stem cells showed low expression of α4β1 integrin. Therefore, we believe that LLP2A can be used as a targeted therapy for childhood ALL. The Lam lab has developed novel telodendrimer-based nanoparticles (NPs) which can carry drugs efficiently. We have also developed a human leukemia mouse model using immunodeficient NOD/SCID/IL2Rγ null mice engrafted with primary childhood ALL cells from our patients. LLP2A-conjugated NPs will be evaluated both in vitro and in vivo using primary leukemia cells and this mouse model. NPs will be loaded first with DiD near infra-red dye, and then with the chemotherapeutic agents daunorubicin or vincristine. Both drugs are mainstays of current chemotherapy for childhood ALL. Targeting properties of LLP2A-conjugated NPs will be evaluated by fluorescent microscopy, flow cytometry, MTS assay, and mouse survival after treatment. We expect that LLP2A-conjugated NPs will be preferentially delivered and endocytosed to leukemia cells as an effective targeted therapy.

  11. Target volumes in radiation therapy of childhood brain tumours

    International Nuclear Information System (INIS)

    Habrand, J.L.; Abdulkarim, B.; Beaudre, A.; El Khouri, M.; Kalifa, C.

    2001-01-01

    Pediatric tumors have enjoyed considerable improvements for the past 30 years. This is mainly due to the extensive use of combined therapeutical modalities in which chemotherapy plays a prominent role. In many children, local treatment including radiotherapy, can nowadays be adapted in terms of target volume and dose to the 'response' to an initial course of chemotherapy almost on a case by case basis. This makes precise recommendation on local therapy highly difficult in this age group. We will concentrate in this paper on brain tumors in which chemotherapy is of limited value and radiotherapy still plays a key-role. (authors)

  12. Interleukin-1 beta targeted therapy for type 2 diabetes

    DEFF Research Database (Denmark)

    Maedler, K.; Dharmadhikari, G.; Schumann, D.M.

    2009-01-01

    Since having been cloned in 1984, IL-1beta has been the subject of over 22,000 citations in Pubmed, among them over 800 reviews. This is because of its numerous effects. IL-1beta is a regulator of the body's inflammatory response and is produced after infection, injury, and antigenic challenge. I....... We highlight recent clinical studies and experiments in animals and isolated islets using IL-1beta as a potential target for the therapy of type 2 diabetes Udgivelsesdato: 2009/9...

  13. Bremsstrahlung parameters of praseodymium-142 in different human tissues. A dosimetric perspective for 142Pr radionuclide therapy

    International Nuclear Information System (INIS)

    Bakht, M.K.; Jabal-Ameli, H.; Ahmadi, S.J.; Sadeghi, M.; Sadjadi, S.; Tenreiro, Claudio

    2012-01-01

    Praseodymium-142 [T 1/2 =19.12 h, E β -=2.162 MeV (96.3%), E γ =1575 keV (3.7%)] is one of the 141 Pr radioisotopes. Many studies have been attempted to assess the significance of usage 142 Pr in radionuclide therapy. In many studies, the dosimetric parameters of 142 Pr sources were calculated by modeling 142 Pr sources in the water phantom and scoring the energy deposited around it. However, the medical dosimetry calculations in water phantom consider Bremsstrahlung production, raising the question: ''How important is to simulate human tissues instead of using water phantom?'' This study answers these questions by estimation of 142 Pr Bremsstrahlung parameters. The Bremsstrahlung parameters of 142 Pr as therapeutic beta nuclides in different human tissues (adipose, blood, brain, breast, cell nucleus, eye lens, gastrointestinal tract, heart, kidney, liver, lung deflated, lymph, muscle, ovary, pancreas, cartilage, red marrow, spongiosa, yellow marrow, skin, spleen, testis, thyroid and different skeleton bones) were calculated by extending the national council for radiation protection model. The specific Bremsstrahlung constant (Γ Br ), probability of energy loss by beta during Bremsstrahlung emission (P Br ) and Bremsstrahlung activity (A release ) Br were estimated. It should be mentioned that Monte Carlo simulation was used for estimation of 142 Pr Bremsstrahlung activity based on the element compositions of different human tissues and the calculated exposures from the anthropomorphic phantoms. Γ Br for yellow marrow was smallest amount (1.1962 x 10 -3 C/kg-cm 2 /MBq-h) compared to the other tissues and highest for cortical bone (2.4764 x 10 -3 C/kg-cm 2 /MBq-h), and, overall, Γ Br for skeletal tissues were greater than other tissues. In addition, Γ Br breast was 1.8261 x 10 -3 C/kg-cm 2 /MBq-h which was greater than sacrum and spongiosa bones. Moreover, according to (A release ) Br of 142 Pr, the patients receiving 142 Pr do not have to be hospitalized for

  14. Carcinoid crisis induced by receptor radionuclide therapy with 90Y-DOTATOC in a case of liver metastases from bronchial neuroendocrine tumor (atypical carcinoid).

    Science.gov (United States)

    Davì, M V; Bodei, L; Francia, G; Bartolomei, M; Oliani, C; Scilanga, L; Reghellin, D; Falconi, M; Paganelli, G; Lo Cascio, V; Ferdeghini, M

    2006-06-01

    SS receptors are overexpressed in many tumors, mainly of neuroendocrine origin, thus enabling the treatment with SS analogs. The clinical experience of receptor radionuclide therapy with the new analog [90Y-DOTA0-Tyr3 ]-octreotide [90Y-DOTATOC] has been developed over the last decade and is gaining a pivotal role in the therapeutic workout of these tumors. It is well known that some procedures performed in diagnostic and therapeutic management of endocrine tumors, such as agobiopsy and hepatic chemoembolization, can be associated with the occurrence of symptoms related to the release of vasoactive amines and/or hormonal peptides from tumor cell lysis. This is the first report of a severe carcinoid crisis developed after receptor radionuclide therapy with 90Y-DOTATOC administered in a patient affected by liver metastases from bronchial neuroendocrine tumor (atypical carcinoid). Despite protection with H1 receptor antagonists, octreotide and corticosteroids, few days after the therapy the patient complained of persistent flushing of the face and upper trunk, severe labial and periocular oedema, diarrhoea and loss of appetite. These symptoms increased and required new hospitalisation. The patient received iv infusion of octreotide associated with H1 and H2 receptor antagonists and corticosteroid therapy, which induced symptom remission within few days. The case here reported confirms that radionuclide therapy is highly effective in determining early rupture of metastatic tissue and also suggests that pre-medication should be implemented before the radiopeptide administration associated with a close monitoring of the patient in the following days.

  15. Novel drugs targeting Toll-like receptors for antiviral therapy.

    Science.gov (United States)

    Patel, Mira C; Shirey, Kari Ann; Pletneva, Lioubov M; Boukhvalova, Marina S; Garzino-Demo, Alfredo; Vogel, Stefanie N; Blanco, Jorge Cg

    2014-09-01

    Toll-like receptors (TLRs) are sentinel receptors of the host innate immune system that recognize conserved 'pathogen-associated molecular patterns' of invading microbes, including viruses. The activation of TLRs establishes antiviral innate immune responses and coordinates the development of long-lasting adaptive immunity in order to control viral pathogenesis. However, microbe-induced damage to host tissues may release 'danger-associated molecular patterns' that also activate TLRs, leading to an overexuberant inflammatory response and, ultimately, to tissue damage. Thus, TLRs have proven to be promising targets as therapeutics for the treatment of viral infections that result in inflammatory damage or as adjuvants in order to enhance the efficacy of vaccines. Here, we explore recent advances in TLR biology with a focus on novel drugs that target TLRs (agonists and antagonists) for antiviral therapy.

  16. Histone lysine demethylases as targets for anticancer therapy

    DEFF Research Database (Denmark)

    Højfeldt, Jonas W; Agger, Karl; Helin, Kristian

    2013-01-01

    It has recently been demonstrated that the genes controlling the epigenetic programmes that are required for maintaining chromatin structure and cell identity include genes that drive human cancer. This observation has led to an increased awareness of chromatin-associated proteins as potentially...... interesting drug targets. The successful introduction of DNA methylation and histone deacetylase (HDAC) inhibitors for the treatment of specific subtypes of cancer has paved the way for the use of epigenetic therapy. Here, we highlight key biological findings demonstrating the roles of members of the histone...... lysine demethylase class of enzymes in the development of cancers, discuss the potential and challenges of therapeutically targeting them, and highlight emerging small-molecule inhibitors of these enzymes....

  17. Biomedical nanotechnology for molecular imaging, diagnostics, and targeted therapy.

    Science.gov (United States)

    Nie, Shuming

    2009-01-01

    Biomedical nanotechnology is a cross-disciplinary area of research in science, engineering and medicine with broad applications for molecular imaging, molecular diagnosis, and targeted therapy. The basic rationale is that nanometer-sized particles such as semiconductor quantum dots and iron oxide nanocrystals have optical, magnetic or structural properties that are not available from either molecules or bulk solids. When linked with biotargeting ligands such as monoclonal antibodies, peptides or small molecules, these nanoparticles can be used to target diseased cells and organs (such as malignant tumors and cardiovascular plaques) with high affinity and specificity. In the "mesoscopic" size range of 5-100 nm diameter, nanoparticles also have large surface areas and functional groups for conjugating to multiple diagnostic (e.g., optical, radioisotopic, or magnetic) and therapeutic (e.g., anticancer) agents.

  18. C595 antibody: A potential vector for targeted alpha therapy

    International Nuclear Information System (INIS)

    Perkins, A.C.; Allen, B.J.

    2005-01-01

    Full text: Mucins are high molecular-weight heavily glycosylated glycoproteins with many oligosaccharide side-chains, linked to a protein backbone called apomucin. A total of 19 different mucin genes (MUC1-MUC4, MUC5B, MUC5AC, MUC6-MUC18) have been identified to date. Mucins are present on the surface of most epithelial cells and play a role in their protection and lubrication. In cancer cells the mucin molecule becomes altered, thus representing an important target for diagnosis and therapy. Urinary epithelial mucin1 (MUC1) is found to be frequently up-regulated and abnormally glycosylated in a number of common malignancies, including breast, bladder, colon, ovarian and gastric cancer. The monoclonal antibody C595 is an IgG3 murine MAb raised against the protein core of human MUC1. Epitope mapping has shown that C595 recognizes a tetrapeptide motif (RPAP) within the protein core of MUC1 mucin that contains a large domain of multiples of a highly conserved 20-amino-acid-repeat sequence (PDTRPAPGSTAPPAHGVTSA). This antibody has previously been radiolabelled with 99m Tc and 111 In and used for imaging a range of tumour types including ovary, breast and bladder. The antibody has also been radiolabelled with 67 Cu and 188 Re for the therapy of superficial bladder cancer. More recently we have investigated the pre-clinical use of the C595 antibody for targeted alpha therapy using 213 Bi which emits alpha particles with high linear energy transfer (LET), short range (80 m) radiation and has a short physical half-life of 45.6 minutes. Alpha particles are some 7300 times heavier than beta particles and in theory, following binding of an alpha immunocongugates to the target, a large fraction of the alpha particle energy is delivered to cancer cells, with minimal concomitant radiation of normal tissues. 213 Bi was produced from the 225 Ac/ 213 Bi generator. For antibody conjugation the chelator, cyclic diethylenetriaminepentacetic acid anhydride (DTPA) was used. Initial

  19. Country report: India. Development of Radiopharmaceuticals Based on 188Re and 90Y for Radionuclide Therapy

    International Nuclear Information System (INIS)

    Venkatesh, M.; Pandey, U.; Dhami, P.S.; Chakravarty, R.; Kameswaran, M.; Subramanian, S.; Dash, A.; Samuel, G.

    2010-01-01

    During the past decade, our group has focused attention on the development of therapeutic radiopharmaceuticals incorporating radioisotopes such as 90 Y, 188 Re etc. As the primary source of the radioisotopes 90 Y and 188 Re are the 90 Sr/ 90 Y generators and 188 W/ 188 Re generators respectively, the local availability of these generator systems is very important for the successful development of radiopharmaceuticals incorporating these radioisotopes. In this context, 90 Sr/ 90 Y generators based on Supported Liquid Membrane (SLM) [1-3] and electrochemical techniques [4] could be designed and deployed in our laboratories for the elution of 90 Y to be used for preparation of 90 Y labeled products. This work formed a part of the IAEA co-ordinated CRP on “Development of Generator Technologies for Therapeutic Radionuclides: 90 Y and 188 Re”. In this report, work on the development of 90 Y radiopharmaceuticals for treatment of liver cancer and non-Hodgkin’s lymphoma (NHL) is reported. In addition, comparison of the Extraction Paper Chromatography technique (EPC) developed for determination of 90 Sr contamination in 90 Y samples with the US Pharmacopeia recommended method as well as the validation of the EPC technique is presented

  20. Peptide Receptor Radionuclide Therapy with ''9''0Y DOTA TATE - First Results

    International Nuclear Information System (INIS)

    Artiko, V.; Sobic-Saranovic, D.; Petrovic, N.; Damjanovic, S.; Obradovic, V.

    2009-01-01

    Aim: The aim of this work is presentation of the preliminary results of the therapy of NETs with 90 Y DOTA TATE. Patients and methods: We investigated 15 patients with various neuroendocrine tumors. In all of them, together with other laboratory analyses and imaging methods, scintigraphy with somatostatin analogues was performed (in 3 with 111 In Octreoscan and in the other 4 with 99m Tc Tektrotyd) and high tumor uptake observed. The therapy was performed with 2-4,5 GBq 90 Y DOTA TATE per patient per one cycle, in the slow infusion in the physiological liquid (150 ml/15 min).Between the cycles, there was a time delay of 6-8 weeks. 30 minutes before the therapy, patients began receiving the infusion of amino acids (arginine and lysine) which lasted 4h. Before that, all therapies with somatostatin analogues were withdrawn. 24h-96h after the therapy, ''bremsstrahlung'' whole body imaging, SPECT and particular planar images were performed with gamma camera. Results: Analysis of the ''bremsstrahlung'' images showed uptake of the radiopharmaceutical in the liver, but the most of the activity was observed in the regions of the ''hot spots'' registered with previous 99m Tc Tektrotyd and 111 In Octreoscan images. According to our results, after the therapy, in two patients occurred progressive disease (PD), in seven stable disease (SD), and in six partial remission (PR). Up to now, there were no major clinical side effects hepatic function. Transient pancytopenia occurred in two patients, and impairment of kidney function in one. Conclusion: In spite of insufficient data, beneficial effects on clinical symptoms, hormone production and tumor proliferation were found, without major clinical side effects. Thus, according to preliminary results, treatment with 90 Y DOTA TATE is feasible method and might be useful for the management of patients with inoperable or disseminated neuroendocrine tumors. (author)

  1. Autoradiography Imaging in Targeted Alpha Therapy with Timepix Detector

    Directory of Open Access Journals (Sweden)

    Ruqaya AL Darwish

    2015-01-01

    Full Text Available There is a lack of data related to activity uptake and particle track distribution in targeted alpha therapy. These data are required to estimate the absorbed dose on a cellular level as alpha particles have a limited range and traverse only a few cells. Tracking of individual alpha particles is possible using the Timepix semiconductor radiation detector. We investigated the feasibility of imaging alpha particle emissions in tumour sections from mice treated with Thorium-227 (using APOMAB, with and without prior chemotherapy and Timepix detector. Additionally, the sensitivity of the Timepix detector to monitor variations in tumour uptake based on the necrotic tissue volume was also studied. Compartmental analysis model was used, based on the obtained imaging data, to assess the Th-227 uptake. Results show that alpha particle, photon, electron, and muon tracks were detected and resolved by Timepix detector. The current study demonstrated that individual alpha particle emissions, resulting from targeted alpha therapy, can be visualised and quantified using Timepix detector. Furthermore, the variations in the uptake based on the tumour necrotic volume have been observed with four times higher uptake for tumours pretreated with chemotherapy than for those without chemotherapy.

  2. Targeted magnetic iron oxide nanoparticles for tumor imaging and therapy

    Directory of Open Access Journals (Sweden)

    Xiang-Hong Peng

    2008-10-01

    Full Text Available Xiang-Hong Peng1,4, Ximei Qian2,4, Hui Mao3,4, Andrew Y Wang5, Zhuo (Georgia Chen1,4, Shuming Nie2,4, Dong M Shin1,4*1Department of Medical Oncology/Hematology; 2Department of Biomedical Engineering; 3Department of Radiology; 4Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 5Ocean Nanotech, LLC, Fayetteville, AR, USAAbstract: Magnetic iron oxide (IO nanoparticles with a long blood retention time, biodegradability and low toxicity have emerged as one of the primary nanomaterials for biomedical applications in vitro and in vivo. IO nanoparticles have a large surface area and can be engineered to provide a large number of functional groups for cross-linking to tumor-targeting ligands such as monoclonal antibodies, peptides, or small molecules for diagnostic imaging or delivery of therapeutic agents. IO nanoparticles possess unique paramagnetic properties, which generate significant susceptibility effects resulting in strong T2 and T*2 contrast, as well as T1 effects at very low concentrations for magnetic resonance imaging (MRI, which is widely used for clinical oncology imaging. We review recent advances in the development of targeted IO nanoparticles for tumor imaging and therapy.Keywords: iron oxide nanoparticles, tumor imaging, MRI, therapy

  3. New Targets for End-Stage Chronic Kidney Disease Therapy

    Directory of Open Access Journals (Sweden)

    Prakoura Niki

    2015-05-01

    Full Text Available Severe forms of chronic kidney disease can lead to a critical, end-stage condition, requiring renal replacement therapy, which may involve a form of dialysis or renal transplantation. Identification and characterization of novel markers and/or targets of therapy that could be applied in these critically ill patients remains the focus of the current research in the field of critical care medicine and has been the objective of our studies for some years past. To this end, we used models of renal vascular disease, Ang II, L-NAME or mice overexpressing renin, treated with AT1 antagonists at different stages of progression, to create cohorts of animals during progression, reversal or escape from therapy. Transcriptomic analysis and comparisons were performed and genes were selected according to the following criteria: a not previously described in the kidney, b highly upregulated during progression and returning to the normal levels during reversal, and c producing proteins that are either circulating or membrane receptors.

  4. Update in Systemic and Targeted Therapies in Gastrointestinal Oncology

    Directory of Open Access Journals (Sweden)

    Nelson S. Yee

    2018-03-01

    Full Text Available Progress has been made in the treatment of gastrointestinal cancers through advances in systemic therapies, surgical interventions, and radiation therapy. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this sub-specialty. This conference paper highlights the new development in systemic treatment of various malignant diseases in the digestive system. Results of the recent clinical trials that investigated the clinical efficacy of pegylated hyaluronidase, napabucasin, and L-asparaginase in pancreatic carcinoma are presented. The use of peri-operative chemotherapy comprised of 5-fluorouracil or capecitabine, leucovorin, oxaliplatin, and docetaxel (FLOT, and immunotherapy including pembrolizumab, nivolumab, and ipilimumab in gastroesophageal carcinoma are discussed. Data from clinical trials that investigated the targeted therapeutics including nivolumab, ramucirumab, lenvatinib, and BLU-554 are reported. The role of adjuvant capecitabine in resected biliary tract carcinoma (BTC and nab-paclitaxel in combination with gemcitabine and cisplatin in advanced BTC are presented. In colorectal carcinoma, the efficacy of nivolumab, adjuvant FOLFOX or CAPOX, irinotecan/cetuximab/vemurafenib, and trifluridine/tipiracil/bevacizumab, is examined. In summary, some of the above systemic therapies have become or are expected to become new standard of care, while the others demonstrate the potential of becoming new treatment options.

  5. Stem cells’ guided gene therapy of cancer: New frontier in personalized and targeted therapy

    Directory of Open Access Journals (Sweden)

    Mavroudi M

    2014-01-01

    Full Text Available Diagnosis and therapy of cancer remain to be the greatest challenges for all physicians working in clinical oncology and molecular medicine. The grim statistics speak for themselves with reports of 1,638,910 men and women diagnosed with cancer and nearly 577,190 patients passed away due to cancer in the USA in 2012. For practicing clinicians, who treat patients suffering from advanced cancers with contemporary systemic therapies, the main challenge is to attain therapeutic efficacy, while minimizing side effects. Unfortunately, all contemporary systemic therapies cause side effects. In treated patients, these side effects may range from nausea to damaged tissues. In cancer survivors, the iatrogenic outcomes of systemic therapies may include genomic mutations and their consequences. Therefore, there is an urgent need for personalized and targeted therapies. Recently, we reviewed the current status of suicide gene therapy for cancer. Herein, we discuss the novel strategy: genetically engineered stem guided gene therapy. Stem cells have the unique potential for self-renewal and differentiation. This potential is the primary reason for introducing them into medicine to regenerate injured or degenerated organs, as well as to rejuvenate aging tissues. Recent advances in genetic engineering and stem cell research have created the foundations for genetic engineering of stem cells as the vectors for delivery of therapeutic transgenes. Specifically in oncology, the stem cells are genetically engineered to deliver the cell suicide inducing genes selectively to the cancer cells. Expression of the transgenes kills the cancer cells, while leaving healthy cells unaffected. Herein, we present various strategies to bioengineer suicide inducing genes and stem cell vectors. Moreover, we review results of the main preclinical studies and clinical trials. However, the main risk for therapeutic use of stem cells is their cancerous transformation. Therefore, we

  6. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    Directory of Open Access Journals (Sweden)

    Ilaria Naldi

    Full Text Available Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine, hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap and hormone refractory (DU145 prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs drug delivery system (DDS carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  7. Novel epigenetic target therapy for prostate cancer: a preclinical study.

    Science.gov (United States)

    Naldi, Ilaria; Taranta, Monia; Gherardini, Lisa; Pelosi, Gualtiero; Viglione, Federica; Grimaldi, Settimio; Pani, Luca; Cinti, Caterina

    2014-01-01

    Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

  8. Targeted therapies for diarrhea-predominant irritable bowel syndrome

    Science.gov (United States)

    Olden, Kevin W

    2012-01-01

    Irritable bowel syndrome (IBS) causes gastrointestinal symptoms such as abdominal pain, bloating, and bowel pattern abnormalities, which compromise patients’ daily functioning. Common therapies address one or two IBS symptoms, while others offer wider symptom control, presumably by targeting pathophysiologic mechanisms of IBS. The aim of this targeted literature review was to capture clinical trial reports of agents receiving the highest recommendation (Grade 1) for treatment of IBS from the 2009 American College of Gastroenterology IBS Task Force, with an emphasis on diarrhea-predominant IBS. Literature searches in PubMed captured articles detailing randomized placebo-controlled trials in IBS/diarrhea-predominant IBS for agents receiving Grade I (strong) 2009 American College of Gastroenterology IBS Task Force recommendations: tricyclic antidepressants, nonabsorbable antibiotics, and the 5-HT3 receptor antagonist alosetron. Studies specific for constipation-predominant IBS were excluded. Tricyclic antidepressants appear to improve global IBS symptoms but have variable effects on abdominal pain and uncertain tolerability; effects on stool consistency, frequency, and urgency were not adequately assessed. Nonabsorbable antibiotics show positive effects on global symptoms, abdominal pain, bloating, and stool consistency but may be most efficacious in patients with altered intestinal microbiota. Alosetron improves global symptoms and abdominal pain and normalizes bowel irregularities, including stool frequency, consistency, and fecal urgency. Both the nonabsorbable antibiotic rifaximin and the 5-HT3 receptor antagonist alosetron improve quality of life. Targeted therapies provide more complete relief of IBS symptoms than conventional agents. Familiarization with the quantity and quality of evidence of effectiveness can facilitate more individualized treatment plans for patients with this heterogeneous disorder. PMID:22754282

  9. Gastroenteropancreatic Neuroendocrine Tumors: Standardizing Therapy Monitoring with 68Ga-DOTATOC PET/CT Using the Example of Somatostatin Receptor Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    Wolfgang Luboldt

    2010-11-01

    Full Text Available The purpose of this study was to standardize therapy monitoring of hepatic metastases from gastroenteropancreatic neuroendocrine tumors (GEP-NETs during the course of somatostatin receptor radionuclide therapy (SRRT. In 21 consecutive patients with nonresectable hepatic metastases of GEP-NETs, chromogranin A (CgA and 68Ga-DOTATOC PET/CT were compared before and after the last SRRT. On 68Ga-DOTATOC PET/CT, the maximum standard uptake values (SUVmax of normal liver and hepatic metastases were calculated. In addition, the volumes of hepatic metastases (volume of interest [VOI] were measured using four cut-offs to separate normal liver tissue from metastases (SUVmax of the normal liver plus 10% [VOIliver+10%], 20% [VOIliver+20%], 30% [VOIliver+30%] and SUV = 10 [VOI10SUV]. The SUVmaxof the normal liver was below 10 (7.2 ± 1.3 in all patients and without significant changes. Overall therapy changes (Δ per patient (mean [95% CI] were statistically significant with p < .01 for ΔCgA = −43 (−69 to −17, ΔSUVmax = −22 (−29 to −14, and ΔVOI10SUV = −53 (−68 to −38% and significant with p < .05 for ΔVOIliver+10% = −29 (−55 to −3%, ΔVOIliver+20% = −32 (−62 to −2 and ΔVOIliver+30% = −37 (−66 to −8. Correlations were found only between ΔCgA and ΔVOI10SUV (r = .595; p < .01, ΔSUVmax and ΔVOI10SUV (0.629, p < .01, and SUVmax and ΔSUVmax (r = .446; p < .05. 68Ga-DOTATOC PET/CT allows volumetric therapy monitoring via an SUV-based cut-off separating hepatic metastases from normal liver tissue (10 SUV recommended.

  10. Radionuclide assessment of the effects of chest physical therapy on ventilation in cystic fibrosis

    International Nuclear Information System (INIS)

    DeCesare, J.A.; Babchyck, B.M.; Colten, H.R.; Treves, S.

    1982-01-01

    This study assesses the use of /sup 81m/Kr scintigraphy as a measurement tool in evaluating the effectiveness of bronchial drainage with percussion and vibration on peripheral ventilation in patients with cystic fibrosis. Ten patients with cystic fibrosis participated. Each patient underwent a /sup 81m/Kr ventilation study and traditional pulmonary function tests. Forty-five minutes later, these studies were repeated before and after a chest physical therapy treatment. Each patient acted as his own control. All /sup 81m/Kr scintiscans were recorded and analyzed visually and numerically using a digital computer to assess distribution of ventilation. Visual analysis of the scintiscans indicated individual variation in treatment response: in some patients ventilation improved with therapy; in others, no change was noted; still others had changes independent of treatment. Numerical data derived from the scintiscans and pulmonary function tests showed no important differences among the three studies of each patient. Airway abnormalities characteristic of cystic fibrosis, progression of the disease, sputum production, or a combination of these factors may account for the individual variation in response to treatment. /sup 81m/Kr scintigraphy is a reliable measure of regional ventilation and should be useful for assessing the efficacy of chest physical therapy because of the consistent, high quality visual data retrieved

  11. Radiation protection in radionuclide therapies with (90)Y-conjugates: risks and safety.

    Science.gov (United States)

    Cremonesi, Marta; Ferrari, Mahila; Paganelli, Giovanni; Rossi, Annalisa; Chinol, Marco; Bartolomei, Mirco; Prisco, Gennaro; Tosi, Giampiero

    2006-11-01

    The widespread interest in (90)Y internal radionuclide treatments has drawn attention to the issue of radiation protection for staff. Our aim in this study was to identify personnel at risk and to validate the protection devices used. (90)Y-MoAb (Zevalin, 15 cases, 1.1 GBq/patient) and (90)Y-peptide ((90)Y-DOTATOC) systemic (i.v., 50 cases, 3.0 GBq/patient) and locoregional (l.r., 50 cases, 0.4 GBq/patient) treatments were considered. Radiolabelling was carried out in a dedicated hot cell. Tele-tongs, shielded (PMMA: polymethylmethacrylate) syringes/vials and an automatic dose fractionating system were used. Operators wore anti-X-ray and anti-contamination gloves, with TLD dosimeters placed over the fingertips. For i.v. administration, activity was administered by a dedicated system; for l.r. administration, during activity infusion in the brain cavity, tongs were used and TLDs were placed over the fingertips. The air kerma-rate was measured around the patients. The use of devices provided a 75% dose reduction, with mean fingertip doses of 2.9 mGy (i.v. MoAbs), 0.6 mGy (i.v. peptides)/radiolabelling procedure and 0.5 mGy/l.r. administration. The mean effective dose to personnel was 5 microSv/patient. The air kerma-rate around the patients administered i.v. (90)Y-peptides were 3.5 (1 h) and 1.0 (48 h) microGy/h at 1 m. Patient hospitalisation of 6 h (l.r.)/48 h (i.v.) guaranteed that the recommended limits of 3 mSv/year to family members and 0.3 mSv/year to the general population (Council Directive 97/43/Euratom) were respected. When specific procedures are adopted, a substantial improvement in (90)Y manipulation is attainable, reducing doses and increasing safety. For the widespread clinical use of (90)Y-conjugates, a completely automatic labelling procedure is desirable.

  12. Biologic Drugs: A New Target Therapy in COPD?

    Science.gov (United States)

    Yousuf, Ahmed; Brightling, Christopher E

    2018-04-23

    Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease associated with significant morbidity and mortality. Current diagnostic criteria based on the presence of fixed airflow obstruction and symptoms do not integrate the complex pathological changes occurring within the lung and they do not define different airway inflammatory patterns. The current management of COPD is based on 'one size fits all' approach and does not take the importance of heterogeneity in COPD population into account. The available treatments aim to alleviate symptoms and reduce exacerbation frequency but do not alter the course of the disease. Recent advances in molecular biology have furthered our understanding of inflammatory pathways in pathogenesis of COPD and have led to development of targeted therapies (biologics and small molecules) based on predefined biomarkers. Herein we shall review the trials of biologics in COPD and potential future drug developments in the field.

  13. Physics at the biomolecular interface fundamentals for molecular targeted therapy

    CERN Document Server

    Fernández, Ariel

    2016-01-01

    This book focuses primarily on the role of interfacial forces in understanding biological phenomena at the molecular scale. By providing a suitable statistical mechanical apparatus to handle the biomolecular interface, the book becomes uniquely positioned to address core problems in molecular biophysics. It highlights the importance of interfacial tension in delineating a solution to the protein folding problem, in unravelling the physico-chemical basis of enzyme catalysis and protein associations, and in rationally designing molecular targeted therapies. Thus grounded in fundamental science, the book develops a powerful technological platform for drug discovery, while it is set to inspire scientists at any level in their careers determined to address the major challenges in molecular biophysics. The acknowledgment of how exquisitely the structure and dynamics of proteins and their aqueous environment are related attests to the overdue recognition that biomolecular phenomena cannot be effectively understood w...

  14. Vibrio cholerae infection, novel drug targets and phage therapy.

    Science.gov (United States)

    Fazil, Mobashar Hussain Urf Turabe; Singh, Durg V

    2011-10-01

    Vibrio cholerae is the causative agent of the diarrheal disease cholera. Although antibiotic therapy shortens the duration of diarrhea, excessive use has contributed to the emergence of antibiotic resistance in V. cholerae. Mobile genetic elements have been shown to be largely responsible for the shift of drug resistance genes in bacteria, including some V. cholerae strains. Quorum sensing communication systems are used for interaction among bacteria and for sensing environmental signals. Sequence analysis of the ctxB gene of toxigenic V. cholerae strains demonstrated its presence in multiple cholera toxin genotypes. Moreover, bacteriophage that lyse the bacterium have been reported to modulate epidemics by decreasing the required infectious dose of the bacterium. In this article, we will briefly discuss the disease, its clinical manifestation, antimicrobial resistance and the novel approaches to locate drug targets to treat cholera.

  15. The nucleolus: an emerging target for cancer therapy.

    Science.gov (United States)

    Hein, Nadine; Hannan, Katherine M; George, Amee J; Sanij, Elaine; Hannan, Ross D

    2013-11-01

    For over 100 years, pathologists have utilised an increase in size and number of nucleoli, the subnuclear site of ribosome synthesis, as a marker of aggressive tumours. Despite this, the contribution of the nucleolus and ribosomal RNA synthesis to cancer has been largely overlooked. This concept has recently changed with the demonstration that the nucleolus indirectly controls numerous other cellular functions, in particular, the cellular activity of the critical tumour suppressor protein, p53. Moreover, selective inhibition of ribosomal gene transcription in the nucleolus has been shown to be an effective therapeutic strategy to promote cancer-specific activation of p53. This article reviews the largely untapped potential of the nucleolus and ribosomal gene transcription as exciting new targets for cancer therapy. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Chemokine Signaling in Allergic Contact Dermatitis: Toward Targeted Therapies.

    Science.gov (United States)

    Smith, Jeffrey S; Rajagopal, Sudarshan; Atwater, Amber Reck

    2018-06-22

    Allergic contact dermatitis (ACD) is a common skin disease that results in significant cost and morbidity. Despite its high prevalence, therapeutic options are limited. Allergic contact dermatitis is regulated primarily by T cells within the adaptive immune system, but also by natural killer and innate lymphoid cells within the innate immune system. The chemokine receptor system, consisting of chemokine peptides and chemokine G protein-coupled receptors, is a critical regulator of inflammatory processes such as ACD. Specific chemokine signaling pathways are selectively up-regulated in ACD, most prominently CXCR3 and its endogenous chemokines CXCL9, CXCL10, and CXCL11. Recent research demonstrates that these 3 chemokines are not redundant and indeed activate distinct intracellular signaling profiles such as those activated by heterotrimeric G proteins and β-arrestin adapter proteins. Such differential signaling provides an attractive therapeutic target for novel ACD therapies and other inflammatory diseases.

  17. Structural and functional imaging for vascular targeted photodynamic therapy

    Science.gov (United States)

    Li, Buhong; Gu, Ying; Wilson, Brian C.

    2017-02-01

    Vascular targeted photodynamic therapy (V-PDT) has been widely used for the prevention or treatment of vascular-related diseases, such as localized prostate cancer, wet age-related macular degeneration, port wine stains, esophageal varices and bleeding gastrointestinal mucosal lesions. In this study, the fundamental mechanisms of vascular responses during and after V-PDT will be introduced. Based on the V-PDT treatment of blood vessels in dorsal skinfold window chamber model, the structural and functional imaging, which including white light microscopy, laser speckle imaging, singlet oxygen luminescence imaging, and fluorescence imaging for evaluating vascular damage will be presented, respectively. The results indicate that vessel constriction and blood flow dynamics could be considered as the crucial biomarkers for quantitative evaluation of vascular damage. In addition, future perspectives of non-invasive optical imaging for evaluating vascular damage of V-PDT will be discussed.

  18. Combination of peptide receptor radionuclide therapy with fractionated external beam radiotherapy for treatment of advanced symptomatic meningioma

    International Nuclear Information System (INIS)

    Kreissl, Michael C; Flentje, Michael; Sweeney, Reinhart A; Hänscheid, Heribert; Löhr, Mario; Verburg, Frederik A; Schiller, Markus; Lassmann, Michael; Reiners, Christoph; Samnick, Samuel S; Buck, Andreas K

    2012-01-01

    External beam radiotherapy (EBRT) is the treatment of choice for irresectable meningioma. Due to the strong expression of somatostatin receptors, peptide receptor radionuclide therapy (PRRT) has been used in advanced cases. We assessed the feasibility and tolerability of a combination of both treatment modalities in advanced symptomatic meningioma. 10 patients with irresectable meningioma were treated with PRRT ( 177 Lu-DOTA0,Tyr3 octreotate or - DOTA0,Tyr3 octreotide) followed by external beam radiotherapy (EBRT). EBRT performed after PRRT was continued over 5–6 weeks in IMRT technique (median dose: 53.0 Gy). All patients were assessed morphologically and by positron emission tomography (PET) before therapy and were restaged after 3–6 months. Side effects were evaluated according to CTCAE 4.0. Median tumor dose achieved by PRRT was 7.2 Gy. During PRRT and EBRT, no side effects > CTCAE grade 2 were noted. All patients reported stabilization or improvement of tumor-associated symptoms, no morphologic tumor progression was observed in MR-imaging (median follow-up: 13.4 months). The median pre-therapeutic SUV max in the meningiomas was 14.2 (range: 4.3–68.7). All patients with a second PET after combined PRRT + EBRT showed an increase in SUV max (median: 37%; range: 15%–46%) to a median value of 23.7 (range: 8.0–119.0; 7 patients) while PET-estimated volume generally decreased to 81 ± 21% of the initial volume. The combination of PRRT and EBRT is feasible and well tolerated. This approach represents an attractive strategy for the treatment of recurring or progressive symptomatic meningioma, which should be further evaluated

  19. Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate

    International Nuclear Information System (INIS)

    Rolleman, Edgar J.; Forrer, Flavio; Bernard, Bert; Bijster, Magda; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de; Vermeij, Marcel

    2007-01-01

    In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate. Male Lewis rats were injected with 278 or 555 MBq [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of 99m Tc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Treatment with 555 MBq [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of 99m Tc-DMSA SPECT scintigrams at 130 days after [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate therapy correlated well with 1/creatinine (r 2 = 0.772, p 177 Lu-DOTA 0 ,Tyr 3 ]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy. (orig.)

  20. Osteosarcoma target therapy with stem cell transplant: A case review

    International Nuclear Information System (INIS)

    Fawzy, A.

    2005-01-01

    Full text: Radioisotopes with medium-energy beta emission and half life of a few days are attractive option for systemic delivery of targeted irradiation. Samarium-153 ethylene diamine tetra-ethylene phosphonale (153Sm-EDTMP), a bone-seeking radiopharmaceutical, provides therapeutic irradiation to osteoblastic osseous lesion. The usual dose of Sm-153 in metastatic disease is 1mCi/Kg (37MBq/Kg) and the dose limiting toxicity is thrombocytopenia. As local radiotherapy has only a limited therapeutic role in the treatment of osteosarcoma, and some types of the tumour portray an unpredictable response to chemotherapy. High dose Sm-153 (30mCi/Kg) was proposed for the target management of recurrent osteosarcoma, this was followed by stem cell transplant (peripheral-blood progenitor, PBPCs). A female child, 10 years old, with polyostotic osteosarcoma with local recurrence in the right hipbone was chosen for therapy. She had left knee prosthesis, right lower limb dis-articulation, and was given chemotherapy in multiple regions. She was subjected to MDP bone scan showing active uptake in an expanding bone lesion in the right hip bone, and was also subjected to MIBI scan, which showed negative uptake. She received 30mCi/Kg Sm-153 (660mCi in total dose), with no major events occurring in the post-injection period. After 10 days the patient went into pancytopenia, which necessitated haematological support. By day 14, there was minimal radiation in the whole body image and the child received her bone marrow transplant. There was marked improvement in the tumour size after 6 weeks of therapy, with improvement in the alkaline phosphatase level (from 1350Iu, before treatment to 350 post treatment). This was confirmed by serial MDP bone scan. High dose Sm-153 with stem cell transplant is considered view a promising method in the management of osteosarcoma. (author)

  1. HIV-derived vectors for gene therapy targeting dendritic cells.

    Science.gov (United States)

    Rossetti, Maura; Cavarelli, Mariangela; Gregori, Silvia; Scarlatti, Gabriella

    2013-01-01

    Human immunodeficiency virus type 1 (HIV-1)-derived lentiviral vectors (LV) have the potential to mediate stable therapeutic gene transfer. However, similarly to other viral vectors, their benefit is compromised by the induction of an immune response toward transgene-expressing cells that closely mimics antiviral immunity. LV share with the parental HIV the ability to activate dendritic cells (DC), while lack the peculiar ability of subverting DC functions, which is responsible for HIV immune escape. Understanding the interaction between LV and DC, with plasmacytoid and myeloid DC playing fundamental and distinct roles, has paved the way to novel approaches aimed at regulating transgene-specific immune responses. Thanks to the ability to target either DC subsets LV might be a powerful tool to induce immunity (i.e., gene therapy of cancer), cell death (i.e., in HIV/AIDS infection), or tolerance (i.e., gene therapy strategies for monogenic diseases). In this chapter, similarities and differences between the LV-mediated and HIV-mediated induction of immune responses, with specific focus on their interactions with DC, are discussed.

  2. A saturable repair model for radionuclide therapy using low LET radiation emitters

    International Nuclear Information System (INIS)

    Calderon, Carlos F.; Joaquin Gonzalez; Guido Martin

    2004-01-01

    Purpose: In conventional radiotherapy doses of about 60Gy are necessary to achieve the tumor control or eradication. For systemic applications in radionuclide radiotherapy (RT) 0.1-0.5cGy/min and total dose 15-20 Gy could be reached with effective irradiation times of few days. The dose rate in tumor change exponentially as a time function where an uptake phase well differentiated from an elimination phase-will- appear both determined by the effective uptake and elimination times respectively. The biological response in RT will be determined not only by the total dose, but also by initial dose rate, the length of irradiation time (effective half-life) and biological factors, like radiosensitivity, repair and doubling times. Most quantitative models of radiation action on cells make the assumption that cell repair mechanisms are relevant in the response and it proceed in a dose-dependent way. The cell proliferation will influence too the response when the overall irradiation is comparable or greater than cell population doubling time. Many proposal had been made to apply radiobiological model for the prediction of the treatment response in RN. Saturable repair models are able, in principle, to explain the usual data base of radiobiological phenomena including which where other biophysical model does not work good. It is presented here an analytical expression to calculate the survival fraction in a cell population after irradiation based on a saturable repair radiobiological model proposed by Sanchez-Reyes [Sanchez-Reyes A. Radiact. Res., 1992;130:139-147] as function of radiobiological and biokinetics parameters which could be used in RN. The original radiobiological model consider a cell population where the DNA repair mechanisms are saturable and it could be affected by radiation action. The contribution of cell proliferation were considered keeping in mind that cell population grow up exponentially at constant rate. The dose rate was considered uniformly

  3. Peptide receptor radionuclide therapy in the management of gastrointestinal neuroendocrine tumors: efficacy profile, safety, and quality of life

    Directory of Open Access Journals (Sweden)

    Severi S

    2017-01-01

    Full Text Available Stefano Severi,1 Ilaria Grassi,1 Silvia Nicolini,1 Maddalena Sansovini,1 Alberto Bongiovanni,2 Giovanni Paganelli1 1Nuclear Medicine Unit, 2Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST IRCCS, Meldola, Italy Abstract: Peptide receptor radionuclide therapy (PRRT, developed over the last two decades, is carried out using radiopharmaceuticals such as 90Y-DOTA-Tyr3-octreotide and 177Lu-DOTA-Tyr3-octreotate (177Lu-Dotatate. These radiocompounds are obtained by labeling a synthetic somatostatin analog with a β-emitting radioisotope. The compounds differ from each other in terms of their energetic features (due to the radionuclide and peptide receptor affinity (due to the analog but share the common characteristic of binding specific membrane somatostatin receptors that are (generally overexpressed in neuroendocrine neoplasms (NENs and their metastases. NENs are tumors arising from diffuse neuroendocrine system cells that are classified according to grading based on Ki67 percentage values (Grades 1 and 2 are classed as neuroendocrine tumors [NETs] and to the anatomical site of occurrence (in this paper, we only deal with gastroenteropancreatic [GEP]-NETs, which account for 60%–70% of all NENs. They are also characterized by specific symptoms such as diarrhea and flushing (30% of cases. Despite substantial experience gained in the area of PRRT and its demonstrable effects in terms of efficacy, safety, and improvement in quality of life, these compounds are still not registered (registration of 177Lu-Dotatate for the treatment of midgut NETs is expected soon. Thus, PRRT can only be used in experimental protocols. We provide an overview of the work of leading groups with wide-ranging experience and continuity in data publication in the area of GEP-NET PRRT and report our own personal experience of using different dosage schedules based on the presence of kidney and bone marrow risk factors

  4. Endolymphatic radionuclide therapy (ERT) in malignant melanomas and its immunological side effects

    International Nuclear Information System (INIS)

    Richter, G.; Heidenbluth, I.; Heidelbach, U.

    1982-01-01

    Doses of some thousands Gy affecting the retroperitoneal lymph nodes, but hardly causing reduction of subjective well-being, are interesting as to the endolymphatic instillation of 32 P tri-n-octylphosphate as an additional prophylactic therapy in operated stage 1 melanomas of the extremities. A real proof for its utility, however, has been missed till now, not only in our hitherto controlled 46 patients but also in the literature. On the other hand we found a significant lymphopenia for more than 1 year and reduced percentages of stimulated lymphocytes and rosette forming cells for 3 months. Compared to 3 control groups (melanomas before treatment, effect of operation and anaesthesia, patients without immunological alterations) these immunological changes proved to be caused by the ERT itself. They suggest a limitation of ERT to melanomas with a high likelihood of separating tumor cells or micrometastases as well as further immunological follow-up checks. (author)

  5. Dermatologic adverse events associated with chemotherapy and targeted anticancer therapy

    Directory of Open Access Journals (Sweden)

    Maria Kowalska

    2016-05-01

    Full Text Available Chemotherapeutic agents and drugs used for targeted tumor therapy often cause undesirable side effects of the skin which typically are toxic cutaneous reactions (toxicity grade 1 to 4. The first group of drugs that cause toxicities affecting the skin are inhibitors of epidermal growth factor receptor (EGFR. They cause a variety of skin changes (PRIDE syndrome, which are mainly manifested by papulopustular rash, also referred to as acneiform rash, occurring in 44–74% of patients. Another drug which causes cutaneous toxicities is inhibitor of CTLA4 (cytotoxic T lymphocyte-associated protein 4, which is represented by ipilimumab, used in the treatment of metastatic melanoma. The most common dermatological adverse event, observed in 40–64% of patients receiving ipilimumab, is generalized maculopapular rash with pruritus and dry skin, and in some cases vitiligo is also observed. BRAF and MEK inhibitors introduced for the treatment of advanced melanoma also cause skin rashes. BRAF inhibitors also affecting the proliferation of keratinocytes stimulate hypertrophic changes and cause the whole spectrum of lesions from benign and keratoacanthoma to squamous cell carcinoma. A hedgehog pathway inhibitor (vismodegib is used for the treatment of metastatic basal cell carcinoma. The most common adverse events it causes are reversible alopecia and dysgeusia, but it can also cause the development of keratoacanthoma and squamous cell carcinoma. Among the most common side effects of chemotherapy and targeted therapy are toxic changes within the hands and feet (hand-foot skin reaction – HFSR that early manifest as a neurological symptoms (numbness, paresthesia, and skin symptoms (erythematous swelling changes, blisters, hyperkeratosis occur later. Anti-cancer drugs can also cause serious skin diseases such as Stevens-Johnson syndrome (SJS, toxic epidermal necrolysis (TEN and DRESS (drug rash with eosinophilia and systemic symptoms, whose course and prognosis

  6. Optimization of combination of peptide receptor radionuclide therapy (PRRT) and temozolomide therapy using SPECT/CT and MRI in mice

    International Nuclear Information System (INIS)

    Bison, S.M.; Haeck, J.C.; Bemsen, M.R.; Jong, M. de; Koelewijn, S.J.; Groen, H.C.; Bemdsen, S.; Melis, M.

    2015-01-01

    Full text of publication follows. Aim: successful treatment of patients with somatostatin receptor over-expressing neuroendocrine tumours (NET) with Lutetium-177-labelled octreotate, (PRRT) or temozolomide (TMZ) as single treatments has been described. Their combination might result in additive response, so we studied tumour characteristics and therapeutic responses after different administration schemes in mice to obtain the optimal strategy to combine PRRT and TMZ. Materials and methods: Initially we performed imaging studies of nu/nu mice, (n=5-8) bearing somatostatin receptor-expressing human H69 small cell lung carcinoma xenografts, after single administration of 177 Lu-octreotate (30 MBq/μg) or TMZ therapy (50 mg/kg/day (d) 5 x/ week for 2 weeks). Weekly tumour perfusion was measured by DCE-MRI and tumour 111 In-uptake 24 hours after administration of 30 MBq 111 In-octreotide was quantified using SPECT/CT. Based on the imaging results, seven groups were included in a combination therapy study in H69 tumour-bearing mice (n=8-9): 1: control (saline), 2: TMZ, 3: PRRT, 4: PRRT + TMZ both d1, 5: PRRT d1, TMZ from d15, 6: TMZ from d1, PRRT d15, 7: PRRT d1 and d15. Study endpoint was tumour volume >1800-2000 mm 3 . Results: single treatment with 177 Lu-octreotate or TMZ therapy resulted in reduction of tumour size, which led to changes in MRI characteristics such as intrinsic T2, T2* and perfusion values. Moreover, TMZ treatment not only showed tumour size reduction 9 days after start of treatment and an increase in MRI perfusion parameters but uptake of 111 In-octreotide peaked at day 15 followed by a decrease afterwards. In the combination therapy study no complete cure was found in control, single TMZ and single and double PRRT groups, while in the TMZ/PRRT combination groups resp. 44%, 38% and 55% of mice (groups 4, 5 and 6) showed cure without recurrence of tumour growth during follow-up. This was also reflected in an extended median survival time (MST), resp

  7. Nanotargeted Radionuclides for Cancer Nuclear Imaging and Internal Radiotherapy

    Directory of Open Access Journals (Sweden)

    Gann Ting

    2010-01-01

    Full Text Available Current progress in nanomedicine has exploited the possibility of designing tumor-targeted nanocarriers being able to deliver radionuclide payloads in a site or molecular selective manner to improve the efficacy and safety of cancer imaging and therapy. Radionuclides of auger electron-, α-, β-, and γ-radiation emitters have been surface-bioconjugated or after-loaded in nanoparticles to improve the efficacy and reduce the toxicity of cancer imaging and therapy in preclinical and clinical studies. This article provides a brief overview of current status of applications, advantages, problems, up-to-date research and development, and future prospects of nanotargeted radionuclides in cancer nuclear imaging and radiotherapy. Passive and active nanotargeting delivery of radionuclides with illustrating examples for tumor imaging and therapy are reviewed and summarized. Research on combing different modes of selective delivery of radionuclides through nanocarriers targeted delivery for tumor imaging and therapy offers the new possibility of large increases in cancer diagnostic efficacy and therapeutic index. However, further efforts and challenges in preclinical and clinical efficacy and toxicity studies are required to translate those advanced technologies to the clinical applications for cancer patients.

  8. Relationship between internal dosimetry and DNA double strand breaks in lymphocytes after radionuclide therapy; Zusammenhang zwischen physikalischer Dosimetrie und DNA Doppelstrangbruechen in Lymphozyten nach Radionuklidtherapie

    Energy Technology Data Exchange (ETDEWEB)

    Eberlein, Uta

    2015-09-30

    In radionuclide therapy radiopharmaceuticals are administered mostly systemically. Primarily, beta-emitters are used because of their short range in tissue. As a result the radiopharmaceutical distributes within the human body and accumulates in organs and target structures. Thus, the body is irradiated internally, in contrast to external irradiation in radiotherapy. The pattern of the activity distribution within the human body is determined by the physical and chemical properties of the radiopharmaceutical. Furthermore, the amount of activity and its accumulation in organs or tissues is essential for the calculation of the absorbed dose which defines the energy deposited in the body by ionizing radiation. During internal or external irradiation, patients are exposed to ionizing radiation which does not only destroy the malignant cells but also damages healthy tissue and cells. This is mainly caused by direct and indirect interaction of the radiation with the DNA which damages the DNA structure. Most frequently, there are single strand breaks and base damages. DNA double strand breaks (DSBs) are rare; nevertheless, they are the most critical lesions for cells as repairing the damage is difficult. Unrepaired or misrepaired DNA could cause mutations, chromosomal aberrations or lead to cell death. The formation of a DNA DSB in nuclear chromatin results in the rapid phosphorylation of the histone H2 variant H2AX, then called gamma-H2AX. Furthermore, DSBs also recruit the damage sensor 53BP1 to the chromatin surrounding the DSBs, which leads to 53BP1 and gamma-H2AX co-localization in the chromatin surrounding a DSB. By immunofluorescence staining with gamma-H2AX and 53BP1 antibodies those biomarkers can be addressed by microscopically visible DNA damage protein foci, this is also known as the DNA damage focus assay. With progression of DSB repair, gamma-H2AX and 53BP1 foci disappear. It is assumed that one focus corresponds to one DSB. Therefore, the number of foci per

  9. New Trends in Cancer Therapy: Targeting Ion Channels and Transporters

    Directory of Open Access Journals (Sweden)

    Annarosa Arcangeli

    2010-04-01

    Full Text Available The expression and activity of different channel types mark and regulate specific stages of cancer establishment and progression. Blocking channel activity impairs the growth of some tumors, both in vitro and in vivo, which opens a new field for pharmaceutical research. However, ion channel blockers may produce serious side effects, such as cardiac arrhythmias. For instance, Kv11.1 (hERG1 channels are aberrantly expressed in several human cancers, in which they control different aspects of the neoplastic cell behaviour. hERG1 blockers tend to inhibit cancer growth. However they also retard the cardiac repolarization, thus lengthening the electrocardiographic QT interval, which can lead to life-threatening ventricular arrhythmias. Several possibilities exist to produce less harmful compounds, such as developing specific drugs that bind hERG1 channels in the open state or disassemble the ion channel/integrin complex which appears to be crucial in certain stages of neoplastic progression. The potential approaches to improve the efficacy and safety of ion channel targeting in oncology include: (1 targeting specific conformational channel states; (2 finding ever more specific inhibitors, including peptide toxins, for channel subtypes mainly expressed in well-identified tumors; (3 using specific ligands to convey traceable or cytotoxic compounds; (4 developing channel blocking antibodies; (5 designing new molecular tools to decrease channel expression in selected cancer types. Similar concepts apply to ion transporters such as the Na+/K+ pump and the Na+/H+ exchanger. Pharmacological targeting of these transporters is also currently being considered in anti-neoplastic therapy.

  10. Triple-negative breast cancer: new perspectives for targeted therapies

    Directory of Open Access Journals (Sweden)

    Tomao F

    2015-01-01

    Full Text Available Federica Tomao,1 Anselmo Papa,2 Eleonora Zaccarelli,2 Luigi Rossi,2 Davide Caruso,2 Marina Minozzi,2 Patrizia Vici,3 Luigi Frati,4 Silverio Tomao21Department of Gynecology and Obstetrics, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, 2Department of Medico-Surgical Sciences and Biotechnologies, “Sapienza” University of Rome, Oncology Unit, Istituto Chirurgico Ortopedico Traumatologico, Latina, 3Division of Medical Oncology B, Regina Elena National Cancer Institute, Rome, Italy; 4Department of Molecular Medicine, “Sapienza” University of Rome, Policlinico “Umberto I”, Rome, ItalyAbstract: Breast cancer is a heterogeneous disease, encompassing a large number of entities showing different morphological features and having clinical behaviors. It has became apparent that this diversity may be justified by distinct patterns of genetic, epigenetic, and transcriptomic aberrations. The identification of gene-expression microarray-based characteristics has led to the identification of at least five breast cancer subgroups: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2, and basal-like. Triple-negative breast cancer is a complex disease diagnosed by immunohistochemistry, and it is characterized by malignant cells not expressing estrogen receptors or progesterone receptors at all, and human epidermal growth factor receptor 2. Along with this knowledge, recent data show that triple-negative breast cancer has specific molecular features that could be possible targets for new biological targeted drugs. The aim of this article is to explore the use of new drugs in this particular setting, which is still associated with poor prognosis and high risk of distant recurrence and death.Keywords: basal-like breast cancer, estrogen–progesterone receptors, gene-expression microarray, human epidermal growth factor receptor 2, chemotherapy, target therapy

  11. Individualized targeted therapy for glioblastoma: fact or fiction?

    Science.gov (United States)

    Weller, Michael; Stupp, Roger; Hegi, Monika; Wick, Wolfgang

    2012-01-01

    This review will address the current state of individualized cancer therapy for glioblastoma. Glioblastomas are highly malignant primary brain tumors presumably originating from neuroglial progenitor cells. Median survival is less than 1 year. Recent developments in the morphologic, clinical, and molecular classification of glioblastoma were reviewed, and their impact on clinical decision making was analyzed. Glioblastomas can be classified by morphology, clinical characteristics, complex molecular signatures, single biomarkers, or imaging parameters. Some of these characteristics, including age and Karnofsky Performance Scale score, provide important prognostic information. In contrast, few markers help to choose between various treatment options. Promoter methylation of the O-methylguanine methyltransferase gene seems to predict benefit from alkylating agent chemotherapy. Hence, it is used as an entry criterion for alkylator-free experimental combination therapy with radiotherapy. Screening for a specific type of epidermal growth factor receptor mutation is currently being explored as a biomarker for selecting patients for vaccination. Positron emission tomography for the detection of ανβ3/5 integrins could be used to select patients for treatment with anti-integrin antiangiogenic approaches. Despite extensive efforts at defining biological markers as a basis for selecting therapies, most treatment decisions for glioblastoma patients are still based on age and performance status. However, several ongoing clinical trials may enrich the repertoire of criteria for clinical decision making in the very near future. The concept of individualized or personalized targeted cancer therapy has gained significant attention throughout oncology. Yet, data in support of such an approach to glioblastoma, the most malignant subtype of glioma, are limited, and personalized medicine plays a minor role in current clinical neuro-oncology practice. In essence, this concept proposes

  12. Peptide receptor radionuclide therapy (PRRT): clinical significance of re-treatment?

    Energy Technology Data Exchange (ETDEWEB)

    Virgolini, Irene [Medical University Innsbruck, Department of Nuclear Medicine, Innsbruck (Austria); Collaboration: The Innsbruck Team

    2015-12-15

    PRRT appears to be the most effective therapeutic option in the management of inoperable or metastasized NET patients with limited side effects if dose limits are respected. In patients with relapse after a first treatment period with {sup 90}Y-DOTATOC, multiple re-treatment cycles with {sup 177}Lu-DOTATATE are feasible, safe and efficacious. Quantitative imaging by dosimetry adds to formulate personalized and evidence-based treatment protocols. However, despite the large body of evidence regarding efficacy and safety of PRRT, the absence of prospective randomized controlled trials questions the utility of PRRT in the community. Furthermore, the growing number of pharmacological or liver-directed therapeutic options competes with the confusion based on the variety of somatostatin analogues to determine the optimal choice and sequencing of PRRT in the individual patient. However, the efficacy of PRRT should not be questioned rather than it should be explored as to when PRRT might be optimally applied in the sequence of available therapy modalities. The results of the present study by the Italian group [5] emphasizes that radiopharmaceuticals are still underused. Despite the huge potential of PRRT the non-availability of PRRT in many countries still limits its widespread use. After acquiring the exclusive rights for {sup 177}Lu-DOTATATE with granted orphan designation, the company Advanced Accelerator Applications (AAA) is currently running a phase III study comparing treatment with {sup 177}Lu-DOTATATE to Octreotide LAR in patients with inoperable, progressive, somatostatin receptor-positive, midgut carcinoid tumours with the aim of registering the radiopharmaceutical under the commercial name of Lutathera. Together with orphan designation also to other somatostatin-based radiopharmaceuticals, such as {sup 90}Y-DOTATOC, {sup 177}Lu-DOTATOC and the {sup 68}Ga-labelled somatostatin antagonist OPS202, these developments promote the advancement of PRRT and PET imaging

  13. Colorectal cancer heterogeneity and targeted therapy: a case for molecular disease subtypes

    NARCIS (Netherlands)

    Linnekamp, Janneke F.; Wang, Xin; Medema, Jan Paul; Vermeulen, Louis

    2015-01-01

    Personalized cancer medicine is becoming increasingly important in colorectal cancer treatment. Especially for targeted therapies, large variations between individual treatment responses exist. Predicting therapy response is of utmost significance, as it prevents overtreatment and adverse effects in

  14. Estimates of internal dose equivalent to 22 target organs for radionuclides occurring in routine releases from nuclear fuel-cycle facilities. Vol. 1

    International Nuclear Information System (INIS)

    Killough, G.G.; Dunning, D.E. Jr.; Bernard, S.R.; Pleasant, J.C.

    1978-01-01

    This report is the first of a two-volume tabulation of internal radiation dose conversion factors for man for radionuclides of interest in environmental assessments of light-water-reactor fuel cycles. This volume treats 68 radionuclides, all of mass number less than 150. Intake by inhalation and ingestion is considered. In the former case, the ICRP Task Group Lung Model has been used to simulate the behavior of particulate matter in the respiratory tract. Results corresponding to activity median aerodynamic diameters (AMAD) of 0.3, 1.0, and 5.0 μm are given. The GI tract has been represented by a four-segment catenary model with exponential transfer of radioactivity from one segment to the next. Retention of radionuclides in other organs was characterized by linear combinations of decaying exponential functions. Dose equivalent per microcurie intake of each parent nuclide is given for 22 target organs with contributions from specified source organs plus surplus activity in the rest of the body. Cross irradiation due to penetrating radiations has also been considered in the calculations

  15. SFACTOR: a computer code for calculating dose equivalent to a target organ per microcurie-day residence of a radionuclide in a source organ - supplementary report

    Energy Technology Data Exchange (ETDEWEB)

    Dunning, Jr, D E; Pleasant, J C; Killough, G G

    1980-05-01

    The purpose of this report is to describe revisions in the SFACTOR computer code and to provide useful documentation for that program. The SFACTOR computer code has been developed to implement current methodologies for computing the average dose equivalent rate S(X reverse arrow Y) to specified target organs in man due to 1 ..mu..Ci of a given radionuclide uniformly distributed in designated source orrgans. The SFACTOR methodology is largely based upon that of Snyder, however, it has been expanded to include components of S from alpha and spontaneous fission decay, in addition to electron and photon radiations. With this methodology, S-factors can be computed for any radionuclide for which decay data are available. The tabulations in Appendix II provide a reference compilation of S-factors for several dosimetrically important radionuclides which are not available elsewhere in the literature. These S-factors are calculated for an adult with characteristics similar to those of the International Commission on Radiological Protection's Reference Man. Corrections to tabulations from Dunning are presented in Appendix III, based upon the methods described in Section 2.3. 10 refs.

  16. Chemo-radionuclide therapy for thyroid cancer. Initial experimental study with cultured cells

    International Nuclear Information System (INIS)

    Misaki, Takashi; Iwata, Masahiro; Iida, Yasuhiro; Kasagi, Kanji; Konishi, Junji

    2002-01-01

    Radioiodine therapy has long been used for distant metastases of thyroid cancer. Although partially effective in most cases, it can render a complete cure only in a limited number of patients. One way to enhance its efficacy would be to combine it with antineoplastic agents. Here we describe an initial in vitro evaluation with 4 thyroid cancer cell lines. Cells were sparsely seeded in microtiter plates and allowed to grow for 2 days; then they were exposed to sublethal concentrations of cisplatin (CDDP), doxorubicin (Dox), or 5-fluorouracil (5-FU), followed by treatment with I-131 for 48 hr. Cell survival was measured with a commercial kit based on the colorimetry of succinate dehydrogenase activity. Chemotherapeutic drugs exerted similar concentration-dependent cytotoxic effects in all 4 cell lines. The doses necessary to reduce the surviving fraction to half of the control were about 3 μg/ml for CDDP, 0.3 μg/ml for Dox, and 3 μg/ml for 5-FU (when used continuously for 48 hours). On the other hand, sensitivity to I-131 irradiation differed among the lines; same doses (7.4-14.8 MBq/ml) caused the greatest damage in FRO cells, a modest effect in NPA and WRO, and only minimal change in B-CPAP. The combined effect was most demonstrable in wells treated with Dox and radioiodine, whereas the addition of CDDP or 5-FU had marginal or insignificant merit, respectively. In FRO cells, half-lethal doses of the above mentioned CDDP, Dox, and 5-FU, when used together with 14.8 MBq/ml I-131, reduced cell survival to 54.5%, 29.4% and 33.4%, respectively, vs. 60.2% with radioiodine alone. In vitro, clinical concentrations of Dox can accelerate the killing of thyroid cancer cells by radioiodine. These favorable experimental results warrant future studies to evaluate whether this new bidisciplinary approach is clinically relevant and feasible. (author)

  17. Chemo-radionuclide therapy for thyroid cancer. Initial experimental study with cultured cells

    Energy Technology Data Exchange (ETDEWEB)

    Misaki, Takashi; Iwata, Masahiro; Iida, Yasuhiro; Kasagi, Kanji; Konishi, Junji [Kyoto Univ. (Japan). Graduate School of Medicine

    2002-09-01

    Radioiodine therapy has long been used for distant metastases of thyroid cancer. Although partially effective in most cases, it can render a complete cure only in a limited number of patients. One way to enhance its efficacy would be to combine it with antineoplastic agents. Here we describe an initial in vitro evaluation with 4 thyroid cancer cell lines. Cells were sparsely seeded in microtiter plates and allowed to grow for 2 days; then they were exposed to sublethal concentrations of cisplatin (CDDP), doxorubicin (Dox), or 5-fluorouracil (5-FU), followed by treatment with I-131 for 48 hr. Cell survival was measured with a commercial kit based on the colorimetry of succinate dehydrogenase activity. Chemotherapeutic drugs exerted similar concentration-dependent cytotoxic effects in all 4 cell lines. The doses necessary to reduce the surviving fraction to half of the control were about 3 {mu}g/ml for CDDP, 0.3 {mu}g/ml for Dox, and 3 {mu}g/ml for 5-FU (when used continuously for 48 hours). On the other hand, sensitivity to I-131 irradiation differed among the lines; same doses (7.4-14.8 MBq/ml) caused the greatest damage in FRO cells, a modest effect in NPA and WRO, and only minimal change in B-CPAP. The combined effect was most demonstrable in wells treated with Dox and radioiodine, whereas the addition of CDDP or 5-FU had marginal or insignificant merit, respectively. In FRO cells, half-lethal doses of the above mentioned CDDP, Dox, and 5-FU, when used together with 14.8 MBq/ml I-131, reduced cell survival to 54.5%, 29.4% and 33.4%, respectively, vs. 60.2% with radioiodine alone. In vitro, clinical concentrations of Dox can accelerate the killing of thyroid cancer cells by radioiodine. These favorable experimental results warrant future studies to evaluate whether this new bidisciplinary approach is clinically relevant and feasible. (author)

  18. EMMPRIN as a novel target for pancreatic cancer therapy

    Science.gov (United States)

    Kim, Hyunki; Zhai, Guihua; Liu, Zhiyong; Samuel, Sharon; Shah, Nemil; Helman, Emily E.; Knowles, Joseph A.; Stockard, Cecil R.; Fineberg, Naomi S.; Grizzle, William E.; Zhou, Tong; Zinn, Kurt R.; Rosenthal, Eben L.

    2013-01-01

    The objective of this study was to evaluate extracelluar matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic-cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3-7, while MIA PaCa-2 EMMPRIN knockdown cells were implanted in group 2. Dosing with anti-EMMPRIN antibody started immediately after implantation for groups 1-3 (residual tumor model) and at 21 days after cell implantation for groups 4-7 (established tumor model). Groups 3, 5, and 7 were treated with anti-EMMRPIN antibody (0.2-1.0 mg) twice weekly for 2-3 weeks, while the other groups served as the control. In residual tumor model, tumor growth of anti-EMMPRIN treated group was successfully arrested for 21 days (15±4 mm3), significantly lower than that of EMMPRIN knockdown group (80±15 mm3; p=0.001) or control group (240±41 mm3; pEMMPRIN therapy lowered tumor-volume increase about 40% compared with control regardless of dose amount. Ki67-expressed cell densities of group 5 was 939±150 mm−2, significantly lower than that of group 4 (1709±145 mm−2; p=0.006). Microvessel density of group 5 (30±6 mm−2) was also significantly lower than that of group 4 (53±5 mm−2; p=0.014), while the microvessel size of group 5 (191±22 μm2) was significantly larger than that of group 4 (113±26 μm2; p=0.049). These data show the high potential of anti-EMMPRIN therapy for pancreatic cancer, and support its clinical translation. PMID:21730821

  19. Tuning flux: autophagy as a target of heart disease therapy

    Science.gov (United States)

    Xie, Min; Morales, Cyndi R.; Lavandero, Sergio; Hill, Joseph A.

    2013-01-01

    Purpose of review Despite maximum medical and mechanical support therapy, heart failure remains a relentlessly progressive disorder with substantial morbidity and mortality. Autophagy, an evolutionarily conserved process of cellular cannibalization, has been implicated in virtually all forms of cardiovascular disease. Indeed, its role is context dependent, antagonizing or promoting disease depending on the circumstance. Here, we review current understanding of the role of autophagy in the pathogenesis of heart failure and explore this pathway as a target of therapeutic intervention. Recent findings In preclinical models of heart disease, cardiomyocyte autophagic flux is activated; indeed, its role in disease pathogenesis is the subject of intense investigation to define mechanism. Similarly, in failing human heart of a variety of etiologies, cardiomyocyte autophagic activity is upregulated, and therapy, such as with mechanical support systems, elicits declines in autophagy activity. However, when suppression of autophagy is complete, rapid and catastrophic cell death occurs, consistent with a model in which basal autophagic flux is required for proteostasis. Thus, a narrow zone of ‘optimal’ autophagy seems to exist. The challenge moving forward is to tune the stress-triggered autophagic response within that ‘sweet spot’ range for therapeutic benefit. Summary Whereas we have known for some years of the participation of lysosomal mechanisms in heart disease, it is only recently that upstream mechanisms (autophagy) are being explored. The challenge for the future is to dissect the underlying circuitry and titrate the response into an optimal, proteostasis-promoting range in hopes of mitigating the ever-expanding epidemic of heart failure. PMID:21415729

  20. Thick-target neutron, gamma-ray, and radionuclide production for protons below 12 MeV on nickel and carbon beam-stops

    International Nuclear Information System (INIS)

    Chadwick, M.B.; Young, P.G.; Wilson, W.B.

    1998-03-01

    Nuclear model calculations using the GNASH code are described for protons below 12 MeV incident on nickel and carbon isotopes, for beam stop design in the Los Alamos Accelerator Production of Tritium Low Energy Demonstration Accelerator (LEDA) project. The GNASH calculations apply Hauser-Feshbach and preequilibrium reaction theories and can make use of pre-calculated direct reaction cross sections to low-lying residual nucleus states. From calculated thin target cross sections, thick target 6.7 MeV and 12 MeV proton-induced production of neutrons, gamma rays, and radionuclides are determined. Emission spectra of the secondary neutrons and gamma rays are also determined. The model calculations are validated through comparisons with experimental thin- and thick-target measurements. The results of this work are being utilized as source terms in MCNP analyses for LEDA

  1. The tumour sink effect on the biodistribution of 68Ga-DOTA-octreotate: implications for peptide receptor radionuclide therapy

    International Nuclear Information System (INIS)

    Beauregard, Jean-Mathieu; Hofman, Michael S.; Kong, Grace; Hicks, Rodney J.

    2012-01-01

    Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of 68 Ga-DOTA-octreotate. Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on 68 Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion. There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake. Our results suggest that tumour sequestration of 68 Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues. (orig.)

  2. SU-G-TeP3-08: Pre-Clinical Radionuclide Therapy Dosimetry in Several Pediatric Cancer Xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Marsh, I; Otto, M; Weichert, J; Baiu, D; Bednarz, B [University of Wisconsin, Madison, WI (United States)

    2016-06-15

    Purpose: The focus of this work is to perform Monte Carlo-based dosimetry for several pediatric cancer xenografts in mice treated with a novel radiopharmaceutical {sup 131}I-CLR1404. Methods: Four mice for each tumor cell line were injected with 8–13 µCi/g of the {sup 124}124I-CLR1404. PET/CT images of each individual mouse were acquired at 5–6 time points over the span of 96–170 hours post-injection. Following acquisition, the images were co-registered, resampled, rescaled, corrected for partial volume effects (PVE), and masked. For this work the pre-treatment PET images of {sup 124}I-CLR1404 were used to predict therapeutic doses from {sup 131}I-CLR1404 at each time point by assuming the same injection activity and accounting for the difference in physical decay rates. Tumors and normal tissues were manually contoured using anatomical and functional images. The CT and the PET images were used in the Geant4 (v9.6) Monte Carlo simulation to define the geometry and source distribution, respectively. The total cumulated absorbed dose was calculated by numerically integrating the dose-rate at each time point over all time on a voxel-by-voxel basis. Results: Spatial distributions of the absorbed dose rates and dose volume histograms as well as mean, minimum, maximum, and total dose values for each ROI were generated for each time point. Conclusion: This work demonstrates how mouse-specific MC-based dosimetry could potentially provide more accurate characterization of efficacy of novel radiopharmaceuticals in radionuclide therapy. This work is partially funded by NIH grant CA198392.

  3. Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate

    International Nuclear Information System (INIS)

    Forrer, Flavio; Krenning, Eric P.; Kooij, Peter P.; Bernard, Bert F.; Bakker, Willem H.; Teunissen, Jaap J.M.; Jong, Marion de; Kwekkeboom, Dik J.; Konijnenberg, Mark; Lom, Kirsten van; Herder, Wouter W. de

    2009-01-01

    Adequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys, the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of the radiopharmaceutical in the blood. This may underestimate the absorbed dose since stem cells express somatostatin receptors. We verified the blood-based method by comparing the activity in the blood with the radioactivity in bone marrow aspirates. Also, we evaluated the absorbed cross-dose from the source organs (liver, spleen, kidneys and blood), tumours and the so-called ''remainder of the body'' to the bone marrow. Bone marrow aspirates were drawn in 15 patients after treatment with [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate. Radioactivity in the bone marrow was compared with radioactivity in the blood drawn simultaneously. The nucleated cell fraction was isolated from the bone marrow aspirate and radioactivity was measured. The absorbed dose to the bone marrow was calculated. The results were correlated to the change in platelet counts 6 weeks after treatment. A strong linear correlation and high agreement between the measured radioactivities in the bone marrow aspirates and in the blood was found (r=0.914, p 177 Lu-DOTA 0 ,Tyr 3 ]octreotate, the radioactivity concentration in the bone marrow is identical to that in the blood; (2) There is no significant binding of the radiopharmaceutical to bone marrow precursor stem cells; (3) The contribution of the cross dose from source organs and tumours to the bone marrow dose is significant; and (4) There is considerable variation in bone marrow absorbed dose between patients. These findings imply that for individual dose optimization, individual calculation of the bone marrow absorbed dose is necessary. (orig.)

  4. Effect of chronic L-thyroxine-suppressive therapy on cardiac function in patients with differentiated thyroid carcinoma: Radionuclide techniques

    International Nuclear Information System (INIS)

    Ziada, G.; Farouk, S.; Zidan, A.; Mustafa, S.; El-Reffaie, S.

    2005-01-01

    Differentiated thyroid carcinoma (DTC) is usually treated by a combination of surgery, radioiodine (I-131) and suppressive doses of thyroid hormones [L-thyroxine (Eltroxine)]. It is well-known that thyroid hormone affects the function of cardiovascular system. However there is no study to objectively substantiate this phenomenon. The objective of this study was to assess the left ventricular function with the help of radionuclide ventriculography in patients of DTC. Various parameters of systolic function [ejection fraction (EF), peak ejection rate (PER) and time to peak ejection rate (TPER)], diastolic function [peak filling rate (PFR) and time to peak filling rate (TPFR)] and heart rate were determined. Ten healthy control subjects and 50 patients of DTC on suppressive doses of eltroxine following surgery and radio-iodine (I-131) therapy were evaluated. The patients were divided into 5 groups according to their clinical status and thyroid hormone profile. These groups were: euthyroid, sub-clinical hypothyroid, hypothyroid, sub-clinical hyperthyroid and hyperthyroid groups. The results of the study revealed that Eltroxine significantly affected left ventricular function. Although it did not affect the systolic function, the diastolic function was significantly impaired. Prolongation of TPER was noted in hypothyroid patients, while the same was significantly decreased in hyper- and sub-clinical hyper-thyroids patients. Such abnormalities in cardiac function would be responsible for serious morbidity and could affect the lives of patients' in several ways. Hence, early effective treatment of thyroid function is important in patients of DTC, which would improve their quality of life and avoid long-term serious or irreversible cardiovascular disorder. (author)

  5. Peptide receptor radionuclide therapy with 177Lu-DOTA-octreotate: dosimetry, nephrotoxicity, and the effect of hematological toxicity on survival.

    Science.gov (United States)

    Löser, Anastassia; Schwarzenböck, Sarah M; Heuschkel, Martin; Willenberg, Holger S; Krause, Bernd J; Kurth, Jens

    2018-03-01

    Peptide receptor radionuclide therapy (PRRT) with lutetium-177 (Lu)-DOTATATE is regarded as a safe treatment option with promising results for patients with neuroendocrine neoplasia (NEN). We aimed to study the absorbed organ and tumor doses, the renal and hematological toxicity as well as their mutual interaction. Another aim was the identification of adverse effects as possible predictors which may affect survival. A total of 30 (14 female and 16 male) patients with inoperable/metastatic NEN were treated with 7.4 GBq of Lu-DOTATATE. Occurrence of renal and hematological toxicity wasretrospectively studied. Morever, we examined the effects of hematological toxicity on survival after Lu-DOTATATE-PRRT. In 49 treatment cycles, the mean absorbed dose to the kidneys was 5.13±2.12, 4.49±2.49 Gy to the liver, and 14.44±8.97 Gy to the spleen, whereas tumor lesions absorbed a mean dose of 31.43±36.86 Gy. Comparing different localizations of metastases, no significant differences in absorbed dose were observed. Clinical response status revealed regressive disease in 47.6%, stable disease in 38.1%, and progressive disease in 14.3% of cases (n=21). Biochemically, 81.3% of patients showed reduced serotonin values (n=16; P<0.05) following Lu-DOTATATE-PRRT. No severe subacute renal or hematological toxicity occurred (one Common Terminology Criteria for Adverse Events-grade 3 for thrombocytopenia and another one for leukocytopenia). No statistically significant relation between baseline kidney function and post-therapeutic hematological changes was identified. The findings indicate that Lu-DOTATATE-PRRT is a safe and effective treatment method for patients with NEN. Moreover, these data strongly suggest that hematological parameters may affect survival so a further re-evaluation in prospective studies is warranted.

  6. 177 Lu-Dota-octreotate radionuclide therapy of advanced gastrointestinal neuroendocrine tumors: results from a phase II study

    Energy Technology Data Exchange (ETDEWEB)

    Paganelli, Giovanni; Sansovini, Maddalena; Ambrosetti, Alice; Severi, Stefano; Ianniello, Annarita; Matteucci, Federica [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine and Radiometabolic Units, Meldola, FC (Italy); Monti, Manuela; Scarpi, Emanuela [IRST IRCCS, Unit of Biostatistics and Clinical Trials, Meldola (Italy); Donati, Caterina [IRST IRCCS, Oncology Pharmacy Laboratory, Meldola (Italy); Amadori, Dino [IRST IRCCS, Department of Medical Oncology, Meldola (Italy)

    2014-10-15

    We evaluated the activity and safety profile of {sup 177}Lu-Dotatate peptide receptor radionuclide therapy (Lu-PRRT) in patients with advanced, well-differentiated (G1-G2) gastrointestinal neuroendocrine tumors (GI-NETs). Forty-three patients with radiological tumor progression at baseline and a positive Octreoscan registered completed the treatment with Lu-PRRT, resulting in the cumulative activity of 18.5 or 27.8 GBq in five cycles. Total activity was scheduled on the basis of kidney function or bone marrow reserve. Twenty-five (58 %) patients were treated with a ''standard'' Lu-PRRT full dosage (FD) of 25.7 GBq (range 22.2-27.8), while the remaining 18 patients (42 %) who, at enrolment, showed a higher probability of developing kidney or bone marrow toxicity received a reduced dosage (RD) of 18.4 GBq (range 14.4-20.4). According to SWOG criteria, the overall response was complete response (CR) in (7 %) cases and stable disease (SD) in 33 (77 %), with a disease control rate (DCR) of 84 %. Median response duration was 25 months (range 7-50). Median progression-free survival (PFS) was 36 months (95 % CI 24-nr), and median overall survival (OS) has not yet been reached. Remarkably, none of the patients, including those at a higher risk of toxicity, showed side-effects after either dosage of Lu-PRRT. Lu-PRRT was shown to be an effective therapeutic option in our patients with advanced progressive GI-NETs, showing an 84 % DCR (95 % CI 73-95) that lasted for 25 months and a PFS of 36 months. Both activities of 27.8 GBq and 18.5 GBq proved safe and effective in all patients, including those with a higher probability of developing kidney or bone marrow toxicity. (orig.)

  7. The tumour sink effect on the biodistribution of {sup 68}Ga-DOTA-octreotate: implications for peptide receptor radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Beauregard, Jean-Mathieu [Peter MacCallum Cancer Centre and University of Melbourne, Centre for Cancer Imaging, Melbourne (Australia); Centre hospitalier universitaire de Quebec and Laval University, Molecular Imaging Research Group, Medical Imaging Department, Quebec City, QC (Canada); Hofman, Michael S.; Kong, Grace; Hicks, Rodney J. [Peter MacCallum Cancer Centre and University of Melbourne, Centre for Cancer Imaging, Melbourne (Australia)

    2012-01-15

    Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of {sup 68}Ga-DOTA-octreotate. Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on {sup 68}Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion. There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake. Our results suggest that tumour sequestration of {sup 68}Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues. (orig.)

  8. Synthesis of Poly[APMA]-DOTA-64Cu Conjugates for Interventional Radionuclide Therapy of Prostate Cancer: Assessment of Intratumoral Retention by Micro–Positron Emission Tomography

    Directory of Open Access Journals (Sweden)

    Jianchao Yuan

    2007-01-01

    Full Text Available To develop new radiopharmaceuticals for interventional radionuclide therapy of locally recurrent prostate cancer, poly[N-(3-aminopropylmethacrylamide] [poly(APMA] polymers were synthesized by free radical precipitation polymerization in acetonedimethylsulfoxide using N,N‘-azobis(isobutyronitrile as the initiator. The polymers were characterized with nuclear magnetic resonance, size exclusion chromatography, and dynamic light scattering (Mn 5 2.40 × 104, Mw/Mn = 1.87. Subsequently, poly[APMA] was coupled with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA using 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride as an activator, followed by conjugation with 64Cu radionuclide. Prolonged retention of poly[APMA]-DOTA-64Cu conjugates within the tumor tissues was demonstrated by micro–positron emission tomography at 24 hours following intra-tumoral injection of the conjugates to human prostate xenografts in mice. The data suggest that the poly[APMA]-DOTA-64Cu conjugates might be useful for interventional radionuclide therapy of locally recurrent prostate cancer in humans.

  9. Radionuclide trap

    International Nuclear Information System (INIS)

    McGuire, J.C.

    1978-01-01

    The deposition of radionuclides manganese-54, cobalt-58 and cobalt-60 from liquid sodium coolant is controlled by providing surfaces of nickel or high nickel alloys to extract the radionuclides from the liquid sodium, and by providing surfaces of tungsten, molybdenum or tantalum to prevent or retard radionuclide deposition

  10. In vitro and preclinical targeted alpha therapy for cancer

    International Nuclear Information System (INIS)

    Allen, B.J.; Rizvi, S.; Li, Y.; Tian, Z.; University of Wollongong, NSW; Ranson, M.; Russell, P.J.

    2000-01-01

    Full text: Targeted Alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The alpha emitting radioisotope Bi-213 is produced by generator and chelated to a cancer affined monoclonal antibody or protein to form the alpha-conjugate (AC) against melanoma, leukaemia, colorectal, bladder, breast and prostate cancers. These ACs are tested for stability, specificity and cytotoxicity. Subcutaneous inoculation of 1.5 million cells into the flanks of nude mice causes tumours to grow in all mice. The tumour growth is compared between untreated controls, nonspecific RIC and specific RIC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. Results: Stable alpha-ACs can be produced which are highly specific and cytotoxic in vitro. Local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Local TAT can also completely regress (11/12) sc melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts. These results point to the potential application of local TAT and systemic TAT in the management of these cancers. A phase 1 and 2 clinical trial is planned for local TAT of sc recurrent melanoma. Copyright (2000) Australasian College of Physical Scientists and Engineers in Medicine

  11. Aptamer-Targeted Plasmonic Photothermal Therapy of Cancer

    Directory of Open Access Journals (Sweden)

    Olga S. Kolovskaya

    2017-12-01

    Full Text Available Novel nanoscale bioconjugates combining unique plasmonic photothermal properties of gold nanoparticles (AuNPs with targeted delivery using cell-specific DNA aptamers have a tremendous potential for medical diagnostics and therapy of many cell-based diseases. In this study, we demonstrate the high anti-cancer activity of aptamer-conjugated, 37-nm spherical gold nanoparticles toward Ehrlich carcinoma in tumor-bearing mice after photothermal treatment. The synthetic anti-tumor aptamers bring the nanoparticles precisely to the desired cells and selectively eliminate cancer cells after the subsequent laser treatment. To prove tumor eradication, we used positron emission tomography (PET utilizing radioactive glucose and computer tomography, followed by histological analysis of cancer tissue. Three injections of aptamer-conjugated AuNPs and 5 min of laser irradiations are enough to make the tumor undetectable by PET. Histological analysis proves PET results and shows lower damage of healthy tissue in addition to a higher treatment efficiency and selectivity of the gold nanoparticles functionalized with aptamers in comparison to control experiments using free unconjugated nanoparticles.

  12. Targeting sarcoma tumor-initiating cells through differentiation therapy

    Directory of Open Access Journals (Sweden)

    Dan Han

    2017-05-01

    Full Text Available Human leukocyte antigen class I (HLA-I down-regulation has been reported in many human cancers to be associated with poor clinical outcome. However, its connection to tumor-initiating cells (TICs remains unknown. In this study, we report that HLA-I is down-regulated in a subpopulation of cells that have high tumor initiating capacity in different types of human sarcomas. Detailed characterization revealed their distinct molecular profiles regarding proliferation, apoptosis and stemness programs. Notably, these TICs can be induced to differentiate along distinct mesenchymal lineages, including the osteogenic pathway. The retinoic acid receptor signaling pathway is overexpressed in HLA-1 negative TICs. All-trans retinoic acid treatment successfully induced osteogenic differentiation of this subpopulation, in vitro and in vivo, resulting in significantly decreased tumor formation. Thus, our findings indicate down-regulated HLA-I is a shared feature of TICs in a variety of human sarcomas, and differentiation therapy strategies may specifically target undifferentiated TICs and inhibit tumor formation.

  13. A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Deng L

    2012-09-01

    Full Text Available Li Deng,1,# Xingfa Ke,4,# Zhiying He,3,# Daoqiu Yang,5 Hai Gong,6 Yingying Zhang,1 Xiaolong Jing,4 Jianzhong Yao,2 Jianming Chen11Department of Pharmaceutics, 2Department of Medicinal Chemistry, School of Pharmacy, 3Department of Cell Biology, Second Military Medical University, Shanghai, People's Republic of China; 4Department of Pharmacy, Fujian University of Traditional Chinese Medicine, Fujian, People's Republic of China; 5Department of Dermatology, 107th Hospital of PLA, Yantai, People's Republic of China; 6Department of Radiation Oncology, General Hospital of Jinan Military Region, Jinan, People’s Republic of China#These authors contributed equally to this workAbstract: Pancreatic cancer is a highly lethal disease with a 5-year survival rate less than 5% due to the lack of an early diagnosis method and effective therapy. To provide a novel early diagnostic method and targeted therapy for pancreatic cancer, a multifunctional nanoimmunoliposome with high loading of ultrasmall superparamagnetic iron oxides (USPIOs and doxorubicin (DOX was prepared by transient binding and reverse-phase evaporation method, and was conjugated with anti-mesothelin monoclonal antibody by post-insertion method to target anti-mesothelin-overexpressed pancreatic cancer cells. The in vitro and in vivo properties of this anti-mesothelin antibody-conjugated PEGlyated liposomal DOX and USPIOs (M-PLDU; and PEGlyated nanoimmunoliposome without antibody conjugation [PLDU] were evaluated both in human pancreatic cancer cell line Panc-1 cell and in a pancreatic cancer xenograft animal model. Results showed that M-PLDUs were spherical and uniform with a diameter about ~180 nm, with a zeta potential of about −28~−30 mV, and had good efficacy encapsulating DOX and USPIOs. The in vitro study demonstrated that M-PLDUs possessed good magnetic resonance imaging (MRI capability with a transverse relaxivity (r2 of about 58.5 mM–1 • s–1. Confocal microscopy showed more

  14. Opportunity of interventional radiology: advantages and application of interventional technique in biological target therapy

    International Nuclear Information System (INIS)

    Teng Gaojun; Lu Qin

    2007-01-01

    Interventional techniques not only provide opportunity of treatment for many diseases, but also alter the traditional therapeutic pattern. With the new century of wide application of biological therapies, interventional technique also shows extensive roles. The current biological therapy, including gene therapy, cell transplantation therapy, immunobiologic molecule therapy containing cell factors, tumor antibody or vaccine, recombined proteins, radioactive-particles and targeting materials therapy, can be locally administrated by interventional techniques. The combination of targeting biological therapies and high-targeted interventional technique holds advantages of minimal invasion, accurate delivery, vigorous local effect, and less systemic adverse reactions. Authors believe that the biological therapy may arise a great opportunity for interventional radiology, therefore interventional colleagues should grasp firmly and promptly for the development and extension in this field. (authors)

  15. Preclinical targeted alpha therapy for melanoma, leukaemia, breast, prostate and colorectal cancers

    International Nuclear Information System (INIS)

    Allen, B.J.; Rizvi, S.; Li, Y.; Tian, Z.; University of Wollongong, NSW; Ranson, M.

    2000-01-01

    Full text: Targeted Alpha therapy (TAT) offers the potential to inhibit the growth of micro-metastases by selectively killing isolated and preangiogenic clusters of cancer cells. The alpha emitting radioisotopes Tb-149 and Bi-213 are produced by accelerator and generator respectively and are chelated to a cancer specific monoclonal antibody, peptide or protein to form the alpha-conjugates (AC) against melanoma, leukaemia, breast, prostate and colorectal cancers. These ACs are tested for stability, specificity and cytotoxicity in vitro and in vivo using several nude mouse models. The Australian TAT program began some 7 years at ANSTO but was still-born. Later, TAT had a second wind at St George Hospital, where collaborative research led to the investigation of Tb-149 as a new alpha emitting radionuclide. Subsequently, increased emphasis was placed on the Ac-225 generator to produce Bi-213. Although in-house funding was terminated in 1998, the project received its third wind with local fund raising in the Shire and a US grant in 1999, and continues to break new ground in the control of the above cancers. Stable alpha-ACs are produced which are highly specific and cytotoxic in vitro against melanoma, leukaemia, colorectal, breast and prostate cancers. Subcutaneous inoculation of 11.5 million cells into the flanks of nude mice causes tumours to grow in all mice. The tumour growth is compared with untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. Local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can completely regress melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of melanoma xenografts and gives almost complete control of breast cancer tumour growth in the primary site and metastatic invasion of the lymph nodes. These results point to the application of local

  16. Pilot study using technetium-99m pertechnetate sequential radionuclide-sialography for assessing salivary gland function of nasopharyngeal cancer patients on radiation therapy

    International Nuclear Information System (INIS)

    Ng, K.S.; Sundram, F.; Somanesan, S.; Tan, H.S.K.; Gao, F.; Chung, B.; Machin, D.

    2003-01-01

    Nasopharyngeal carcinoma (NPC) is mainly treated by radiation therapy. A common complication of radiotherapy is xerostomia. Direct measurements of the amount of saliva produced using suction cups and volumetric assessments are cumbersome and time consuming. Sequential radionuclide sialography is a reproducible and convenient method of measuring salivary function. Patients with newly diagnosed NPC underwent a pilot study using technetium-99m pertechnetate sequential radionuclide sialography to assess their salivary function before and at 3 months post radiation therapy. From the sialography, time-activity-curves were obtained for analysis of salivary function. The shape of the time-activity-curve with citric acid stimulation was classified into 4 types according to the degree of radiation-induced dysfunction. All 14 patients had worse time-activity curves for both parotids and submandibular glands after radiation therapy. The P values for the change in time-activity-curves for all the salivary glands were less than 0.005. All patients with abnormal type of curves before radiation therapy presented type IV(non-functioning) curve after radiation therapy. A ratio (Rc) of pre- and post-stimulation counts allowed for quantification of the degree of stimulatory response. We found a significant decrease in Rc before and after radiation therapy for all the salivary glands (P < 0.001). The salivary gland to background ratio, which is a reflection of the degree of salivary gland functional uptake, also had a significant reduction after radiation. It is feasible to use technetium 99m pertechnetate in the measurement of salivary gland function in nasopharyngeal cancer patients treated with radiation therapy

  17. Suicide genes or p53 gene and p53 target genes as targets for cancer gene therapy by ionizing radiation

    International Nuclear Information System (INIS)

    Liu Bing; Chinese Academy of Sciences, Beijing; Zhang Hong

    2005-01-01

    Radiotherapy has some disadvantages due to the severe side-effect on the normal tissues at a curative dose of ionizing radiation (IR). Similarly, as a new developing approach, gene therapy also has some disadvantages, such as lack of specificity for tumors, limited expression of therapeutic gene, potential biological risk. To certain extent, above problems would be solved by the suicide genes or p53 gene and its target genes therapies targeted by ionizing radiation. This strategy not only makes up the disadvantage from radiotherapy or gene therapy alone, but also promotes success rate on the base of lower dose. By present, there have been several vectors measuring up to be reaching clinical trials. This review focused on the development of the cancer gene therapy through suicide genes or p53 and its target genes mediated by IR. (authors)

  18. Emerging targeted therapies for plaque psoriasis – impact of ixekizumab

    Directory of Open Access Journals (Sweden)

    Kazemi T

    2017-04-01

    Full Text Available Tiana Kazemi,1 Benjamin Farahnik,2 John Koo,3 Kourosh Beroukhim1 1University of California – Los Angeles, David Geffen School of Medicine, Los Angeles, CA, 2University of Vermont College of Medicine, Burlington, VT, 3University of California – San Francisco, Department of Dermatology, Psoriasis and Skin Treatment Center, San Francisco, CA, USA Background: Recent studies into the pathogenesis of psoriasis have identified the importance of interleukin 17 (IL-17 in disease activity and have thus provided a new target for biologic therapy. Ixekizumab, the most recent US Food and Drug Administration (FDA-approved anti-IL-17 biologic agent, appears to be a promising medication for patients suffering from moderate-to-severe plaque psoriasis. Methods: We reviewed the results of phase III trials for ixekizumab in order to assess the efficacy, safety, and impact on quality of life of this agent in the treatment of plaque psoriasis. Additionally, we compared these results to phase II and phase III trials for other biologic psoriasis medications including the anti-IL-23 agents tildrakizumab and guselkumab, the combined anti-IL-12 and anti-IL-23 agent ustekinumab, and the anti-IL-17 agents brodalumab and secukinumab. Results: Pooled results from individual studies demonstrate that among the most efficacious dosing regimens of these anti-interleukin therapies, ixekizumab achieves higher Psoriasis Area and Severity Index 75 rates and similar or higher static Physician Global Assessment 0-1 rates than the other anti-IL-17 and anti-IL-23 agents. The safety profile of ixekizumab is similar to these agents, with nasopharyngitis, upper respiratory infection, headache, arthralgia, and injection-site erythema as the most commonly reported adverse events. Conclusion: Ixekizumab is a highly efficacious, newly FDA-approved treatment for moderate-to-severe plaque psoriasis that demonstrates a robust clinical response, significant improvement in patient quality of

  19. Targeted alpha therapy for melanoma : from bench to bedside

    International Nuclear Information System (INIS)

    Allen, B.J.; Rizvi, S.M.A.; Li, Y.; Tsui, W.; Douglas, S.; Raja, C.; Graham, P.; Smart, R.; Butler, P.; Kearsley, J.; Thompson, J.

    2001-01-01

    Full text: The control of metastatic melanoma remains an elusive objective. Targeted alpha therapy (TAT) offers a new approach to the control of micrometastases and regression of tumours. The alpha emitting immunoconjugate (AIC) against malignant melanoma has been prepared by chelating Bi-213 to the anti-melanoma antibody 9.2.27, and injected locally at 2 d post-inoculation of 1.5 million melanoma cells, or intralesionally into skin tumours. Human subjects receive 50μCi intralesional dose, escalating to 1 mCi. The clearances from the tumour, kidneys and bladder are monitored by a NaI detector that detects the 440 keV gamma ray. Blood samples and tumour photographs are taken at O. 2 and 4 weeks; tumours are excised at 4 weeks. Isolated cancer cells and preangiogenic cell clusters in mice can be eliminated with 25 μCi local AIC injection, and intra-lesional injections of 100 μCi are sufficient to completely regress melanomas with volumes up to 300 mm 3 without side-effects. Systemic TAT with a single administration is less effective with 100% growth delay of tumours observed, and ∼20% complete inhibition. The clinical TAT trial for recurrent subcutaneous melanoma has been approved by the NSW Radiation Advisory Committee and the SES Human Ethics Committee. In a world first phase 1 study, the first 5 subjects have been treated by intralesional injection, 3 at 50 μCi, and 2 at 150 μCi. All subjects having unchanged blood profiles at 2 and 4 weeks post-therapy. Tumour volumes appear little changed. However, histology of a 3 cm melanoma shows that almost complete cell kill occurred at 150 μCi, with only a few small cell clusters surviving. Local TAT inhibits tumourogenesis and intralesional TAT completely regresses melanoma in mice. Intralesional TAT for melanoma in human subjects is non-toxic so far and appears to be a promising modality. The ultimate objective is to apply systemic TAT for the control of melanoma micrometastases. Copyright (2001) Australasian

  20. Vascular-targeted therapies for Duchenne muscular dystrophy

    Science.gov (United States)

    2013-01-01

    -receptor type 1 (VEGFR-1 or Flt-1). The pro-angiogenic approaches also seem to be pro-myogenic and could resolve the age-related decline in satellite cell (SC) quantity seen in mdx models through expansion of the SC juxtavascular niche. Here we review these four vascular targeted treatment strategies for DMD and discuss mechanisms, proof of concept, and the potential for clinical relevance associated with each therapy. PMID:23618411

  1. New strategy of cancer therapy by targeting the hypoxic circumstances

    International Nuclear Information System (INIS)

    Yasui, Hironobu; Yamamori, Tohru; Meike, Shunsuke; Eitaki, Masato; Kuwabara, Mikinori; Inanami, Osamu; Iizuka, Daisuke

    2010-01-01

    Described are studies on the sensitization of tumor cells in hypoxic circumstances (known as radio-resistant cells) by authors' recent molecular targeting to adaptive response as well as by the usual agents like nitro-imidazole compounds, and on the intermittent hypoxia, a new topic in this field. The hypoxia-inducible factor-1 (HIF-1) is a transcriptional factor and has been known to activate its many downstream genes to cause adoptive response of hypoxic cells. Authors have studied the anti-tumor and radiation sensitizing effects of ethynyl-cytidine (EC) which is found to suppress RNA synthesis through cytidine kinase (CK) inhibition, and the compound is of specificity to tumor cells as they have 5-10 times higher CK activity than normal cells. Authors have also found that EC is of the sensitizing efficacy to normoxic and hypoxic cells by enhancing the radiation-induced apoptosis essentially through inhibition of HIF-1 expression. Intermittent hypoxia in the tumor which has characteristic abnormal vascular morphology and function, occurs by the transient reduction of blood flow and occlusion of vessels in the tissue within minute to hour time cycles. Little is known about the regional hypoxic region and its distribution in the tumor due to difficulty of their detection and quantification. For this, authors have measured the temporal changes of oxygen levels in the mouse tumor with triaryl methyl radical, an oxygen-sensitive contrast compound continuously injected, by microwave-pulsed electron spin resonance imaging (EPRI). By superimposing the EPRI and T2-weighted MRI, the oxymetric imaging is possible in the tumor, which reveals the difference of oxygen level variation depending on the cell type and tissue size. Findings in the field are expected to give important information for more effective cancer therapy and its prognostic prediction in future. (T.T.)

  2. Tunneling nanotubes: A versatile target for cancer therapy.

    Science.gov (United States)

    Sahoo, Pragyaparamita; Jena, Soumya Ranjan; Samanta, Luna

    2017-11-29

    Currently Cancer is the leading cause of death worldwide. Malignancy or cancer is a class of diseases characterized by uncontrolled cell growth that eventually invade other tissues and dvelop secondary malignant growth at other sites by metastasis. Intercellular communication plays a major in cancer, particularly in the process of cell proliferation and coordination which in turn leads to tumor invasion, metastasis and development of resistance to therapy. Cells communicate among themselves in a variety of ways, namely, i) via gap junctions with adjacent cells, ii) via exosomes with nearby cells and iii) via chemical messengers with distant cells. Besides, cell - cell connection by tunneling nanotubes (TnTs) is recently gaining importance where intercellular components are transferred between cells. In general cell organelles like Golgi vesicle and mitochondria; and biomolecules like nucleic acids and proteins are transferred through these TnTs. These TnTs are long cytoplasmic extensions made up of actin that function as intercellular bridge and connect a wide verity of cell types. Malignant cells form TnTs with either another malignant cells or cells of the surrounding tumor matrix. These TnTs help in the process of initiation of tumor formation, its organization and propagation. The current review focuses on the role of TnTs mediated cell – cell signaling in cancer micro-environment. Drugs that inhibit TnT-formation such as metformin and everolimus can be targeted towards TnTs in the management of cancer growth, proliferation, tumor invasion and metastasis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Assessing the Response to Targeted Therapies in Renal Cell Carcinoma: Technical Insights and Practical Considerations

    NARCIS (Netherlands)

    Bex, A.; Fournier, L.; Lassau, N.; Mulders, P.F.A.; Nathan, P.; Oyen, W.J.G.; Powles, T.

    2014-01-01

    CONTEXT: The introduction of targeted agents for the treatment of renal cell carcinoma (RCC) has resulted in new challenges for assessing response to therapy, and conventional response criteria using computed tomography (CT) are limited. It is widely recognised that targeted therapies may lead to

  4. Prostate Specific Membrane Antigen (PSMA) Targeted Bio-orthogonal Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0595 TITLE: Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate Cancer...Sep 2016 - 14 Sep 2017 4. TITLE AND SUBTITLE Prostate-Specific Membrane Antigen (PSMA) Targeted Bio -orthogonal Therapy for Metastatic Prostate

  5. Peptide receptor radionuclide therapy with {sup 177}Lu-DOTATATE: the IEO phase I-II study

    Energy Technology Data Exchange (ETDEWEB)

    Bodei, Lisa; Grana, Chiara M.; Baio, Silvia M.; Lombardo, Dario; Chinol, Marco; Paganelli, Giovanni [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); Cremonesi, Marta; Ferrari, Mahila E. [European Institute of Oncology, Division of Medical Physics, Milan (Italy); Fazio, Nicola [European Institute of Oncology, Division of Medical Oncology, Milan (Italy); Iodice, Simona [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Bartolomei, Mirco [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); M. Bufalini Hospital, Division of Nuclear Medicine, Cesena, FC (Italy); Sansovini, Maddalena [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Unit of Radiometabolic Medicine, Meldola, FC (Italy)

    2011-12-15

    Peptide receptor radionuclide therapy (PRRT) is used in tumours expressing type 2 somatostatin receptors (sst{sub 2}), mainly neuroendocrine. The aim of this prospective phase I-II study was to evaluate the toxicity and efficacy of {sup 177}Lu-DOTATATE in multiple cycles. Fifty-one consecutive patients with unresectable/metastatic sst{sub 2}-positive tumours, divided into two groups, received escalating activities (3.7-5.18 GBq/cycle, group 1; 5.18-7.4 GBq/cycle, group 2) of {sup 177}Lu-DOTATATE. Cumulative activities ranged from 3.7 to 29.2 GBq (median 26.4 GBq in median 6 cycles, group 1, 21 patients) and 5.55 to 28.9 GBq (median 25.2 GBq in 4 cycles, group 2, 30 patients), based on dosimetry. No major acute or delayed renal or haematological toxicity occurred (one grade 3 leukopenia and thrombocytopenia). Cumulative renal absorbed doses were 8-37 Gy (9-41 Gy bioeffective doses). A median decrease of creatinine clearance of 21.7% 6 months after PRRT, 23.9% after 1 year and 27.6% after 2 years was observed. Higher losses (>20%) occurred in patients with risk factors for renal toxicity, particularly hypertension and diabetes. Cumulative bone marrow doses were <1.5 Gy. Blood elements showed a progressive mild drop during cycles and recovered during follow-up (median 30 months). Thirty-nine patients were progressive at enrolment. Partial and complete responses occurred in 15 of 46 (32.6%) assessable patients. The median time to progression was 36 months. Overall survival was 68% at 36 months. Non-responders and patients with extensive tumour involvement had lower survival. {sup 177}Lu-DOTATATE was well tolerated up to 29 GBq cumulative activity (up to 7.4 GBq/cycle). The maximum tolerated dose/cycle was not reached. However, considering the individual bone marrow function and the presence of risk factors for kidney toxicity, it seems safer to divide cumulative activities into lower activity cycles. (orig.)

  6. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with {sup 177}Lu-octreotate

    Energy Technology Data Exchange (ETDEWEB)

    Sabet, Amir; Ezziddin, Khaled; Reichman, Karl; Haslerud, Torjan; Ahmadzadehfar, Hojjat; Biersack, Hans-Juergen; Ezziddin, Samer [University Hospital Bonn, Department of Nuclear Medicine, Bonn (Germany); Pape, Ulrich-Frank [Charite, University Medicine Berlin, Campus Virchow Clinic, Department of Hepatology and Gastroenterology, Berlin (Germany); Nagarajah, James [University Hospital, Department of Nuclear Medicine, Essen (Germany)

    2014-03-15

    Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine - allowing only approximate estimates of GFR - the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement. Nephrotoxicity was analysed using {sup 99m}Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with {sup 177}Lu-octreotate. The mean follow-up period was 21 months (range 12-50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by {sup 99m}Tc-DTPA clearance versus serum creatinine. The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m{sup 2} per year, relative yearly reduction -1.8 ± 18.9 %). Fifteen patients (21 %) experienced a mild (2-10 ml/min/m{sup 2} per year) and 16 patients (22 %) a significant (>10 ml/min/m{sup 2} per year) decline of GFR following PRRT. However, 11 patients (15 %) showed an increase of >10 ml/min/m{sup 2} per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3 %) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15 % of the assessments and led to underestimation in 12 % of

  7. Peptide receptor radionuclide therapy with 90Y/177Lu-labelled peptides for inoperable head and neck paragangliomas (glomus tumours)

    International Nuclear Information System (INIS)

    Puranik, Ameya D.; Kulkarni, Harshad R.; Singh, Aviral; Baum, Richard P.

    2015-01-01

    Head and neck paragangliomas (HNPGLs) are rare tumours arising from autonomic nervous system ganglia. Although surgery offers the best chance of complete cure, there is associated morbidity due to the crucial location of these tumours. Radiotherapy arrests tumour growth and provides symptomatic improvement, but has long-term consequences. These tumours express somatostatin receptors (SSTR) and hence peptide receptor radionuclide therapy (PRRT) is now a treatment option. We assessed the molecular, morphological and clinical responses of inoperable HNPGLs to PRRT. Nine patients with inoperable HNPGL assessed between June 2006 and June 2014 were included. Four patients had a solitary lesion, four had multifocal involvement and one had distant metastases (bone and lungs). The patients were treated with PRRT using 90 Y/ 177 Lu-labelled peptides after positive confirmation of SSTR expression on 68 Ga-DOTATOC PET/CT. All patients received two to four courses of PRRT. Subsequent serial imaging with 68 Ga-DOTATOC PET/CT was carried out every 6 months to assess response to treatment. Clinical (symptomatic) response was also assessed. Based on molecular response (EORTC) criteria, four of the nine patients showed a partial molecular response to treatment seen as significant decreases in SUV max , accompanied by a reduction in tumour size. Five patients showed stable disease on both molecular and morphological criteria. Six out of nine patients were symptomatic at presentation with manifestations of cranial nerve involvement, bone destruction at the primary site and metastatic bone pain. Molecular responses were correlated with symptomatic improvement in four out of these six patients; while two patients showed small reductions in tumour size and SUV max . The three asymptomatic patients showed no new lesions or symptomatic worsening. PRRT was effective in all patients, with no disease worsening seen, either in the form of neurological symptoms or distant spread. Though these

  8. Accurate assessment of long-term nephrotoxicity after peptide receptor radionuclide therapy with 177Lu-octreotate

    International Nuclear Information System (INIS)

    Sabet, Amir; Ezziddin, Khaled; Reichman, Karl; Haslerud, Torjan; Ahmadzadehfar, Hojjat; Biersack, Hans-Juergen; Ezziddin, Samer; Pape, Ulrich-Frank; Nagarajah, James

    2014-01-01

    Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine - allowing only approximate estimates of GFR - the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement. Nephrotoxicity was analysed using 99m Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with 177 Lu-octreotate. The mean follow-up period was 21 months (range 12-50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by 99m Tc-DTPA clearance versus serum creatinine. The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m 2 per year, relative yearly reduction -1.8 ± 18.9 %). Fifteen patients (21 %) experienced a mild (2-10 ml/min/m 2 per year) and 16 patients (22 %) a significant (>10 ml/min/m 2 per year) decline of GFR following PRRT. However, 11 patients (15 %) showed an increase of >10 ml/min/m 2 per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3 %) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15 % of the assessments and led to underestimation in 12 % of patients. None of the investigated

  9. Radionuclide therapy of skin cancers and Bowen's disease using specially designed skin patch: A pilot study in an animal model and clinical trial

    International Nuclear Information System (INIS)

    Lee, J. D.; Park, K. K.; Lee, M. G.; Lee, J. T.; Yoo, H. S.; Kim, E. H.; Rhim, K. J.; Kim, Y. M.; Park, K. B.; Kim, J. R.

    1997-01-01

    Skin cancer is the most common malignant tumors in human. Therapeutic modalities of the skin cancers are local destruction, radiotherapy and surgery. External radiation therapy leads to good results, however, overall 5-6 weeks of treatment period is needed to deliver optimal radiation dose to tumors. In this study, β-emitting radionuclide, Ho-166, impregnated in a specially designed patch was utilized to superficial skin cancers and Bowen's disease for local irradiation. Methods; Animal study was employed in 10 mice with chemically induced skin tumors. Five- mm size patches containing 22.2 -72.15 MBq(0.6 - 1.95 mCi) of Ho-166 were applied to the tumor surface for 1 -2 hr. In clinical trial, patients with squamous carcinoma(n=3), basal cell carcinoma(n=1), and Bowen's disease(n=1) were treated with patches containing 273.8 - 999 MBq (7.4 - 27 mCi) of Ho-166 for 30 minutes to 1 hour. Pathologic examination was performed 4 - 7 weeks after the treatment in animal model. Skin biopsy was performed 8 weeks post-treatment in four patients. Results; Tumor destruction was seen 1 week post the treatment, however, radiation dermatitis or ulceration developed at the site of radionuclide application. Those reactions healed gradually with fibrosis or epithelialization, which was confirmed pathologically. No significant adverse reaction to radiation except subcutaneous fibrosis was found. Conclusion; Superficial skin tumors could be successfully treated by topical application of β-emitting radionuclides. (author)

  10. Risky business: target choice in adoptive cell therapy.

    Science.gov (United States)

    Morgan, Richard A

    2013-11-14

    In this issue of Blood, Casucci et al present an elegant study that describes a potential new target for adoptive cell transfer (ACT), in this case CD44 splice variant 6 (CD44v6), and detail why it may be a good target for ACT and how to manage expected off-tumor/on-target toxicities.

  11. Specifically targeted gene therapy for small-cell lung cancer

    DEFF Research Database (Denmark)

    Christensen, C.L.; Zandi, R.; Gjetting, T.

    2009-01-01

    Small-cell lung cancer (SCLC) is a highly malignant disease with poor prognosis. Hence, there is great demand for new therapies that can replace or supplement the current available treatment regimes. Gene therapy constitutes a promising strategy and relies on the principle of introducing exogenous...

  12. Radionuclide toxicity

    International Nuclear Information System (INIS)

    Galle, P.

    1982-01-01

    The aim of this symposium was to review the radionuclide toxicity problems. Five topics were discussed: (1) natural and artificial radionuclides (origin, presence or emission in the environment, human irradiation); (2) environmental behaviour of radionuclides and transfer to man; (3) metabolism and toxicity of radionuclides (radioiodine, strontium, rare gas released from nuclear power plants, ruthenium-activation metals, rare earths, tritium, carbon 14, plutonium, americium, curium and einsteinium, neptunium, californium, uranium) cancerogenous effects of radon 222 and of its danghter products; (4) comparison of the hazards of various types of energy; (5) human epidemiology of radionuclide toxicity (bone cancer induction by radium, lung cancer induction by radon daughter products, liver cancer and leukaemia following the use of Thorotrast, thyroid cancer; other site of cancer induction by radionuclides) [fr

  13. Combination of vascular targeting agents with thermal or radiation therapy

    International Nuclear Information System (INIS)

    Horsman, Michael R.; Murata, Rumi

    2002-01-01

    Purpose: The most likely clinical application of vascular targeting agents (VTAs) is in combination with more conventional therapies. In this study, we report on preclinical studies in which VTAs were combined with hyperthermia and/or radiation. Methods and Materials: A C3H mammary carcinoma grown in the right rear foot of female CDF1 mice was treated when at 200 mm 3 in size. The VTAs were combretastatin A-4 disodium phosphate (CA4DP, 25 mg/kg), flavone acetic acid (FAA, 150 mg/kg), and 5,6-dimethylxanthenone-4-acetic acid (DMXAA, 20 mg/kg), and were all injected i.p. Hyperthermia and radiation were locally administered to tumors of restrained, nonanesthetized mice, and response was assessed using either a tumor growth or tumor control assay. Results: Heating tumors at 41.5 degree sign C gave rise to a linear relationship between the heating time and tumor growth with a slope of 0.02. This slope was increased to 0.06, 0.09, and 0.08, respectively, by injecting the VTAs either 30 min (CA4DP), 3 h (FAA), or 6 h (DMXAA) before heating. The radiation dose (±95% confidence interval) that controls 50% of treated tumors (the TCD 50 value) was estimated to be 53 Gy (51-55 Gy) for radiation alone. This was decreased to 48 Gy (46-51 Gy), 45 Gy (41-49 Gy), and 42 Gy (39-45 Gy), respectively, by injecting CA4DP, DMXAA, or FAA 30-60 min after irradiating. These values were further decreased to around 28-33 Gy if the tumors of VTA-treated mice were also heated to 41.5 degree sign C for 1 h, starting 4 h after irradiation, and this effect was much larger than the enhancement seen with either 41.5 degree sign C or even 43 degree sign C alone. Conclusions: Our preclinical studies and those of others clearly demonstrate that VTAs can enhance tumor response to hyperthermia and/or radiation and support the concept that such combination studies should be undertaken clinically for the full potential of VTAs to be realized

  14. Treatment outcome of radiation therapy and concurrent targeted molecular therapy in spinal metastasis from renal cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sang Joon; Kim, Kyung Hwan; Rhee, Woo Joong; Lee, Jeong Shin; Cho, Yeo Na; Koom, Woong Sub [Dept. of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of)

    2016-06-15

    To evaluate the clinical outcomes of patients who underwent radiation therapy with or without targeted molecular therapy for the treatment of spinal metastasis from renal cell carcinoma (RCC). A total of 28 spinal metastatic lesions from RCC patients treated with radiotherapy between June 2009 and June 2015 were retrospectively reviewed. Thirteen lesions were treated concurrently with targeted molecular therapy (concurrent group) and 15 lesions were not (nonconcurrent group). Local control was defined as lack of radiographically evident local progression and neurological deterioration. At a median follow-up of 11 months (range, 2 to 58 months), the 1-year local progression-free rate (LPFR) was 67.0%. The patients with concurrent targeted molecular therapy showed significantly higher LPFR than those without (p = 0.019). After multivariate analysis, use of concurrent targeted molecular therapy showed a tendency towards improved LPFR (hazard ratio, 0.13; 95% confidence interval, 0.01 to 1.16). There was no difference in the incidence of systemic progression between concurrent and nonconcurrent groups. No grade ≥2 toxicities were observed during or after radiotherapy. Our study suggests the possibility that concurrent use of targeted molecular therapy during radiotherapy may improve LPFR. Further study with a large population is required to confirm these results.

  15. Treatment outcome of radiation therapy and concurrent targeted molecular therapy in spinal metastasis from renal cell carcinoma

    International Nuclear Information System (INIS)

    Park, Sang Joon; Kim, Kyung Hwan; Rhee, Woo Joong; Lee, Jeong Shin; Cho, Yeo Na; Koom, Woong Sub

    2016-01-01

    To evaluate the clinical outcomes of patients who underwent radiation therapy with or without targeted molecular therapy for the treatment of spinal metastasis from renal cell carcinoma (RCC). A total of 28 spinal metastatic lesions from RCC patients treated with radiotherapy between June 2009 and June 2015 were retrospectively reviewed. Thirteen lesions were treated concurrently with targeted molecular therapy (concurrent group) and 15 lesions were not (nonconcurrent group). Local control was defined as lack of radiographically evident local progression and neurological deterioration. At a median follow-up of 11 months (range, 2 to 58 months), the 1-year local progression-free rate (LPFR) was 67.0%. The patients with concurrent targeted molecular therapy showed significantly higher LPFR than those without (p = 0.019). After multivariate analysis, use of concurrent targeted molecular therapy showed a tendency towards improved LPFR (hazard ratio, 0.13; 95% confidence interval, 0.01 to 1.16). There was no difference in the incidence of systemic progression between concurrent and nonconcurrent groups. No grade ≥2 toxicities were observed during or after radiotherapy. Our study suggests the possibility that concurrent use of targeted molecular therapy during radiotherapy may improve LPFR. Further study with a large population is required to confirm these results

  16. Targeted Therapies in Hematology and Their Impact on Patient Care: Chronic and Acute Myeloid Leukemia

    Science.gov (United States)

    Cortes, Elias Jabbour Jorge; Ravandi, Farhad; O’Brien, Susan; Kantarjian, Hagop

    2014-01-01

    Advances in the genetic and molecular characterizations of leukemias have enhanced our capabilities to develop targeted therapies. The most dramatic examples of targeted therapy in cancer to date are the use of targeted BCR-ABL protein tyrosine kinase inhibitors (TKI) which has revolutionized the treatment of chronic myeloid leukemia (CML). Inhibition of the signaling activity of this kinase has proved to be a highly successful treatment target, transforming the prognosis of patients with CML. In contrast, acute myeloid leukemia (AML) is an extremely heterogeneous disease with outcomes that vary widely according to subtype of the disease. Targeted therapy with monoclonal antibodies and small molecule kinase inhibitors are promising strategies to help improve the cure rates in AML. In this review, we will highlight the results of recent clinical trials in which outcomes of CML and AML have been influenced significantly. Also, novel approaches to sequencing and combining available therapies will be covered. PMID:24246694

  17. Targeted Therapies for Myeloma and Metastatic Bone Cancers

    National Research Council Canada - National Science Library

    Vail, Neal

    2008-01-01

    ... done. Quantified functional groups available for ligand conjugation using S35-labeled ligands. Developed alternative assay to confirm affinity of bone-targeting nanoparticles to hydroxyapatite substrates...

  18. Radiolabeled enzyme inhibitors and binding agents targeting PSMA: Effective theranostic tools for imaging and therapy of prostate cancer

    International Nuclear Information System (INIS)

    Pillai, Maroor Raghavan Ambikalmajan; Nanabala, Raviteja; Joy, Ajith; Sasikumar, Arun; Knapp, Furn F.

    2016-01-01

    Because of the broad incidence, morbidity and mortality associated with prostate-derived cancer, the development of more effective new technologies continues to be an important goal for the accurate detection and treatment of localized prostate cancer, lymphatic involvement and metastases. Prostate-specific membrane antigen (PSMA; Glycoprotein II) is expressed in high levels on prostate-derived cells and is an important target for visualization and treatment of prostate cancer. Radiolabeled peptide targeting technologies have rapidly evolved over the last decade and have focused on the successful development of radiolabeled small molecules that act as inhibitors to the binding of the N-acetyl-L-aspartyl-L-glutamate (NAAG) substrate to the PSMA molecule. A number of radiolabeled PSMA inhibitors have been described in the literature and labeled with SPECT, PET and therapeutic radionuclides. Clinical studies with these agents have demonstrated the improved potential of PSMA-targeted PET imaging agents to detect metastatic prostate cancer in comparison with conventional imaging technologies. Although many of these agents have been evaluated in humans, by far the most extensive clinical literature has described use of the 68 Ga and 177 Lu agents. This review describes the design and development of these agents, with a focus on the broad clinical introduction of PSMA targeting motifs labeled with 68 Ga for PET-CT imaging and 177 Lu for therapy. In particular, because of availability from the long-lived 68 Ge (T 1/2 = 270 days)/ 68 Ga (T 1/2 = 68 min) generator system and increasing availability of PET-CT, the 68 Ga-labeled PSMA targeted agent is receiving widespread interest and is one of the fastest growing radiopharmaceuticals for PET-CT imaging.

  19. IGF-IR targeted therapy: Past, present and future

    NARCIS (Netherlands)

    J.A.M.J.L. Janssen (Joseph); A.J. Varewijck (Aimee)

    2014-01-01

    textabstractThe IGF-I receptor (IGF-IR) has been studied as an anti-cancer target. However, monotherapy trials with IGF-IR targeted antibodies or with IGF-IR specific tyrosine kinase inhibitors have, overall, been very disappointing in the clinical setting. This review discusses potential reasons

  20. Targeted alpha therapy in vivo: direct evidence for single cancer cell kill using 149Tb-rituximab

    International Nuclear Information System (INIS)

    Beyer, G.J.; Soloviev, D.; Buchegger, F.; Miederer, M.; Vranjes-Duric, S.; Comor, J.J.; Kuenzi, G.; Hartley, O.; Senekowitsch-Schmidtke, R.

    2004-01-01

    This study demonstrates high-efficiency sterilisation of single cancer cells in a SCID mouse model of leukaemia using rituximab, a monoclonal antibody that targets CD20, labelled with terbium-149, an alpha-emitting radionuclide. Radio-immunotherapy with 5.5 MBq labelled antibody conjugate (1.11 GBq/mg) 2 days after an intravenous graft of 5.10 6 Daudi cells resulted in tumour-free survival for >120 days in 89% of treated animals. In contrast, all control mice (no treatment or treated with 5 or 300 μg unlabelled rituximab) developed lymphoma disease. At the end of the study period, 28.4%±4% of the long-lived daughter activity remained in the body, of which 91.1% was located in bone tissue and 6.3% in the liver. A relatively high daughter radioactivity concentration was found in the spleen (12%±2%/g), suggesting that the killed cancer cells are mainly eliminated through the spleen. This promising preliminary in vivo study suggests that targeted alpha therapy with 149 Tb is worthy of consideration as a new-generation radio-immunotherapeutic approach. (orig.)

  1. Peptide receptor radionuclide therapy of Merkel cell carcinoma using 177lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy. A potential novel treatment based on molecular pathology

    International Nuclear Information System (INIS)

    Salavati, A.; Prasad, V.; Baum, R.P.; Schneider, C.P.; Herbst, R.

    2012-01-01

    Few studies have been published on the safety and feasibility of synchronous use of peptide receptor radionuclide therapy (PRRNT), as source of internal radiation therapy, in combination with chemotherapy. In this study we reported a 53-year-old man with stage IV Merkel cell carcinoma (MCC), who underwent synchronous internal radiation therapy and chemotherapy. Based on presumable poor prognosis with chemotherapy only, functional similarities of MCC with other neuroendocrine tumors and available evidence of effectiveness and safety of synchronous use of external beam radiation therapy and chemotherapy in treatment of high-risk MCC patients, our interdisciplinary neuroendocrine tumor board recommended him to add PRRNT to his ongoing chemotherapy. He received 2 courses of 177 Lu-DOTATATE(1, 4, 7, 10-Tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-D-Phe1-Tyr3-Thr8-octreotide) in combination with ongoing 8 cycles of liposomal doxorubicin based on standard protocols. Response to therapy was evaluated by 18 F-fluorodeoxyglucose ( 18 F-FDG) and 68 gallium-somatostatin-receptor PET/CT. There was an impressive improvement of the clinical symptoms. However, follow-up positron emission tomography (PET)/CT studies showed mixed pattern of response. Synchronous use of PRRNT and radiosensitizing chemotherapy seems safe and feasible in high risk MCC patients, however, further prospective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of PRRNT and 68 Ga-somatostatin-receptor PET/CT in the management of MCC. (author)

  2. Radionuclide cisternography

    International Nuclear Information System (INIS)

    Song, H.H.

    1980-01-01

    The purpose of this thesis is to show that radionuclide cisternography makes an essential contribution to the investigation of cerebrospinal fluid (CSF) dynamics, especially for the investigation of hydrocephalus. The technical details of radionuclide cisternography are discussed, followed by a description of the normal and abnormal radionuclide cisternograms. The dynamics of CFS by means of radionuclide cisternography were examined in 188 patients in whom some kind of hydrocephalus was suspected. This study included findings of anomalies associated with hydrocephalus in a number of cases, such as nasal liquorrhea, hygromas, leptomeningeal or porencephalic cysts. The investigation substantiates the value of radionuclide cisternography in the diagnosis of disturbances of CSF flow. The retrograde flow of radiopharmaceutical into the ventricular system (ventricular reflux) is an abnormal phenomenon indicating the presence of communicating hydrocephalus. (Auth.)

  3. PLGA nanoparticles for peptide receptor radionuclide therapy of neuroendocrine tumors: a novel approach towards reduction of renal radiation dose.

    Directory of Open Access Journals (Sweden)

    Geetanjali Arora

    Full Text Available BACKGROUND: Peptide receptor radionuclide therapy (PRRT, employed for treatment of neuroendocrine tumors (NETs is based on over-expression of Somatostatin Receptors (SSTRs on NETs. It is, however, limited by high uptake and retention of radiolabeled peptide in kidneys resulting in unnecessary radiation exposure thus causing nephrotoxicity. Employing a nanocarrier to deliver PRRT drugs specifically to the tumor can reduce the associated nephrotoxicity. Based on this, (177Lu-DOTATATE loaded PLGA nanoparticles (NPs were formulated in the present study, as a potential therapeutic model for NETs. METHODOLOGY AND FINDINGS: DOTATATE was labeled with Lutetium-177 ((177Lu (labeling efficiency 98%; R(f∼0.8. Polyethylene Glycol (PEG coated (177Lu-DOTATATE-PLGA NPs (50:50 and 75:25 formulated, were spherical with mean size of 304.5±80.8 and 733.4±101.3 nm (uncoated and 303.8±67.2 and 494.3±71.8 nm (coated for PLGA(50:50 and PLGA(75:25 respectively. Encapsulation efficiency (EE and In-vitro release kinetics for uncoated and coated NPs of PLGA (50:50 & 75:25 were assessed and compared. Mean EE was 77.375±4.98% & 67.885±5.12% (uncoated and 65.385±5.67% & 58.495±5.35% (coated. NPs showed initial burst release between 16.64-21.65% with total 42.83-44.79% over 21 days. The release increased with coating to 20.4-23.95% initially and 60.97-69.12% over 21 days. In-vivo studies were done in rats injected with (177Lu-DOTATATE and (177Lu-DOTATATE-NP (uncoated and PEG-coated by imaging and organ counting after sacrificing rats at different time points over 24 hr post-injection. With (177Lu-DOTATATE, renal uptake of 37.89±10.2%ID/g was observed, which reduced to 4.6±1.97% and 5.27±1.66%ID/g with uncoated and coated (177Lu-DOTATATE-NP. The high liver uptake with uncoated (177Lu-DOTATATE-NP (13.68±3.08% ID/g, reduced to 7.20±2.04%ID/g (p = 0.02 with PEG coating. CONCLUSION: PLGA NPs were easily formulated and modified for desired release properties. PLGA

  4. Paving the way to personalized medicine. Production of some theragnostic radionuclides at Brookhaven National Laboratory

    International Nuclear Information System (INIS)

    Srivastava, S.C.

    2011-01-01

    This paper introduces a relatively novel paradigm that involves specific individual radionuclides or radionuclide pairs that have emissions that allow pre-therapy low-dose imaging plus higher-dose therapy in the same patient. We have made an attempt to sort out and organize a number of such theragnostic radionuclides and radionuclide pairs that may potentially bring us closer to the age-long dream of personalized medicine for performing tailored low-dose molecular imaging (SPECT/CT or PET/CT) to provide the necessary pre-therapy information on biodistribution, dosimetry, the limiting or critical organ or tissue, and the maximum tolerated dose (MTD), etc. If the imaging results then warrant it, it would be possible to perform higher-dose targeted molecular therapy in the same patient with the same radiopharmaceutical. A major problem that remains yet to be fully resolved is the lack of availability, in sufficient quantities, of a majority of the best candidate theragnostic radionuclides in a no-carrier-added (NCA) form. A brief description of the recently developed new or modified methods at BNL for the production of four theragnostic radionuclides, whose nuclear, physical, and chemical characteristics seem to show great promise for personalized cancer therapy are described.

  5. IGF system targeted therapy: Therapeutic opportunities for ovarian cancer.

    Science.gov (United States)

    Liefers-Visser, J A L; Meijering, R A M; Reyners, A K L; van der Zee, A G J; de Jong, S

    2017-11-01

    The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  6. Development of an electrochemical 90Sr-90Y generator for separation of 90Y suitable for targeted therapy

    International Nuclear Information System (INIS)

    Chakravarty, Rubel; Pandey, Usha; Manolkar, Remani B.; Dash, Ashutosh; Venkatesh, Meera; Pillai, M.R. Ambikalmajan

    2008-01-01

    90 Y of high specific activity and very high radionuclidic purity (>99.998%) is essential for targeted therapy. Since the current methods used for the preparation of 90 Y from 90 Sr are not adaptable for use in a central/hospital radiopharmacy, a simple 90 Sr- 90 Y generator system based on electrochemical separation technique was developed. Methods: Two-cycle electrolysis procedure was developed for separation of 90 Y from 90 Sr in nitrate solution. The first electrolysis was performed for 90 min in 90 Sr(NO 3 ) 2 feed solution at pH 2-3 at a potential of -2.5V with 100-200 mA current using platinum electrodes. The second electrolysis was performed for 45 min in 3 mM HNO 3 at a potential of -2.5V with 100 mA current. In this step, the cathode from the first electrolysis containing 90 Y was used as anode along with a fresh circular platinum electrode as cathode. The 90 Y deposited on the circular cathode after the second electrolysis was dissolved in acetate buffer to obtain 90 Y acetate, suitable for radiolabeling. Results: >96% recovery of 90 Y could be achieved in each cycle, with an overall decay corrected yield of >90%. The recovered 90 Y had high radionuclidic purity with barely 30.2±15.2 kBq (817±411 nCi) of 90 Sr per 37 GBq (1 Ci) of 90 Y (0.817±0.411 ppm). Consistent and repeated separation could be demonstrated using up to 1.85 GBq (50 mCi) of 90 Sr. The generator was named 'Kamadhenu,' the eternally milk-yielding Indian mythological cow. Conclusions: A technique suitable for adaptation at central radiopharmacies for obtaining therapeutic quantities of pure 90 Y has been developed

  7. Prostate Cancer Clinical Consortium Clinical Research Site: Targeted Therapies

    Science.gov (United States)

    2017-10-01

    prostate cancer . Cancer Res 70: 7992-8002, 2010 8. Nelson PS: Molecular states underlying an- drogen receptor activation: A framework for thera- peutics...targeting androgen signaling in prostate cancer . J Clin Oncol 30:644-646, 2012 9. Thadani-Mulero M, Nanus DM, Giannakakou P: Androgen receptor on the... prostate cancer . Clin Cancer Res 21:795-807, 2015 17. van Soest RJ, de Morrée ES, Kweldam CF, et al: Targeting the androgen receptor confers in vivo

  8. Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy

    International Nuclear Information System (INIS)

    Kim, Dong Wook; Huamani, Jessica; Fu, Allie; Hallahan, Dennis E.

    2006-01-01

    The tumor microenvironment, in particular, the tumor vasculature, as an important target for the cytotoxic effects of radiation therapy is an established paradigm for cancer therapy. We review the evidence that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated in endothelial cells exposed to ionizing radiation (IR) and is a molecular target for the development of novel radiation sensitizing agents. On the basis of this premise, several promising preclinical studies that targeted the inhibition of the PI3K/Akt activation as a potential method of sensitizing the tumor vasculature to the cytotoxic effects of IR have been conducted. An innovative strategy to guide cytotoxic therapy in tumors treated with radiation and PI3K/Akt inhibitors is presented. The evidence supports a need for further investigation of combined-modality therapy that involves radiation therapy and inhibitors of PI3K/Akt pathway as a promising strategy for improving the treatment of patients with cancer

  9. RANKL-Targeted Therapies: The Next Frontier in the Treatment of Male Osteoporosis

    Directory of Open Access Journals (Sweden)

    Alicia K. Morgans

    2011-01-01

    Full Text Available Male osteoporosis is an increasingly recognized problem in aging men. A common cause of male osteoporosis is hypogonadism. Thousands of men with prostate cancer are treated with androgen deprivation therapy, a treatment that dramatically reduces serum testosterone and causes severe hypogonadism. Men treated with androgen deprivation therapy experience a decline in bone mineral density and have an increased rate of fracture. This paper describes prostate cancer survivors as a model of hypogonadal osteoporosis and discusses the use of RANKL-targeted therapies in osteoporosis. Denosumab, the only RANKL-targeted therapy currently available, increases bone mineral density and decreases fracture rate in men with prostate cancer. Denosumab is also associated with delayed time to first skeletal-related event and an increase in bone metastasis-free survival in these men. It is reasonable to investigate the use of RANKL-targeted therapy in male osteoporosis in the general population.

  10. Apoptosis and cancer stem cells : Implications for apoptosis targeted therapy

    NARCIS (Netherlands)

    Kruyt, Frank A. E.; Schuringa, Jan Jacob

    2010-01-01

    Evidence is accumulating showing that cancer stem cells or tumor-initiating cells are key drivers of tumor formation and progression. Successful therapy must therefore eliminate these cells, which is hampered by their high resistance to commonly used treatment modalities. Thus far, only a limited

  11. Stimuli-responsive biodegradable polymeric micelles for targeted cancer therapy

    NARCIS (Netherlands)

    Talelli, M.A.

    2011-01-01

    Thermosensitive and biodegradable polymeric micelles based on mPEG-b-pHPMAmLacn have shown very promising results during the past years. The results presented in this thesis illustrate the high potential of these micelles for anticancer therapy and imaging and fully justify further pharmaceutical

  12. Graves' disease radioiodine-therapy: Choosing target absorbed doses for therapy planning

    Energy Technology Data Exchange (ETDEWEB)

    Willegaignon, J., E-mail: j.willegaignon@gmail.com; Sapienza, M. T.; Coura-Filho, G. B.; Buchpiguel, C. A. [Cancer Institute of São Paulo State (ICESP), Clinical Hospital, School of Medicine, University of São Paulo, São Paulo 01246-000 (Brazil); Nuclear Medicine Service, Department of Radiology, School of Medicine, University of São Paulo, Sao Paulo 01246-000 (Brazil); Watanabe, T. [Nuclear Medicine Service, Department of Radiology, School of Medicine, University of São Paulo, São Paulo 01246-000 (Brazil); Traino, A. C. [Unit of Medical Physics, Azienda Ospedaliero-Universitaria Pisana, Pisa 56126 (Italy)

    2014-01-15

    {sup ~} was determined by the integration of measured {sup 131}I activity in the thyroid gland and based on T{sub eff}, respectively. No statistically significant relationship was found between therapeutic response and patients’ age, administered {sup 131}I activity (MBq), 24-h thyroid {sup 131}I uptake (%) or T{sub eff} (p ≥ 0.064); nonetheless, a good relationship was found between the therapeutic response and m{sub th} (p ≤ 0.035). Conclusions: According to the results of this study, the most effective thyroid absorbed dose to be targeted in GD therapy should not be based on a fixed dose but rather should be individualized based on the patient'sm{sub th} and A{sup ~}. To achieve a therapeutic success (i.e., durable euthyroidism or hypothyroidism) rate of at least 95%, a thyroid absorbed dose of 200 or 330 Gy is required depending on the methodology used for estimating m{sub th} and A{sup ~}.

  13. Development of a Novel Targeted RNAi Delivery Technology inTherapies for Metabolic Diseases

    Science.gov (United States)

    2017-10-01

    report Impact on other disciplines: Nothing to report Impact on technology transfer: Nothing to report Impact on society : Nothing to report 5. CHANGES...AWARD NUMBER: W81XWH-15-1-0569 TITLE: Development of a Novel Targeted RNAi Delivery Technology in Therapies for Metabolic Diseases PRINCIPAL...COVERED 30Sep2016 - 29Sep2017 4. TITLE AND SUBTITLE Development of a Novel Targeted RNAi Delivery Technology in Therapies for Metabolic Diseases 5a

  14. Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    2017-09-01

    AWARD NUMBER: W81XWH-15-1-0419 TITLE: Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease...COVERED 1 Sep 2016 - 31 Aug 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal...inappropriate cell growth, fluid secretion, and dysregulation of cellular energy metabolism. The enzyme AMPK regulates a number of cellular pathways, including

  15. Effectiveness of Targeted Musical Therapy on Sleep Quality and Overcoming Insomnia in Seniors

    Directory of Open Access Journals (Sweden)

    Reza Mottaghi

    2016-07-01

    Conclusion: The present study showed that targeted music therapy can lead to the improvement in the overall sleep quality, daily functioning, and subjective sleep quality thereby resulting in a sharp decline in the number of sleep drugs in seniors with primary insomnia disorder. Therefore, it is highly recommended by the music therapy and mental health experts for overcoming the sleep problems in older adults.

  16. Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly & Cushing Disease Paradigms

    Directory of Open Access Journals (Sweden)

    Michael Anthony Mooney

    2016-07-01

    Full Text Available The current treatment of pituitary adenomas requires a balance of conservative management, surgical resection, and in select tumor types, molecular therapy. Acromegaly treatment is an evolving field where our understanding of molecular targets and drug therapies has improved treatment options for patients with excess growth hormone levels. We highlight the use of molecular therapies in this disease process and advances in this field, which may represent a paradigm shift for the future of pituitary adenoma treatment.

  17. Advancing Treatment of Pituitary Adenomas through Targeted Molecular Therapies: The Acromegaly and Cushing Disease Paradigms.

    Science.gov (United States)

    Mooney, Michael A; Simon, Elias D; Little, Andrew S

    2016-01-01

    The current treatment of pituitary adenomas requires a balance of conservative management, surgical resection, and in select tumor types, molecular therapy. Acromegaly treatment is an evolving field where our understanding of molecular targets and drug therapies has improved treatment options for patients with excess growth hormone levels. We highlight the use of molecular therapies in this disease process and advances in this field, which may represent a paradigm shift for the future of pituitary adenoma treatment.

  18. Companion diagnostics for the targeted therapy of gastric cancer.

    Science.gov (United States)

    Yoo, Changhoon; Park, Young Soo

    2015-10-21

    Gastric cancer is the fourth most common type of cancer and represents a major cause of cancer-related deaths worldwide. With recent biomedical advances in our understanding of the molecular characteristics of gastric cancer, many genetic alterations have been identified as potential targets for its treatment. Multiple novel agents are currently under development as the demand for active agents that improve the survival of gastric cancer patients constantly increases. Based on lessons from previous trials of targeted agents, it is now widely accepted that the establishment of an optimal diagnostic test to select molecularly defined patients is of equal importance to the development of active agents against targetable genetic alterations. Herein, we highlight the current status and future perspectives of companion diagnostics in the treatment of gastric cancer.

  19. High current Tl-203, Rh-103 targets preparation for cyclotron production of Tl-201 and Pd-103 radionuclides

    International Nuclear Information System (INIS)

    Arzumanov, A.; Berger, V.; Borissenko, A.; Gorodisskaya, N.; Ilmatov, I.; Knyazev, A.; Koptev, V.; Lyssukhin, S.; Platov, A.; Sychikov, G.; Zheltov, D.

    2004-01-01

    The objectives of the present work are to increase thermal stability of cyclotron targets for production of Tl-201 isotope, increase Tl-203 regeneration rate at radiochemical reprocessing of the targets and develop production technology for radiochemical sources based on Rd-103 isotope. Electrochemical coating of copper substrate with Tl increased the beam current at target irradiation from 100 μA to 125 μA. Further increase of the beam current results in sharp decrease of target stability time at irradiation to 15 min at beam current 150 μA. Thermal calculations and tests at the electron-beam stand predict satisfactory stability at such currents. The discrepancy with the irradiation results has not been explained. More accurate specification of regimes for Tl-203 electrochemical recovery from irradiated targets and better matching of the electrolyte composition made it possible to increase the recovery rate up to 99.5%. Before the present Project, the INP had no experience in production of radioactive sources based on Pd-103. Thermo-diffusion extraction of Pd-103 from irradiated rhodium foil has been chosen as a technology-defining method. The process assures good extraction rate and high purity of extracted isotope. Production of Pd-103 sources based on this technology is much simpler compared to the same based on electrochemical processes. (author)

  20. Cannabinoid Receptors: A Novel Target for Therapy of Prostate Cancer

    Science.gov (United States)

    2007-02-01

    study could be to develop nonhabit-forming cannabi - noid agonist (s) for the management of prostate cancer . REFERENCES 1. Jemal, A., Siegel, R.W...for Therapy of Prostate Cancer PRINCIPAL INVESTIGATOR: Prof. Hasan Mukhtar, Ph.D (PI) Dr. Farrukh Afaq, Ph.D (Co-Investigator...REPORT DATE: February 2007 TYPE OF REPORT: Annual PREPARED FOR: U.S. Army Medical Research and Materiel Command

  1. Targeting dendritic cells in vivo for cancer therapy

    Directory of Open Access Journals (Sweden)

    Irina eCaminschi

    2012-02-01

    Full Text Available Monoclonal antibodies that recognise cell surface molecules have been used deliver antigenic cargo to dendritic cells (DC for induction of immune responses. The encouraging anti-tumour immunity elicited using this immunisation strategy suggests its suitability for clinical trials. This review discusses the complex network of DC, the functional specialisation of DC-subsets, the immunological outcomes of targeting different DC-subsets and their cell surface receptors, and the requirements for the induction of effective anti-tumour immunity. Finally, we review preclinical experiments and the progress towards targeting human DC in vivo.

  2. Targeting post-translational modifications of histones for cancer therapy.

    Science.gov (United States)

    Hsu, Y-C; Hsieh, Y-H; Liao, C-C; Chong, L-W; Lee, C-Y; Yu, Y-L; Chou, R-H

    2015-10-30

    Post-translational modifications (PTMs) on histones including acetylation, methylation, phosphorylation, citrullination, ubiquitination, ADP ribosylation, and sumoylation, play important roles in different biological events including chromatin dynamics, DNA replication, and transcriptional regulation. Aberrant histones PTMs leads to abnormal gene expression and uncontrolled cell proliferation, followed by development of cancers. Therefore, targeting the enzymes required for specific histone PTMs holds a lot of potential for cancer treatment. In this review article, we retrospect the latest studies in the regulations of acetylation, methylation, and phosphorylation of histones. We also summarize inhibitors/drugs that target these modifications for cancer treatment.

  3. Targeted gene therapy and cell reprogramming in Fanconi anemia

    Science.gov (United States)

    Rio, Paula; Baños, Rocio; Lombardo, Angelo; Quintana-Bustamante, Oscar; Alvarez, Lara; Garate, Zita; Genovese, Pietro; Almarza, Elena; Valeri, Antonio; Díez, Begoña; Navarro, Susana; Torres, Yaima; Trujillo, Juan P; Murillas, Rodolfo; Segovia, Jose C; Samper, Enrique; Surralles, Jordi; Gregory, Philip D; Holmes, Michael C; Naldini, Luigi; Bueren, Juan A

    2014-01-01

    Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective lentiviral vectors to demonstrate for the first time that FANCA can be efficiently and specifically targeted into the AAVS1 safe harbor locus in fibroblasts from FA-A patients. Strikingly, up to 40% of FA fibroblasts showed gene targeting 42 days after gene editing. Given the low number of hematopoietic precursors in the bone marrow of FA patients, gene-edited FA fibroblasts were then reprogrammed and re-differentiated toward the hematopoietic lineage. Analyses of gene-edited FA-iPSCs confirmed the specific integration of FANCA in the AAVS1 locus in all tested clones. Moreover, the hematopoietic differentiation of these iPSCs efficiently generated disease-free hematopoietic progenitors. Taken together, our results demonstrate for the first time the feasibility of correcting the phenotype of a DNA repair deficiency syndrome using gene-targeting and cell reprogramming strategies. PMID:24859981

  4. Sphingolipid metabolism enzymes as targets for anticancer therapy

    NARCIS (Netherlands)

    Kok, JW; Sietsma, H

    Treatment with anti-cancer agents in most cases ultimately results in apoptotic cell death of the target tumour cells. Unfortunately, tumour cells can develop multidrug resistance, e.g., by a reduced propensity to engage in apoptosis by which they become insensitive to multiple chemotherapeutics.

  5. Targeted gene therapy and cell reprogramming in Fanconi anemia.

    Science.gov (United States)

    Rio, Paula; Baños, Rocio; Lombardo, Angelo; Quintana-Bustamante, Oscar; Alvarez, Lara; Garate, Zita; Genovese, Pietro; Almarza, Elena; Valeri, Antonio; Díez, Begoña; Navarro, Susana; Torres, Yaima; Trujillo, Juan P; Murillas, Rodolfo; Segovia, Jose C; Samper, Enrique; Surralles, Jordi; Gregory, Philip D; Holmes, Michael C; Naldini, Luigi; Bueren, Juan A

    2014-06-01

    Gene targeting is progressively becoming a realistic therapeutic alternative in clinics. It is unknown, however, whether this technology will be suitable for the treatment of DNA repair deficiency syndromes such as Fanconi anemia (FA), with defects in homology-directed DNA repair. In this study, we used zinc finger nucleases and integrase-defective lentiviral vectors to demonstrate for the first time that FANCA can be efficiently and specifically targeted into the AAVS1 safe harbor locus in fibroblasts from FA-A patients. Strikingly, up to 40% of FA fibroblasts showed gene targeting 42 days after gene editing. Given the low number of hematopoietic precursors in the bone marrow of FA patients, gene-edited FA fibroblasts were then reprogrammed and re-differentiated toward the hematopoietic lineage. Analyses of gene-edited FA-iPSCs confirmed the specific integration of FANCA in the AAVS1 locus in all tested clones. Moreover, the hematopoietic differentiation of these iPSCs efficiently generated disease-free hematopoietic progenitors. Taken together, our results demonstrate for the first time the feasibility of correcting the phenotype of a DNA repair deficiency syndrome using gene-targeting and cell reprogramming strategies. © 2014 The Authors. Published under the terms of the CC BY 4.0 license.

  6. Small molecules and targeted therapies in distant metastatic disease

    DEFF Research Database (Denmark)

    Hersey, P; Bastholt, L; Chiarion-Sileni, V

    2009-01-01

    with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib...

  7. Blood clearance and occupational exposure for {sup 177}Lu-DOTATATE compared to {sup 177}Lu-PSMA radionuclide therapy

    Energy Technology Data Exchange (ETDEWEB)

    Abuqbeitah, Mohammad; Demir, Mustafa; Uslu-Besli, Lebriz; Yeyin, Nami; Soenmezoglu, Kerim [Istanbul University, Department of Nuclear Medicine, Cerrahpasa Faculty of Medicine, Istanbul (Turkey)

    2018-03-15

    The main target of this work is to examine blood clearance and external exposure for {sup 177}Lu-DOTATATE compared with new emerging {sup 177}Lu-PSMA therapy. Blood clearance and radiation exposure of 31 patients treated with 5.5 ± 1.1 GBq {sup 177}Lu-DOTATATE were compared to those of 23 patients treated with 7.4 GBq {sup 177}Lu-PSMA. Dose rates were measured at several distances and time points up to 120 h after treatment. Blood samples were collected conjunctively after infusion. Caregiver's cumulative dose was measured by means of an OSL (optically stimulated luminescence) dosimeter for 4-5 days and medical staff's dose was also estimated using electronic personal dosimeters. Finger dose was determined via ring TLD (Thermoluminescence Dosimeter) for radiopharmacists and nurses. Dose rates due to {sup 177}Lu-DOTATATE at a distance of 1 m, 4 h and 6 h after infusion, were 3.0 ± 2.8 and 2 ± 1.9 μSv/(h GBq), respectively, while those due to {sup 177}Lu-PSMA were 3.1 ± 0.8 and 2.2 ± 0.9 μSv/(h GBq). Total effective dose of 17 caregivers was 100-200 μSv for {sup 177}Lu-DOTATATE therapy. Mean effective doses to nurses and radiopharmacists were 5 and 4 μSv per patient, respectively, while those for physicists and physicians were 2 μSv per patient. For {sup 177}Lu-DOTATATE, effective half-life in blood and early elimination phase were 0.31 ± 0.13 and 4.5 ± 1 h, while they were found as 0.4 ± 0.1 and 5 ± 1 h, respectively, for {sup 177}Lu-PSMA. The first micturition time following {sup 177}Lu-DOTATATE infusion was noted after 36 ± 14 min, while the second and third voiding times were after 74 ± 9 and 128 ± 41 min, respectively. It is concluded that blood clearance and radiation exposure for {sup 177}Lu-DOTATATE are very similar to those for {sup 177}Lu-PSMA, and both treatment modalities are reasonably reliable for outpatient treatment, since the mean dose rate [2.1 μSv/(h GBq)] decreased below the dose rate that allows release of the patient

  8. Radionuclide carrier

    International Nuclear Information System (INIS)

    Hartman, F.A.; Kretschmar, H.C.; Tofe, A.J.

    1978-01-01

    A physiologically acceptable particulate radionuclide carrier is described. It comprises a modified anionic starch derivative with 0.1% to 1.5% by weight of a reducing agent and 1 to 20% by weight of anionic substituents

  9. Reimbursement of targeted cancer therapies within 3 different European health care systems

    NARCIS (Netherlands)

    Mihajlović, Jovan; Dolk, Christiaan; Tolley, Keith; Simoens, Steven; Postma, Maarten J.

    2015-01-01

    PURPOSE: Targeted cancer therapies (TCTs) are drugs that specifically act on molecular targets within the cancer cell, causing its regression and/or destruction. Although TCTs offer clinically important gains in survival in one of the most challenging therapeutic areas, these gains are followed by

  10. mTOR in squamous cell carcinoma of the oesophagus: a potential target for molecular therapy?

    NARCIS (Netherlands)

    Boone, J.; ten Kate, F. J. W.; Offerhaus, G. J. A.; van Diest, P. J.; Borel Rinkes, I. H. M.; van Hillegersberg, R.

    2008-01-01

    AIMS: The mammalian target of rapamycin (mTOR), an important regulator of protein translation and cell proliferation, is activated in various malignancies. In a randomised controlled trial of advanced renal cell carcinoma patients, targeted therapy to mTOR by means of rapamycin analogues has been

  11. Gene therapy of cancer and development of therapeutic target gene

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene.

  12. Gene therapy of cancer and development of therapeutic target gene

    International Nuclear Information System (INIS)

    Kim, Chang Min; Kwon, Hee Chung

    1998-04-01

    We applied HSV-tk/GCV strategy to orthotopic rat hepatoma model and showed anticancer effects of hepatoma. The increased expression of Lac Z gene after adenovirus-mediated gene delivery throughout hepatic artery was thought that is increased the possibility of gene therapy for curing hepatoma. With the construction of kGLP-laboratory, it is possible to produce a good quantity and quality of adenovirus in lage-scale production and purification of adenovirus vector. Also, the analysis of hepatoma related genes by PCR-LOH could be used for the diagnosis of patients and the development of therapeutic gene

  13. Molecular targets in cancer therapy: the Ron approach

    Directory of Open Access Journals (Sweden)

    Serena Germano

    2011-12-01

    Full Text Available The receptor tyrosine kinase Ron and its ligand, Macrophage Stimulating Protein (MSP, mediate multiple processes involved in the control of cell proliferation, migration and protection from apoptosis. Dysregulated signaling of Ron, due to hyperactivation or loss of negative regulation, is involved in tumor progression and metastasis. Growing evidence indicates that Ron is abnormally expressed and activated in certain types of primary epithelial cancers (i.e. breast, colon, lung, pancreas, bladder and thyroid, where it critically contributes to the maintenance of tumorigenic and invasive phenotype. Furthermore, a positive association between aberrant Ron expression and aggressive biological indicators as well as a worse clinical outcome have been reported in breast, bladder and thyroid carcinomas. Different approaches have proved effective in targeting receptor activation/expression both in vitro and in animal models, leading to reversion of the tumorigenic phenotype. Altogether these results show that Ron is an attractive molecular target for clinical intervention.

  14. Molecular targeting of angiogenesis for imaging and therapy

    International Nuclear Information System (INIS)

    Brack, Simon S.; Neri, Dario; Dinkelborg, Ludger M.

    2004-01-01

    Angiogenesis, i.e. the proliferation of new blood vessels from pre-existing ones, is an underlying process in many human diseases, including cancer, blinding ocular disorders and rheumatoid arthritis. The ability to selectively target and interfere with neovascularisation would potentially be useful in the diagnosis and treatment of angiogenesis-related diseases. This review presents the authors' views on some of the most relevant markers of angiogenesis described to date, as well as on specific ligands which have been characterised in pre-clinical animal models and/or clinical studies. Furthermore, we present an overview on technologies which are likely to have an impact on the way molecular targeting of angiogenesis is performed in the future. (orig.)

  15. Adverse Renal Effects of Novel Molecular Oncologic Targeted Therapies: A Narrative Review

    Directory of Open Access Journals (Sweden)

    Kenar D. Jhaveri

    2017-01-01

    Full Text Available Novel targeted anti-cancer therapies have resulted in improvement in patient survival compared to standard chemotherapy. Renal toxicities of targeted agents are increasingly being recognized. The incidence, severity, and pattern of renal toxicities may vary according to the respective target of the drug. Here we review the adverse renal effects associated with a selection of currently approved targeted cancer therapies, directed to EGFR, HER2, BRAF, MEK, ALK, PD1/PDL1, CTLA-4, and novel agents targeted to VEGF/R and TKIs. In summary, electrolyte disorders, renal impairment and hypertension are the most commonly reported events. Of the novel targeted agents, ipilumumab and cetuximab have the most nephrotoxic events reported. The early diagnosis and prompt recognition of these renal adverse events are essential for the general nephrologist taking care of these patients.

  16. Catching moving targets: cancer stem cell hierarchies, therapy-resistance & considerations for clinical intervention.

    LENUS (Irish Health Repository)

    Gasch, Claudia

    2017-01-01

    It is widely believed that targeting the tumour-initiating cancer stem cell (CSC) component of malignancy has great therapeutic potential, particularly in therapy-resistant disease. However, despite concerted efforts, CSC-targeting strategies have not been efficiently translated to the clinic. This is partly due to our incomplete understanding of the mechanisms underlying CSC therapy-resistance. In particular, the relationship between therapy-resistance and the organisation of CSCs as Stem-Progenitor-Differentiated cell hierarchies has not been widely studied. In this review we argue that modern clinical strategies should appreciate that the CSC hierarchy is a dynamic target that contains sensitive and resistant components and expresses a collection of therapy-resisting mechanisms. We propose that the CSC hierarchy at primary presentation changes in response to clinical intervention, resulting in a recurrent malignancy that should be targeted differently. As such, addressing the hierarchical organisation of CSCs into our bench-side theory should expedite translation of CSC-targeting to bed-side practice. In conclusion, we discuss strategies through which we can catch these moving clinical targets to specifically compromise therapy-resistant disease.

  17. Advances in targeting strategies for nanoparticles in cancer imaging and therapy.

    Science.gov (United States)

    Yhee, Ji Young; Lee, Sangmin; Kim, Kwangmeyung

    2014-11-21

    In the last decade, nanoparticles have offered great advances in diagnostic imaging and targeted drug delivery. In particular, nanoparticles have provided remarkable progress in cancer imaging and therapy based on materials science and biochemical engineering technology. Researchers constantly attempted to develop the nanoparticles which can deliver drugs more specifically to cancer cells, and these efforts brought the advances in the targeting strategy of nanoparticles. This minireview will discuss the progress in targeting strategies for nanoparticles focused on the recent innovative work for nanomedicine.

  18. Medical Physics Staffing Needs in Diagnostic Imaging and Radionuclide Therapy: An Activity Based Approach [Endorsed by International Organization for Medical Physics

    International Nuclear Information System (INIS)

    2018-01-01

    Over the last decades, the rapid technological development of diagnostic and interventional radiology and nuclear medicine has made them major tools of modern medicine. However, at the same time the involved risks, the growing number of procedures and the increasing complexity of the procedures require competent professional staff to ensure safe and effective patient diagnosis, treatment and management. Medical physicists (or clinically qualified medical physicists) have been recognized as vital health professionals with important and clear responsibilities related to quality and safety of applications of ionizing radiation in medicine. This publication describes an algorithm developed to determine the recommended staffing levels for clinical medical physics services in medical imaging and radionuclide therapy, based on current best practice, as described in international guidelines.

  19. Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy

    Science.gov (United States)

    Sihver, Wiebke; Pietzsch, Jens; Krause, Mechthild; Baumann, Michael; Steinbach, Jörg; Pietzsch, Hans-Jürgen

    2014-01-01

    The epidermal growth factor receptor (EGFR) has evolved over years into a main molecular target for the treatment of different cancer entities. In this regard, the anti-EGFR antibody cetuximab has been approved alone or in combination with: (a) chemotherapy for treatment of colorectal and head and neck squamous cell carcinoma and (b) with external radiotherapy for treatment of head and neck squamous cell carcinoma. The conjugation of radionuclides to cetuximab in combination with the specific targeting properties of this antibody might increase its therapeutic efficiency. This review article gives an overview of the preclinical studies that have been performed with radiolabeled cetuximab for imaging and/or treatment of different tumor models. A particularly promising approach seems to be the treatment with therapeutic radionuclide-labeled cetuximab in combination with external radiotherapy. Present data support an important impact of the tumor micromilieu on treatment response that needs to be further validated in patients. Another important challenge is the reduction of nonspecific uptake of the radioactive substance in metabolic organs like liver and radiosensitive organs like bone marrow and kidneys. Overall, the integration of diagnosis, treatment and monitoring as a theranostic approach appears to be a promising strategy for improvement of individualized cancer treatment. PMID:24603603

  20. Peptide-Mediated Liposomal Drug Delivery System Targeting Tumor Blood Vessels in Anticancer Therapy

    Directory of Open Access Journals (Sweden)

    Han-Chung Wu

    2010-01-01

    Full Text Available Solid tumors are known to recruit new blood vessels to support their growth. Therefore, unique molecules expressed on tumor endothelial cells can function as targets for the antiangiogenic therapy of cancer. Current efforts are focusing on developing therapeutic agents capable of specifically targeting cancer cells and tumor-associated microenvironments including tumor blood vessels. These therapies hold the promise of high efficacy and low toxicity. One recognized strategy for improving the therapeutic effectiveness of conventional chemotherapeutics is to encapsulate anticancer drugs into targeting liposomes that bind to the cell surface receptors expressed on tumor-associated endothelial cells. These anti-angiogenic drug delivery systems could be used to target both tumor blood vessels as well as the tumor cells, themselves. This article reviews the mechanisms and advantages of various present and potential methods using peptide-conjugated liposomes to specifically destroy tumor blood vessels in anticancer therapy.

  1. Nonalcoholic steatohepatitis: emerging targeted therapies to optimize treatment options

    Directory of Open Access Journals (Sweden)

    Milic S

    2015-08-01

    Full Text Available Sandra Milic,1 Ivana Mikolasevic,1,2 Irena Krznaric-Zrnic,1 Marija Stanic,3 Goran Poropat,1 Davor Stimac,1 Vera Vlahovic-Palcevski,4 Lidija Orlic2 1Department of Gastroenterology, UHC Rijeka, Rijeka, Croatia; 2Department of Nephrology, Dialysis and Kidney Transplantation, UHC Rijeka, Rijeka, Croatia; 3Department of Hematology, UHC Rijeka, Rijeka, Croatia; 4Department for Clinical Pharmacology, University of Rijeka Medical School, UHC Rijeka, Rijeka, Croatia Abstract: Diet and lifestyle changes have led to worldwide increases in the prevalences of obesity and metabolic syndrome, resulting in substantially greater incidence of nonalcoholic fatty liver disease (NAFLD. NAFLD is considered a hepatic manifestation of metabolic syndrome and is related to diabetes, insulin resistance, central obesity, hyperlipidemia, and hypertension. Nonalcoholic steatohepatitis (NASH is an entity that describes liver inflammation due to NAFLD. Growing evidence suggests that NAFLD is a multisystem disease with a clinical burden that is not only confined to liver-related morbidity and mortality, but that also affects several extra-hepatic organs and regulatory pathways. Thus, NAFLD is considered an important public health issue, but there is currently no effective therapy for all NAFLD patients in the general population. Studies seeking optimal therapy for NAFLD and NASH have not yet led to development of a universal protocol for treating this growing problem. Several pharmacological agents have been studied in an effort to improve insulin resistance and the proinflammatory mediators that may be responsible for NASH progression. Cardiovascular risk factors are highly prevalent among NASH patients, and the backbone of treatment regimens for these patients still comprises general lifestyle interventions, including dietary changes and increased physical activity. Vitamin E and thiazolidinedione derivatives are currently the most evidence-based therapeutic options, but only

  2. [111In-DTPA]octreotide tumor uptake in GEPNET liver metastases after intra-arterial administration: An overview of preclinical and clinical observations and implications for tumor radiation dose after peptide radionuclide therapy

    NARCIS (Netherlands)

    S.E. Pool (Stefan); B.L. Kam (Boen); G.A. Koning (Gerben); M. Konijnenberg (Mark); T.L.M. ten Hagen (Timo); W.A.P. Breeman (Woulter); E.P. Krenning (Eric); M. de Jong (Marcel); C.H.J. van Eijck (Casper)

    2014-01-01

    textabstractAims: With the aim to improve peptide receptor radionuclide therapy effects in patients with gastroenteropancreatic neuroendocrine tumor (GEPNET) liver metastases we explored the effect of intra-arterial (IA) administration of [111In-DTPA]octreotide (111In-DTPAOC) on tumor uptake in an

  3. Complement, a target for therapy in inflammatory and degenerative diseases.

    Science.gov (United States)

    Morgan, B Paul; Harris, Claire L

    2015-12-01

    The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.

  4. GPNMB expression in uveal melanoma: a potential for targeted therapy.

    Science.gov (United States)

    Williams, Michelle D; Esmaeli, Bita; Soheili, Aydin; Simantov, Ronit; Gombos, Dan S; Bedikian, Agop Y; Hwu, Patrick

    2010-06-01

    Uveal melanoma is an aggressive disease without effective adjuvant therapy for metastases. Despite genomic differences between cutaneous and uveal melanomas, therapies based on shared biological factors could be effective against both tumor types. High expression of glycoprotein-NMB (GPNMB) in cutaneous melanomas led to the development of CDX-011 (glembatumumab vedotin), a fully human monoclonal antibody against the extracellular domain of GPNMB conjugated to the cytotoxic microtubule toxin monomethylauristatin E. Ongoing phase II trials suggest that CDX-011 has activity against advanced cutaneous melanomas. To determine the potential role of CDX-011 in uveal melanomas, we studied their GPNMB expression. Paraffin-embedded tissues from 22 uveal melanomas treated by enucleation from 2004-2007 at one institution were evaluated immunohistochemically for expression of GPNMB using biotinylated CDX-011 (unconjugated) antibody. Melanoma cells were evaluated for percentage and intensity of expression. Spectral imaging was used in one case with high melanin content. Clinical data were reviewed. Twelve women and 10 men with a median age of 58.7 years (range: 28-83 years) were included. Eighteen of 21 tumors evaluated immunohistochemically (85.7%) expressed GPNMB in 10-90% of tumor cells with variable intensity (5 tumors, 1+; 11, 2+; and 2, 3+). Eleven of 18 tumors (61.1%) expressed GPNMB in >or=50% of cells. Spectral imaging showed diffuse CDX-011 (unconjugated) reactivity in the remaining case. Uveal melanoma, like cutaneous melanoma, commonly expresses GPNMB. Ongoing clinical trials of CDX-011 should be extended to patients with metastatic uveal melanoma to determine potential efficacy in this subse