Dosimetry and microdosimetry of 188 Re-anti-CD20 and 131 I-anti-CD20 for the treatment of No Hodgkin lymphomas

International Nuclear Information System (INIS)

Torres G, E.

2007-01-01

The purpose of this investigation was to prepare 131 I-anti-CD20 and 188 Re-anti-CD20 and to estimate the radiation absorbed dose at macro- and micro- level during a NHL treatment. The work was divided in 4 general objectives: 1) preparation of 131 I-anti-CD20 and 188 Re-anti-CD20, 2) application in patients to obtain biokinetic parameters and estimate the organ absorbed doses 3) estimation of the cellular dosimetry using the MIRD methodology and the MCNP4C2 code and 4) estimation of the cellular microdosimetry using the NOREC code. 188 Re-anti-CD20 was prepared by a direct labelling method using sodium tartrate as a weak ligand. To evaluate the biological recognition a comparative study of the in vitro binding of 188 Re-anti-CD20, 125 I-anti-CD20 (positive control) and 188 Re-anti-CEA (negative control) to normal B Iymphocytes was performed. Biodistribution studies in normal mice were accomplished to assess the in vivo Re-anti-CD20 complex stability. The binding of ' Re-anti-CD20 to cells was in the same range as '251-anti-CD20 (>80%) considered as the positive control. 188 Re-anti-CD20 and '3'1-anti-CD20 prepared were administered in patients diagnosed with B cell NHL at the Centro Medico Siglo XXI (IMSS). The protocol was approved by the hospital's Medical Ethics Committee. AJI patients signed a consent form after receiving detailed information on the aims of the study. N data were the input for the OLINDA/EXM software to calculate the radiation absorbed dose to organs and whole body. Dosimetric studies indicate that after administration of 6.4 GBq and 4.87 to 8.75 GBq of '3'1-anti-CD20 and 188 Re-anti-CD20 respectively, the absorbed dose to total body would be 0.75 Gy which corresponds to the recommended dose for NHL therapies. The calculated organ absorbed doses indicate that 188 Re-anti-CD20 may be used in radioimmunotherapy without the risk of toxicity to red marrow or healthy organs. The absorbed dose (D) into cellular nucleus was calculated by two

Effect of carrier on labeling and biodistribution of Re-188-Hydroxyethylidene diphosphonate

International Nuclear Information System (INIS)

Chang, Young Soo; Jeong, Jae Min; Kim, Bo Kwang; Cho, Jung Hyuk; Lee, Dong Soo; Chung, June Key; Lee, Myung Chul; Lee, Seung Jin; Jin, Ren Jie; Lee, Sang Eun

2000-01-01

Re-188-Hydroxyethylidene diphosphonate (HEDP) is a new cost-effective agent for systemic radioisotope therapy of metastatic bone pain. We investigated the influence of carrier for labeling and biodistribution of Re-188-HEDP using HEDP kit with or without carrier (KReO 4 ). The kits (HEDP 15 mg, gentisic acid 4 mg and SnC1 2 .2H 2 O 4.5 mg) with or without carrier (KReO 4 0.1 mg) were labeled with Re-188 solution, made available from an in-house generator by boiling for 15 min. We compared the labeling efficiency and stability of carrier-added and carrier-free preparations of Re-188-HEDP. Biodistribution and imaging studies of each preparation were performed in ICR mice (1.85-3.7 MBq/0.1 ml) and SD rats (74.1-85.2 MBq/0.5 ml). The carrier-added preparation showed high labeling efficiency (95% at pH 5) and high stability in serum (88%, 3hr). However, the carrier-free preparation showed low labeling efficiency (59% at pH 5) and low stability (43%, 3 hr). The carrier-added preparation showed high uptake in bone and low uptake in stomach and kidneys. However, the carrier-free preparation showed lower uptake in bone and higher uptake in both stomach and kidneys, which is supposed to be due to released perrhenate. The carrier-added preparation also showed better images with higher skeletal accumulation, lower uptake in other organs and lower soft tissue uptake than the carrier-free preparation. The results of these studies clearly demonstrate that addition of carrier perrhenate is required for high labeling efficiency, stability, bone uptake and good image quality of Re-188-HEDP.=20

99mTc labeled anti EGFR Nanobody pentamer for tumor radioimmunoimaging

International Nuclear Information System (INIS)

Ding Zhiling; Lan Xiaoli; Li Chongjiao; Pei Zhijun; Zhang Yongxue; Wang Lifei; Gao Bin

2014-01-01

Novel Nanobody has small molecular weight and lower affinity. Appropriate polymer would be more suitable for radioimmunoimaging. In this study, we labeled anti EGFR Nanobody pentamer with 99m Tc to prepare tumor targeting imaging agent and to investigate its binding characteristics of tumor cells and tissues in vitro and in vivo, and to explore the feasibility of 99m Tc-EGFR Nanobody pentamer for tumor radioimmunoimaging compared with anti EGFR Nanobody monomer. EGFR Nanobody labeled with 99m Tc through tricarbonyl intermediate. The labeled compounds were purified by an ultra centrifugal filter; The labeling efficiency was determined by thin layer chromatography (TLC), and the radiochemical purity more than 95%. In vitro, 99m Tc-EGFR Nanobody monomer and pentamer have the specific binding capability with EGFR overexpression A431 tumor cell. the binding rate of 99m Tc-EGFR Nanobody monomer higher than that of pentamer (11.32% ± 2.73% vs 5.80% ± 0.92%, P < O.05). In A431 xenografted tumor was clearly displayed after intravenous injection of 99m Tc-EGFR Nanobody pentamer at l.5 h, T/NT maximum was 2.9 (1.5 h), whereas, the tumor tissues was not obviously found using 99m Tc-EGFR Nanobody monomer. The negative EGFR expression OCM-I xenografted tumor was not showed in both monomer and pentamer tracer. The experiment indicated that 99m Tc-EGFR Nanobody pentamer are appropriate for tumor radioimmunoimaging and has the potential value for the further study. (authors)

Dosimetry and microdosimetry of {sup 188} Re-anti-CD20 and {sup 131} I-anti-CD20 for the treatment of No Hodgkin lymphomas; Dosimetria y microdosimetria del {sup 188} Re-anti-CD20 y {sup 131} I-anti-CD20 para el tratamiento de linfomas No Hodgkin

Energy Technology Data Exchange (ETDEWEB)

Torres G, E

2007-07-01

The purpose of this investigation was to prepare {sup 131}I-anti-CD20 and {sup 188}Re-anti-CD20 and to estimate the radiation absorbed dose at macro- and micro- level during a NHL treatment. The work was divided in 4 general objectives: 1) preparation of {sup 131}I-anti-CD20 and {sup 188}Re-anti-CD20, 2) application in patients to obtain biokinetic parameters and estimate the organ absorbed doses 3) estimation of the cellular dosimetry using the MIRD methodology and the MCNP4C2 code and 4) estimation of the cellular microdosimetry using the NOREC code. {sup 188}Re-anti-CD20 was prepared by a direct labelling method using sodium tartrate as a weak ligand. To evaluate the biological recognition a comparative study of the in vitro binding of {sup 188}Re-anti-CD20, {sup 125}I-anti-CD20 (positive control) and {sup 188}Re-anti-CEA (negative control) to normal B Iymphocytes was performed. Biodistribution studies in normal mice were accomplished to assess the in vivo Re-anti-CD20 complex stability. The binding of ' Re-anti-CD20 to cells was in the same range as '251-anti-CD20 (>80%) considered as the positive control. {sup 188}Re-anti-CD20 and '3'1-anti-CD20 prepared were administered in patients diagnosed with B cell NHL at the Centro Medico Siglo XXI (IMSS). The protocol was approved by the hospital's Medical Ethics Committee. AJI patients signed a consent form after receiving detailed information on the aims of the study. N data were the input for the OLINDA/EXM software to calculate the radiation absorbed dose to organs and whole body. Dosimetric studies indicate that after administration of 6.4 GBq and 4.87 to 8.75 GBq of '3'1-anti-CD20 and {sup 188}Re-anti-CD20 respectively, the absorbed dose to total body would be 0.75 Gy which corresponds to the recommended dose for NHL therapies. The calculated organ absorbed doses indicate that {sup 188}Re-anti-CD20 may be used in radioimmunotherapy without the risk of toxicity to red marrow or

Dosimetry and microdosimetry of {sup 188} Re-anti-CD20 and {sup 131} I-anti-CD20 for the treatment of No Hodgkin lymphomas; Dosimetria y microdosimetria del {sup 188} Re-anti-CD20 y {sup 131} I-anti-CD20 para el tratamiento de linfomas No Hodgkin

Energy Technology Data Exchange (ETDEWEB)

Torres G, E

2007-07-01

The purpose of this investigation was to prepare {sup 131}I-anti-CD20 and {sup 188}Re-anti-CD20 and to estimate the radiation absorbed dose at macro- and micro- level during a NHL treatment. The work was divided in 4 general objectives: 1) preparation of {sup 131}I-anti-CD20 and {sup 188}Re-anti-CD20, 2) application in patients to obtain biokinetic parameters and estimate the organ absorbed doses 3) estimation of the cellular dosimetry using the MIRD methodology and the MCNP4C2 code and 4) estimation of the cellular microdosimetry using the NOREC code. {sup 188}Re-anti-CD20 was prepared by a direct labelling method using sodium tartrate as a weak ligand. To evaluate the biological recognition a comparative study of the in vitro binding of {sup 188}Re-anti-CD20, {sup 125}I-anti-CD20 (positive control) and {sup 188}Re-anti-CEA (negative control) to normal B Iymphocytes was performed. Biodistribution studies in normal mice were accomplished to assess the in vivo Re-anti-CD20 complex stability. The binding of ' Re-anti-CD20 to cells was in the same range as '251-anti-CD20 (>80%) considered as the positive control. {sup 188}Re-anti-CD20 and '3'1-anti-CD20 prepared were administered in patients diagnosed with B cell NHL at the Centro Medico Siglo XXI (IMSS). The protocol was approved by the hospital's Medical Ethics Committee. AJI patients signed a consent form after receiving detailed information on the aims of the study. N data were the input for the OLINDA/EXM software to calculate the radiation absorbed dose to organs and whole body. Dosimetric studies indicate that after administration of 6.4 GBq and 4.87 to 8.75 GBq of '3'1-anti-CD20 and {sup 188}Re-anti-CD20 respectively, the absorbed dose to total body would be 0.75 Gy which corresponds to the recommended dose for NHL therapies. The calculated organ absorbed doses indicate that {sup 188}Re-anti-CD20 may be used in radioimmunotherapy without the risk of toxicity to red marrow or healthy organs. The absorbed dose

Stability of rhenium-188 labeled antibody

International Nuclear Information System (INIS)

Lim, B. K.; Jung, J. M.; Jung, J. K.; Lee, D. S.; Lee, M. C.

1999-01-01

For clinical application of beta-emitter labeled antibody, high specific activity is important. Carrier-free Re-188 from W-188/Re-188 generator is an ideal radionuclide for this purpose. However, low stability of Re-188 labeled antibody, especially in high specific activity, due to radiolytic decomposition by high energy (2.1 MeV) beta ray was problem. We studied the stability of Re-188 labeled antibody, and stabilizing effect of several nontoxic radical-quenching agents. Pre-reduced monoclonal antibody (CEA79.4) was labeled with Re-188 by incubating with generator-eluted Re-188-perrhenate in the presence of stannous tartrate for 2 hr at room temperature. Radiochemical purity of each preparation was determined by chromatography (ITLC-SG/acetone, ITLC-SG/Umezawa, Whatman No.1/saline). Human serum albumin was added to the labeled antibodies(2%). Stability of Re-188-CEA79.4 was investigated in the presence of vitamin C, ethanol, or Tween 80 as radical-quenching agents. Specific activities of 4.29∼5.11 MBq/μg were obtained. Labeling efficiencies were 88±4%(n=12). Very low stability after removal of stannous tartrate from the preparation was observed. If stored after purging with N 2 , all the preparations were stable for 10 hr. However, if contacted with air, stability decreased. Perrhenate and Re-188-tartrate was major impurity in declined preparation (12∼47 and 9∼38% each, after 10 hr). Colloid-formation was not a significant problem in all cases. Addition of vitamin C stabilized the labeled antibodies either under N 2 or under air by reducing the formation of perrhenate. High specific activity Re-188 labeled antibody is unstable, especially, in the presence of oxygen. Addition of vitamin C increased the stability

Development of methods of labeling pentavalent DMSA with 99mTc and 188Re

International Nuclear Information System (INIS)

Brambilla, Tania de Paula

2009-01-01

Technetium-99 m is the most useful radionuclide in diagnostic imaging procedures in Nuclear Medicine, more than 80 percent of radiopharmaceuticals are 99m Tc-labeled compounds. 99m Tc-DMSA(V) has been used for imaging of soft tissue, head and neck tumors. It shows a particularly high specificity for medullary thyroid carcinoma and bone metastases in a variety of cancers. Biodistribution studies of 188 Re-DMSA(V) have shown that its general pharmacokinetic properties are similar to that of 99m Tc-DMSA(V), so this agent could be used for targeted radiotherapy of these tumors. The aim of this work is the development of methods of labeling DMSA(V) with 99m Tc and 188 Re. 99m Tc-DMSA(V) can be prepared by two methods. One of them is the indirect one, through the use of a commercial kit of DMSA (III), by adjusting the pH from 2.5 to ∼ 8.5 with NaHCO 3 . This method was evaluated and optimized presenting high labeling yields. The other method is the direct one, through the preparation of a lyophilised kit ready for labeling with 99m Tc, being the method of interest of this work, due to the easy of its clinical use. The most adequate formulation of the kit was: 1.71 mg of DMSA, 0.53 mg of SnCl 2 .2H 2 O and 0.83 mg of ascorbic acid (pH 9). Labeling yields higher than 95% were achieved labeling this kit with 1 to 2 m L of 99m Tc with activities up to 4736 MBq (128 mCi). The kit was stable up to 6 months and biodistribution studies confirmed the quality of the DMSA (V) labeled with 99m Tc using this kit. The reduction potential of Re is lower than the one for Tc, so the labeling conditions of 188 Re-DMSA(V) are different from the ones used for 99m Tc- DMSA(V). 188 Re-DMSA(V) is prepared in acid solution, that makes it possible to use the DMSA (III) commercial kit developed for labeling with 99m Tc, prepared in pH 2.5, for labeling with 188 Re. Labeling yields higher than 95% were achieved with this methodology, with a rection time of 30 minutes at 100 deg C using no more

A study of factors affecting the labelling of tartrate with 188Re and the transchelation of the 188Re from the tartrate to a protein

International Nuclear Information System (INIS)

Sailerova, Eva; Billinghurst, M.W.

2003-01-01

The formation of 188 Re-tartrate for use in transchelation reactions and the transchelation of the 188 Re onto albumin was studied. Two labelled tartrate products were separated using a non-traditional mobile phase on ITLC strips. Tartrate labelling yield increases with pH but so does the instability when the product is exposed to air. Lower pH's are preferred when oxygen-free labelling conditions can be achieved. Higher tin levels protect against air oxidation. Stability of the Re-tartrate complex is supported by addition of ascorbic acid and ferrous sulphate, however both these agents decreased the rate of the formation of the Re-tartrate complex. The labelling efficiency of a perrhenate solution decreased with the time for which it is stored prior to the labelling reaction, depending on the radioactive concentration. Re-albumin transchelation efficiency increases with the tartrate concentration, while increased stability of the Re-tartrate complex lowers the transchelation yields of Re-albumin

Non-carrier-added 186,188Re labeled 17α-ethynylestradiol: a potential breast cancer imaging and therapy agent

International Nuclear Information System (INIS)

Fassbender, M.E.; Phillips, Dennis R.; Peterson, E.J.; Ott, K.C.; Arterburn, J.B.

2001-01-01

Receptor-targeted radiopharmaceuticals constitute potential agents for the diagnosis and therapy of cancer. Breast cancer is the most prevalent form of diagnosed cancer in women in the United States, and it accounts for the second highest number of cases of cancer fatalities (1). In Approximately two-thirds of the breast tumors, estrogen and progesterone steroid hormone receptors can be found. Such tumors can often be treated successfully with anti-estrogen hormone therapy (2). Hence, the ability to determine the estrogen receptor (ER) contend of the breast tumor is essential for making the most appropriate choice of treatment for the patient. Along with this diagnostic aspect, steroid-based radiopharmaceuticals with high specific activity offer an encouraging prospect for therapeutic applications: 186,188 Re labeled steroids binding to receptors expressed by cancer cells appear to be potential agents for the irradiation of small to medium-sized tumors. 186 Re has been regarded as an ideal radionuclide for radiotherapy due to its appropriate half-live of 90 h and β-energy of 1.07 MeV. Moreover, the γ-emission of 137 keV that allows in vivo imaging while in therapy is an additional bonus. 188 Re is obtained from a 188 W/ 188 Re radionuclide generator system, representing an advantage for availability at radiopharmacy laboratory by daily elution. In addition, 188 Re emits high energy beta particles with an average energy of 769 keV, and the emission of the 155 keV allows simultaneous imaging for biodistribution evaluation in vivo. In order to avoid competitive saturation of the binding sites of the ligand receptor, Re labeled steroids with high specific activity are required, and the removal of all excess unlabeled ligands is mandatory. 188 Re is eluted from a 188 W/ 188 Re generator produced and provided by Oak Ridge National Laboratory (3). This paper outlines the solid phase-supported preparation of an n.c.a. ( 188 Re)Re-imido estradiol compound. The

Effect of carrier on labeling and biodistribution of Re-188-hydroxyethylidene disphosphonate (HEDP)

International Nuclear Information System (INIS)

Jang, Y. S.; Jeong, J. M.; Kim, B. K.; Lee, D. S.; Jeong, J. K.; Lee, M. C.; Cho, J. H.

1998-01-01

Re-188- hydroxyethylidene disphosphonate (HEDP) is a new cost-effective agent for systemic radioisotope therapy of metastatic bone pain. We investigated the influence of carrier for labeling and biodistribution of Re-188-HEDP using HEDP kit(HEDP 15 mg, gentisic acid 4 mg and SnCl 2 2H 2 O 4.5 mg) with or without carrier (KReO 4 0.1 mg). The kits labeled with Re-188 solution available from an in-house generator by boiling for 15 min. The generator provides high 70-80 % equil yields and has an indefnite self-life. We compared the stability of carrier-added(CA) and carrier-free(CF) preparations of Re-188-HEDP. Biodistribution and imaging studies of each preparation were performed in ICR mice(1.85-3.7 MBq/0.1 ml) and SD rats(74.1-85.2 MBq/0.5 ml). The CA preparation showed high labeling efficiency(95% at pH 5) and high stability in serum(88%, 3 hr). However, the CF preparation showed low labeling efficiency(59% at pH 5) and low stability(43%, 3 hr). The CA preparation showed high uptake in bone and low uptake in stomach and kidneys. However, the CF preparation showed lower uptake in bone and higher uptake in both stomach and kidney, which is supposed to be due to released perrhenate. The CA preparation also showed better images with higher skeletal accumulation, lower uptake in other organs and lower soft tissue uptake than the CF preparation of carrier perrhenate is required for high labeling efficiency, stability, bone uptake and good image quality of Re-188-HEDP

Study on therapy of 188Re labelled stannic sulfur suspension in nude mice bearing human colon tumor

International Nuclear Information System (INIS)

Li Huiyuan; Wu Yuanfang; Dong Mo

2003-01-01

The effect of therapy, tissue distribution and stability are studied in nude mice bearing human colon tumor after injections of 188 Re labelled stannic sulfur suspension. The tissues are observed with electric microscope. The results show that 188 Re labelled stannic sulfur suspension is stabilized in the tumor and its inhibitive effects on human colon tumor cells are obvious. 188 Re labelled stannic sulfur suspension is a potential radiopharmaceuticals for therapy of human tumor

Clinical application of antibody monoclonal humanized anti-EGFrnimotuzumab labeled

International Nuclear Information System (INIS)

Perera Pintado, Alejandro; Peña Quián, Yamilé; Batista Cuéllar, Juan F.; Prats Capote, Anaís; Torres Aroche, Leonel A.; Casacó Santana, Caridad; Sánchez Mendosa, Elvia L.; Sánchez González, Yolaine; Romero Collado, Susana; Quesada Pozo, Rodobaldo; Valladares Oviedo, Lourdes; Masquida García, Elsa M.; Leyva Montaña, René; Casacó, Angel; Ramos Suzarte, Mayra; Crombet, Tania

2016-01-01

Most malignant tumors are of epithelial origin. These are characterized by overexpression of the receptor of epidermal growth factor (EGFR), which the neoplastic cells escape the regulatory mechanisms are allowed, so its high concentration of membrane is generally associated with a poor prognosis . By binding an antibody specifically to this receptor, preventing binding of EGF latter and activation mechanism tyrosine kinase inhibiting cell mitosis and apoptosis causing tumor cell. For this reason, the EGFr has been considered as an attractive target for anti-tumor therapy. The humanized monoclonal antibody anti-EGFr nimotuzumab was developed by the Center of Molecular Immunology (Havana, Cuba). Numerous clinical trials have been developed in the Department of Clinical Research Center Isotopes (Cuba), in which it has been applied this antibody, both labeled with 99mTc for immuno gammagraphic detection of tumors, as labeled with 188 Re for radioimmunotherapy of gliomas high degree of malignancy. The aim of this paper is to show the experience of the Department of Clinical Research of CENTIS in various clinical trials with marking for both immuno gammagraphics detection of tumors, such as for radioimmunotherapy nimotuzumab. (author)

Compartmental and dosimetric studies of anti-CD20 labeled with 188Re

International Nuclear Information System (INIS)

Barrio Kuramoto Graciela; Mie Nakamura Matsuda Margareth; Osso Joao Jr, Alberto

2016-01-01

Radioimmunotherapy has the potential to deliver lethal radiation energy directly to malignant cells via targeting of radioisotope-conjugated monoclonal antibodies (MAbs) to specific antigens. Rituximab (RTX) is specifically targeted against CD20, a surface antigen expressed by B-lymphocytes. The use of 188 Re from a 188 W/ 188 Re generator system represents an alternative radionuclide for therapy. Rhenium has chemical properties similar to technetium and both can be conjugated to antibodies using similar chemistry methods. The objective of this work is to prove the usefulness of this radiopharmaceutical based on dosimetric and pharmacokinetic studies that are also required by the Brazilian Regulatory Agency. (author)

Radiolabeling of anti-CD20 with Re-188 for treatment of non-Hodgkin's lymphoma: radiochemical control

International Nuclear Information System (INIS)

Dias, Carla R.; Osso Junior, Joao A.

2009-01-01

The development of tumor-selective radiopharmaceuticals is clinically desirable as a means of detecting or confirming the presence and location of primary and metastatic lesions and monitoring tumor response to (chemo)therapy. In addition, the application of targeted radiotherapeutics provides a unique and effective modality for direct tumor treatment. In this manner the radioimmunotherapy (RIT) uses the targeting features of monoclonal antibody to deliver radiation from an attached radionuclide. Antibody therapy directed against the CD20 antigen on the surface of B-cells is considered one of the first successful target-specific therapies in oncology. The radionuclide rhenium-188 ( 188 Re) is currently produced from the father nuclide tungsten-188 ( 188 W) through a transportable generator system. Because of its easy availability and suitable nuclear properties (EβMAX = 2.1 MeV, t 1/2 = 16.9 h, Eγ = 155 keV), this radionuclide is considered an attractive candidate for application as therapeutic agent and could be conveniently utilized for imaging and dosimetric purposes. The purpose of this work is to show the radiochemical control of the optimized formulation (solution) and lyophilized formulation (kit) of labeled rituximab (anti-CD20) with 188 Re. Rituximab was reduced by incubation with 2-mercaptoethanol at room temperature. The number of resulting free sulfhydryl groups was assayed with Ellman's reagent. Radiochemical purity of 188 Re-rituximab was evaluated using instant thin layer chromatography-silica gel (ITLC-SG). Quality control methods for evaluation of radiochemical purity showed good labeling yield of the antibody. (author)

Preparation of cyclotron-produced {sup 186}Re and comparison with reactor-produced {sup 186}Re and generator-produced {sup 188}Re for the labeling of bombesin

Energy Technology Data Exchange (ETDEWEB)

Moustapha, Moustapha E. [Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211 (United States); University of Missouri Research Reactor (MURR), University of Missouri-Columbia, Columbia, MO 65211 (United States); Ehrhardt, Gary J. [Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211 (United States); University of Missouri Research Reactor (MURR), University of Missouri-Columbia, Columbia, MO 65211 (United States); Smith, Charles J. [Department of Radiology, University of Missouri-Columbia, Columbia, MO 65211 (United States); University of Missouri Research Reactor (MURR), University of Missouri-Columbia, Columbia, MO 65211 (United States); Research Services, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201 (United States); Szajek, Lawrence P. [Positron Emission Tomography Department, National Institutes of Health, Bethesda, MD 20892-1180 (United States); Eckelman, William C. [Positron Emission Tomography Department, National Institutes of Health, Bethesda, MD 20892-1180 (United States); Jurisson, Silvia S. [Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211 (United States)]. E-mail: jurissons@missouri.edu

2006-01-15

-expressing cells. This study showed that the N{sub 3}S-5-Ava-BBN(7-14)NH{sub 2} could be labeled with {sup 186,188}Re following the preconjugation, postmetallation approach. The {sup 186,188}Re{sup V}O-N{sub 3}S-5-Ava-BBN(7-14)NH{sub 2} complexes were found to form stable complexes following the reduction of perrhenate (Re{sup VII}O{sub 4} {sup -}) with stannous chloride at room temperature, as verified by HPLC and stability studies. The radiolabeling yield was found to be >90%. The HPLC chromatograms of {sup 186,188}Re-N{sub 3}S-5-Ava-BBN(7-14)NH{sub 2} complexes revealed two peaks for each conjugate, reflecting the presence of syn- and anti-isomers, which were resolvable by HPLC but re-isomerized on separation. The biodistribution studies showed that the compounds were excreted through the renal and hepatobiliary systems and demonstrated receptor-specific uptake with an average pancreas accumulation of 8.15% ID/g at 1 h postinjection. Administration of cold BBN effectively blocked pancreatic uptake and further reflects the high specificity this conjugate has for the GRP receptors. At low levels of radioactivity, radiolysis effects were not observed. Scale-up may or may not elicit this effect, particularly for the higher energy {beta} emitter {sup 188}Re. The biodistribution studies demonstrated that the CA and NCA {sup 186,188}Re conjugates behaved similarly, raising the question of whether NCA {sup 186,188}Re is necessary for specific tumor receptor targeting.

Improved conditions for labeling EDTMP with 188Re for bone pain palliation

International Nuclear Information System (INIS)

Faintuch, B.L.; Osso, J.A. Jr.; Muramoto, E.; Faintuch, S.

2002-01-01

Introduction: Ethilenediamine tetramethylene phosphonate (EDTMP) is a tetraphosphonate ligand which, when labeled with 188 Re, can be used for relief of metastatic bone pain. The preferential localization of phosphonate complexes in bone is attributed to their affinity for calcium, and tetraphosphonates may be equal or superior to diphosphonates in this regard. In the present study, it was aimed to determine optimal conditions for preparation of a kit of EDTMP to be labeled with 188 Re. Methods: EDTMP was dissolved in NaOH 1N, and alkalinity was reversed with HCl till pH 2, when SnCl 2 . 2H 2 0 and also ascorbic acid were introduced in the mixture, followed by Na 188 ReO 4 . The preparation was incubated in water bath for 30 minutes and after cooling radiochemical purity was assessed. Optimization of the process consisted in varying the values of EDTMP mass (20, 30, 40 mg) SnCl 2 .2H 2 0 concentration (0.5, 1.0, 2.0 and 3.0 mg/mL), and reaction time (15 and 30 minutes). Radiochemical purity and stability were ascertained in vitro and also in Swiss mice. Bone/muscle uptake ratio was calculated from %ID/g of these organs. Results: The best 188 Re-EDTMP complex was obtained with 40 mg of the ligand and 2 mg/mL of stannous chloride heated during 15 minutes, and the product was radiochemically stable during 24 hours. Kidney and bone uptake were very significant (respectively 4.5 ± 0.5% and 3.1 ± 0.3 %ID/g). Bone/muscle ratio observed four hours post-injection was also very adequate (28.5). Conclusions: A stable and biologically useful complex of 188 Re-EDTMP can be prepared with high concentration of EDTMP and considerable uptake by bone. It compares favorably with 153 Sm-EDTMP, as 188 Re has more advantageous radioisotopic properties than 153 Sm, and it can be recommended for further studies in conditions of painful bone metastases

Study on the preparation and stability of 188Re biomolecules via EHDP

International Nuclear Information System (INIS)

Ferro-Flores, G.; Garcia-Salinas, L.; Paredes-Gutierrez, L.; Hashimoto, K.; Melendez-Alafort, L.; Murphy, C.A.

2001-01-01

A direct labelling technique via ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) as a weak competing ligand was developed for the preparation of several biomolecules: 188 Re-monoclonal antibody ior cea1 against carcinoembryonic antigen ( 188 Re-MoAb), biotinylated 188 Re-MoAb ( 188 Re-MoAb-biotin), 188 Re-polyclonal IgG ( 188 Re-IgG), 188 Re-peptide (somatostatine analogue peptide b-(2-naphtyl)-D-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-amide), 188 Re-MoAb fragments ( 188 Re-F(ab') 2 ) and biotinylated 188 Re-F(ab') 2 ( 188 Re-F(ab') 2 -biotin). The reaction conditions such as pH, temperature, weak ligand concentration and stannous chloride concentration were optimized during the radiolabelling of each biomolecule. Before the labelling procedure, disulphide bridge groups of the biomolecules were reduced with 2-mercaptoethanol (2-ME). To obtain 188 Re labelled antibodies and peptides in high radiochemical yields (>90%) via EHDP, it was necessary to use acidic conditions and a high concentration of stannous chloride to allow the redox reaction Re +7 →Re +5 :Re +4 . The labelling of MoAb and F(ab') 2 with 188 Re via EHDP was also evaluated employing a pretargeted technique by avidin-biotin strategy in normal mice, demonstrating that the 188 Re-labelled biotinylated antibodies are stable complexes in vivo. The 188 Re-peptide complex prepared by this method, was stable for 24 h and no radiolytic degradation was observed. (author)

Development of methods of labeling pentavalent DMSA with {sup 99m}Tc and {sup 188}Re; Desenvolvimento de metodos para marcacao de DMSA pentavalente com {sup 99m}Tc e {sup 188}Re

Energy Technology Data Exchange (ETDEWEB)

Brambilla, Tania de Paula, email: jtoniolo@ipen.br

2009-07-01

Technetium-99 m is the most useful radionuclide in diagnostic imaging procedures in Nuclear Medicine, more than 80 percent of radiopharmaceuticals are {sup 99m}Tc-labeled compounds. {sup 99m}Tc-DMSA(V) has been used for imaging of soft tissue, head and neck tumors. It shows a particularly high specificity for medullary thyroid carcinoma and bone metastases in a variety of cancers. Biodistribution studies of {sup 188}Re-DMSA(V) have shown that its general pharmacokinetic properties are similar to that of {sup 99m}Tc-DMSA(V), so this agent could be used for targeted radiotherapy of these tumors. The aim of this work is the development of methods of labeling DMSA(V) with {sup 99m}Tc and {sup 188}Re. {sup 99m}Tc-DMSA(V) can be prepared by two methods. One of them is the indirect one, through the use of a commercial kit of DMSA (III), by adjusting the pH from 2.5 to {approx} 8.5 with NaHCO{sub 3}. This method was evaluated and optimized presenting high labeling yields. The other method is the direct one, through the preparation of a lyophilised kit ready for labeling with {sup 99m}Tc, being the method of interest of this work, due to the easy of its clinical use. The most adequate formulation of the kit was: 1.71 mg of DMSA, 0.53 mg of SnCl{sub 2}.2H{sub 2}O and 0.83 mg of ascorbic acid (pH 9). Labeling yields higher than 95% were achieved labeling this kit with 1 to 2 m L of {sup 99m}Tc with activities up to 4736 MBq (128 mCi). The kit was stable up to 6 months and biodistribution studies confirmed the quality of the DMSA (V) labeled with {sup 99m}Tc using this kit. The reduction potential of Re is lower than the one for Tc, so the labeling conditions of {sup 188}Re-DMSA(V) are different from the ones used for {sup 99m}Tc- DMSA(V). {sup 188}Re-DMSA(V) is prepared in acid solution, that makes it possible to use the DMSA (III) commercial kit developed for labeling with {sup 99m}Tc, prepared in pH 2.5, for labeling with {sup 188}Re. Labeling yields higher than 95% were

The Chemistry of Re-188 Radiopharmaceuticals: Could Re-188 Play the Same Role in Therapy as Tc-99m in Diagnostics?

International Nuclear Information System (INIS)

Duatti, A.

2009-01-01

Radiopharmaceuticals incorporating the β-emitting radionuclide Re-188 are still attracting much interest for their potential application in nuclear medicine as therapeutic agents. There are many advantages of employing this class of radioactive compounds as briefly summarized in the following. (1) Re-188 emits a high-energy β- particle (2.1 MeV) that can be efficiently used to deliver high-dose radiation to the target. (2) Re-188 concomitantly emits a 155-keV γ photon that can be conveniently employed to obtain good-quality SPECT images of the biodistribution of Re-188 radiopharmaceuticals and, ultimately, following in vivo the course of the therapy. (3) Re-188 has a relatively short half-life (17 hours) that may allow multiple treatments of the same patient's disease. (4) Re-188 is a radiometal belonging to the same group of Tc-99m in the transition metal series of the Periodic Table, and shares with its cogener similar (though not identical) chemical properties that could be useful for designing a broad class of Re-188 radiopharmaceuticals having the same biodistribution properties of the corresponding Tc-99m analogues. (5) Similarly to Tc-99m, the radionuclide Re-188 is produced in high-specific activity through the 188 W/ 188 Re transportable generator system. A first challenge encountered in the attempt to develop efficient labeling procedures for Re-188 was related to the low radiochemical yield usually observed in tracer-level preparations of Re-188 radiopharmaceuticals starting from generator-produced [ 188 ReO 4 ]-. This drawback is commonly associated with the low value of the standard reduction potential of the tetraoxo anion as compared to the corresponding Tc-99m pertechnetate anion. In recent years, we reported a simple and efficient procedure for overcoming this problem based on a general chemical principle called 'expansion of the coordination sphere' and involving the addition to the reaction vial of an ancillary ligand (usually, chelating hard

Dosimetric studies of anti-CD20 labeled with therapeutic radionuclides at IPEN/CNEN-SP

Energy Technology Data Exchange (ETDEWEB)

Barrio, G.; Dias, C.R.B.R.; Osso Junior, J.A., E-mail: gracielabarrio@gmail.com [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

2012-07-01

Radioimmunotherapy (RIT) makes use of monoclonal antibodies (MAb) labeled with alpha/beta radionuclides for therapeutical purposes, leading to tumor irradiation and destruction, preserving the normal organs on the radiation excess. The therapeutic activity to be injected in a specific patient is based on information obtained in dosimetric studies. Beta emitting radionuclides such as {sup 131}I, {sup 188}Re, {sup 90}Y, {sup 177}Lu and {sup 166}Ho are useful for the development of therapeutic radiopharmaceuticals. Anti-CD20 (Rituximab) is a chimeric MAb directed against antigen surface CD20 on B-lymphocytes, used in non-Hodgkin lymphoma treatment (NHL). The association with beta radionuclides have shown greater therapeutic efficacy. Currently, two radiopharmaceuticals with Anti-CD20 for radioimmunotherapy have FDA approval for NHL treatment: {sup 131}I-AntiCD20 (Bexar) and {sup 90}Y-AntiCD20 (Zevalin). Techniques for the radiolabeling of {sup 188}Re-antiCD20 have been recently developed by IPEN-CNEN/SP in order to evaluate the clinical use of this radionuclide in particular. The use of {sup 188}Re (T{sub 1/2} 17h) produced by the decay of {sup 188}W (T{sub 1/2} 69d), from an {sup 188}W/{sup 188}Re generator system, has represented an alternative to RIT. Beyond high energy beta emission for therapy, {sup 188}Re also emits gamma rays (155keV) suitable for image. The aim of this new project is to compare the labeling of anti-CD20 with {sup 188}Re with the same MAb labeled with {sup 131}I, {sup 177}Lu, {sup 90}Y and even {sup 99m}Tc. The first step in this project is the review of the published data available concerning the labeling of this MAb with different radionuclides, along with data obtained at IPEN, taking into account labeling procedures, labeling yields, reaction time, level and kind of impurities and biodistribution studies. The pharmacokinetic code will be developed in Visual Studio.NET platform through VB.NET and C{sup ++} for biodistribution and dosimetric

In vivo examination of {sup 188}Re(I)-tricarbonyl-labeled trastuzumab to target HER2-overexpressing breast cancer

Energy Technology Data Exchange (ETDEWEB)

Chen, K.-T. [Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Lee, T.-W. [Institute of Nuclear Energy Research, Longtan 32546, Taiwan (China); Lo, Jem-Mau [Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan (China); Institute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu 30013, Taiwan (China)], E-mail: jmlo@mx.nthu.edu.tw

2009-05-15

Introduction: Trastuzumab (Herceptin), a humanized IgG1 monoclonal antibody directed against the extracellular domain of the HER2 protein, acts as an immunotherapeutic agent for HER2-overexpressing human breast cancers. Radiolabeled trastuzumab with {beta}- or {alpha} emitters can be used as radioimmunotherapeutic agent for the similar purpose but with additional radiation effect. Methods: In this study, trastuzumab was labeled with {sup 188}Re for radioimmunotherapy of HER2/neu-positive breast cancer. {sup 188}Re(I)-tricarbonyl ion, [{sup 188}Re(OH{sub 2}){sub 3}(CO){sub 3}]{sup +}, was employed as a precursor for directly labeling the monoclonal antibody with {sup 188}Re. The immunoreactivity of {sup 188}Re(I)-trastuzumab was estimated by competition receptor-binding assay using HER2/neu-overexpressive BT-474 human breast cancer cells. The localization properties of {sup 188}Re(I)-trastuzumab within both tumor and normal tissues of athymic mice bearing BT-474 human breast cancer xenografts (HER2/neu-overexpressive) and similar mice bearing MCF-7 human breast cancer xenografts (HER2/neu-low expressive) were investigated. Results: When incubated with human serum albumin and histidine at 25{sup o}C, {sup 188}Re(I)-trastuzumab was found to be stable within 24 h. The IC{sub 50} of {sup 188}Re(I)-trastuzumab was found to be 22.63{+-}4.57 nM. {sup 188}Re(I)-trastuzumab was shown to accumulate specifically in BT-474 tumor tissue in in vivo biodistribution studies. By microSPECT/CT, the image of {sup 188}Re localized BT-474 tumor was clearly visualized within 24 h. In contrast, {sup 188}Re(I)-trastuzumab uptake in HER2-low-expressing MCF-7 tumor was minimal, and the {sup 188}Re image at the localization of the tumor was dim. Conclusion: These results reveal that {sup 188}Re(I)-trastuzumab could be an appropriate radioimmunotherapeutic agent for the treatment of HER2/neu-overexpressing cancers.

Preparation, biodistribution, and dosimetry of 188Re-Labeled MoAb ior cea1 and its f(ab')2 fragments by avidin-biotin strategy

International Nuclear Information System (INIS)

Ferro-Flores, Guillermina; Pimentel-Gonzalez, Gilmara; Gonzalez-Zavala, Maria Antonia; Murphy, Consuelo Arteaga de; Melendez-Alafort, Laura; Tendilla, Jose I.; Croft, Barbara Y.

1999-01-01

The biotinylated monoclonal antibody (MoAb) ior cea1 and its F(ab') 2 fragments were labeled with Re-188 by combination of avidin-biotin strategy. 188 Re-MoAb, 188 Re-MoAb-biotin, 188 Re-F(ab') 2 , and 188 Re-F(ab') 2 -biotin preparations were produced for these studies with specific activities of 1.30±0.18 GBq/mg and from instant freeze-dried kit formulations using ethane-1-hydroxy-1,1-diphosphonic acid (EHDP) as a weak competing ligand. There were no significant differences (p>0.05) between the biodistribution in mice of biotinylated and unbiotinylated 188 Re-labeled immunoconjugates. When avidin was injected as a chase after injection of 188 Re-MoAb-biotin or 188 Re-F(ab') 2 -biotin, the blood radioactivity level decreased approximately 75% (cumulated activity) and the effective dose decreased almost 25% with respect to that of the radioimmunoconjugates in which the chase effect was not used. Our results suggest that 188 Re-labeled biotinylated MoAb ior cea1 and its F(ab') 2 fragments prepared by this method are stable complexes in vivo

Development of pharmaceuticals with radioactive rhenium for cancer therapy. Production of {sup 186}Re and {sup 188}Re, synthesis of labeled compounds and their biodistributions

Energy Technology Data Exchange (ETDEWEB)

NONE

1998-03-01

Production of the radioactive rhenium isotopes {sup 186}Re and {sup 188}Re, and synthesis of their labeled compounds have been studied together with the biodistributions of the compounds. This work was carried out by the Working Group on Radioactive Rhenium, consisting of researchers of JAERI and some universities, in the Subcommittee for Production and Radiolabeling under the Consultative Committee of Research on Radioisotopes. For {sup 186}Re, production methods by the {sup 185}Re(n,{gamma}){sup 186}Re reaction in a reactor and by the {sup 186}W(p,n){sup 186}Re reaction with an accelerator, which can produce nocarrier-added {sup 186}Re, have been established. For {sup 188}Re, a production method by the double neutron capture reaction of {sup 186}W, which produces a {sup 188}W/{sup 188}Re generator, has been established. For labeling of bisphosphonate, DMSA, DTPA, DADS, aminomethylenephosphonate and some monoclonal antibodies with the radioactive rhenium isotopes, the optimum conditions, including pH, the amounts of reagents and so on, have been determined for each compound. The biodistributions of each of the labeled compounds in mice have been also obtained. (author)

Rhenium-188: Availability from the W-188/Re-188 Generator and Status of Current Applications

International Nuclear Information System (INIS)

Pillai, M.R.A.; Dash, A.; Knapp, Russ F. Jr.

2012-01-01

Rhenium-188 is one of the most readily available generator derived and useful radionuclides for therapy emitting β-particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 KeV, 15.1%). The 188W/188Re generator is an ideal source for the long term (4-6 months) continuous availability of no carrier added (nca) 188Re suitable for the preparation of radiopharmaceuticals for radionuclide therapy. The challenges associated with the double neutron capture route of production of the parent 188W radionuclide have been a major impediment in the progress of application of 188Re. Tungsten-188 of adequate specific activity can be prepared only in 2-3 of the high flux reactors operating in the World. Several useful technologies have been developed for the preparation of clinical grade 188W/188Re generator. Since the specific activity of 188W used in the generator is relatively low (<5 Ci/g), the eluted 188ReO4- can have low radioactive concentration often insufficient for radiopharmaceutical preparation. However, several efficient post elution concentration techniques have been developed that yield clinically useful 188ReO4-. Rhenium-188 has been used for the preparation of therapeutic radiopharmaceuticals for the management of diseases such as bone metastasis, rheumatoid arthritis and primary cancers. Several early phase clinical studies using radiopharmaceuticals based on 188Re-labeled phosphonates, antibodies, peptides, lipiodol and particulates have been reported. This article reviews the availability, and use of188Re including a discussion of why broader use of 188Re has not progressed as ecpected as a popular radionuclide for therapy.

Labeling Lanreotide with 125I and 188Re. China

International Nuclear Information System (INIS)

Bai Hongsheng

2000-01-01

Lanreotide (D-β-Nal-Cys-Try-D-Trp-Lys-Val-Cys-Thr-NH2) is a new somatostatin analogue. It can bind to human somatostatin receptor (hSSTR) subtype 2 through 5 with high affinity and to hSSTR subtype 1 with low affinity. We investigate labeling condition, quality control and stability in vitro of 125 I-Lanreotide and 188 Re-lanreotide respectively. (A) Lanreotide is labeled with 125 I using Chloramine T. The effect of reaction condition (such as reaction time, pH value, Lanreotide amount, quantity of Chloramine T and reaction volume) on labeling yield is investigated in detail. (B) The labeling yield and radiochemical purity (RP) is measured with paper chromatography (PC) and Sep-Pak C 18 Cartridge. For PC method, 125 I-Lanreotide is spotted on the Whatman No.1 paper and developed in the mixture of CH 3 CH 2 CH 2 CH 2 OH and CH 3 CH 2 OH and NH 4 OH (v/v/v=5:2:1), the Rf value of every component in the mobile phase is given in table 1. For Sep-Pak C 18 Cartridge methods each cartridge is washed with 10 ml of ethanol followed by 10 ml of iso-CH 3 CH 2 CH 2 OH solution. Aliquots of 0.1 mI sample is loaded onto the cartridge, unbound peptide (sodium iodine-125) is eluted with 5 ml of 0.5mol/L sodium acetate solution, 125 I-Lanreotide is eluted with 5 mI of 95% aqueous ethanol solution. (C) The stability of 125 I-Lanreotide in vitro is investigated by labeling compound incubating for 48 hours at 37 deg. C in the 0.9% sodium chloride solution and RP is tested by PC at specific time intervals. (D) Lanreotide is labeled directly with 188 Re via the mixture of citrate and tartate using stannous chloride as reduced agent. The influence of reaction conditions such as pH, temperature, amount of stannous chloride, amount of Lanreotide and reaction time on labeling yield is investigated in detail. At the time, the stability in vitro quality control and animal test are evaluated

Automation of labelling of Lipiodol with high-activity generator-produced 188Re

International Nuclear Information System (INIS)

Lepareur, Nicolas; Ardisson, Valerie; Noiret, Nicolas; Boucher, Eveline; Raoul, Jean-Luc; Clement, Bruno; Garin, Etienne

2011-01-01

This work describes optimisation of the kit formulation for labelling of Lipiodol with high-activity generator-produced rhenium-188. Radiochemical purity (RCP) was 92.52±2.3% and extraction yield was 98.56±1.2%. The synthesis has been automated with a TADDEO module (Comecer) giving a mean final yield of 52.68±9.6%, and reducing radiation burden to the radiochemist by 80%. Radiolabelled Lipiodol ( 188 Re-SSS/Lipiodol) is stable for at least 7 days (RCP=91.07±0.9%).

Optimization of labelling procedure of 188rE-DMSA(v)

International Nuclear Information System (INIS)

Dantas, Danielle M.; Brambilla, Tania P.; Reis, Nicoli F.; Osso Junior, Joao A.

2011-01-01

Radionuclide therapy (RNT) is emerging as an important tool of nuclear medicine. Apart from the well established 131 I, several other promising radionuclides have been identified, among them 188 Re, 90 Y and 177 Lu. 188 Re has received a lot of attention in the past decade, due to its favourable nuclear characteristics [t 1/2 16.9 h, E b eta m ax 2.12 MeV and E g amma 155 keV (15%) suitable for imaging, including the fact that it is carrier-free and can be obtained cost-effectively through the generator 188 W- 188 Re. Biodistribution studies of 188 Re-DMSA(V) have shown that its general pharmacokinetic properties are similar to that of 99m Tc-DMSA(V), so this agent could be used for targeted radiotherapy of medullary thyroid carcinoma, bone metastases, soft tissue and others tumors. The aim of this work is to evaluate two labeling procedures for the preparation of 188 Re-DMSA(V). The first method was prepared using a commercial kit of DMSA(III) for labeling with 99m Tc at high temperature (100 deg C). The second method was prepared in a vial containing 2.5 mg of DMSA, 1.00 mg of SnCl 2 .2H 2 O and 10 mg of sodium oxalate, 10 mg of cyclodextrin, in a total volume of 2.0 mL. The pH was adjusted to 3 with 37% HCl. After labeling the solution was stirred and incubated for 30 min at room temperature. The radiochemical purity was determined using TLC-SG developed with two different solvent systems: Acetone and glycine. Preliminary results for both methods of labeling 188 Re-DMSA(V) showed that the labeling yield was >95%. Further experiments are also necessary to optimize the labeling methodology of 188 Re-DMSA(V).author)

Absolute counting of 188Re radiopharmaceuticals

International Nuclear Information System (INIS)

Ravindra, Anuradha; Kulkarni, D.B.; Joseph, Leena; Kulkarni, M.S.

2018-01-01

Rhenium-188 is radiopharmaceutical that belongs to the group of strong beta-weak gamma emitters. It emits high energy beta particles, (E β m ax = 2.12MeV) and weak gamma rays (E γ = 155 keV) hence makes it suitable for wide variety of therapeutic as well as diagnostic applications. Therapeutic applications include therapy of tumors, radionuclide synovectomy, bone pain palliation, intra vascular radiation therapy etc. 188 Re-labeled medicines have been employed increasingly in the therapy of tumors and vascular restenosis. To ensure that patient receives the appropriate radiation dose during the treatment, both the activity standardization and the determination of sensitivity coefficient of the secondary standard for 188 Re have become important tasks. This paper presents the methods and results obtained for the following measurements a) Standardisation of the 188 Re by using the 4π proportional counter (4πPC)-gamma extrapolation method b) Determination of sensitivity coefficient (pA/MBq) of the secondary standard ionization chamber type Centronic IG12, 20A for 188 Re

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.

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

Optimization of labelling procedure of {sup 188}rE-DMSA(v)

Energy Technology Data Exchange (ETDEWEB)

Dantas, Danielle M.; Brambilla, Tania P.; Reis, Nicoli F.; Osso Junior, Joao A., E-mail: jaosso@ipen.br [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

2011-07-01

Radionuclide therapy (RNT) is emerging as an important tool of nuclear medicine. Apart from the well established {sup 131}I, several other promising radionuclides have been identified, among them {sup 188}Re, {sup 90}Y and {sup 177}Lu. {sup 188}Re has received a lot of attention in the past decade, due to its favourable nuclear characteristics [t{sub 1/2} 16.9 h, E{sub b}eta{sub m}ax 2.12 MeV and E{sub g}amma 155 keV (15%) suitable for imaging, including the fact that it is carrier-free and can be obtained cost-effectively through the generator {sup 188}W-{sup 188}Re. Biodistribution studies of {sup 188}Re-DMSA(V) have shown that its general pharmacokinetic properties are similar to that of {sup 99m}Tc-DMSA(V), so this agent could be used for targeted radiotherapy of medullary thyroid carcinoma, bone metastases, soft tissue and others tumors. The aim of this work is to evaluate two labeling procedures for the preparation of {sup 188}Re-DMSA(V). The first method was prepared using a commercial kit of DMSA(III) for labeling with {sup 99m}Tc at high temperature (100 deg C). The second method was prepared in a vial containing 2.5 mg of DMSA, 1.00 mg of SnCl{sub 2}.2H{sub 2}O and 10 mg of sodium oxalate, 10 mg of cyclodextrin, in a total volume of 2.0 mL. The pH was adjusted to 3 with 37% HCl. After labeling the solution was stirred and incubated for 30 min at room temperature. The radiochemical purity was determined using TLC-SG developed with two different solvent systems: Acetone and glycine. Preliminary results for both methods of labeling {sup 188}Re-DMSA(V) showed that the labeling yield was >95%. Further experiments are also necessary to optimize the labeling methodology of {sup 188}Re-DMSA(V).author)

Preparation of 188 Re-lanreotide as a potential tumor therapeutic agent

International Nuclear Information System (INIS)

Bai Hongsheng; Jin Xiaohai; Fan Hongqiang; Jia Bing; Wang Yuqing; Lu Weiwei

2001-01-01

Radiolabeled peptides hold unlimited potential in diagnostic applications and therapy of malignant tumor. Somatostatin analogue peptide (Lanreotide) is labeled directly with 188 Re via the mixture of citrate and tartrate. The influences of reaction conditions such as pH, temperature, amount of stannous chloride, Lanreotide quantity, reaction time on labeling yield are investigated in detail. At the same time, the stability in vitro, quality control and animal test are evaluated. The experimental results show that Lanreotide reacts with 188 Re for 40 min at pH 2 - 3 and 60 degree C, the labeling yield is at range of 88% - 94%. After purification of 188 Re-Lanreotide with Sep-Pak C 18 reverse phase extraction cartridge, the radiochemical purity (RP) is more than 95%. 188 Re-Lanreotide is eliminated rapidly from the blood and is excreted through liver, the uptake of lung and intestine is high

Rhenium 188 labelling of peptide conjugates

International Nuclear Information System (INIS)

Melendez-Alafort, Laura

2001-01-01

Many human tumours express high levels, of somatostatin receptors. In order to make possible a radiotherapeutic treatment of this kind for tumour a series of somatostatin analogues that can tightly chelate beta emitting isotopes have been developed in recent years. The work carried out for this thesis has been aimed towards development of a new therapeutic radiopharmaceutical for treatment of somatostatin receptor positive tumours. The first chapters describe work with technetium-99m to establish the labelling and analytical conditions for a somatostatin analogue, [Tyr 3 ]-octreotide (TOC), as a precursor to undertaking labelling studies with the beta emitter rhenium-188. 6-Hydrazinopyridine-3-carboxylic acid (HYNIC) was conjugated to TOC and labelled with 99m using different coligands. Then the stability, receptor binding and biodistribution of each complex were assessed. 99m Tc-HYNIC-TOC using EDDA as coligand showed the best characteristics, and was superior for tumour imaging in humans than the commercially available 111 In-DTPA-octreotide. The conditions for labelling the HYNIC-TOC conjugate with 188 Re were then optimised using tricine as a co-ligand. A labelling yield of ∼80% was achieved. After purification however, the stability of the complex was low. The use of other coligand systems which had proved useful for 99m Tc labelling was explored, but yields were very poor. Other chelators such as diethylenetriamine pentaacetic acid (DTPA), dimercaptosuccinic acid (DMSA) and mercaptoacetyltriglycine (MAG 3 ) were studied as potential co-ligand agents to label the HYNIC-TOC conjugate with 188 Re but, again low yields of the labelled peptide complexes were achieved. A novel 188 Re-HYNIC complex was prepared in high yields using N-N-disubstituted dithiocarbamates as coligands. However to date, the specific activities achieved with this system are relatively low. The use of the [ 99m Tc(CO) 3 (H 2 O) 3 ] complex to label the HYNIC-TOC conjugate was investigated

Production of {sup 186}Re and {sup 188}Re, and synthesis of {sup 188}Re-DTPA

Energy Technology Data Exchange (ETDEWEB)

Hashimoto, Kazuyuki; Motoishi, Shoji; Kobayashi, Katsutoshi; Izumo, Mishiroku [Department of Radioisotopes, Japan Atomic Energy Research Institute, Tokai, Ibaraki (Japan); Musdja, Muhammad Yanis

1999-08-01

Production of radioactive rhenium isotopes {sup 186}Re and {sup 188}Re, and synthesis of {sup 188}Re-DTPA have been studied. For {sup 186}Re, a production method by the {sup 185}Re(n, {gamma}) {sup 186}Re reaction in a reactor has been established. For {sup 188}Re, a production method by the double neuron capture reaction of {sup 186}W, which produces a {sup 188}W/{sup 188}Re generator, has been established. For synthesis of {sup 188}Re-DTPA, the optimum conditions, including pH, the amounts of regents and so on, have been determined. (author)

Production of carrier-free 188Re in the past ten years in Taiwan

International Nuclear Information System (INIS)

Bor-Tsung Hsieh; Institute of Nuclear Energy Research, Taiwan; Wan-Yu Lin; Tsai-Yueh Luo; Kai-Yuan Cheng

2007-01-01

Twenty clinical scale alumina-based 188 W/ 188 Re generators and carrier-free 188 Re has been produced at the Institute of Nuclear Energy Research (INER-Taiwan) for over ten years. 2845.6 GBq (76.9 Ci) of 188 Re-perrhenate solution has been eluted from generators during the past ten years. We have used the harvesting 188 Re solution for labeling radiopharmaceuticals, such as 188 Re-HEDP, 188 Re-MDP, 188 Re-microsphere, 188 Relipiodol, and 188 Re-sulfur colloid, etc. The average eluting yield of 188 Re is 78.6±5.8% that was investigated at 1115 harvesting times from 20 generators. Each generator can be used more than six months but the Millipore needs to be changed every two months for smooth harvesting and high yield of 188 Re solution. (author)

Preventive study of gastric cancer peritoneal micrometastasis in nude mice with 188Re-labelled monoclonal antibody 3H11

International Nuclear Information System (INIS)

Yang Zhi; Zhang Meiying; Lin Baohe; Zhao Changying; Han Yan; Mou Aping; Ma Yunxia

2001-01-01

In advanced gastric cancer, especially when the serosa is invaded, the implantation of cancer cells in the peritoneum is common, and it affects patients' survival time severely. Based on successfully labelled monoclonal antibody 3H11 with 188 Re, we investigated the effect of RIT (radioimmunotherapy) with 188 Re-3H11 on preventing the establishment of gastric cancer cell peritoneal micrometastasis in nude mice. After 1x10 6 BGC-823, gastric cancer cells were injected into the peritoneal cavity of each mouse, 45 BABL/C nude mice were divided into 9 groups. Each group received the various doses of 188 Re-3H11 or 188 Re-IgG or saline I.P.16 hours postoperation. The injected volume of each mouse was 1.0 mL. The results showed that the survival time depended on injected doses from 0 to 37MBq. The survival time was 170 ± 25.3 days after 37MBq 188 Re-3H11 were treated . It was over 5 times that of the saline group and about 3 times that of the 74MBq 188 Re-IgG group (p 188 Re-3H11 I.P. is effective and safe in the prevention of intra-peritoneally injected gastric cancer cells from surviving, growing and disseminating in nude mice. (author)

Quantitative PET of EGFR expression in xenograft-bearing mice using 64Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody

International Nuclear Information System (INIS)

Cai, Weibo; Chen, Kai; He, Lina; Cao, Qizhen; Chen, Xiaoyuan; Koong, Albert

2007-01-01

Cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR) on the surface of cancer cells, was approved by the FDA to treat patients with metastatic colorectal cancer. It is currently also in advanced-stage development for the treatment of several other solid tumors. Here we report for the first time the quantitative positron emission tomography (PET) imaging of EGFR expression in xenograft-bearing mice using 64 Cu-labeled cetuximab. We conjugated cetuximab with macrocyclic chelating agent 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA), labeled with 64 Cu, and tested the resulting 64 Cu-DOTA-cetuximab in seven xenograft tumor models. The tracer uptake measured by PET was correlated with the EGFR expression quantified by western blotting. The estimated human dosimetry based on the PET data in Sprague-Dawley rats was also calculated. MicroPET imaging showed that 64 Cu-DOTA-cetuximab had increasing tumor activity accumulation over time in EGFR-positive tumors but relatively low uptake in EGFR-negative tumors at all times examined ( 2 0.80) between the tracer uptake (measured by PET) and the EGFR expression level (measured by western blotting). Human dosimetry estimation indicated that the tracer may be safely administered to human patients for tumor diagnosis, with the dose-limiting organ being the liver. The success of EGFR-positive tumor imaging using 64 Cu-DOTA-cetuximab can be translated into the clinic to characterize the pharmacokinetics, to select the right population of patients for EGFR-targeted therapy, to monitor the therapeutic efficacy of anti-EGFR treatment, and to optimize the dosage of either cetuximab alone or cetuximab in combination with other therapeutic agents. (orig.)

MAG2GABA-biocytin synthesized with new intermediates for radiolabelling 99mTc and 188Re

International Nuclear Information System (INIS)

Ahn, S.H.; Choi, T.H.; Choi, C.W.; Yang, S.D.; Woo, K.S.; Chung, W.S.; Lim, S.M.

2001-01-01

188 Re from 188 W- 188 Re generator, is recently introduced in therapeutic nuclear medicine and made it possible to use whenever needed. We synthesized MAG 2 GABA-Biocytin (MGB), labelled with 188 Re for pretargeted radioimmunotherapy and evaluated biological behavior of 188 Re-MGB. N-hydroxysuccinimidyl ester of S-benzoyl mercaptoacetyldiglycine (NHS-MAG 2 ) was synthesized first, reacted with aminobutyric acid(GABA) to give MAG 2 GABA and then converted to NHS-MAG 2 GABA and conjugated to biocytin to give the MGB. To label MGB with 188 Re (50mA), ag, 200ml 1M tartrate pH7, 200 l stannous (10mg/mL) and 180MBq perrhenate were mixed and heated for 30min at 100 deg. C. The reactant was purified with C 18 Sep-Pak. HPLC analysis of the 188 Re-MGB performed on reverse phase C 18 column with a gradient. To see the stability, 188 Re-MGB was added to serum at 37 deg. C. Binding capacity of 188 Re-MGB to avidin or streptavidin was determined by size exclusion HPLC system. Biodistribution was studied in ICR normal mice(n=4/group), from 5min to 120min. In Raji cells tumour bearing nude mice(n=3), biotinylated Lym-1(40MEG) injection after 48 h, streptavidin(50MEG) was injected. 24 h later, 188 Re-MGB(0.5MEG) was injected, and biodistribution was observed 2 h later. 188 Re-MGB was obtained with labelling yield 98%. Stability in serum was maintained over 70% until 3 h. Binding capacity of 188 Re-MGB to streptavidin was greater than avidin. In normal mice, 188 Re-MGB was excreted via hepatobiliary pathway,%ID/g of GI tract was 52.1 at 120min. In Raji cells tumour bearing nude mice, liver and colon were higher than those of normal mouse. Tumour uptake at 120min was 0.05%ID/g. 188 Re-MGB was effectively labelled and retained binding activity with streptavidin. 188 Re-MGB may have a role in pretargeted radioimmunotherapy. (author)

Development of a technology for the preparation of 188W-188Re generators

International Nuclear Information System (INIS)

Oliveira, Alexandre de

2004-01-01

A big interest has recently arisen concerning the use of Rhenium-188 (188Re) for various medical applications. Tumor therapy with antibodies labeled with 188Re is the main application, but it is being studied its application in carcinomas of medullar thyroid, bone pain palliation and radionuclide synovectomy, among others. Rhenium-188 decays 79% to the ground state of stable 188Os (Eβ1max - 2,11 MeV) and 20% to the first excited state (Eβ2max = 1,97 MeV). The deexcitation of this state gives a 155 keV gamma ray (15r%) which can be detected by imaging. Another great advantage is the viability of carrier-free 188Re from the decay of 188W (t 1/2 = 69.4 days) in a generator system. The objective of this work is the development of the technology for the preparation of 188W- 188Re generators. To accomplish this, the steps of the work are: preparation of the targets of W; irradiation of W targets in order to measure the activation and radionuclidic impurities; development of 188W-188Re generators; development of a method for the quality control of 188Re: chemical, radiochemical and radionuclidic purities. The study of alumina-based generators was performed with the irradiation of targets of natural metallic W and W03 and showed that this kind of generator will only be viable with the importation of 188W, due to the low neutron flux of the Reactor IEA-R1 Reactor for the commercial routine production of this radioisotope, but the technology of production and quality control were successful. The gel type chromatographic generators of WZr were produced with natural WO3 targets and showed that, if enriched targets are to be used and with the power upgrade of the IEA-R1 Reactor, they can be produced by the Radiopharmacy Center at IPEN-SP. The quality control methodology were determined and the results were inside the limits given by the Pharmacopoeia. (author)

188W→188Re generator for biomedical applications

International Nuclear Information System (INIS)

Kamioki, Hiroshi; Mirzadeh, S.; Lambrecht, R.M.; Knapp, R. Jr.; Dadachova, K.

1994-01-01

An alumina-based 188 W → 188 Re generator was evaluated for 188 Re yield and elution profile and 188 W breakthrough using various reagents for a three-month period. To address the problem of low specific volume, the generator was eluted with reagents which could be easily destroyed by gentle evaporation from acidic solutions (e.g. NH 4 Cl and NH 4 NO 3 ). We also evaluated a proposed ''alumina/anion-exchange'' tandem generator for the preparation of highly purified 188 Re as perrhenic acid. In parallel studies, the adsorption dynamics of tungsten on alumina showed a sharp rise in the tungsten breakthrough at W/Al 2 O 3 ratio of ∼ 120 mg/g corresponding to a distribution constant of ∼ 8400 from nitrate solution at 0.05 M ionic strength. In adsorption on anion exchange resins, carrier-free 188 Re exhibited a behavior very similar to that of macroscopic quantities of Re. These studies further demonstrated the long and useful shelf-life of 188 W → 188 Re generator. (orig.)

A new technique for labeling of Lipiodol with 188Re in the treatment of hepatic tumor

International Nuclear Information System (INIS)

Shyh-Jen Wang; Wan-Yu Lin; Bor-Tsung Hsieh; Kai-Yuan Cheng; Lie-Hang Shen; Ming-Ja Su

2004-01-01

A new method for the synthesis of 188 Re-Lipiodol without using a chelating agent and to evaluate the stability and biodistribution of the new agent in rats with hepatic tumors was attempted. Eighteen male Sprague -Dawley rats with liver tumors were sacrificed at 1, 24, and 48 hours (six rats at each time) after injection of approximately 7.4 MBq (0.2 mCi) of 188 Re Lipiodol via the hepatic artery. Samples of tumor, liver and other organs were collected and tissue concentration (%ID/g) of the markers were calculated. A high level of radioactivity in the hepatic tumors was found at every time of the study. The ratios of tumor to normal liver tissue concentration (T/N ratio) were 7.62 at 1 hour, 8.03 at 24 hours, and 7.70 at 48 hours. Except for the liver, kidneys and lungs, concentrations in other organs were low. The new method for labeling Lipiodol with 188 Re is simple and has potential for the treatment of hepatic tumors. (author)

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)

Country Report: Rep. of Korea. {sup 188}re-Tricabonyl Labeling Strategy: Preparation of 1{sup 188}Re(I) Tricarbonyl Precursor [{sup 188}Re(OH{sub 2}){sub 3}(CO){sub 3}]+ for the Labeling of Biomolecules

Energy Technology Data Exchange (ETDEWEB)

Park, Sang Hyun [Radiation Research Division for Biotechnology, Korea Atomic Energy Research Institute (Korea, Republic of)

2010-07-01

The {sup 99m}Tc(I) and {sup 188}Re(I) tricarbonyl precursors [M(OH{sub 2}){sub 3}(CO){sub 3}]{sup +} have been shown to be excellent starting materials for the synthesis of {sup 99m}Tc(I) and {sup 188}Re(I) tricarbonyl complexes as well as radiolabeling of target-specific biomolecules.{sup 1-8} Recently, a user-friendly kit formulation (IsoLink{sup TM}) was developed using potassium boranocarbonate, K{sub 2}[BH{sub 3}CO{sub 2}], for preparation of the {sup 99m}Tc precursor complex. This solid reagent serves both as a source of carbon monoxide and a reducing agent for technetium. It was also used by Schibli and coworkers for the preparation of the corresponding {sup 188}Re precursor complex (“Schibili’s kit”).{sup 9} This approach involved the reduction of [{sup 188}Re]perrhenate eluate (1 ml) in neutral solution with 3 mg K{sub 2}[BH{sub 3}CO{sub 2}] and 5 mg BH3≅NH3 by incubation at 60 °C for 15 min. The amounts of reducing agents and acid (concentrated phosphoric acid) were carefully balanced not only to avoid fast hydrolysis of the boranes, but also to maintain a sufficiently low pH to stabilize reduced rhenium intermediates. The preparations resulted in yields >85 % of the desired precursor complex. In addition, perrhenate (7±3 %), colloidal {sup 188}ReO{sub 2} (<5 %), and a byproduct of unknown composition were also detected. To increase the yields even further, we evaluated the recently described borohydride exchange resin (BER) as an additional reducing agent and an anion scavengers.

188W/188Re Generator System and Its Therapeutic Applications

Directory of Open Access Journals (Sweden)

A. Boschi

2014-01-01

Full Text Available The 188Re radioisotope represents a useful radioisotope for the preparation of radiopharmaceuticals for therapeutic applications, particularly because of its favorable nuclear properties. The nuclide decay pattern is through the emission of a principle beta particle having 2.12 MeV maximum energy, which is enough to penetrate and destroy abnormal tissues, and principle gamma rays (Eγ=155 keV, which can efficiently be used for imaging and calculations of radiation dose. 188Re may be conveniently produced by 188W/188Re generator systems. The challenges related to the double neutron capture reaction route to provide only modest yield of the parent 188W radionuclide indeed have been one of the major issues about the use of 188Re in nuclear medicine. Since the specific activity of 188W used in the generator is relatively low (<185 GBq/g, the eluted Re188O4- can have a low radioactive concentration, often ineffective for radiopharmaceutical preparation. However, several efficient postelution concentration techniques have been developed, which yield clinically useful Re188O4- solutions. This review summarizes the technologies developed for the preparation of 188W/188Re generators, postelution concentration of the 188Re perrhenate eluate, and a brief discussion of new chemical strategies available for the very high yield preparation of 188Re radiopharmaceuticals.

Quantitative PET of EGFR expression in xenograft-bearing mice using {sup 64}Cu-labeled cetuximab, a chimeric anti-EGFR monoclonal antibody

Energy Technology Data Exchange (ETDEWEB)

Cai, Weibo; Chen, Kai; He, Lina; Cao, Qizhen; Chen, Xiaoyuan [Stanford University School of Medicine, The Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford, CA (United States); Koong, Albert [Stanford University School of Medicine, Department of Radiation Oncology, Stanford, CA (United States)

2007-06-15

Cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR) on the surface of cancer cells, was approved by the FDA to treat patients with metastatic colorectal cancer. It is currently also in advanced-stage development for the treatment of several other solid tumors. Here we report for the first time the quantitative positron emission tomography (PET) imaging of EGFR expression in xenograft-bearing mice using {sup 64}Cu-labeled cetuximab. We conjugated cetuximab with macrocyclic chelating agent 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA), labeled with {sup 64}Cu, and tested the resulting {sup 64}Cu-DOTA-cetuximab in seven xenograft tumor models. The tracer uptake measured by PET was correlated with the EGFR expression quantified by western blotting. The estimated human dosimetry based on the PET data in Sprague-Dawley rats was also calculated. MicroPET imaging showed that {sup 64}Cu-DOTA-cetuximab had increasing tumor activity accumulation over time in EGFR-positive tumors but relatively low uptake in EGFR-negative tumors at all times examined (<5%ID/g). There was a good correlation (R {sup 2} = 0.80) between the tracer uptake (measured by PET) and the EGFR expression level (measured by western blotting). Human dosimetry estimation indicated that the tracer may be safely administered to human patients for tumor diagnosis, with the dose-limiting organ being the liver. The success of EGFR-positive tumor imaging using {sup 64}Cu-DOTA-cetuximab can be translated into the clinic to characterize the pharmacokinetics, to select the right population of patients for EGFR-targeted therapy, to monitor the therapeutic efficacy of anti-EGFR treatment, and to optimize the dosage of either cetuximab alone or cetuximab in combination with other therapeutic agents. (orig.)

The influence of proteasome inhibitor MG132, external radiation and unlabeled antibody on the tumor uptake and biodistribution of 188Re-labeled anti-E6 C1P5 antibody in cervical cancer in mice

Science.gov (United States)

Phaeton, Rébécca; Wang, Xing Guo; Einstein, Mark H.; Goldberg, Gary L.; Casadevall, Arturo; Dadachova, Ekaterina

2009-01-01

Background Human Papillomavirus (HPV) infection is considered a necessary step for the development of cervical cancer and >95% of all cervical cancers have detectable HPV sequences. We have recently demonstrated the efficacy of radioimmunotherapy (RIT) which targeted viral oncoprotein E6 in treatment of experimental cervical cancer We hypothesized that pre-treatment of tumor cells with various agents which cause cell death and/or elevation of E6 levels would increase the accumulation of radiolabeled antibodies to E6 in cervical tumors. Methods HPV-16 positive CasKi cells were treated in vitro with up to 6 Gy of external radiation, or proteasome inhibitor MG-132 or unlabeled anti-E6 antibody C1P5 and cell death was assessed. Biodistribution of 188Rhenium (188Re)-labeled C1P5 antibody was performed in both control and radiation MG-132 treated CasKi tumor-bearing nude mice. Results . 188Re-C1P5 antibody demonstrated tumor specificity and very low uptake and fast clearance from the major organs. The amount of tumor uptake was enhanced by MG-132 but was unaffected by pre-treatment with radiation. In addition, in vitro studies demonstrated an unanticipated effect of unlabeled antibody on the amount of cell death, a finding that was suggested by our previous in vivo studies in CasKi tumor model. Conclusion We demonstrated that pre-treatment of cervical tumors with proteasome inhibitor MG-132 and with unlabeled antibody to E6 can serve as a means to generate non-viable cancer cells and to elevate the levels of target oncoproteins in the cells for increasing the accumulation of targeted radiolabeled antibodies in tumors. These results favor further development of RIT of cervical cancers targeting viral antigens. PMID:20127955

Evaluation of 188Re-labeled PEGylated nanoliposome as a radionuclide therapeutic agent in an orthotopic glioma-bearing rat model

Directory of Open Access Journals (Sweden)

Huang FYJ

2015-01-01

Full Text Available Feng-Yun J Huang,1 Te-Wei Lee,2 Chih-Hsien Chang,2 Liang-Cheng Chen,2 Wei-Hsin Hsu,2 Chien-Wen Chang,1 Jem-Mau Lo1 1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan; 2Institute of Nuclear Energy Research, Longtan, Taiwan Purpose: In this study, the 188Re-labeled PEGylated nanoliposome (188Re-liposome was prepared and evaluated as a therapeutic agent for glioma.Materials and methods: The reporter cell line, F98luc was prepared via Lentivector expression kit system and used to set up the orthotopic glioma-bearing rat model for non-invasive bioluminescent imaging. The maximum tolerated dose applicable in Fischer344 rats was explored via body weight monitoring of the rats after single intravenous injection of 188Re-liposome with varying dosages before the treatment study. The OLINDA/EXM 1.1 software was utilized for estimating the radiation dosimetry. To assess the therapeutic efficacy, tumor-bearing rats were intravenously administered 188Re-liposome or normal saline followed by monitoring of the tumor growth and animal survival time. In addition, the histopathological examinations of tumors were conducted on the 188Re-liposome-treated rats.Results: By using bioluminescent imaging, the well-established reporter cell line (F98luc showed a high relationship between cell number and its bioluminescent intensity (R2=0.99 in vitro; furthermore, it could also provide clear tumor imaging for monitoring tumor growth in vivo. The maximum tolerated dose of 188Re-liposome in Fischer344 rats was estimated to be 333 MBq. According to the dosimetry results, higher equivalent doses were observed in spleen and kidneys while very less were in normal brain, red marrow, and thyroid. For therapeutic efficacy study, the progression of tumor growth in terms of tumor volume and/or tumor weight was significantly slower for the 188Re-liposome-treated group than the control group (P<0.05. As a result, the

Bone uptake by di and tetraphosphonates labeled with Rhenium-188

International Nuclear Information System (INIS)

Faintuch, B.L.; Osso, J.A. Jr.; Muramoto, E.; Faintuch, S.

2002-01-01

MDP (methylenediphosphonate) and HEDP (hydroxyethylidenediphosphonate), both diphosphonates, and EDTMP (ethylenediamine tetramethylene phosphonic acid) a tetraphosphonate ligand, have been labeled with 188 Re for use in metastatic bone-pain palliation. The aim of this study was a comparison between the three complexes 188 Re-MDP, 188 Re-HEDP and 188 Re-EDTMP concerning the complexation conditions, in order to achieve maximum yield, stability and bone uptake. Methods: MDP was dissolved in water and HEDP and EDTMP were dissolved in NaOH 1N followed by decreasing pH with HCl 1N. To all mixtures stannous chloride and 188 ReO 4 were added in a nitrogen atmosphere. The preparations were heated in a boiling water bath for 15 min. The yields as well as the radiochemical stability were estimated by ITLC. Different concentrations of phosphonates and stannous chloride were evaluated. Biodistribution studies in swiss mice were done for the three 188 Re-phosphonates that presented the best radiochemical yield. Results: For 188 Re-MDP and 188 Re-HEDP the optimal ligand concentration for maximum complexation was 30 mg whereas for 188 Re-EDTMP, it was 40 mg. The best amount of SnCl 2 .2H 2 O was 2 mg/mL for MDP, 3 mg/mL for HEDP and 1 mg/mL for EDTMP. In these conditions the three complexes showed a complexation yield above 95%. All of them presented 4-hour radiochemical stability without the need for ascorbic acid solution, but for 24 hours this stability existed only in the presence of that substance otherwise re-oxidation of 188 Re occurred. All products showed a great uptake by the kidneys. 188 Re-EDTMP had the greatest uptake by the bone (3.13 ± 0.18% ID/g) followed by 188 Re-MDP (1.18 ± 0.05%ID/g) and 188 Re-HEDP (1.03 ± 0.12 %ID/g), 4 hour postinjection. 188 Re-EDTMP displayed a bone/muscle ratio of 28.5, 188 Re-MDP 4.9 and 188 Re-HEDP 4.9. Conclusion: 188 Re-EDTMP demonstrated the best potential as a radiopharmaceutical for bone cancer pain relief, encouraging further

In-house Preparation of 188W/188Re Generators

International Nuclear Information System (INIS)

Sriwiang, Wiranee; Minsakorn, Napharat; Wardwilai, Charudej; Yindirum, Chareon; Sangsuriyan, Jatupol

2007-08-01

Full text: Low activity 188W/188Re generators were developed for the purpose of routinely supplying rhenium-188 for laboratory experiments and research works. Chromatography technology was applied in the construction of the generators. The chromatography columns containing 1.74 g alumina (Al2O3) were housed in plastic (PE) shielding inside the 30mm thick lead shield. Three generators were loaded with three different 188W activities; 25mCi (RG1), 25 mCi (RG2) and 50 mCi (RG3). Generator performances were determined in terms of elution yields, radiochemical purity, Al-breakthrough, 188W-breakthrough, and radionuclidic purity of the eluted products. These generators can be used for more than 6 months with average elution yields greater than 90 %. Radiochemical purity of 188ReO4- was high (> 99.7 % by ITLC), low level of 188W -breakthrough and low contamination of 192Ir and 191Os. There were only less than 1 ppm of 186W carrier and less than 3 ppm of Al-breakthrough. Key words: 188W/188Re, Generator, 188Re, Radionuclide

Complexation of 188Re-phosphonates: in vitro and in vivo studies

International Nuclear Information System (INIS)

Faintuch, B.L.; Muramoto, E.; Faintuch, S.

2003-01-01

MDP (methylenediphosphonate) and HEDP (hydroxyethylidene diphosphonate), both disphosphonates, and EDTMP (ethylenediamine tetramethylene phosphonic acid), a tetraphosphonate ligand, have been previously labeled with 188 Re for use in metastatic bone-pain palliation. The aim of this study was a comparison between the three complexes 188 Re-MDP, 188 Re-HEDP and 188 Re-EDTMP concerning the complexation conditions, in order to achieve maximum yield, stability and bone uptake. Methods: MDP was dissolved in water and HEDP and EDTMP were dissolved in NaOH 1 N followed by reduction of pH with HCl 1 N. To all mixtures stannous chloride and 188 ReO 4 - were added in a nitrogen atmosphere. The preparations were heated in boiling water bath for 15 min. Yield as well as radiochemical stability was estimated by ITLC. Different concentrations of phosphonates and stannous chloride were evaluated. Biodistribution studies in Swiss mice were done for the three 188 Re-phosphonates that presented the best radiochemical yield. The optimal ligand concentration for maximum complexation was 85.2 mM for MDP, 72.8 mM for HEDP and 45.8 mM for EDTMP. The best amount of SnCl 2 .2H 2 O was 1.5 mg/mL for 188 Re-HEDP and 1 mg/mL for both 188 Re-MDP and 188 Re-EDTMP. In these conditions the three complexes showed a complexation rate above 95%. Reasonable radiochemical stability for 24 hours was achieved by 188 Re-EDTMP when employing ascorbic acid. All products showed a great uptake by the kidneys. 188 Re-EDTMP had the greatest uptake by femur (3.1 ± 0.2% ID/g) followed by 188 Re-MDP (1.2 ± 0.1% ID/g) and 188 Re-HEDP (1.0 ± 0.1% ID/g), 4 hours post injection. 188 Re-EDTMP displayed a femur bone/muscle ratio of 28.5, 188 Re-MDP 4.9 and 188 Re-HEDP 4.9. In conclusion 188 Re-EDTMP demonstrated the best potential as a radiopharmaceutical for bone cancer pain relief, encouraging further dosimetric studies and clinical trials. (orig.)

166Ho and 90Y labeled 6D2 monoclonal antibody for targeted radiotherapy of melanoma: Comparison with 188Re radiolabel

International Nuclear Information System (INIS)

Thompson, S.; Ballard, B.; Jiang, Z.; Revskaya, E.; Sisay, N.; Miller, W.H.; Cutler, C.S.; Dadachova, E.; Francesconi, L.C.

2014-01-01

Introduction: An approach to radioimmunotherapy (RIT) of metastatic melanoma is the targeting of melanin pigment with monoclonal antibodies (mAbs) to melanin radiolabeled with therapeutic radionuclides. The proof of principle experiments were performed using a melanin-binding antibody 6D2 of IgM isotype radiolabeled with a β emitter 188 Re and demonstrated the inhibition of tumor growth. In this study we investigated the efficacy of 6D2 antibody radiolabeled with two other longer lived β emitters 90 Y and 166 Ho in treatment of experimental melanoma, with the objective to find a possible correlation between the efficacy and half-life of the radioisotopes which possess high energy β (E max > 1.5 MeV) emission properties. Methods: 6D2 was radiolabeled with longer lived β emitters 90 Y and 166 Ho in treatment of experimental melanoma in A2058 melanoma tumor-bearing nude mice. The immunoreactivity of the radiolabeled 6D2 mAb, its in vitro binding to the MNT1 human melanoma cells, the biodistribution and therapy in A2058 human melanoma bearing nude mice as well as dosimetry calculations were performed. Results: When labeled with the longer lived 90 Y radionuclide, the 6D2 mAb did not produce any therapeutic effect in tumor bearing mice while the reduction of the tumor growth by 166 Ho-6D2 was very similar to the previously reported therapy results for 188 Re-6D2. In addition, 166 Ho-labeled mAb produced the therapeutic effect on the tumor without any toxic effects while the administration of the 90 Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. Conclusions: 166 Ho-labeled mAb to melanin produced some therapeutic effect on the tumor without any toxic effects while the administration of the 90 Y-labeled radioconjugate was toxic to mice with no appreciable anti-tumor effect. We concluded that the serum half-life of the 6D2 carrier antibody matched well the physical half-life of 166 Ho to deliver the tumoricidal absorbed dose to the

188Re-SSS lipiodol: radiolabelling and biodistribution following injection into the hepatic artery of rats bearing hepatoma.

Science.gov (United States)

Garin, Etienne; Denizot, Benoit; Noiret, Nicolas; Lepareur, Nicolas; Roux, Jerome; Moreau, Myriam; Herry, Jean-Yves; Bourguet, Patrick; Benoit, Jean-Pierre; Lejeune, Jean-Jacques

2004-10-01

Although intra-arterial radiation therapy with 131I-lipiodol is a useful therapeutic approach to the treatment of hepatocellular carcinoma, various disadvantages limit its use. To describe the development of a method for the labelling of lipiodol with 188Re-SSS (188Re (S2CPh)(S3CPh)2 complex) and to investigate its biodistribution after injection into the hepatic artery of rats with hepatoma. 188Re-SSS lipiodol was obtained after dissolving a chelating agent, previously labelled with 188Re, in cold lipiodol. The radiochemical purity (RCP) of labelling was checked immediately. The 188Re-SSS lipiodol was injected into the hepatic artery of nine rats with a Novikoff hepatoma. They were sacrificed 1, 24 and 48 h after injection, and used for ex vivo counting. Labelling of 188Re-SSS lipiodol was achieved with a yield of 97.3+/-2.1%. The immediate RCP was 94.1+/-1.7%. Ex vivo counting confirmed a predominantly hepatic uptake, with a good tumoral retention of 188Re-SSS lipiodol, a weak pulmonary uptake and a very faint digestive uptake. The 'tumour/non-tumoral liver' ratio was high at 1, 24 and 48 h after injection (2.9+/-1.5, 4.1+/-/4.1 and 4.1+/-0.7, respectively). Using the method described here, 188Re-SSS lipiodol can be obtained with a very high yield and a satisfactory RCP. The biodistribution in rats with hepatoma indicates a good tumoral retention of 188Re-SSS lipiodol associated with a predominant hepatic uptake, a weak pulmonary uptake and a very faint digestive uptake. This product should be considered for intra-arterial radiation therapy in human hepatoma.

Efficacy of Re-188-labelled sulphur colloid on prolongation of survival time in melanoma-bearing animals

International Nuclear Information System (INIS)

Chen, F.D.; Hsieh, B.T.; Wang, H.E.; Ou, Y.H.; Yang, W.K.; Whang-Peng, J.; Liu, R.S.; Knapp, F.F.; Ting, G.; Yen, S.H.

2001-01-01

In this study, the effectiveness of a 188 Re labeled sulfur colloid with two particle size ranges was used to evaluate the effectiveness of this agent on melanoma tumors in mice in terms of animal lifespan. Methods: Two separate group of animals were used for investigating biodistribution and survival time. A total of 188 B16F10-melanoma-bearing BDF 1 mice were injected intraperitoneally with 3.7 MBq (0.1mCi)/2mL of radiolabeled sulfur colloid ten days after intraperitoneal inoculation of 5x10 5 B16F10 melanoma cells/2ml. For group 1, 30 mice were sacrificed at 1, 4, 24, 48 and 72 hours for biodistribution studies. In group 2, 158 mice were divided into 9 groups (n=16∼18/groups)each receiving respectively tumor alone, tumor with normal saline, cold colloid or hot colloid with 16, 23, 31, 46, 62, or 124 MBq activity. Each of these colloid groups was further divided into two groups, one receiving smaller particle sizes ( 188 Re-sulfur colloid is an effective agent in controlling tumor cells in the abdominal cavity in animals

SKLB188 inhibits the growth of head and neck squamous cell carcinoma by suppressing EGFR signalling.

Science.gov (United States)

Barzegar, Mansoureh; Ma, Shuang; Zhang, Chao; Chen, Xin; Gu, Ying; Shang, Chaowei; Jiang, Xiaojuan; Yang, Jiao; Nathan, Cherie-Ann; Yang, Shengyong; Huang, Shile

2017-10-10

Overexpression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of head and neck squamous cell carcinoma (HNSCC), and is correlated with poor prognosis. Thus, targeting EGFR is a promising strategy for treatment of HNSCC. Several small molecule EGFR inhibitors have been tested in clinical trials for treatment of HNSCC, but none of them are more effective than the current chemotherapeutic drugs. Thus, it is urgently needed to develop novel EGFR inhibitors for HNSCC treatment. By screening an in-house focused library containing approximately 650 000 known kinase inhibitors and kinase inhibitor-like compounds containing common kinase inhibitor core scaffolds, we identified SKLB188 as a lead compound for inhibition of EGFR. The anticancer effects of SKLB188 on HNSCC cells were investigated by in vitro cell growth, cell cycle and apoptosis assays, as well as in vivo FaDu xenograft mouse model. Molecular docking, in vitro kinase profiling and western blotting were performed to characterise EGFR as the molecular target. SKLB188 inhibited HNSCC cell proliferation by inducing G 1 cell cycle arrest, which was associated with downregulating the expression of Cdc25A, cyclins D1/A and cyclin-dependent kinases (CDK2/4), and upregulating the expression of cyclin-dependent kinase (CDK) inhibitors (p21 Cip1 and p27 Kip1 ), leading to decreased phosphorylation of Rb. SKLB188 also induced caspase-dependent apoptosis of HNSCC cells by downregulating the expression of Mcl-1 and survivin. Molecular docking revealed that SKLB188 could bind to the kinase domain of EGFR through hydrogen bonds and hydrophobic interactions. In vitro kinase assay showed that SKLB188 inhibited the activity of a recombinant human EGFR very potently (IC 50 =5 nM). Western blot analysis demonstrated that SKLB188 inhibited the phosphorylation of EGFR and its downstream targets, extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and Akt in the cells. In addition, SKLB188 dose

Transarterial Re-188 labeled Lipiodol therapy in cases of inoperable hepatocellular carcinoma

International Nuclear Information System (INIS)

Kumar, Ajay; Pant, G.S.; Bandopadhyaya, G.P.; Bal, C.S.; Srivastava, D.N.; Acharya, S.K.; Pandey, G.K.; DattaGupta, S.; Sundaram, K.R.; Zanzonicog, Pat; Sundaram, Felix X.; Padhy, A.K.

2004-01-01

-absorbed dose to the various organs (including that to tumor) was calculated according to MIRD scheme using specially developed software by IAEA. From this value, the MTA of Re-188, which could be safely injected to the patient, was calculated and injected through hepatic artery after femoral catheterisation. Mean age, height and weight of the patients were 47.4+8.6 years, 165.8+9.3 cm and 58.4+10.7 Kg, respectively (M:F=9:1). Mean radiation absorbed dose was calculated to be 0.37+0.18, 0.045+0.05, 0.00017+0.00006 and 1.61+0.93 cGy/MBq to the normal liver parenchyma, lungs, bone marrow and tumor, respectively. The mean MTA was calculated to be 9432+3650 MBq, with the normal liver parenchyma being the critical organ in 74% cases. With administered MTA, 115+39 Gy of radiation dose could be delivered to the tumor, which was much more than the desired tumoricidal dose. All patients tolerated therapy very well. We conclude that with individual dosimetry, one can safely administer the maximum possible amount of Re-188 labeled lipiodol to the patients with hepatocellular carcinoma; delivering the tumoricidal radiation dose to the tumor without jeopardizing the other organs. (author)

Rhenium-188-Lipiodol therapy of liver cancer: Optimization of conjugate-view imaging of 188Re for patient-specific dosimetry

International Nuclear Information System (INIS)

Chaudakshetrin, P.; Osorio, M.; Padhy, A.K.; Divgi, C.; Zanzonico, P.

2004-01-01

Full text: Intrahepatic artery Lipiodol labeled with generator-produced, β-emitting 188Re (17 hr; Eβ=0.53-0.70 MeV; Range=4 mm) localizes in and may effectively treat inoperable liver tumors. Although 188Re emits an imageable 155-keV γ ray (15%), its 478- and 633-keV β rays (2.3%) complicate imaging. Our objective was to optimize 188Re image quality and conjugate-view accuracy for quantitative imaging-based patient-specific dosimetry for 188Re-Lipiodol. Using an ADAC dual-EpicO-circumflex-detector gamma camera, 188Re intrinsic and extrinsic (with LEGP, MEGP, and HEGP collimation) uniformities using either 99mTc intrinsic or 188Re extrinsic flood corrections were evaluated. 188Re conjugate view count rate vs. activity concentration linearity as a function of scattering/attenuating medium thickness was then evaluated with and without corrections for attenuation (a 188Re transmission image) and for scatter and septal penetration, subtracting a fraction of counts in a lower-energy (109-140 keV)- and a higher-energy (170-201 keV)-window image, respectively, from the 20% (140-171 keV) photopeak image. Our phantom consisted of 5 10-ml vials containing 25 to 400 μCi/ml of 188Re with 0 to 6 cm at different positions (∼5 cm apart) between the detectors (60 cm apart) and with a 0- to 6-cm thickness of non-radioactive water between the vials and each detector. With a 99mTc intrinsic correction, 188Re intrinsic uniformity was excellent ( 10% and 'tubey'), and was poorer the lower the energy rating of the collimation. Uniformity with HEGP collimation and an extrinsic 188Re correction was acceptable ( 0.95) and the slope (cps/pixel/μCi/ml) was constant +25% (vs +10% for 99mTc) for 0- to 6-cm thicknesses of water. Regardless of the fraction of counts subtracted, neither scatter nor septal-penetration correction improved the slope constancy. Conclusion: Downscatter/septal penetration of the 478- and 633-keV 188Re γ-rays complicates imaging of its 155-keV γ-ray. Using HEGP

Experimental study of the biological properties of 188Re-Hepama-1 biologic superparamagnetic nanoparticles

International Nuclear Information System (INIS)

Feng Yanlin; Tan Jiaju; Sun Jing; Wen Guanghua; Wu Xiaolian; Liang Sheng; Xia Jiaoyun

2007-01-01

Objective: To investigate a new biologic-superparamagnetic nanoparticles's characteristics of immunological activity, biological distributing in vivo, targeting and inhibiting tumor effect. Methods: The experimental group 188 Re-Hepama-l-superparamagnetic nanoparticles, and control groups, including 188 ReO 4 - , 188 Re-Hepama-1, and 188 Re-superparamagnetic nanoparticles, were set up. The distributions were measured after injection 4 h and 24 h by caudal vein of Kuming mice. The magnetic targeting experiments in vivo were clone with and without magnetic field in liver after injection in New Zealand rabbit. The inhibiting tumor effect on hepatic cancer cell lines SMMC-7721 of the above four 188 Re labeled products were measured by mono nuclear cell direct cytotoxicity assay method. Results: After injection 4 h and 24 h by vein, the liver taking was highest in group 188 Re-Hepama-l-superparamagnetic nanoparticles. The radiative activity in liver in magnetism zoo was higher than in non magnetism zoo in 188 Re- Hepama-1-superparamagnetic nanoparticles after applying magnetic field in left lobe of liver, and the ratio of in magnetism zoo to non magnetism zoo was 1.87. And the half effective inhibition radioactive concentrations (IC 50 ) in 188 Re-Hepama-l-superparamagnetic nanoparticles was one forth of 188 ReO 4 - . Conclusion: 188 Re- Hepama-l-superparamagnetic nanoparticles showed its fine stability in intro, good immunological activity and significant liver target. (authors)

Concentration of 188Re-Perrhenate for Therapeutic Radiopharmaceuticals

International Nuclear Information System (INIS)

Bokhari, T.H.; Hina, S.; Ahmad, M.; Iqbal, M.

2013-01-01

Summary: Rhenium-188 (T1/2=16.9h) has great potential for a variety of therapeutic applications, including radionuclide synovectomy, oncology and bone pain palliation. The radioactive concentration of 188Re is dependent upon the specific activity of 188W, which dictates the bed size of the alumina/gel column. Due to the high content of inactive tungsten in neutron irradiated WO3, large columns containing aluminum oxide or gel are needed to prepare to double neutron capture based 188W/188Re generators that results in large elution volumes containing relatively high188W contents and low concentrations of /sup 188/ ReO/sub 4/ This decrease in specific volume of 188ReO/sub 4/ places a limitation because a high radioactive concentration of 188ReO4 - is always needed for filling angioplasty balloons or other therapeutic radiopharmaceuticals like188Re -EHDP 188Re -EDTMP, 188Re - MAG3 and 188Re -DTPA. We report post elution concentration of 188ReO4 - using in- house prepared lead cation exchange and alumina columns. Using these columns high bolus volume (10 mL saline) of 188ReO4 - can conveniently be concentrated in 1 mL of physiological saline for therapeutic use. (author)

A software package for patient-specific dosimetry in the locoregional RIT of gliomas using 188Re labelled NIMOTUZUMAB

International Nuclear Information System (INIS)

Torres, L.A.; Coca, M.A.; Sanchez, Y.; Cornejo, N.; Catasus, C.; Denaro, M. de

2008-01-01

Full text: The locoregional treatment of high-grade gliomas using beta emitter compounds allows delivering high radiation doses in the tumor bed and the brain adjacent tissues of patients suffering these aggressive malignancies. The main goal of this work was to implement patient-specific dosimetry procedures using a voxel-based methodology in order to compute and analyze the three-dimensional doses distributions received by the patients undergoing loco-regional treatment of gliomas with the 188 Re labeled MAb NIMOTUZUMAB. A software package called TRIDOSE has been developed to perform the image managing, volume registration, dose calculations and qualitative and quantitative analysis of the results, including dose-volume histograms and isodose curves. The dosimetric factors at voxel level for 188 Re ('S' values) were estimated using two different methods, Monte Carlo simulations of energy transport and deposition and the integration of the dose kernel functions. A quality control module was also implemented in order to test the software using well-known 3D distribution of activities or counts. The TRIDOSE outputs were compared with other commercial software showing relative differences lower than 1.10% for different sphere sizes. The established dosimetric procedures constitute a useful tool to compute the absorbed doses received by patients undergoing radioimmunotherapy of brain tumors with 188 Re-NIMOTUZUMAB. (author)

46 CFR 188.10-37 - Label.

Science.gov (United States)

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Label. 188.10-37 Section 188.10-37 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OCEANOGRAPHIC RESEARCH VESSELS GENERAL PROVISIONS Definition of Terms Used in This Subchapter § 188.10-37 Label. This term means the label required by 49 CFR part 172...

Synthesis of insulin-like growth factor 1 analogue (188Re/99Tcm-IGF-1A) and the binding with pancreatic carcinoma cell

International Nuclear Information System (INIS)

Zhang Bin; Wu Yiwei; Fan Guanglei; Fan Wo

2007-01-01

Objective: An useful and stable method was developed for labeling insulin-like growth factor 1 analogue (IGF-1A) with 188 Re/ 99 Tc m , and its binding characteristic was studied with human pancreatic cancer cell Patu8988 in this study. Methods: The direct labeling method was adopted to label IGF- 1A under different conditions: 2 to 10 μl Tween80; 0.75 to 25 g/L SnCl 2 ·2H 2 O; 20 to 100 μg IGF-1A; 10 to 500 μl 188 ReO 4 - . The labeling rate was dynamically measured from 5 min to 6 h after labeling. The in vitro stabilities of 188 Re/ 99 Tc m -IGF-1A were accessed by dynamic labeling rates measured at 2 to 24 h. SPECT imaging after intravenous injection of 99 Tc m -IGF-1A and intratumoral injection of 188 Re-IGF-1A in nude mice was performed. Results: The best condition for labeling 188 Re was: 100 μl SnCl 2 ·2H 2 O (10 g/L), 50 μl IGF-1A (2 g/L), 300 μl Na 3 PO 4 , l0 μl 0.1% Tween80, 50 μl 188 ReO 4 - with 30 min reaction time at room temperature and pH 7.0. The maximum labeling rate of 188 Re-IGF-1A was (94.07 ± 0.32)%. The radiochemical purity was (76.57 ± 9.96)% at 24 h after mixing with human serum. The maximum binding efficiency of 188 Re-IGF-1A with Patu8988 cell was (24.13 ± 2.03)% , and the specific binding was 12.68%. The best labeling condition of 99 Tc m was: 100 μl SnCl 2 ·2H 2 O (3 g/L), 40 μl IGF-1A (2 g/L), 2 μl 0.1% Tween80, 50 μl 99 Tc m O - 4. The maximum labeling rate of 99 Tc m -IGF-1A was (94.43 ± 0.75)% and the radiochemical purity was (54.07 ± 3.86)% at 24 h after mixing with human serum. The maximum binding with Patu8988 cell was (22.95 ± 3.94)%, and the specific binding rate was 19.31%. The tumors in nude mice could be best imaged at 6 h after intravenous injection of 99 Tc m -IGF-1A and 48 h after intratumoral injection of 188 Re-IGF-1A. Conclusions: The presented method of labeling IGF-1A with 188 Re/ 99 Tc m was stable and efficient. 188 Re/ 99 Tc m -IGF-1A could bind with the pancreatic cancer cell Patu8988

Biological behavior of 188Re-biotin chelate for multistep therapy with the avidin-biotin system

International Nuclear Information System (INIS)

Choi, T. H.; Ahn, S. H.; Choi, C. W.; Woo, K. S.; Jung, W. S.; Lim, S. J.; Lim, S. M.

1999-01-01

The purpose of this study was to test the three-step targeting of tumors in mice using biotinylated antibody, streptavidin and radiolabeled biotin for radioimmunotherapy (RAIT). Three-step pretargetting can potentially decreases harmful radiation to normal tissues in radioimmunotherapy. 188 Re from 188 W- 188 Re generator, is recently introduced in therapeutic nuclear medicine and made it possible to use whenever needed. We studied biotin-chelates MGB for use in the avidin/biotin pretargetting system. Chelates that hold radiometals with high stability under physiological conditions are essential to avoid excessive radiation damage to non-target cells. We synthesized MAG 2 GABA-Biocytin (MGB), labeled with 188 Re and evaluated biological behavior of 188 Re-MGB. biotinyl MAG 2 GABA bind the therapeutic radiometal 188 Re with excellent in vitro stability and have the required physiological properties for pretargetted therapy. In normal mice, 188 Re-MGB was excreted via hepatobiliary pathway, %ID/g of GI tract was 52.1 at 120min. In Raji cells tumor bearing nude mice, liver and colon were higher than those of normal mouse. Tumor uptake at 120min was 0.05%ID/g. 188 Re-MGB may have a role in pretargetted radioimmunotherapy

188Re-microspheres of albumin - the potential preparation for radiotherapy

International Nuclear Information System (INIS)

Dyomin, D.N.; Petriev, V.M.

2000-01-01

In this paper author describe preparation the albumin microspheres labelled with rhenium-188. We undertake an attempt to develop kits to the generator of rhenium-188 on the basis of albumin microspheres for radiotherapy of both oncological and non-oncological diseases. Microspheres, rhenium-188 with sizes 1 0-20 micron for treatment of rheumatoid arthritis (damage of large and intermediate joints), intraperitoneal administration and intrapleural administration at metastases covering a cavity. Microspheres, Re-188 with sizes 40-60 micron for treatment of disseminated kidney cancer (intraarterial, selectively), intratumoral administration to damaged nodules less than 2-3 cm. Microspheres, Re-188 with sizes 80-100 micron for large neoplasms and metastases of liver (intraarterial, selectively), intratumoral administration to damaged nodules with sizes over 3 cm. Preparation of albumin microspheres is carried out by thermal denaturation of protein in vegetable oil. Microspheres are obtained with the necessary range of sizes by ultrasonic fractionation. At our laboratory the method of preparation of albumin microspheres with any sizes of particles (from 5 -10 up to 800 -1000 microns) has been developed. (authors)

Evaluating the potential of {sup 188}Re-SOCTA-trastuzumab as a new radioimmunoagent for breast cancer treatment

Energy Technology Data Exchange (ETDEWEB)

Luo, T.-Y. [Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan (China)], E-mail: tylo@iner.gov.tw; Tang, I-C.; Wu, Y.-L.; Hsu, K.-L. [Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan (China); Liu, S.-W. [Chemistry Division, Institute of Nuclear Energy Research, Taoyuan 325, Taiwan (China); Kung, H.-C. [Department of Electrical Engineering, Tung Nan University, Taipei 222, Taiwan (China); Lai, P.-S. [Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan (China); Lin, W.-J. [Isotope Application Division, Institute of Nuclear Energy Research, P.O. Box 3-27, Longtan, Taoyuan 325, Taiwan (China)

2009-01-15

Introduction: Radioimmunotherapy, which utilizes monoclonal antibodies and therapeutic radioisotopes against antigen-expressing tumor tissues, is an attractive therapeutic approach for cancer therapy. Trastuzumab (Herceptin) is a humanized anti-HER-2/neu monoclonal antibody for breast cancer treatment. In this paper, we introduce a new radioimmunoagent, {sup 188}Re-trastuzumab, via a bifunctional ligand, succinimidyl 3,6-diaza-5-oxo-3-[2-((triphenylmethyl)thio)ethyl] -8-[(triphenylmethyl)thio]octanoate (SOCTA), and evaluate its potential to be a therapeutic radiopharmaceutical for breast cancer treatment. Methods: Equimolar amounts of SOCTA and trastuzumab were selected to react, and the conjugation ratio of SOCTA-trastuzumab was evaluated by the MALDI-TOF method. The immunoreactivity of SOCTA-trastuzumab was compared with nonconjugated trastuzumab in HER-2/neu overexpressing human breast cancer cell BT-474. Biodistribution experiment and microSPECT/CT images of {sup 188}Re-SOCTA-trastuzumab being administered intravenously to SCID mice bearing xenografted BT-474 breast cancer were investigated to evaluate the tumor-targeting capability. Results: The covalent attachment of SOCTA to trastuzumab (at 1:1 molar ratio) resulted in the averaged conjugation ratio of 0.27{+-}0.06 (n=3). The complex could easily be labeled with {sup 188}Re and achieve 95% radiochemical purity (RCP) after 1 h of reaction at room temperature. The in vitro stability study also revealed that the RCP of {sup 188}Re-SOCTA-trastuzumab was at a value of more than 85% after 48 h of incubation with human serum. The immunoreactivity evaluation showed that SOCTA-trastuzumab and nonconjugated trastuzumab had similar binding capacity (B{sub max}) to HER-2/neu receptor in BT-474 cells. The animal experiments showed that {sup 188}Re-SOCTA-trastuzumab accumulated more intensively in the tumor site as compared to normal tissue. Conclusion: We suggest that {sup 188}Re-SOCTA-trastuzumab could be a potential

Biokinetic and dosimetric studies of 188Re-hyaluronic acid: a new radiopharmaceutical for treatment of hepatocellular carcinoma

International Nuclear Information System (INIS)

Melendez-Alafort, Laura; Nadali, Anna; Zangoni, Elena; Banzato, Alessandra; Rondina, Maria; Rosato, Antonio; Mazzi, Ulderico

2009-01-01

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has very limited therapeutic options. Recently, it has been found that hyaluronic acid (HA) shows selective binding to CD44 receptors expressed in most cancer histotypes. Since the trend in cancer treatment is the use of targeted radionuclide therapy, the aim of this research was to label HA with rhenium-188 and to evaluate its potential use as a hepatocarcinoma therapeutic radiopharmaceutical. Methods: 188 Re-HA was prepared by a direct labelling method to produce a ReO(O-COO) 2 -type coordination complex. 188 Re-HA protein binding and its stability in saline, phosphate buffer, human serum and cysteine solutions were determined. Biokinetic and dosimetric data were estimated in healthy mice (n=60) using the Medical Internal Radiation Dose methodology and mouse model beta-absorbed fractions. To evaluate liver toxicity, alanine aminotranferase (AST) and aspartate aminotranferase (ALT) levels in mice were assessed and the liver maximum tolerated dose (MTD) of 188 Re-HA was determined. Results: A stable complex of 188 Re-HA was obtained with high radiochemical purity (>90%) and low serum protein binding (2%). Biokinetic studies showed a rapid blood clearance (T 1/2 α=21 min). Four hours after administration, 188 Re-HA was almost totally removed from the blood by the liver due to the selective uptake via HA-specific receptors (73.47±5.11% of the injected dose). The liver MTD in mice was ∼40 Gy after 7.4 MBq of 188 Re-HA injection. Conclusions: 188 Re-HA complex showed good stability, pharmacokinetic and dosimetric characteristics that confirm its potential as a new agent for HCC radiation therapy.

Radiolabeling of rituximab with 188Re and 99mTc using the tricarbonyl technology

International Nuclear Information System (INIS)

Dias, Carla Roberta; Jeger, Simone; Osso, Joao Alberto; Mueller, Cristina; De Pasquale, Christine; Hohn, Alexander; Waibel, Robert; Schibli, Roger

2011-01-01

Introduction: The most successful clinical studies of immunotherapy in patients with non-Hodgkin's lymphoma (NHL) use the antibody rituximab (RTX) targeting CD20 + B-cell tumors. Rituximab radiolabeled with β - emitters could potentiate the therapeutic efficacy of the antibody by virtue of the particle radiation. Here, we report on a direct radiolabeling approach of rituximab with the 99m Tc- and 188 Re-tricarbonyl core (IsoLink technology). Methods: The native format of the antibody (RTX wt ) as well as a reduced form (RTX red ) was labeled with 99m Tc/ 188 Re(CO) 3 . The partial reduction of the disulfide bonds to produce free sulfhydryl groups (-SH) was achieved with 2-mercaptoethanol. Radiolabeling efficiency, in vitro human plasma stability as well as transchelation toward cysteine and histidine was investigated. The immunoreactivity and binding affinity were determined on Ramos and/or Raji cells expressing CD20. Biodistribution was performed in mice bearing subcutaneous Ramos lymphoma xenografts. Results: The radiolabeling efficiency and kinetics of RTX red were superior to that of RTX wt ( 99m Tc: 98% after 3 h for RTX red vs. 70% after 24 h for RTX wt ). 99m Tc(CO) 3 -RTX red was used without purification for in vitro and in vivo studies whereas 188 Re(CO) 3 -RTX red was purified to eliminate free 188 Re-precursor. Both radioimmunoconjugates were stable in human plasma for 24 h at 37 o C. In contrast, displacement experiments with excess cysteine/histidine showed significant transchelation in the case of 99m Tc(CO) 3 -RTX red but not with pre-purified 188 Re(CO) 3 -RTX red . Both conjugates revealed high binding affinity to the CD20 antigen (K d =5-6 nM). Tumor uptake of 188 Re(CO) 3 -RTX red was 2.5 %ID/g and 0.8 %ID/g for 99m Tc(CO) 3 -RTX red 48 h after injection. The values for other organs and tissues were similar for both compounds, for example the tumor-to-blood and tumor-to-liver ratios were 0.4 and 0.3 for 99m Tc(CO) 3 -RTX red and for 188 Re

The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule.

Science.gov (United States)

Garousi, Javad; Andersson, Ken G; Dam, Johan H; Olsen, Birgitte B; Mitran, Bogdan; Orlova, Anna; Buijs, Jos; Ståhl, Stefan; Löfblom, John; Thisgaard, Helge; Tolmachev, Vladimir

2017-07-20

Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The 111 In-labelled DOTA-conjugated Z EGFR:2377 Affibody molecule was successfully used for imaging of EGFR-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-Z EGFR:2377 . DOTA-Z EGFR:2377 was labelled with 57 Co (T 1/2  = 271.8 d), 55 Co (T 1/2  = 17.5 h), and, for comparison, with the positron-emitting radionuclide 68 Ga (T 1/2  = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope 57 Co was used in animal studies. Both 57 Co-DOTA-Z EGFR:2377 and 68 Ga-DOTA-Z EGFR:2377 demonstrated EGFR-specific accumulation in A431 xenografts and EGFR-expressing tissues in mice. Tumour-to-organ ratios for the radiocobalt-labelled DOTA-Z EGFR:2377 were significantly higher than for the gallium-labelled counterpart already at 3 h after injection. Importantly, 57 Co-DOTA-Z EGFR:2377 demonstrated a tumour-to-liver ratio of 3, which is 7-fold higher than the tumour-to-liver ratio for 68 Ga-DOTA-Z EGFR:2377 . The results of this study suggest that the positron-emitting cobalt isotope 55 Co would be an optimal label for DOTA-Z EGFR:2377 and further development should concentrate on this radionuclide as a label.

Monoclonal Antibodies Radiolabeling with Rhenium-188 for Radioimmunotherapy

Science.gov (United States)

Martini, Petra; Pasquali, Micol

2017-01-01

Rhenium-188, obtained from an alumina-based tungsten-188/rhenium-188 generator, is actually considered a useful candidate for labeling biomolecules such as antibodies, antibody fragments, peptides, and DNAs for radiotherapy. There is a widespread interest in the availability of labeling procedures that allow obtaining 188Re-labeled radiopharmaceuticals for various therapeutic applications, in particular for the rhenium attachment to tumor-specific monoclonal antibodies (Mo)Abs for immunotherapy. Different approaches have been developed in order to obtain 188Re-radioimmunoconjugates in high radiochemical purity starting from the generator eluted [188Re]ReO4−. The aim of this paper is to provide a short overview on 188Re-labeled (Mo)Abs, focusing in particular on the radiolabeling methods, quality control of radioimmunoconjugates, and their in vitro stability for radioimmunotherapy (RIT), with particular reference to the most important contributions published in literature in this topic. PMID:28951872

Hydroxyapatite based 99Mo-99mTc and 188W-188Re generator systems

International Nuclear Information System (INIS)

Monroy-Guzman, F.; Badillo-Almaraz, V.E.; Flores de la Torre, J.A.; Cosgrove, J.; Knapp, F.F. Jr.

2007-01-01

This paper describes studies evaluating the use of hydroxyapatite as the adsorbent material for both 90M o- 90m Tc and 89W - 188 Re generator systems. Hydroxyapatite is an insoluble solid with anion exchange properties. A study of the sorption behaviour of 90M o, 90m Tc, 188 W and 188 Re on hydroxyapatite in NaCl medium was evaluated by batch experiments. The results demonstrated that while 90M o, 90m Tc and 188 Re are not adsorbed by the hydroxyapatite in NaCl solutions (Kd 89W is strongly adsorbed (Kd >500). On the basis of these measurements, hydroxyapatite 89W - 188 Re generator systems were then constructed and eluted in NaCl solutions. The hydroxyapatite based 89W - 188 Re generator performances are presented. (author)

Chromatographic 188W →188Re generator

International Nuclear Information System (INIS)

Khujaev, S.

2005-01-01

Full text: The main purpose of the generator - reception of daughter radioisotope Rhenium-188 from it by periodic elution for a long period of time (more than half-year). It is generally known that Rhenium-188, in the form of its complex connections, is applied in nuclear medicine in treatment and removal of painful syndromes. The generator possesses convenient nuclear-physical characteristics of a daughter radioisotope Rhenium-188. It is a source of (Irradiation with energy 2.12 MeV (98 %) with small contribution soft γ-radiation with energy 0.155 MeV (15 %). The Period of half-life destruction of radioisotope is 17 hours. The 188 W parent radioisotope for the generator is formed by irradiation of 186 W neutrons based on the following reaction: 186 W (n,γ) 187 W (n,γ) 188 W (69 days) → 188 Re (17 hours) + β The following were used as targets for irradiation: 1) Metal Tungsten (powder) of natural structure; 2) Metal Tungsten (plate) of natural structure; 3) Metal Tungsten (wire) of natural structure, d = 12 mm; 4) Metal Tungsten (powder) with enrichment on isotope 186 W - 99.79 %. The irradiated material was exposed to chemical processing with reception of radioactive solution of tungsten-188, from which sorption Tungsten was carried out onto sorbent as poly-wolframate-ions. It is established that Tungsten sorption depends on many factors as there are various chemical forms of Tungsten (VI) in water solutions, ratio of which depends on pH of the solution, concentration of Tungsten in the solution and presence of foreign ions. Tungsten sorption was carried out in static and in dynamic regimes. At dynamic regime the sorbent was placed directly in the generating column. The generator consisted of chromatographic columns with sorbent and radioisotope 188 W, eluting system and radiation protection. Rhenium-188 was taken from the generator as perrhenate sodium by elution of 0.9 % solution of chloride sodium in 10 ml. Technical characteristics of the generator

Development of radiolabeling procedures of bioconjugates with 135Sm and 186-188 Re: In-vitro and in-vivo studies

International Nuclear Information System (INIS)

Gomez de Castiglia, S.

2000-01-01

Mercaptoacetyltriglycine (MAG3) is a compound that has been extensively used in nuclear medicine as a prosthetic group, following carbodiimide activation, for labeling antibodies with 99m Tc and also 188 Re. MAG3 and related derivatives are attractive ligands for coupling to biomolecules in that they provide very stable complexes. The aim of this project is to label biomolecules with 188 Re using an active ester of the MAG3. The labeled chelating agent was conjugated with a biotin derivative and with the Polyclonal Immunoglobulin IgG (Sandoz). During this multistep procedure an active ester of tetrafluorophenol and MAG3 carrying the radioisotope is prepared, which is subsequently conjugated to amino groups of the biomolecule. Of the commercially available biotin derivatives we used biocytin which contains a free amino group for conjugation to MAG3 via the MAG3TFP ester. Another derivative DTPA-biocytinamide (DB2) was also labeled with 188 Re. Quality assurance tests were performed on the final preparation of the radiolabeled biomolecules

Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma

Directory of Open Access Journals (Sweden)

M. Klein

2013-01-01

Full Text Available There is a need for effective “broad spectrum” therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of 188Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi 188Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of 188Re-6D2 was escalated to 54 mCi. SPECT/CT revealed 188Re-6D2 uptake in melanoma metastases. The mean effective half-life of 188Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that 188Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

Development of radiolabeling procedures of bioconjugates with 153Sm and 186-188Re: In-vitro and in-vivo studies. Argentina

International Nuclear Information System (INIS)

Gomez de Castiglia, Silvia

2000-01-01

Mercaptoacetyltriglycine (MAG3) is a compound that has been extensively used in nuclear medicine as a prosthetic group, following carbodiimide activation, for labeling antibodies with 99m Tc and also 188 Re. MAG3 and related derivatives are attractive ligands for coupling to biomolecules in that they provide very stable complexes. In the preconjugate approach radiolabeled MAG3 is chemically activated to obtain Re188-MAG3-activated ester and then this ester is coupled to amines. 188 Re has several potential advantages over other therapeutic radionuclides including the fact that carrier-free 188 Re(T1/2=17 h) can be obtained cost-effectively and on demand from an ''in house'' 188 W/ 189 Re generator. 189 Re decays by emission of a relatively high energy beta particle(Emax=2,11 Mev) which is suitable for radiotherapy followed by emission of 155KeV gamma photons in 10% abundance. The average penetration of the beta particle is 3.3 mm (maximum 10.8 mm), which provides a highly localised region of high energy deposition with little or no damage to adjacent organs. The gamma photon can be used to monitor biodistribution and estimate dosimetry with standard scintigraphic equipment. The aim of this project is to label biomolecules with 188 Re using an active ester of the MAG3. The labeled chelating agent was conjugated with a biotin derivative and with the Polyclonal Immunoglobulin IgG (Sandoz). During this multistep procedure an active ester of tetrafluorophenol and MAG3 carrying the radioisotope is prepared, which is subsequently conjugated to amino groups of the biomolecule. Of the commercially available biotin derivatives we used biocytin which contains a free amino group for conjugation to MAG3 via the MAG3TFP ester. Another derivative DTPA-biocytinamide (DB2) was also labeled with 188 Re. Quality assurance tests were performed on the final preparation of the radiolabeled biomolecules

A review on the current status and production technology for 188W-188Re generator system

International Nuclear Information System (INIS)

Kuznetsov, R. A.; Han, H. S.; Cho, W. K.; Park, U. J.; Kim, Y. M.

1998-11-01

The current status of 188 W- 188 Re generator production technology were reviewed in PART 1. Main interests were given to the aspects of 188 W reactor production, irradiated targets reprocessing and generator loading technologies, such as alumina type and gel type generators. In order to develop the more convenient and advanced 188 W- 188 Re generator, further studies must be carried out to get the precise evaluation of production and burn-up cross section of 188 W, the more easily realizable generator loading procedure, and also to optimize the column and generator design to compensate the deterioration of generator performance because of parent radionuclide decay. By irradiation of 186 W enriched sample, 188 W- 188 Re generator production experiments were performed to evaluate the possibility of 188 W- 188 Re generator production using HANARO, and PART 2 describes about the experiments. The experimental results shows the possibility of practical 188 W- 188 Re generator production using of low-specific activity 188 W produced in HANARO. (author). 79 refs., 4 tabs., 26 figs

Biokinetic and dosimetric studies of {sup 188}Re-hyaluronic acid: a new radiopharmaceutical for treatment of hepatocellular carcinoma

Energy Technology Data Exchange (ETDEWEB)

Melendez-Alafort, Laura [Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Padova, 35131 Padua (Italy); Nadali, Anna; Zangoni, Elena [Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Padova, 35131 Padua (Italy); Banzato, Alessandra; Rondina, Maria [Dipartimento di Scienze Oncologiche e Chirurgiche, Universita degli Studi di Padova, Padua (Italy); Rosato, Antonio [Dipartimento di Scienze Oncologiche e Chirurgiche, Universita degli Studi di Padova, Padua (Italy); Istituto Oncologico Veneto, IOV, Padova, Padua (Italy); Mazzi, Ulderico [Dipartimento di Scienze Farmaceutiche, Universita degli Studi di Padova, 35131 Padua (Italy)

2009-08-15

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has very limited therapeutic options. Recently, it has been found that hyaluronic acid (HA) shows selective binding to CD44 receptors expressed in most cancer histotypes. Since the trend in cancer treatment is the use of targeted radionuclide therapy, the aim of this research was to label HA with rhenium-188 and to evaluate its potential use as a hepatocarcinoma therapeutic radiopharmaceutical. Methods: {sup 188}Re-HA was prepared by a direct labelling method to produce a ReO(O-COO){sub 2}-type coordination complex. {sup 188}Re-HA protein binding and its stability in saline, phosphate buffer, human serum and cysteine solutions were determined. Biokinetic and dosimetric data were estimated in healthy mice (n=60) using the Medical Internal Radiation Dose methodology and mouse model beta-absorbed fractions. To evaluate liver toxicity, alanine aminotranferase (AST) and aspartate aminotranferase (ALT) levels in mice were assessed and the liver maximum tolerated dose (MTD) of {sup 188}Re-HA was determined. Results: A stable complex of {sup 188}Re-HA was obtained with high radiochemical purity (>90%) and low serum protein binding (2%). Biokinetic studies showed a rapid blood clearance (T{sub 1/2}{alpha}=21 min). Four hours after administration, {sup 188}Re-HA was almost totally removed from the blood by the liver due to the selective uptake via HA-specific receptors (73.47{+-}5.11% of the injected dose). The liver MTD in mice was {approx}40 Gy after 7.4 MBq of {sup 188}Re-HA injection. Conclusions: {sup 188}Re-HA complex showed good stability, pharmacokinetic and dosimetric characteristics that confirm its potential as a new agent for HCC radiation therapy.

188Re labeled MPEG-modified superparamagnetic nanogels: preparation and preliminary application in mice

International Nuclear Information System (INIS)

Sun Hanwen; Gong Peijun; Liu Xiuqing; Hong Jun; Xu Dongmei; Zhang Chunfu; Wang Yongxian; Yao Side

2005-01-01

Superparamagnetic poly(acrylamide) magnetic nanogels produced via photochemical method have been developed. After Hoffmann degradation of carbonyl, the nanogels with amino groups, or poly(acrylamide-vinyl amine) magnetic nanogels, were also obtained. And the magnetic nanogels were further modified by methoxy poly(ethylene glycol) (MPEG) for higher dispersibility and stability. The MPEG-modified magnetic nanogels were characterized by X-ray diffraction (XRD), photo correlation spectroscopy (PCS) and scanning electron microscopy (SEM), respectively. The MPEG-modified magnetic nanogels were labeled by 188 Re radiopharmaceuticals and intravenously injected into tails of mice in the presence and absence of a 0.5 T external magnetic field targeted on the bellies. The radioactivity distribution was monitored in vivo. In the absence of magnetic field, the radioactivity was mainly distributed in liver, spleen, kidney, stomach and lung. In the presence of the magnetic field, the radioactivity was mainly accumulated on the targeted point, verifying the magnetically targeted character. (authors)

Synthesis and in Vitro evaluation of ''1''8''8Re-biotinyl-hydrazino-etda

International Nuclear Information System (INIS)

Pervez, S; Mushtaq, A.; Jehangir, M.

2002-01-01

Pretargeting strategies have overcome many drawbacks associated with the use of directly labelled MoAbs in the diagnosis / treatment of various solid tumors. In particular the avidin-biotin system has received much attention due to extremely high affinity between avidin and biotin. An EDTA derivative of biotin has been synthesized (yield-35%). In order or label biotin derivative (biotinyl-hydrazino-EDTA) , stannous ion was used to reduce ''1''8''8ReO 4 (VII) to lower oxidation state and weak chelating agent glucoheptonate as stabilizer and trans chelating agent. Thin layer chromatography and high performance liquid chromatography techniques were employed to monitor the radiolabeling efficiency. The radiolabeling yield of ''1''8''8Re-EDTA B1 was >95%. The radiolabeled product was found to bind to avidin (70-80%), thereby demonstrating retention of its biological integrity

188Re-loaded lipid nanocapsules as a promising radiopharmaceutical carrier for internal radiotherapy of malignant gliomas

International Nuclear Information System (INIS)

Allard, E.; Hindre, F.; Passirani, C.; Lemaire, L.; Benoit, J.P.; Lepareur, N.; Noiret, N.; Menei, P.

2008-01-01

Lipid nanocapsules (LNC) entrapping lipophilic complexes of 188 Re( 188 Re(S 3 CPh) 2 (S 2 CPh) [ 188 Re-SSS]) were investigated as a novel radiopharmaceutical carrier for internal radiation therapy of malignant gliomas. The present study was designed to evaluate the efficacy of intra-cerebral administration of 188 Re-SSS LNC by means of convection-enhanced delivery (CED) on a 9L rat brain tumour model. Female Fischer rats with 9L glioma were treated with a single injection of 188 Re-SSS LNC by CED 6days after cell implantation. Rats were put into random groups according to the dose infused: 12, 10, 8 and 3Gy in comparison with blank LNC, perrhenate solution (4Gy) and non-treated animals. The radionuclide brain retention level was evaluated by measuring 188 Re elimination in faeces and urine over 72h after the CED injection. The therapeutic effect of 188 Re-SSS LNC was assessed based on animal survival. CED of 188 Re perrhenate solution resulted in rapid drug clearance with a brain T 1/2 of 7h. In contrast, when administered in LNC, 188 Re tissue retention was greatly prolonged, with only 10% of the injected dose being eliminated at 72h. Rat median survival was significantly improved for the group treated with 8Gy 188 Re-SSS LNC compared to the control group and blank LNC-treated animals. The increase in the median survival time was about 80% compared to the control group; 33% of the animals were long-term survivors. The dose of 8Gy proved to be a very effective dose, between toxic (10-12Gy) and ineffective (3-4Gy) doses. These findings show that CED of 188 Re-loaded LNC is a safe and potent anti-tumour system for treating malignant gliomas. Our data are the first to show the in vivo efficacy of 188 Re internal radiotherapy for the treatment of brain malignancy. (orig.)

188Re radiopharmaceuticals for radiosynovectomy: evaluation and comparison of tin colloid, hydroxyapatite and tin-ferric hydroxide macroaggregates

International Nuclear Information System (INIS)

Savio, Eduardo; Ures, María Cristina; Zeledón, Patricia; Trindade, Victoria; Paolino, Andrea; Mockford, Virginia; Malanga, Antonio; Fernández, Marcelo; Gaudiano, Javier

2004-01-01

Radiosynovectomy is a therapy used to relieve pain and inflammation from rheumatoid arthritis and related diseases. In this study three 188 Re particulate compounds were characterized according to their physico-chemical properties and their biological behavior in rabbits. The results were compared in order to establish which was the radiopharmaceutical that better fits the requirements of this kind of radiotherapy. Three radiopharmaceutical formulations, tin colloid, hydroxyapatite particles (HA) and ferric hydroxide macroaggregates coated with tin colloid (FHMA), were physically characterized (number, volume and surface of the particles). For this purpose laser diffraction methodology was used. To evaluate cavity leakage of activity the following studies in New Zealand rabbits were performed: scintigraphic images for 48 hr after intraarticular injection of each radiopharmaceutical, biodistribution at 48 hr and urine samples collection during the first 24 hr post-radiopharmaceutical administration. Labeling procedures for 188 Re-HA and 188 Re-Sn-FHMA were labour intensive while 188 Re-Sn was easily prepared. Furthermore, 188 Re-Sn colloid offered the greatest surface area in the 2–10 microm range and was obtained with a radiochemical purity over 95%, while percentage of bound activity for 188 Re-HA and 188 Re-Sn-FHMA were 55% and 92% respectively. Stability was verified for the three radiopharmaceuticals for 24 hr. Scintigraphic studies and biodistribution in rabbits after intraarticular administration of the radiopharmaceuticals showed relevant activity only in the knee, this being over 90% of the residual activity in the whole body at 48 hr in every case. Renal elimination of 188 Re-Sn colloid and 188 Re-Sn-FHMA was detected by activity measurements in urine samples, during the first 12 hr post-radiopharmaceutical injection. The percentage of activity retained in the knee was 69.1% for 188 Re-Sn colloid, 55.1% for 188 Re-Sn-FHMA and 33.6% for 188 Re-HA. The 188

Preliminary study of metabolic radiotherapy with 188Re via small animal imaging

International Nuclear Information System (INIS)

Antoccia, A.; Baldazzi, G.; Bello, M.

2006-01-01

188 Re is a β - (Emax=2.12 MeV) and γ (155 keV) emitter. Since its chemistry is similar to that of the largely employed tracer, 99m Tc, molecules of hyaluronic acid (HA) have been labelled with 188 Re to produce a target specific radiopharmaceutical. The radiolabeled compound, i.v. injected in healthy mice, is able to accumulate into the liver after a few minutes. To study the effect of metabolic radiotherapy in mice, we have built a small gamma camera based on a matrix of YAP:Ce crystals, with 0.6x0.6x10 mm 3 pixels, read out by a R2486 Hamamatsu PSPMT. A high-sensitivity 20 mm thick lead parallel-hole collimator, with hole diameter 1.5 mm and septa of 0.18 mm, is placed in front of the YAP matrix. Preliminary results obtained with various phantoms containing a solution of 188 Re and with C57 black mice injected with the 188 Re-HA solution are presented. To increase the space resolution and to obtain two orthogonal projections simultaneously we are building in parallel two new cameras to be positioned at 90 degrees. They use a CsI(Tl) matrix with 1x1x5 mm 3 pixels read out by H8500 Hamamatsu Flat panel PMT

Radiolabeling of rituximab with {sup 188}Re and {sup 99m}Tc using the tricarbonyl technology

Energy Technology Data Exchange (ETDEWEB)

Dias, Carla Roberta [Instituto de Pesquisas Energeticas e Nucleares, Av. Professor Lineu Prestes 2242, 05508-000 Sao Paulo (Brazil); Jeger, Simone [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Osso, Joao Alberto [Instituto de Pesquisas Energeticas e Nucleares, Av. Professor Lineu Prestes 2242, 05508-000 Sao Paulo (Brazil); Mueller, Cristina; De Pasquale, Christine; Hohn, Alexander; Waibel, Robert [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Schibli, Roger, E-mail: roger.schibli@psi.c [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Department of Chemistry and Applied Biosciences of the ETH, 8093 Zurich (Switzerland)

2011-01-15

Introduction: The most successful clinical studies of immunotherapy in patients with non-Hodgkin's lymphoma (NHL) use the antibody rituximab (RTX) targeting CD20{sup +} B-cell tumors. Rituximab radiolabeled with {beta}{sup -} emitters could potentiate the therapeutic efficacy of the antibody by virtue of the particle radiation. Here, we report on a direct radiolabeling approach of rituximab with the {sup 99m}Tc- and {sup 188}Re-tricarbonyl core (IsoLink technology). Methods: The native format of the antibody (RTX{sub wt}) as well as a reduced form (RTX{sub red}) was labeled with {sup 99m}Tc/{sup 188}Re(CO){sub 3}. The partial reduction of the disulfide bonds to produce free sulfhydryl groups (-SH) was achieved with 2-mercaptoethanol. Radiolabeling efficiency, in vitro human plasma stability as well as transchelation toward cysteine and histidine was investigated. The immunoreactivity and binding affinity were determined on Ramos and/or Raji cells expressing CD20. Biodistribution was performed in mice bearing subcutaneous Ramos lymphoma xenografts. Results: The radiolabeling efficiency and kinetics of RTX{sub red} were superior to that of RTX{sub wt} ({sup 99m}Tc: 98% after 3 h for RTX{sub red} vs. 70% after 24 h for RTX{sub wt}). {sup 99m}Tc(CO){sub 3}-RTX{sub red} was used without purification for in vitro and in vivo studies whereas {sup 188}Re(CO){sub 3}-RTX{sub red} was purified to eliminate free {sup 188}Re-precursor. Both radioimmunoconjugates were stable in human plasma for 24 h at 37{sup o}C. In contrast, displacement experiments with excess cysteine/histidine showed significant transchelation in the case of {sup 99m}Tc(CO){sub 3}-RTX{sub red} but not with pre-purified {sup 188}Re(CO){sub 3}-RTX{sub red}. Both conjugates revealed high binding affinity to the CD20 antigen (K{sub d}=5-6 nM). Tumor uptake of {sup 188}Re(CO){sub 3}-RTX{sub red} was 2.5 %ID/g and 0.8 %ID/g for {sup 99m}Tc(CO){sub 3}-RTX{sub red} 48 h after injection. The values for other

Development of a high performance {sup 188}W/{sup 188}Re generator by using a synthetic alumina

Energy Technology Data Exchange (ETDEWEB)

Lee, Jun Sig [Korea Atomic Energy Research Institute, 1045 Daeduk-daero, Yuseong-gu, Daejeon 305-353 (Korea, Republic of)], E-mail: jlee15@kaeri.re.kr; Lee, Jong-Soup; Park, Ul-Jae; Son, Kwang-Jae; Han, Hyon-Soo [Korea Atomic Energy Research Institute, 1045 Daeduk-daero, Yuseong-gu, Daejeon 305-353 (Korea, Republic of)

2009-07-15

A synthetic alumina functionalized with a sulfate moiety has been developed as the column material of {sup 99}Mo/{sup 99m}Tc and {sup 188}W/{sup 188}Re generators. This material is synthesized by a sol-gel processing. In order to characterize the adsorbent for the {sup 188}W/{sup 188}Re separation, both batch and column contact experiments were conducted. As a result of the experiments, it is found that the maximum capacity of the adsorbent for tungsten is higher than 450 mg/g. Hence it is possible to produce {approx}3 Ci {sup 188}W/{sup 188}Re generator with only 1 g of the adsorbent from {sup 188}W solutions supplied from ORNL, USA or RIAR, Russia. A demonstration study was conducted to show the performance of an {sup 188}W/{sup 188}Re generator column. In this study, 1 Ci of {sup 188}W purchased from RIAR, Russia, is loaded on a 0.9 cm ID column packed with 0.7 g of the adsorbent. Elution of {sup 188}Re is performed every 4-7 days by using the saline solution for more than three months. Nearly 100% of tungsten is loaded by passing 5 ml of the {sup 188}W solution (pH=8) through the dry packed column at a 1 ml/min flow rate. Elution efficiency of {sup 188}Re is 70-90% by using 5 ml of the saline solution. The ratio of {sup 188}W/{sup 188}Re in the eluted solution is 0.002-0.003%. When a Sep-Pak containing 0.26 g of acid alumina is installed as a tandem column, the ratio is decreased to less than 10{sup -3}%. Thin layer chromatography for the eluted {sup 188}Re solution shows 100% radiochemical purity. Also, alumina content in the eluted solution shows less than 10 ppm. Through this study, the performance of this adsorbent was successfully demonstrated. By using the developed adsorbent, minimization of the generator column and consequently the volume of eluant could be possible while maintaining the quality of {sup 188}Re just as much as that available in the market.

Country report: Italy (Duatti). Development of a Kit Formulation for Labeling Biotin-Derived Ligands with the Re-188 Nitrido Core

Energy Technology Data Exchange (ETDEWEB)

Pasquali, M.; Boschi, A.; Uccelli, L.; Duatti, A. [Laboratory of Nuclear Medicine, Department of Radiological Sciences, University of Ferrara, 44121 Ferrara (Italy); Janevik-Ivanovska, E. [University of Stip (Macedonia, The Former Yugoslav Republic of)

2010-07-01

Within the scope of this CRP, we developed a series of small-molecule biotinylated Re-188 complexes containing the [{sup 188}Re≡N]{sup 2+} core. These complexes have been prepared using different chemical strategies, but all of them incorporate a biologically active biotin group. The main interest for this effort was brought to us after the introduction by Paganelli et al. of a new approach for the treatment of residual malignant cells after surgical removal of a primary breast tumour, and dubbed IART (Intraoperative Avidination for Radionuclide Therapy) [1]. Since now, the IART approach has been applied using {sup 90}Y as therapeutic radionuclide and a DOTA-functionalized biotin ligand for coordination to the radiometal. A major drawback for using {sup 90}Y as a therapeutic radionuclide comes from the absence of any radioactive decay, associated with the main β-emission, that may allow imaging of the actual biodistribution of injected radioactivity in any individual patient. Other therapeutic radionuclides, such as {sup 177}Lu and {sup 188}Re, possess an additional γ emission that easily allows imaging of target’s uptake, and could be conveniently utilized to monitor the course of therapy. In particular, {sup 188}Re emits a β- particle having almost the same energy as that emitted by {sup 90}Y, but with an associated 155-keV γ-emission that can be efficiently employed for imaging the biodistribution of the injected radiocompound. Considering also that {sup 188}Re is produced through a {sup 188}W/{sup 188}Re transportable generator system, and that deep similarities between the chemistry of congener rhenium and technetium usually allow {sup 99m}Tc compounds to be used for a preliminary evaluation of the biodistribution of the analogous {sup 188}Re compounds, this makes {sup 188}Re as an interesting candidate for application to the IART approach.

Country report: Italy (Duatti). Development of a Kit Formulation for Labeling Biotin-Derived Ligands with the Re-188 Nitrido Core

International Nuclear Information System (INIS)

Pasquali, M.; Boschi, A.; Uccelli, L.; Duatti, A.; Janevik-Ivanovska, E.

2010-01-01

Within the scope of this CRP, we developed a series of small-molecule biotinylated Re-188 complexes containing the [ 188 Re≡N] 2+ core. These complexes have been prepared using different chemical strategies, but all of them incorporate a biologically active biotin group. The main interest for this effort was brought to us after the introduction by Paganelli et al. of a new approach for the treatment of residual malignant cells after surgical removal of a primary breast tumour, and dubbed IART (Intraoperative Avidination for Radionuclide Therapy) [1]. Since now, the IART approach has been applied using 90 Y as therapeutic radionuclide and a DOTA-functionalized biotin ligand for coordination to the radiometal. A major drawback for using 90 Y as a therapeutic radionuclide comes from the absence of any radioactive decay, associated with the main β-emission, that may allow imaging of the actual biodistribution of injected radioactivity in any individual patient. Other therapeutic radionuclides, such as 177 Lu and 188 Re, possess an additional γ emission that easily allows imaging of target’s uptake, and could be conveniently utilized to monitor the course of therapy. In particular, 188 Re emits a β- particle having almost the same energy as that emitted by 90 Y, but with an associated 155-keV γ-emission that can be efficiently employed for imaging the biodistribution of the injected radiocompound. Considering also that 188 Re is produced through a 188 W/ 188 Re transportable generator system, and that deep similarities between the chemistry of congener rhenium and technetium usually allow 99m Tc compounds to be used for a preliminary evaluation of the biodistribution of the analogous 188 Re compounds, this makes 188 Re as an interesting candidate for application to the IART approach

A review on the current status and production technology for {sup 188}W-{sup 188}Re generator system

Energy Technology Data Exchange (ETDEWEB)

Kuznetsov, R. A.; Han, H. S.; Cho, W. K.; Park, U. J.; Kim, Y. M

1998-11-01

The current status of {sup 188}W-{sup 188}Re generator production technology were reviewed in PART 1. Main interests were given to the aspects of {sup 188}W reactor production, irradiated targets reprocessing and generator loading technologies, such as alumina type and gel type generators. In order to develop the more convenient and advanced {sup 188}W-{sup 188}Re generator, further studies must be carried out to get the precise evaluation of production and burn-up cross section of {sup 188}W, the more easily realizable generator loading procedure, and also to optimize the column and generator design to compensate the deterioration of generator performance because of parent radionuclide decay. By irradiation of {sup 186}W enriched sample, {sup 188}W-{sup 188}Re generator production experiments were performed to evaluate the possibility of {sup 188}W-{sup 188}Re generator production using HANARO, and PART 2 describes about the experiments. The experimental results shows the possibility of practical {sup 188}W-{sup 188}Re generator production using of low-specific activity {sup 188}W produced in HANARO. (author). 79 refs., 4 tabs., 26 figs.

The use of radiocobalt as a label improves imaging of EGFR using DOTA-conjugated Affibody molecule

DEFF Research Database (Denmark)

Garousi, Javad; Andersson, Ken G; Dam, Johan H

2017-01-01

-expressing xenografts in mice. An optimal combination of radionuclide, chelator and targeting protein may further improve the contrast of radionuclide imaging. The aim of this study was to evaluate the targeting properties of radiocobalt-labelled DOTA-ZEGFR:2377. DOTA-ZEGFR:2377 was labelled with (57)Co (T1/2 = 271.8 d......), (55)Co (T1/2 = 17.5 h), and, for comparison, with the positron-emitting radionuclide (68)Ga (T1/2 = 67.6 min) with preserved specificity of binding to EGFR-expressing A431 cells. The long-lived cobalt radioisotope (57)Co was used in animal studies. Both (57)Co-DOTA-ZEGFR:2377 and (68)Ga-DOTA......Several anti-cancer therapies target the epidermal growth factor receptor (EGFR). Radionuclide imaging of EGFR expression in tumours may aid in selection of optimal cancer therapy. The (111)In-labelled DOTA-conjugated ZEGFR:2377 Affibody molecule was successfully used for imaging of EGFR...

188Re DD-3B6/22 Fab' for use in therapy of ovarian cancer: labelling and animal studies

International Nuclear Information System (INIS)

Schmidt, Peter F.; Smith, Suzanne V.; Bundesen, Peter G.

1998-01-01

A fast and high yielding method of 188 Re radiolabelling DD-3B6/22 Fab' is described. An inert atmosphere [N 2 (g)] and ascorbic acid was essential for preparation and storage of therapeutic levels (≤2 GBq/mg) for up to 24 h. Immunoreactivity was greater than 75%. Pharmacokinetic studies in nu/nu mice demonstrated localisation of 188 Re DD-3B6/22 Fab' was equivalent and correlated well with the behaviour observed for 99m Tc DD-3B6/22 Fab' used to image ovarian cancer. Excellent stability at the target site in vivo supports the potential use of 188 Re DD-3B6/22 Fab' in the therapy of ovarian cancer

Biomolecule labelling by 186 Re

International Nuclear Information System (INIS)

Lungu, Valeria Viorica; Mihailescu, Gabriela; Dumitrescu, Gabriela

1998-01-01

The aim of this study is to develop and improve the existing radiolabelling techniques of peptides and monoclonal antibodies with 186 Re and 188 Re as potential agents for cancer targeted radiotherapy. We selected the following methods and techniques for direct labelling of peptides and monoclonal antibody: 1. Prereduction of -S-S- bridges of biomolecule to sulfhydryls using reducing agents: ascorbic acid, cysteine, active hydrogen, 2,3 dimercaptopropanol. The prereduction reactions are controlled by massic ratios of reduction agents/biomolecule, pH, temperature and time of incubation; 2. Reduction of 186 Re O 4 - stannous chloride in acid and alkaline pH; 3. Coupling reaction of 186 Re (red) with the biomolecule controlled by the time and temperature of incubation, the influence of pH regarding the binding of 186 Re to the biomolecules. The quality control was effected by chromatography techniques (paper and elution gel chromatography) on labeled biomolecule before and after purification. The elution gel chromatography was spectrophotometricaly monitored at 280 nm. In the same time the radioactivity of samples was measured using a gamma counter. All the results confirm in vitro stability of labeled biomolecule. The biological evaluation studies regarding accumulation and biological affinity will be controlled by scintigraphy method. Biodistribution studies will be effected to Walker tumor bearing animals at 4 and 24 hours after injections. (authors)

Issues associated with the use of the Tungsten-188/Rhenium188 generator and concentrator system and preparation of Re-188 HDD: A report

International Nuclear Information System (INIS)

Knapp, F.F.Jr.; Turner, J.H.; Jeong, J.-M.; Padhy, A.K.

2004-01-01

The ready availability of no-carrier-added Rhenium-188 from the Tungsten-188/Rhenium-188 generator represents an important source of a therapeutic radioisotope for a broad range of therapeutic applications in nuclear medicine, oncology, rheumatology and interventional cardiology. The International Atomic Energy Agency (IAEA) is coordinating a clinical trial involving the use of Rhenium188-Lipiodol for therapy of hepatocellular carcinoma. This report summarizes the experience of investigators at ten participating centres associated with the use and performance of the Tungsten-188/Rhenium-188 generators and the preparation and handling of the Re-188 HDD agent. This evaluation has demonstrated the cost effective provision of on-site therapeutic activities of Rhenium-188 and recommendations are made for further development of the next generator prototype in light of this international experience. The high bolus volumes (20-40 ml) of the ORNL generator requires post elution concentration of the Re-188 bolus by passage through the tandem silver cation/anion column system. The high back pressure often encountered during generator elution through the silver cation/anion concentrator system has been identified as a potential problem. The details of a method involving in house preparation of the silver cation columns were provided and implementation of this method for Re-188 bolus concentration is recommended. It is also recommended that ORNL investigators reassess the possibility of increasing Tungsten generator loading capacity and the use of higher specific activity Tungsten-188, with a view to reducing the generator bolus volume. The Re-188 HDD/Lipiodol conjugate?;ate is used in this IAEA trial for radioembolytic therapy of primary liver cancer, and methods for preparation of Re-188 HDD and its extraction into Lipiodol are discussed. Since Re-188 HDD binds to glass surfaces, the recovery yields are variable and can be as low as 40-45%. In an effort to maximize the

Study on the pharmacal of 186,188Re-SZ39

International Nuclear Information System (INIS)

Zu Jianhua; Wu Yuanfang; Dong Mo; Li Huiyuan; ZhangYulong

2000-01-01

The stability, immunocompetence and cytotoxicity in tumor as well as tumor inhibiting rate of 186,188 Re-SZ39 are investigated. The results indicate that 186,188 Re-SZ39 is stable in vivo by imaging and the volume of tumor of nude mice reduced obviously. So 186,188 Re-SZ39 has a strong cytotoxicity effect against glioma cells and is of good prospect as immuno-radiotherapeutic agent

Labelled biomolecules with Sm-153, Re-188 and Y-90 for targeted radiotherapy

International Nuclear Information System (INIS)

Ahmad, M.; Pervez, S.

2000-01-01

Direct labeling of Lanreotide with Rhenium-188 was studied. Reduction of cysteine bridge was performed by reducing agents (ascorbic acid, 2ME). The perrhenate eluted from the generator was reduced with stannous chloride. Tartarate was used as transchelating agent. After pH adjustment, shaking and incubation for various time intervals were carried out. Thin Layer chromatography and reverse phase chromatography were used to monitor the radiolabelling yield. Stability of radiolabelled Lanreotide was also checked

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

Study of radiation synovectomy using 188Re-sulfide

International Nuclear Information System (INIS)

Chen Gang; Li Peiyong; Jiang Xufeng; Zhang Liying; Wang Xuefeng; Sun Zhenming; Zhang Huan

2002-01-01

Objective: To study the radiation synovectomy with 188 Re-sulfide. Methods: Thirty cases were divided into 2 groups, the group with hemophilia and the group with rheumatoid arthritis (RA). Patients with joint synovitis were injected different doses of 188 Re-sulfide, 222 - 444 MBq intra-articular. MRI was taken before and 3 - 6 months after the radiation synovectomy to evaluate the treatment efficacy, and the symptoms were also evaluated. Results: MRI study showed that after the treatment the synovium became thiner and the edema was reduced in the lesioned joint. The symptoms were improved with the pain relieved and duration of intra-articular hemorrhage reduced. Conclusions: Radiation synovectomy using 188 Re-sulfide has effects on synovitis. It can be used clinically to improve the symptoms of joint synovitis and reduce the duration of intra-articular hemorrhage

Affinity of hydroxyapatite by radionuclides parent/child in 188Re/188W generator for radiotherapy

International Nuclear Information System (INIS)

Carrera D, A. A.; Badillo A, V.; Badillo A, V. E.; Monroy G, F.

2009-10-01

To assess the feasibility of using apatites as matrices of 188 W/ 188 Re generator is essential to obtain the distribution coefficients as much of parent radionuclide as child radionuclide in apatite, that is to say to know their affinity for the solid. It was selected the mineral species more representative as adsorbent, the hydroxyapatite Ca 10 (PO 4 ) 6 (OH) 2 it is known for its great capacity of ions retention and by presenting a large affinity for anionic species in their surface. In this paper we use a synthetic hydroxyapatite marketed by Bio-Rad. This paper presents the preliminary results regarding the affinity of hydroxyapatite for the anionic species tungstates (WO 4 2- ) and perrhenates (ReO 4 - in EDTA, as background electrolyte expressed as distribution coefficients between two immiscible phases obtained with the help of radioactive tracers 187 W and 188 Re respectively. The retention measures of these ions, traces show that Bio-Gel hydroxyapatite presents moderate values of distribution coefficients for anionic species of W(Vi) in EDTA 0.01 mol/L that are in the range p H 5 to 6.5; the parent radionuclide of generator 188 Re/ 188 W is fixed but not enough to consider it a good absorbent. By contrast, the fixation of perrhenate ions is virtually wiped as may be easily removed from a hydroxyapatite column packed with a saline solution. The influence of this saline solution in the removal of perrhenate ions is null practically. (Author)

EGFR Amplification as a Target in Gastroesophageal Adenocarcinoma: Do Anti-EGFR Therapies Deserve a Second Chance?

Science.gov (United States)

Strickler, John H

2018-06-01

Anti-EGFR therapies have failed to improve survival for unselected patients with metastatic gastroesophageal cancer, but in a subset of patients, EGFR amplification may predict treatment benefit. Maron and colleagues report the clinical activity of anti-EGFR therapies in a cohort of patients with EGFR -amplified metastatic gastroesophageal cancer and utilize serial blood and tumor tissue collection to identify molecular drivers of treatment sensitivity and resistance. Their insights offer a path to overcome technical limitations associated with EGFR amplification and facilitate molecularly targeted therapeutic strategies. Cancer Discov; 8(6); 679-81. ©2018 AACR See related article by Maron et al., p. 696 . ©2018 American Association for Cancer Research.

Labelled biomolecules with SM-153, Re-188 and Y-90 for targeted radiotherapy. Pakistan

International Nuclear Information System (INIS)

Ahmad, Mushtaq; Pervez, Shahid

2000-01-01

Direct labeling of Lanreotide with Rhenium-188 was studied. Reduction of cysteine bridge was performed by reducing agents (ascorbic acid, 2ME). The perrhenate eluted from the generator was reduced with stannous chloride. Tartarate was used as transchelating agent. After pH adjustment, shaking and incubation for various time intervals were carried out. Thin layer chromatography and reverse phase chromatography were used to monitor the radiolabelling yield. Stability of radiolabelled Lanreotide was also checked

Therapeutic efficacy and microSPECT/CT imaging of {sup 188}Re-DXR-liposome in a C26 murine colon carcinoma solid tumor model

Energy Technology Data Exchange (ETDEWEB)

Chang, Y.-J.; Chang, C.-H.; Yu, C.-Y.; Chang, T.-J.; Chen, L.-C. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Chen, M.-H. [National Health Research Institutes, Miaoli, Taiwan (China); Lee, T.-W. [Institute of Nuclear Energy Research, Taoyuan, Taiwan (China); Ting Gann [National Health Research Institutes, Miaoli, Taiwan (China)], E-mail: gann.ting@msa.hinet.net

2010-01-15

Nanocarriers can selectively target cancer sites and carry payloads, thereby improving diagnostic and therapeutic effectiveness and reducing toxicity. The objective of this study was to investigate the therapeutic efficacy of a new co-delivery radiochemotherapeutics of {sup 188}Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomal doxorubicin (DXR) ({sup 188}Re-DXR-liposome) in a C26 murine colon carcinoma solid tumor model. To evaluate the targeting and localization of {sup 188}Re-DXR-liposome in C26 murine tumor-bearing mice, biodistribution, microSPECT/CT imaging and pharmacokinetic studies were performed. The antitumor effect of {sup 188}Re-DXR-liposome was assessed by tumor growth inhibition, survival ratio and histopathological hematoxylin-eosin staining. The tumor target and localization of the nanoliposome delivery radiochemotherapeutics of {sup 188}Re-DXR-liposome were demonstrated in the biodistribution, pharmacokinetics and in vivo nuclear imaging studies. In the study on therapeutic efficacy, the tumor-bearing mice treated with bimodality radiochemotherapeutics of {sup 188}Re-DXR-liposome showed better mean tumor growth inhibition rate (MGI) and longer median survival time (MGI=0.048; 74 days) than those treated with radiotherapeutics of {sup 188}Re-liposome (MGI=0.134; 60 days) and chemotherapeutics of Lipo-Dox (MGI=0.413; 38 days). The synergistic tumor regression effect was observed with the combination index (CI) exceeding 1 (CI=1.145) for co-delivery radiochemotherapeutics of {sup 188}Re-DXR-liposome. Two (25%) of the mice treated with radiochemotherapeutics were completely cured after 120 days. The therapeutic efficacy of radiotherapeutics of {sup 188}Re-liposome and the synergistic effect of the combination radiochemotherapeutics of {sup 188}Re-DXR-liposome have been demonstrated in a C26 murine solid tumor animal model, which pointed to the potential benefit and promise of the co-delivery of

Re-188 labelling of DD-3B6/22 Fab' monoclonal antibody fragment for radio immuno therapy

International Nuclear Information System (INIS)

Schmidt, P.F.; Smith, S.V.; Bundesen, P.

1996-01-01

The chemical similarity of technetium and rhenium has created much interest in the nuclear medicine field to make a 'matched pair' of radiopharmaceuticals for radioimmuno- diagnosis and therapy. Clinical trials with the 99 mTc-DD-3B6/22 Fab' has shown promise in the diagnosis of ovarian cancer. The design of the analogous therapeutic agent with rhenium-188 (155 keV γ 15 % abundant, β E max 2.1 MeV, T 1/2 17 h) is under investigation. The present study describes the approach taken for direct radiolabelling of the DD-3B6/22 Fab' with carrier-free 188 Re and its biological evaluation in balb/c and nude mice. The effect of temperature, pH and antibody concentration on the amount and rate of transchelation was also evaluated. The final product had a specific activity of 35 mCi/mg with an immunoreactive fraction of 77%. Stability of the product was assessed under various conditions: temperature, presence and absence of an inert atmosphere and presence of ascorbic acid (stabilised). Pharmacokinetics of the final product was evaluated in balb/c and nude mice transplanted with both D-dimer (+Ve) and Glycine (-Ve) beads. Results show that 188 Re DD-3B6/22 Fab' clears rapidly from the blood (α = 2.4 hr, β = 3.5 hr) and is excreted through the renal system. Localisation to subcutaneous antigen beads shows specific uptake to the D-dimer (antigen) beads was achieved within 6 h (0.23% ID) and was maintained for 24 hour post injection. Specificity to antigen implants was 5:1 (P 99m Tc DD-3B6/22 Fab' in mice. The radiolabelling procedures are congenial for therapeutic levels and hence the authors believe that the 188 Re DD-3B6/22 Fab' has some potential for use in treatment of ovarian cancer

Tumor-targeted Nanobullets: Anti-EGFR nanobody-liposomes loaded with anti-IGF-1R kinase inhibitor for cancer treatment.

Science.gov (United States)

van der Meel, Roy; Oliveira, Sabrina; Altintas, Isil; Haselberg, Rob; van der Veeken, Joris; Roovers, Rob C; van Bergen en Henegouwen, Paul M P; Storm, Gert; Hennink, Wim E; Schiffelers, Raymond M; Kok, Robbert J

2012-04-30

The epidermal growth factor receptor (EGFR) is a validated target for anti-cancer therapy and several EGFR inhibitors are used in the clinic. Over the years, an increasing number of studies have reported on the crosstalk between EGFR and other receptors that can contribute to accelerated cancer development or even acquisition of resistance to anti-EGFR therapies. Combined targeting of EGFR and insulin-like growth factor 1 receptor (IGF-1R) is a rational strategy to potentiate anti-cancer treatment and possibly retard resistance development. In the present study, we have pursued this by encapsulating the kinase inhibitor AG538 in anti-EGFR nanobody-liposomes. The thus developed dual-active nanobody-liposomes associated with EGFR-(over)expressing cells in an EGFR-specific manner and blocked both EGFR and IGF-1R activation, due to the presence of the EGFR-blocking nanobody EGa1 and the anti-IGF-1R kinase inhibitor AG538 respectively. AG538-loaded nanobody-liposomes induced a strong inhibition of tumor cell proliferation even upon short-term exposure followed by a drug-free wash-out period. Therefore, AG538-loaded nanobody-liposomes are a promising anti-cancer formulation due to efficient intracellular delivery of AG538 in combination with antagonistic and downregulating properties of the EGa1 nanobody-liposomes. Copyright © 2011 Elsevier B.V. All rights reserved.

Therapeutic applications of Rhenium-188 in nuclear medicine and oncology - Current status and expected future perspectives

International Nuclear Information System (INIS)

Knapp, F. F. Jr.

2005-01-01

Full text: The increasing use of unsealed radioactive targeting agents for cancer treatment requires the routine availability of cost-effective radioisotopes. Rhenium-188 (Re-188; half-life 16.9 hours) is a high-energy beta-emitter (E max 2.12 MeV), readily available no- max carrier-added from the alumina-based tungsten-188 (half-life 69 days)/rhenium-188 generator system. Rhenium-188 also emits a 155 keV (15%) gamma photon, permitting gamma camera imaging for biodistribution and dosimetry evaluation. The versatile chemistry of rhenium allows attachment to a wide variety of targeting molecules for Re-188 applications in nuclear oncology for both palliative metastatic treatment and targeted tumor therapy - radionuclide synovectomy, and coronary restenosis therapy. The long parent half-life and consistent performance provide an indefinite generator shelf-life of several months with high Re-188 elution yields (75-85 %) and consistently low W-188 parent breakthrough ( -6 ). Simple post-elution concentration methods have been developed which provide very high specific volume solution of Re-188 for radiolabeling (> 700 mCi/mL saline/1 Ci generator). Over 60 physician-sponsored clinical trials are currently in progress worldwide with applications in nuclear medicine, nuclear oncology and interventional cardiology. A variety of Re-188-labeled therapeutic radiopharmaceuticals and devices are being developed for clinical trials currently in progress for treatment of both benign and metastatic oncological disorders. Palliation of metastatic bone pain with Re-188-HEDP - prepared from a simple 'kit' - has been demonstrated as a cost-effective alternative to similar agents. Recent studies have in fact demonstrated the enhancement of progression-free interval and survival time by repeated Re-188-HEDP injections to patients with metastatic disease from prostate cancer. The use of the Re-188-labeled antiNCA95 (CD66) antibody in conjunction with external beam irradiation is an

Study of the therapeutic effect of 188Re labeled folate targeting albumin nanoparticle coupled with cis-diamminedichloroplatinum cisplatin on human ovarian cancer.

Science.gov (United States)

Tang, Qiusha; Chen, Daozhen

2014-01-01

This paper aimed to investigate the treatment efficiency of 188Re labeled folate targeting albumin nanoparticles with cis-Diamminedichloroplatinum Cisplatin (188Re-folate-CDDP/HAS MNP) on human ovarian cancer. SKOV3 cells or tumor-bearing mice were divided into different groups and treated as follow: (A) negative control; (B) chemotherapy; (C) radiotherapy; (D) hyperthermia; (E) chemotherapy and radiotherapy; (F) chemotherapy and hyperthermia; (G) radiotherapy and hyperthermia; (H) chemotherapy, radiotherapy and hyperthermia. Treatment of B to H inhibited proliferation of SKOV3 cells, with the greatest inhibition being observed in group H (P<0.05). Obvious apoptotic hypodiploid peak appeared beside G1 phase in groups of B to H. The apoptotic rates of SKOV3 cells in groups of A to H were 0.08%, 7.56%, 8.64%, 17.14%, 21.64%, 23.77%, 33.94% and 57.16%, respectively. Our findings in vivo study showed that the mass of tumor in each group of B to H was significantly lower than that in the negative control (p <0.05). In addition, compared with each group of B to G, group H showed highest inhibition of tumor growth (p<0.05). In conclusion, the combination of magnetic induced hyperthermia, chemotherapy and targeted radionuclide of radiation exposure can effectively inhibit the growth of ovarian cancer, which indicates a potential applications in ovarian cancer treatment.

Affinity of hydroxyapatite by radionuclides parent/child in {sup 188}Re/{sup 188}W generator for radiotherapy; Afinidad de la hidroxiapatita por los radionuclidos padre/hijo en el generador {sup 188}Re/{sup 188}W para radioterapia

Energy Technology Data Exchange (ETDEWEB)

Carrera D, A. A. [Universidad Autonoma de Zacatecas, Unidad Academica de Ciencias Quimicas, Campus Universitario Siglo XXI, Ejido La Escondida, Carretera a Guadalajara Km. 6 (Mexico); Badillo A, V. [Universidad Autonoma de Zacatecas, Unidad Academica de Estudios Nucleares, Calle Cipres No. 10, Fracc. La Penuela 98068, Zacatecas (Mexico); Badillo A, V. E.; Monroy G, F. [ININ, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico)], e-mail: ana_carrera7@hotmail.com

2009-10-15

To assess the feasibility of using apatites as matrices of {sup 188}W/{sup 188}Re generator is essential to obtain the distribution coefficients as much of parent radionuclide as child radionuclide in apatite, that is to say to know their affinity for the solid. It was selected the mineral species more representative as adsorbent, the hydroxyapatite Ca{sub 10} (PO{sub 4}){sub 6}(OH){sub 2} it is known for its great capacity of ions retention and by presenting a large affinity for anionic species in their surface. In this paper we use a synthetic hydroxyapatite marketed by Bio-Rad. This paper presents the preliminary results regarding the affinity of hydroxyapatite for the anionic species tungstates (WO{sub 4}{sup 2-}) and perrhenates (ReO{sub 4}{sup -} in EDTA, as background electrolyte expressed as distribution coefficients between two immiscible phases obtained with the help of radioactive tracers {sup 187}W and {sup 188}Re respectively. The retention measures of these ions, traces show that Bio-Gel hydroxyapatite presents moderate values of distribution coefficients for anionic species of W(Vi) in EDTA 0.01 mol/L that are in the range p H 5 to 6.5; the parent radionuclide of generator {sup 188}Re/{sup 188}W is fixed but not enough to consider it a good absorbent. By contrast, the fixation of perrhenate ions is virtually wiped as may be easily removed from a hydroxyapatite column packed with a saline solution. The influence of this saline solution in the removal of perrhenate ions is null practically. (Author)

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

Energy Technology Data Exchange (ETDEWEB)

Venkatesh, M.; Pandey, U.; Dhami, P. S.; Chakravarty, R.; Kameswaran, M.; Subramanian, S.; Dash, A.; Samuel, G. [Bhabha Atomic Research Centre, Trombay, Mumbai 400 085 (India)

2010-07-01

During the past decade, our group has focused attention on the development of therapeutic radiopharmaceuticals incorporating radioisotopes such as {sup 90}Y, {sup 188}Re etc. As the primary source of the radioisotopes {sup 90}Y and {sup 188}Re are the {sup 90}Sr/{sup 90}Y generators and {sup 188}W/{sup 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, {sup 90}Sr/{sup 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 {sup 90}Y to be used for preparation of {sup 90}Y labeled products. This work formed a part of the IAEA co-ordinated CRP on “Development of Generator Technologies for Therapeutic Radionuclides: {sup 90}Y and {sup 188}Re”. In this report, work on the development of {sup 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 {sup 90}Sr contamination in {sup 90}Y samples with the US Pharmacopeia recommended method as well as the validation of the EPC technique is presented.

Synthesis, Characterization and Biological Studies of 99mTc and 188Re Peptides

Science.gov (United States)

Sanders, Vanessa

Radiopharmaceuticals are very powerful diagnostic tools for evaluation of a host of medical conditions. These drugs are labeled with radioactive isotopes, which are utilized to create pictures of areas of interest through absorption of the drug. They are currently in high demand due to their ability to image areas that traditional imaging devices cannot. The radioisotope 99mTc, with a half-life of 6.01 hours and a 140 keV gamma emission, is central to many radiopharmaceutical compounds. This isotope is easily obtained from a 99Mo-99mTc generator, through beta decay and column chromatography separations. Very little technetium, less than 6 ng, is needed to label the pharmaceuticals for use in-vivo. Another radioisotope 188Re is also important due to its ability to be used for therapy while being tracked throughout the body. Radiotherapy gives radiopharmaceuticals a huge advantage by their ability to destroy rapidly growing cells. One of the main reasons there is interest in rhenium pharmaceuticals is the chemical similarity between it and technetium. The 188Re isotope also has a considerably short half-life of approximately 17 hours and has emission energy of 155 keV. The 188Re isotope is separated from 188W-188Re generator, analogously to the 99Mo-99mTc generator. The ligand used in this work is a pentapepetide macrocyclic ligand. This ligand, KYCAR (lysyl-tyrosyl-cystyl-alanyl-arginine), has been designed as a potential chelating ligand for imaging and therapeutic in vivo agents. Ligands are chosen based on their in-situ biological behavior, and are used in the complexation with technetium and rhenium. Understanding and exploiting technetium and rhenium chemistry can provide insight into the reaction mechanisms and coordination chemistry of these compounds. The exploration of various oxidation states as a function of the ligands used and the reaction conditions can help develop novel radiopharmaceuticals. The investigations of the manipulation of oxidation states

antiEGFR conjugated gold nanoparticles for increasing radiosensitivity in lung cancer cells

International Nuclear Information System (INIS)

Pujari, Geetanjali; Sarma, Asitikantha; Avasthi, Devesh K.

2014-01-01

One of the set back that lies in lung cancer treatment is the over expression of Epidermal Growth Factor Receptor (EGFR). EGFR is a transmembrane receptor that is highly expressed in lung cancer that leads to cell survival, proliferation and spread of the disease. Over the years, EGFR inhibitors, monoclonal antibodies, are being used in combination with radiotherapy in lung cancer patients so as to achieve better results. In the recent time, application of Au nanoparticles (AuNPs) in diagnosis and treatment of cancer has been extensively used in biomedical research. Among various applications, there is considerable use of AuNPs seen on the dose enhancement effect (radiosensitization) in radiation therapy of cancer. The conjugation of AuNP with monoclonal antibody antiEGFR (antiEGFR-AuNP) may provide excellent agent to sensitize the cells to heavy ion radiation. We synthesized AuNPs by citrate reduction method. Most of AuNPs were in the size range of 6-8 nm as studies by Transmission Electron Microscope (TEM). These AuNPs were found to be non toxic in A549 cells and thus biocompatible. Further, we conjugated AuNPs with antiEGFR (antiEGFR-AuNP). The conjugation was confirmed by UV-Vis spectroscopy. A549 cells were treated with antiEGFR-AuNP. TEM was carried out of ultrathin cross sections of antiEGFR-AuNP treated A549 cells to check the attachment internalization of AuNPs. We observed that the AuNPs are attached on the cell membrane as well as internalized in cytoplasm. Upon exposure of antiEGFR-AuNP treated cells to heavy ion 12 C beam, showed increase in radiosensitization as studied by survival assay and MTT assay. We will also explain the EGFR expression and cell cycle proliferation in A549 cells upon heavy ion beam irradiation of these. The study aims to overcome the current limitations of cancer-targeted therapies and improve the treatment modality of lung cancer. (author)

Anti-EGFR immunonanoparticles containing IL12 and salmosin genes for targeted cancer gene therapy.

Science.gov (United States)

Kim, Jung Seok; Kang, Seong Jae; Jeong, Hwa Yeon; Kim, Min Woo; Park, Sang Il; Lee, Yeon Kyung; Kim, Hong Sung; Kim, Keun Sik; Park, Yong Serk

2016-09-01

Tumor-directed gene delivery is of major interest in the field of cancer gene therapy. Varied functionalizations of non-viral vectors have been suggested to enhance tumor targetability. In the present study, we prepared two different types of anti-EGF receptor (EGFR) immunonanoparticles containing pDNA, neutrally charged liposomes and cationic lipoplexes, for tumor-directed transfection of cancer therapeutic genes. Even though both anti-EGFR immunonanoparticles had a high binding affinity to the EGFR-positive cancer cells, the anti-EGFR immunolipoplex formulation exhibited approximately 100-fold higher transfection to the target cells than anti-EGFR immunoliposomes. The lipoplex formulation also showed a higher transfection to SK-OV-3 tumor xenografts in mice. Thus, IL12 and/or salmosin genes were loaded in the anti-EGFR immunolipoplexes and intravenously administered to mice carrying SK-OV-3 tumors. Co-transfection of IL12 and salmosin genes using anti-EGFR immunolipoplexes significantly reduced tumor growth and pulmonary metastasis. Furthermore, combinatorial treatment with doxorubicin synergistically inhibited tumor growth. These results suggest that anti-EGFR immunolipoplexes containing pDNA encoding therapeutic genes could be utilized as a gene-transfer modality for cancer gene therapy.

Study of radiation synovectomy using 188Re-sulfide in hemophilic arthritis

International Nuclear Information System (INIS)

Li, P.Y.; Cheng, G.; Jiang, X.F.; Wang, X.F.; Shen, Z.M.; Zhang, Z.H.

2002-01-01

Purpose: Based on results of previous animal studies, the efficacy of 188 Re-sulfide on radiation synovectomy in hemophilia synovitis.was evaluated. Material and Methods: 188 Re-sulfide suspension was produced by dispersion method. 25 hemophilic patients with 30 synovitic joints including 22 knees and 8 ankles received the radiation synovectomy. The stage of synovitic joint was classified by joint score including the pain, stability and range of motion and MR score. The doses of 188 Re-sulfide injected into knee and ankle were determined as 12mCi and 6mCi respectively, according to the depth and curve and the results of our previous animal study. To exam the distribution of 188 Re-sulfide in vivo after the injection, a whole-body scan was taken 24 and 48 hours later to calculate the retention of 188 Re-sulfide in joint by percentage of join counts in whole body. The follow up was take place at 6-12 months after the synovectomy by joint score, MRI score, synovial structure, the times and interval of hemorrhage of the joints. Results: Few patients complained discomfort after the injection such as hurt of the superficial tissues around the injected point and swelling (2 patients,.8%).The symptoms in this two patients continued up to 3 days and gradually decreased in severity. All patients felt relief of the pain and swelling in joints. 90% joints including 20 knees and 7 ankles did not bleed any more during the 3-month term of follow up, 3 joints from 2 patients with intra-article bleeding had hemorrhage in one month after long distance walk. 16%(5/30) of joints including 4 knees and 1 ankles had recurrent hemorrhage in 12 months after the radiation synovectomy. However, their interval of intra-article bleeding was prolonged MRI showed the thick synovium became thin, villi reduced and the joint edema relieved. The retention of 188 Re-sulfide in administrated joint was more than 95% until 48 hours later. No any sign of radioactive distribution was found in bone marrow

Rhenium-188 - advantages and clinical potential for use of a readily available, cost effective therapeutic radioisotope for applications in nuclear medicine, oncology and interventional cardiology

International Nuclear Information System (INIS)

Knapp, F.F. jr.

2002-01-01

Full text: Carrier-free rhenium-188 (Re-188) is readily available from the alumina-based tungsten-188/rhenium-188 generator system and has many attractive properties for a wide variety of therapeutic applications. The 16.9 h half-life, emission of the 2.2 MeV beta particle and versatile chemistry make Re-188 an important candidate for applications where high radiation penetration is required. In addition, emission of a gamma photon (155 KeV, 15 %) permits evaluation of biodistribution, pharmacokinetics and dosimetry estimates. The long physical half-life of the tungsten-188 (W-188) parent (t 1/2 69 days) and consistent generator performance - with high Re-188 yields and low W-188 parent breakthrough - result in an indefinite shelf-life of several months, dependent on the levels of Re-188 required. Post generator elution in-growth of 62 % of Re-188 after 24 hours in combination with high elution yields (75-85 %) result in 50 % daily yields of the maximal Re-188 available. In addition to research being conducted for the development of a wide variety of new therapeutic radiopharmaceuticals and devices, Re-188 is also being evaluated in physician-sponsored clinical trials in over 15 countries, with applications in nuclear medicine, oncology and interventional cardiology. One major current clinical application involves post-angiographic treatment of arterial segments following PTCA using Re-188 perrhenate or MAG3 liquid-filled balloons as an effective and cost-effective approach for inhibition of the hyperplastic response to vessel damage, which delivers uniform dose to the vessel wall. Re-188-HEDP is being used for palliation of metastatic bone pain palliation. This agent is readily prepared from a simple 'kit' and provides pain palliation as effective as other commercially available agents. The use of the Re-188-labeled Anti-NCA-95 antibody (BW 50/183; CD66 a,b,c,e) in conjunction which external beam irradiation and chemotherapy is an effective method for

ADCC responses and blocking of EGFR-mediated signaling and cell growth by combining the anti-EGFR antibodies imgatuzumab and cetuximab in NSCLC cells

NARCIS (Netherlands)

Kol, Arjan; Terwisscha van Scheltinga, Anton; Pool, Martin; Gerdes, Christian; de Vries, Elisabeth; de Jong, Steven

2017-01-01

Imgatuzumab is a novel glycoengineered anti-epidermal growth factor receptor (EGFR) monoclonal antibody optimized to induce both antibody-dependent cellular cytotoxicity (ADCC) and EGFR signal transduction inhibition. We investigated antiEGFR monoclonal antibodies imgatuzumab and cetuximab-induced

Synthesis, characterization and biological evaluation of [{sup 188}Re(N)(cys{approx})(PNP)]{sup +/0} mixed-ligand complexes as prototypes for the development of {sup 188}Re(N)-based target-specific radiopharmaceuticals

Energy Technology Data Exchange (ETDEWEB)

Thieme, Stefan [Institute of Radiopharmacy, Forschungszentrum Dresden Rossendorf, P.O. Box 510 119, 01314 Dresden (Germany); Agostini, Stefania [Department of Pharmaceutical Sciences, University of Padua, Via Marzolo 5, 35131 Padova (Italy); Bergmann, Ralf; Pietzsch, Jens; Pietzsch, Hans-Juergen [Institute of Radiopharmacy, Forschungszentrum Dresden Rossendorf, P.O. Box 510 119, 01314 Dresden (Germany); Carta, Davide; Salvarese, Nicola [Department of Pharmaceutical Sciences, University of Padua, Via Marzolo 5, 35131 Padova (Italy); Refosco, Fiorenzo [ICIS-CNR, Corso Stati Uniti 4, 35127 Padova (Italy); Bolzati, Cristina, E-mail: bolzati@icis.cnr.i [Department of Pharmaceutical Sciences, University of Padua, Via Marzolo 5, 35131 Padova (Italy); ICIS-CNR, Corso Stati Uniti 4, 35127 Padova (Italy)

2011-04-15

We report on an efficient procedure for the preparation of [{sup 188}Re(N)(PNP)]-based complexes (where PNP is diphosphinoamine) useful in the development of target-specific radiopharmaceuticals. The radiochemical yield of the compounds was optimized considering such reaction parameters as nature of the nitrido nitrogen donor, reaction times and pH level. The chemical identity of the {sup 188}Re agents was determined by high-performance liquid chromatography comparison with the corresponding well-characterized cold Re compounds. {sup 188}Re(N) mixed compounds have been evaluated with regard to stability toward transchelation with GSH and degradation by serum enzymes. The clearance of selected radiocompounds from normal tissues and their in vivo stability were evaluated in rats by biodistribution and imaging studies. [{sup 188}Re(N)(cys{approx})(PNP)]{sup +/0} mixed-ligand compounds were efficiently prepared in aqueous solution from perrhenate using a multistep procedure based on the preliminary formation of the labile {sup 188}Re{sup III}-EDTA species, which easily undergo oxidation/ligand exchange reaction to afford the [{sup 188}Re{sup V{identical_to}}N]{sup 2+} core in the presence of dithiocarbazate. The final mixed-ligand compounds were obtained, at 100{sup o}C, by adding the two bidentate ligands to the buffered [{sup 188}Re{sup V{identical_to}}N]{sup 2+} solution (pH 3.2-3.6). However, a relatively high amount of cys{approx} ligand was required to obtain a quantitative radiochemical yield. The complexes were stable toward reoxidation to perrhenate and ligand exchange reactions. In vivo studies showed rapid distribution and elimination of the complexes from the body. No specific uptakes in sensitive tissues/organs were detected. A positive correlation of the distribution of the complexes estimated with biodistribution studies (%ID) and with micro-SPECT semiquantification imaging analysis (standard uptake values) was observed. These results support the

Anti-EGFR Therapy: Mechanism and Advances in Clinical Efficacy in Breast Cancer

Directory of Open Access Journals (Sweden)

John F. Flynn

2009-01-01

Full Text Available This review will focus on recent advances in the application of antiepidermal growth factor receptor (anti-EGFR for the treatment of breast cancer. The choice of EGFR, a member of the ErbB tyrosine kinase receptor family, stems from evidence pinpointing its role in various anti-EGFR therapies. Therefore, an increase in our understanding of EGFR mechanism and signaling might reveal novel targets amenable to intervention in the clinic. This knowledge base might also improve existing medical treatment options and identify research gaps in the design of new therapeutic agents. While the approved use of drugs like the dual kinase inhibitor Lapatinib represents significant advances in the clinical management of breast cancer, confirmatory studies must be considered to foster the use of anti-EGFR therapies including safety, pharmacokinetics, and clinical efficacy.

Pharmacokinetic properties of new antitumor radiopharmaceutical on the basis of diamond nanoporous composites labeled with rhenium-188

International Nuclear Information System (INIS)

Petriev, V M; Tishchenko, V K; Kuril’chik, A A; Skvortsov, V G

2017-01-01

Today the development of address therapeutic radionuclide delivery systems directly to tumor tissue is of current interest. It can be achieved by the design of drug containers of specific sizes and shapes from carbon-based composite materials. It will be allowed to enhance the efficacy of anticancer therapy and avoid serious side effects. In this work we studied the pharmacokinetic properties of nanodiamond nanoporous composite labeled with rhenium-188 in rats with hepatocholangioma PC-1 after intratumoral injection. It was established that substantial part of injected radioactivity remained in tumor tissue. Within three hours after 188 Re-nanoporous composites injection activity in tumor constituted 79.1–91.3% of injected dose (ID). Then activity level declined to 45.9% ID at 120 hours. No more than 1.34% ID entered the bloodstream. In soft organs and tissues, except thyroid gland, the content of compound didn’t exceed 0.3% ID/g. The highest activity in thyroid gland was 6.95% ID/g. In conclusion, received results suggest 188 Re-nanoporous composites can be promising radionuclide delivery systems for cancer treatment. (paper)

Experimental Treatment of Bladder Cancer with Bi-213-anti-EGFR MAb

International Nuclear Information System (INIS)

Seidl, Christof; Pfost, Birgit; Müller, Felix

2013-01-01

Therapy of non-muscle-invasive bladder cancer (carcinoma in situ) comprises transurethral resection of the tumour and subsequent instillation of the chemotherapeutic drug mitomycin C in order to eradicate remaining tumour cells. Yet 15 – 40% of treated patients relapse within 5 years. Therefore, new therapeutic strategies to combat tumour recurrence are needed. Alpha-particle emitting radionuclides efficiently kill single tumour cells or small tumour cell clusters. Because the epidermal growth factor receptor (EGFR) is overexpressed on bladder cancer cells, conjugates composed of the alpha-emitter Bi-213 and the anti-EGFR antibody matuzumab should provide a powerful drug to eliminate disseminated bladder cancer cells. Therefore, the aims of our study were (i) to analyse the cytotoxic effects of Bi-213-anti-EGFR radioimmunoconjugates at the cellular level, (ii) to evaluate therapeutic efficacy of intravesically applied Bi-213- anti-EGFR-Mab in a nude mouse model with intravesical human bladder cancer xenografts, (iii) to compare Bi- 213-anti-EGFR-Mab efficacy with chemotherapy using mitomycin C and (iv) to demonstrate that radioimmunotherapy is not toxic to cells of the bladder wall and of the kidneys

Study of different absorbent materials for the preparation of generator systems of 99Mo - 99mTc and 188W-188Re

International Nuclear Information System (INIS)

Lopes, Paula Regina Corain; Osso Junior, Joao Alberto

2009-01-01

Amongst some currently radioisotopes, 99m Tc and 188 Re present adequate decay properties for use in Nuclear Medicine. In the current times the most diagnosis examinations are performed with 99m Tc and 188 Re is one radioisotope of potential use in therapy techniques. The objective of this work consists of determining the capacity of some adsorbent materials for retention of molybdenum and tungsten, aiming the optimization of generator systems of 99 Mo- 99m Tc and 188 W- 188 Re with suitable characteristics for application in Nuclear Medicine. Known amounts, in mass, of molybdenum and tungsten were percolated through different chromatographic columns containing different commercial adsorbent materials such as: PZC (poly-zirconium compound), acid alumina and calcinated alumina used in the routine preparation of 99 Mo- 99m Tc generators at IPEN. The tungsten ( 188 W), as well the PZC used in this project, supplied by Russia and Japan, respectively, through the International Atomic Energy Agency (IAEA) and used without any previous preparation. Also trace amounts of 99 Mo and 188 W were added to the initial solutions and the generators were assembled. The 99 Mo- 99m Tc generators were then eluted with known volumes of 0.9% NaCl solution every 24 hours whereas the 188 W- 188 Re generators were eluted every 48 hours. The eluted samples were analyzed by Gamma Spectroscopy and later submitted to quality control evaluation. The results showed that the PZC presents superior retention capacity for Mo of 97.50mg Mo/gPZC, higher than in acid and calcinated alumina, however the elution efficiency at lower pHs is not so high. With regards to the experiments carried out with 188 W and alumina, it was verified that the elution efficiency of 188 Re was not reproducible and the retention capacity of W was 90.23mgW/gAl 2 O 3 at pH 7. (author)

Bio markers and Anti-EGFR therapies for Krads wild-type tumors in metastatic colorectal cancer patients; Biomarcadores y terapeutica ANTI-EGFR en el cancer colorrectal metastasico en pacientes con K-Ras no mutado

Energy Technology Data Exchange (ETDEWEB)

Diaz Rubio Garcia, E

2009-07-01

The natural history of metastasis colorectal cancer has being clearly modified in terms of response rate, time to progression and overall survival, once the anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have emerged in combination with the standard cytotoxic chemotherapy (FOLFOX and FOLFIRI). However, the benefit from cetuximab and panitumumab is only confined to KRAS-wild type (KRAS-wt) colorectal tumors, while KRAS mutated tumors do not respond to these drugs. The 65 % of colorectal tumors are KRAS-wt tumors, but efficacy of antiEGFR therapies is detected only in 60-70 % of these KRAS-wt tumors. Other biomarkers and molecular pathways must be involved in the response of the antiEGFR therapies for the KRAS-wt colorectal tumors, such as the EGFR ligands, the EGFR-phosphorilated levels, the number of EGFR copies, the status of the KRAS effected B-RAF and the alternative intracellular signaling pathways PIK3CA/PTEN/AKT and JAK/STAT. A battery of these biomarkers is needed to select the most sensitive patients to the antiEGFR therapies. This pattern may represent a novel favorable cost-effectiveness tool to develop tailored treatments. A review of these biomarkers and molecular pathways, involved in the antiEGFR therapies response, is performed. (Author) 68 refs.

Studies on the preparation and isomeric composition of [sup 186]Re- and [sup 188]Re-pentavalent rhenium dimercaptosuccinic acid complex

Energy Technology Data Exchange (ETDEWEB)

Singh, J. (Canterbury Univ. (United Kingdom). Biological Lab.); Reghebi, K.; Lazarus, C.R.; Clarke, S.E.M. (Guy' s Hospital, London (United Kingdom)); Callahan, A.P.; Knapp, F.F. Jr. (Oak Ridge National Lab., TN (United States)); Blower, P.J. (Kent and Canterbury Hospital (United Kingdom))

1993-03-01

The preparative conditions for [sup 186]Re(V)DMSA and [sup 188]Re(V)DMSA (DMSA = meso-dimercaptosuccinic acid), [beta]-emitting radiopharmaceuticals that have been shown to localize in medullary thyroid carcinoma, require modification depending on the amount of carrier rhenium and the chemical form and medium in which the rhenium is supplied. Preparative conditions are described for use with carrier-free [sup 188]ReO[sub 4][sup -] in saline, and for use with [sup 186]ReO[sub 4][sup -] in saline, sodium hydroxide or nitric acid. Preparation of [sup 186]Re(V)DMSA (carrier present up to 2 mg per 2.5 ml reaction volume) requires a DMSA:SnCl[sub 2]:Re ratio of 10:5:1 at 100[sup o]C for 30 min. Addition of excess nitric acid or hydrochloric acid up to a concentration of 155 mM does not reduce the yield from 100%. A commercial DMSA kit vial (e.g. Amerscan DMSA) can be used for preparation of [sup 188]Re(V)DMSA (carrier free) provided the required is in a volume of less than 1 ml per vial. A convenient method of concentrating the [sup 188]Re generator eluate to the required volume is described. (Author).

Studies of gel metal-oxide composite samples as filling materials for W-188/Re-188 generator column

Czech Academy of Sciences Publication Activity Database

Iller, E.; Polkowska-Motrenko, H.; Lada, W.; Wawszczak, D.; Sypula, M.; Doner, K.; Konior, M.; Milczarek, J.; Zoladek, J.; Ráliš, Jan

2009-01-01

Roč. 281, č. 1 (2009), s. 83-86 ISSN 0236-5731. [9th International Conference on Nuclear Analytical Methods in the Life Sciences. Lisbon, 07.09.2008-12.09.2008] Institutional research plan: CEZ:AV0Z10480505 Keywords : W-188/Re-188 generator * W-Zr gels * W-Zr composites * Sol-gel process Subject RIV: CH - Nuclear ; Quantum Chemistry Impact factor: 0.631, year: 2009

Biodistribution of 99mTc-labeled anti-human epidermal growth factor receptor (EGF-R) humanized monoclonal antibody h-R3 in a xenograft model of human lung adenocarcinoma

International Nuclear Information System (INIS)

Morales-Morales, Alejo; Duconge, Jorge; Caballero-Torres, Idania; Nunez-Gandolff, Gilda; Fernandez, Eduardo; Iznaga-Escobar, Normando

1999-01-01

The anti-human epidermal growth factor receptor (EGF-R) humanized monoclonal antibody (MAb) h-R3 is an (IgG 1 ), which binds to an extracellular domain of EGF-R. It was used to evaluate the biodistribution on nude mice xenografted with H-125 human lung adenocarcinoma cell line. Results were compared with its murine version of the MAb ior-egf/r3. Twenty-one athymic female 4NMRI nu/nu mice were injected intraperitoneally with 10 μg/100 μCi of 99m Tc-labeled MAbs. Immunoreactivity of 99m Tc-labeled MAbs were measured by enzyme-linked immunosorbent assay (ELISA) on H-125 cell line and the immunoreactive fractions was determined by the Lindmo method. Among all organs, significant accumulation was found in serum (27.05 ± 2.08 %ID/g) and tumor (3.903 ± 0.89 %ID/g) at 4 h after injection. These values decreased to 5.03 ± 0.50 %ID/g and 2.19 ± 0.56 %ID/g for serum and tumor, respectively. The immunoreactive fraction was found to be 0.70, with a correlation coefficient r=0.9984. With the good biodistribution and tumor uptake of the 99m Tc-labeled humanized antibody h-R3, a phase I diagnostic clinical trial of tumor with epithelial origin should be pursued

Calculus of spatial distribution of absorbed dose to cellular level by Monte Carlo simulation for a radio-labelled peptide with {sup 188}Re and with nuclear internalization : preliminary results; Calculo de la distribucion espacial de dosis absorbida a nivel celular por simulacion Monte Carlo para un peptido radiomarcado con {sup 188}Re y con internalizacion nuclear : resultados preliminares

Energy Technology Data Exchange (ETDEWEB)

Rojas C, E. L. [ININ, Carretera Mexico-Toluca s/n, 52750 Ocoyoacac, Estado de Mexico (Mexico); Santos C, C. L. [Universidad Autonoma del Estado de Mexico, Paseo Tollocan y Jesus Carranza, Toluca 50120, Estado de Mexico (Mexico)], e-mail: leticia.rojas@inin.gob.mx

2009-10-15

The {sup 188}Re is a radionuclide of radiation gamma emitter, useful in obtaining of gamma-graphic images, but it is also emitter of beta radiations and Auger electrons. A bio-molecule directed to a specific receptor of a cancer cell labeled with a emitter radionuclide of beta particles and Auger electrons, as the {sup 188}Re-Tat-Bombesin, it has the potential to be used in radiotherapy of molecular targets for its capacity to penetrate to cellular nucleus. In this system, the radiation dose is distributed in way located at microscopic levels in sub cellular specific places, where Auger emissions contributes of significant way in absorbed dose. The cellular dosimetry is realized in most of cases, using analytic or semi analytical methods, for example the cellular MIRD methodology. However, it is required to complement these calculations simulating the electrons transport and considering experimental bio kinetics data. Therefore, in this work preliminary results are presented of dosimetric calculation to sub cellular level for {sup 188}Re-Tat-Bombesin by Monte Carlo simulation, using the 2008 version of PENELOPE: PENEASY code. The spatial distribution of absorbed dose in membrane, cytoplasm and nucleus, was calculated with geometry of a cell of 10 {mu}m of diameter, a nucleus of 2 {mu}m of ratio and membrane of 0.2 {mu}m of thickness, considering elementary constitution for each cellular compartment proposal in literature. The total number of disintegrations at sub cellular level was evaluated integrating the activity in function of time starting from experimental bio kinetics data in mamma cancer cells MDA-MB231. The preliminary results show that 46.4% of total disintegrations for unit of captured activity by cell occurs in nucleus, 38.4% in membrane and 15.2% in cytoplasm. The due absorbed dose to Auger electrons for 1 Bq of {sup 188}Re located in cellular membrane were respectively of 1.32E-1 and 1.43E-1 Gy in cytoplasm and nucleus. (Author)

Biodistribution of {sup 99m}Tc-labeled anti-human epidermal growth factor receptor (EGF-R) humanized monoclonal antibody h-R3 in a xenograft model of human lung adenocarcinoma

Energy Technology Data Exchange (ETDEWEB)

Morales-Morales, Alejo; Duconge, Jorge; Caballero-Torres, Idania; Nunez-Gandolff, Gilda; Fernandez, Eduardo; Iznaga-Escobar, Normando E-mail: normando@ict.cim.sld.cu

1999-04-01

The anti-human epidermal growth factor receptor (EGF-R) humanized monoclonal antibody (MAb) h-R3 is an (IgG{sub 1}), which binds to an extracellular domain of EGF-R. It was used to evaluate the biodistribution on nude mice xenografted with H-125 human lung adenocarcinoma cell line. Results were compared with its murine version of the MAb ior-egf/r3. Twenty-one athymic female 4NMRI nu/nu mice were injected intraperitoneally with 10 {mu}g/100 {mu}Ci of {sup 99m}Tc-labeled MAbs. Immunoreactivity of {sup 99m}Tc-labeled MAbs were measured by enzyme-linked immunosorbent assay (ELISA) on H-125 cell line and the immunoreactive fractions was determined by the Lindmo method. Among all organs, significant accumulation was found in serum (27.05 {+-} 2.08 %ID/g) and tumor (3.903 {+-} 0.89 %ID/g) at 4 h after injection. These values decreased to 5.03 {+-} 0.50 %ID/g and 2.19 {+-} 0.56 %ID/g for serum and tumor, respectively. The immunoreactive fraction was found to be 0.70, with a correlation coefficient r=0.9984. With the good biodistribution and tumor uptake of the {sup 99m}Tc-labeled humanized antibody h-R3, a phase I diagnostic clinical trial of tumor with epithelial origin should be pursued.

Bio markers and Anti-EGFR therapies for Krads wild-type tumors in metastatic colorectal cancer patients

International Nuclear Information System (INIS)

Diaz Rubio Garcia, E.

2009-01-01

The natural history of metastasis colorectal cancer has being clearly modified in terms of response rate, time to progression and overall survival, once the antiEGFR monoclonal antibodies (cetuximab and panitumumab) have emerged in combination with the standard cytotoxic chemotherapy (FOLFOX and FOLFIRI). However, the benefit from cetuximab and panitumumab is only confined to KRAS-wild type (KRAS-wt) colorectal tumors, while KRAS mutated tumors do not respond to these drugs. The 65 % of colorectal tumors are KRAS-wt tumors, but efficacy of antiEGFR therapies is detected only in 60-70 % of these KRAS-wt tumors. Other biomarkers and molecular pathways must be involved in the response of the antiEGFR therapies for the KRAS-wt colorectal tumors, such as the EGFR ligands, the EGFR-phosphorilated levels, the number of EGFR copies, the status of the KRAS effected B-RAF and the alternative intracellular signaling pathways PIK3CA/PTEN/AKT and JAK/STAT. A battery of these biomarkers is needed to select the most sensitive patients to the antiEGFR therapies. This pattern may represent a novel favorable cost-effectiveness tool to develop tailored treatments. A review of these biomarkers and molecular pathways, involved in the antiEGFR therapies response, is performed. (Author) 68 refs.

In-vitro studies with 188Re-HEDP, a clinically used bone pain palliating agent, on bone cancer cells

International Nuclear Information System (INIS)

Sharma, Rohit; Kumar, Chandan; Mallia, Madhava B.; Banerjee, Sharmila; Kameswaran, Mythili

2017-01-01

Rhenium-188 is an attractive radioisotope for a wide variety of radiotherapy applications. 188 Re-HEDP (HEDPhydroxyethylidene- 1,1-diphosphonic acid) is one such, clinically useful, radiopharmaceutical for palliation of bone pain due to osseous metastasis. Herein, our aim was to study the uptake and retention of 188 Re-HEDP in mineralized bone and to assess its cellular toxicity, along with its underlying mechanism in human osteocarcinoma (MG-63 and Soas-2) cell lines. 188 Re-HEDP uptake was found to be significantly higher in mineralized bone. The 188 Re-HEDP complex also induces G2-M cell cycle arrest and thus contributing to apoptosis and cellular toxicity in bone cancer cells. (author)

Study of different absorbent materials for the preparation of generator systems of {sup 99}Mo - {sup 99m}Tc and {sup 188}W-{sup 188}Re

Energy Technology Data Exchange (ETDEWEB)

Lopes, Paula Regina Corain; Osso Junior, Joao Alberto, E-mail: paulinhacorain@usp.b, E-mail: jaosso@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

2009-07-01

Amongst some currently radioisotopes, {sup 99m}Tc and {sup 188}Re present adequate decay properties for use in Nuclear Medicine. In the current times the most diagnosis examinations are performed with {sup 99m}Tc and {sup 188}Re is one radioisotope of potential use in therapy techniques. The objective of this work consists of determining the capacity of some adsorbent materials for retention of molybdenum and tungsten, aiming the optimization of generator systems of {sup 99}Mo-{sup 99m}Tc and {sup 188}W-{sup 188}Re with suitable characteristics for application in Nuclear Medicine. Known amounts, in mass, of molybdenum and tungsten were percolated through different chromatographic columns containing different commercial adsorbent materials such as: PZC (poly-zirconium compound), acid alumina and calcinated alumina used in the routine preparation of {sup 99}Mo-{sup 99m}Tc generators at IPEN. The tungsten ({sup 188}W), as well the PZC used in this project, supplied by Russia and Japan, respectively, through the International Atomic Energy Agency (IAEA) and used without any previous preparation. Also trace amounts of {sup 99}Mo and {sup 188}W were added to the initial solutions and the generators were assembled. The {sup 99}Mo-{sup 99m}Tc generators were then eluted with known volumes of 0.9% NaCl solution every 24 hours whereas the {sup 188}W-{sup 188}Re generators were eluted every 48 hours. The eluted samples were analyzed by Gamma Spectroscopy and later submitted to quality control evaluation. The results showed that the PZC presents superior retention capacity for Mo of 97.50mg Mo/gPZC, higher than in acid and calcinated alumina, however the elution efficiency at lower pHs is not so high. With regards to the experiments carried out with {sup 188}W and alumina, it was verified that the elution efficiency of {sup 188}Re was not reproducible and the retention capacity of W was 90.23mgW/gAl{sub 2}O{sub 3} at pH 7. (author)

Study of different adsorbent materials for the preparation of generator systems of 99Mo - 99mTc and 188W-188Re

International Nuclear Information System (INIS)

Lopes, Paula Regina Corain

2009-01-01

Amongst some existing radioisotopes, 99m Tc and 188 Re present adequate physical chemical properties for use in Nuclear Medicine in the areas of diagnosis and therapy, respectively. Moreover, these radioisotopes can be distributed to medical centers in the form of generator systems of 99 Mo- 99m Tc and 188 W- 188 Re, allowing autonomy and practicity in use. The objective of this work consists of determining the capacity of some adsorbent materials for retention of molibdenium and tungsten, aiming the optimization of generator systems of 99 Mo- 99 mTc and 188 W- 188 Re with suitable characteristics for application in Nuclear Medicine. Known amounts, in mass, of molybdenum (Mo) and tungsten (W) were added to the loading solutions previously prepared, with values of pH adjusted between 1 and 7, and these were then percolated through different devices containing in its interior alumina, resin or poly-zirconium compound also known as PZC. The elutions were carried out within an interval of time of approximately 24 hours for the generator systems of 99 Mo - 99 mTc and 48 hours for the generator systems of 188 W- 188 Re due to the difference between the half-lives of radionuclides involved in the reactions. The eluted samples from both generator systems containing 99m Tc or 188 Re were submitted to quality control tests aiming to evaluate the radionuclidic, radiochemical and chemical purity, but no significant contamination for 99 Mo, 188 W, technetium or rhenium in the colloidal states and zirconium were detected in the eluted solutions and in the solutions extracted with saline solution for any value of pH studied. The commercial alumina cartridges known as Acid Sep Pak were more efficient in retaining the molybdenum in the loading solutions when compared with the others commercial retention devices employed. However, when this comparison extends to the chromatographic alumina columns, the use of acid alumina as adsorbent is more efficient when compared to the Acid Sep

An in vivo C. elegans model system for screening EGFR-inhibiting anti-cancer drugs.

Directory of Open Access Journals (Sweden)

Young-Ki Bae

Full Text Available The epidermal growth factor receptor (EGFR is a well-established target for cancer treatment. EGFR tyrosine kinase (TK inhibitors, such as gefinitib and erlotinib, have been developed as anti-cancer drugs. Although non-small cell lung carcinoma with an activating EGFR mutation, L858R, responds well to gefinitib and erlotinib, tumors with a doubly mutated EGFR, T790M-L858R, acquire resistance to these drugs. The C. elegans EGFR homolog LET-23 and its downstream signaling pathway have been studied extensively to provide insight into regulatory mechanisms conserved from C. elegans to humans. To develop an in vivo screening system for potential cancer drugs targeting specific EGFR mutants, we expressed three LET-23 chimeras in which the TK domain was replaced with either the human wild-type TK domain (LET-23::hEGFR-TK, a TK domain with the L858R mutation (LET-23::hEGFR-TK[L858R], or a TK domain with the T790M-L858R mutations (LET-23::hEGFR-TK[T790M-L858R] in C. elegans vulval cells using the let-23 promoter. The wild-type hEGFR-TK chimeric protein rescued the let-23 mutant phenotype, and the activating mutant hEGFR-TK chimeras induced a multivulva (Muv phenotype in a wild-type C. elegans background. The anti-cancer drugs gefitinib and erlotinib suppressed the Muv phenotype in LET-23::hEGFR-TK[L858R]-expressing transgenic animals, but not in LET-23::hEGFR-TK[T790M-L858R] transgenic animals. As a pilot screen, 8,960 small chemicals were tested for Muv suppression, and AG1478 (an EGFR-TK inhibitor and U0126 (a MEK inhibitor were identified as potential inhibitors of EGFR-mediated biological function. In conclusion, transgenic C. elegans expressing chimeric LET-23::hEGFR-TK proteins are a model system that can be used in mutation-specific screens for new anti-cancer drugs.

A bi-paratopic anti-EGFR nanobody efficiently inhibits solid tumour growth

Science.gov (United States)

Roovers, Rob C.; Vosjan, Maria J.W.D.; Laeremans, Toon; el Khoulati, Rachid; de Bruin, Renée C.G.; Ferguson, Kathryn M.; Verkleij, Arie J.; van Dongen, Guus A.M.S.; van Bergen en Henegouwen, Paul M. P.

2014-01-01

The epidermal growth factor receptor (EGFR) has been shown to be a valid cancer target for antibody-based therapy. At present, several anti-EGFR monoclonal antibodies (mAbs) have been successfully used, among which cetuximab and matuzumab. X-ray crystallography data show that these antibodies bind to different epitopes on the ecto-domain of EGFR, providing a rationale for the combined use of these two antibody specificities. We have previously reported on the successful isolation of antagonistic anti-EGFR nanobodies. In the present study, we aimed to improve on these molecules by combining nanobodies with specificities similar to both cetuximab and matuzumab into a single bi-paratopic molecule. Carefully designed phage nanobody selections resulted in two sets of nanobodies that specifically blocked the binding of either matuzumab or of cetuximab to EGFR and that did not compete for each others binding. A combination of nanobodies from both epitope groups into the bi-paratopic nanobody CONAN-1 was shown to block EGFR activation more efficiently than monovalent or bivalent (monospecific) nanobodies. In addition, this bi-paratopic nanobody potently inhibited EGF-dependent cell proliferation. Importantly, in an in vivo model of athymic mice bearing A431 xenografts, CONAN-1 inhibited tumour outgrowth with an almost similar potency as the whole mAb cetuximab, despite the fact that CONAN-1 is devoid of an Fc portion that could mediate immune effector functions. Compared to therapy using bivalent, mono-specific nanobodies, CONAN-1 was clearly more potent in tumour growth inhibition. These results show that the rational design of bi-paratopic nanobody-based anti-cancer therapeutics may yield potent lead molecules for further development. PMID:21520037

Development of labelled biomolecules for targeted radiotherapy

International Nuclear Information System (INIS)

Arteaga de Murphy, C.

2000-01-01

The scope of the co-ordinated research project (Dec 15 1997) included the following activities: 1) develop coupling techniques using bifunctional chelating agents for monoclonal antibodies and peptides, 2) optimised radiolabelling procedures and reaction parameters using Sm-153 and Re-188, 3) investigate direct methods of labelling monoclonal antibodies and peptides with Re-188. 4) initiate animal distribution studies. The modifications specified for the period 1999/02/15 to 2000/02/14 are as follows: a) continue with the optimisation of Re-188-peptide labelling, b) continue with the work to prepare a kit, c) in-vivo and in-vitro studies, d) lanreotide labelling. The group formed by researchers from several Mexican Institutions have worked together and in different aspects of the CRP in order to fulfil the proposed aims (our published work listed)

Development of labelled biomolecules for targeted radiotherapy

Energy Technology Data Exchange (ETDEWEB)

Arteaga de Murphy, C [Instituto Nacional de la Nutricion Salvador Zubiran, Departmento de Medicina Nuclear, Mexico D.F. (Mexico). E-mail: cmurphy at data.net.mx

2000-07-01

The scope of the co-ordinated research project (Dec 15 1997) included the following activities: 1) develop coupling techniques using bifunctional chelating agents for monoclonal antibodies and peptides, 2) optimised radiolabelling procedures and reaction parameters using Sm-153 and Re-188, 3) investigate direct methods of labelling monoclonal antibodies and peptides with Re-188. 4) initiate animal distribution studies. The modifications specified for the period 1999/02/15 to 2000/02/14 are as follows: a) continue with the optimisation of Re-188-peptide labelling, b) continue with the work to prepare a kit, c) in-vivo and in-vitro studies, d) lanreotide labelling. The group formed by researchers from several Mexican Institutions have worked together and in different aspects of the CRP in order to fulfil the proposed aims (our published work listed)

Improvement of A.E.S System, using a 188Re-radiolabeled hapten

International Nuclear Information System (INIS)

Morandeau, L.

2002-01-01

Full text: Feasibility of two-step radioimmunotherapy (RIT) of cancer by the Affinity Enhancement System (AES) has been demonstrated in experimental and clinical studies. This technique, associating a bispecific antibody (BsAb) and a radiolabeled bivalent peptide, reduces toxicity and improves therapeutic efficacy of the treatment compared to the one step targeting method. The formation of a cyclic complex (antigen-BsAb- hapten-BsAb-antigen) observed on the tumor allows good tumoral fixation. This is associated with low non-specific uptake, due to the fast clearance of the hapten from the organism. Iodine 131, used currently in clinical applications, has however several disadvantages. These include the mean energy of □ . particles, strong y emission and long physical half-life. Rhenium-188 is the radionuclide of choice to replace iodine-131; its low cost, its availability from a W-188/Re-188 generator and its very favorable radiophysical properties (t 1/2 =16.9h; E□=2.118 MeV; Ey (15%)=155keV) make it a very interesting radionuclide for radioimmunotherapy applications. Unlike the case of iodine-131, the radiolabelling of the peptide by rhenium-188 requires the preliminary coupling of a bifunctional chelating agent. This ensures the formation of an in vivo stable complex with the radionuclide. The object of this post-doctoral project is to obtain a rhenium-188 radiolabeled bivalent hapten. To do this, a monovalent hapten will be coupled to a chelating agent that involves two or three patterns to complex the radionuclide, leading to a bivalent or trivalent radiolabeled hapten, suitable for applications in A.E.S. system. The monovalent hapten used, called HSGL (histaminosuccinylglycyllysine) is a small heteropeptide composed of a chain of four molecules which are histamine, succinic acid, glycine, lysine. It is recognised by the antibody anti-HSG. Two kinds of chelating agents, dithiocarbamates and dithiobenzoates will be studied. They have been synthesised at

Elucidation of the critical epitope of an anti-EGFR monoclonal antibody EMab-134.

Science.gov (United States)

Kaneko, Mika K; Yamada, Shinji; Itai, Shunsuke; Chang, Yao-Wen; Nakamura, Takuro; Yanaka, Miyuki; Kato, Yukinari

2018-07-01

The epidermal growth factor receptor (EGFR) is a type-1 transmembrane receptor tyrosine kinase, which activates the downstream signaling cascades in many tumors, such as oral and lung cancers. We previously developed EMab-134, a novel anti-EGFR monoclonal antibody (mAb), which reacts with endogenous EGFR-expressing cancer cell lines and normal cells independent of glycosylation in Western blotting, flow cytometry, and immunohistochemical analysis. EMab-134 showed very high sensitivity (94.7%) to oral squamous cell carcinomas in immunohistochemical analysis. In this study, we performed enzyme-linked immunosorbent assay (ELISA), flow cytometry, and immunohistochemical analysis to determine the epitope of EMab-134. A blocking peptide (375-394 amino acids of EGFR) neutralized the EMab-134 reaction against oral cancer cells in flow cytometry and immunohistochemistry. The minimum epitope of EMab-134 was found to be the 377- RGDSFTHTPP -386 sequence. Our findings can be applied for the production of more functional anti-EGFR mAbs that in turn can be used for antitumor treatments.

Synthesis and characterization of hydroxyapatite (HAp) for binder tungstate in 188W/188Re generator system

International Nuclear Information System (INIS)

Eni Hartati; Yati B Yuliyati; Duyeh Setiawan

2014-01-01

In this study, the synthesis of hydroxyapatite has been carried out through a process of precipitation of calcium hydroxide (Ca(OH) 2 ) with phosphoric acid (H 3 PO 4 ) based on acid base reaction process that produce crystalline solid and then it will be used for binder tungstate in 188 W/ 188 Re generator system. The purpose of this study were to characterize the results of synthesized hydroxyapatite and to determine the optimum conditions on generator 188 W/ 188 Re performance such as activation of the heating hydroxyapatite, pH of Na 2 WO 4 , reaction temperature, distribution coefficient and the adsorption capacity (adsorption coefficient) of hydroxyapatite. The characterization of synthesized hydroxyapatite was done using FTIR, XRD and SEM-EDAX, while the determination of the optimum condition of each parameters based on distribution coefficient and adsorption capacity hydroxyapatite using spectrophotometric method. The FTIR results of hydroxyapatite (Ca 10 (PO 4 ) 6 (OH) 2 ) showed the appearance of peaks in the O-H stretching wave number (υ) and 3434.9 cm -1 and 563.8 cm -1 , while the group PO 4 -3 is shown by the P-O bond in (υ) 1033.8 cm -1 . The XRD results indicate that hydroxyapatite had three peaks at 2θ region is 31,875° , 32,205° and 33,080°. Characterization by SEM showed columnar morphology with a particle size of 200 nm. The optimum conditions of each parameter obtained at hydroxyapatite heating temperature 100 °C, Na 2 WO 4 solution pH 3, and the reaction temperature of 60 °C, which gave result on distribution coefficients of 193.74 mL/g and adsorption capacity (adsorption coefficient) of 5.20 mg W/g HAp. (author)

Radiolabeled anti-EGFR-antibody improves local tumor control after external beam radiotherapy and offers theragnostic potential

International Nuclear Information System (INIS)

Koi, Lydia; Bergmann, Ralf; Brüchner, Kerstin; Pietzsch, Jens; Pietzsch, Hans-Jürgen; Krause, Mechthild

2014-01-01

Purpose: The effect of radioimmunotherapy (RIT) using the therapeutic radionuclide Y-90 bound to the anti-EGFR antibody cetuximab combined with external beam irradiation (EBRT) (EBRIT) on permanent local tumor control in vivo was examined. Methods: Growth delay was evaluated in three human squamous cell carcinoma models after RIT with [ 90 Y]Y-(CHX-A′′-DTPA) 4 -cetuximab (Y-90-cetuximab). The EBRT dose required to cure 50% of the tumors (TCD 50 ) for EBRT alone or EBRIT was evaluated in one RIT-responder (FaDu) and one RIT-non-responder (UT-SCC-5). EGFR expression and microenvironmental parameters were evaluated in untreated tumors, bioavailability was visualized by PET using ([ 86 Y]Y-(CHX-A′′-DTPA) 4 -cetuximab (Y-86-cetuximab) and biodistribution using Y-90-cetuximab. Results: In UT-SCC-8 and FaDu but not in UT-SCC-5 radiolabeled cetuximab led to significant tumor growth delay. TCD 50 after EBRT was significantly decreased by EGFR-targeted RIT in FaDu but not in UT-SCC-5. In contrast to EGFR expression, parameters of the tumor micromilieu and in particular the Y-90-cetuximab biodistribution or Y-86-cetuximab visualization in PET correlated with the responsiveness to RIT or EBRIT. Conclusion: EGFR-targeted EBRIT can improve permanent local tumor control compared to EBRT alone. PET imaging of bioavailability of labeled cetuximab appears to be a suitable predictor for response to EBRIT. This theragnostic approach should be further explored for clinical translation

Development of labelled biomolecules for targeted radiotherapy. Mexico

International Nuclear Information System (INIS)

Arteaga de Murphy, Consuelo

2000-01-01

The scope of the co-ordinated research project (Dec 15 1997) included the following activities: 1) develop coupling techniques using bifunctional chelating agents for monoclonal antibodies and peptides; 2) optimise radiolabelling procedures and reaction parameters using Sm-153 and Re-188; 3) investigate direct methods of labelling monoclonal antibodies and peptides with Re-188; 4) initiate animal distribution studies. The modifications specified for the period 1999/02/15 to 2000/02/14 are as follows: a) continue with the optimisation of Re-188-peptide labelling; b) continue with the work to prepare a kit; c) in-vivo and in-vitro studies; d) Lanreotide labelling. The group formed by researchers from several Mexican institutions have worked together and in different aspects of the CRP in order to fulfil the proposed aims

Elucidation of the critical epitope of an anti-EGFR monoclonal antibody EMab-134

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Mika K. Kaneko

2018-07-01

Full Text Available The epidermal growth factor receptor (EGFR is a type-1 transmembrane receptor tyrosine kinase, which activates the downstream signaling cascades in many tumors, such as oral and lung cancers. We previously developed EMab-134, a novel anti-EGFR monoclonal antibody (mAb, which reacts with endogenous EGFR-expressing cancer cell lines and normal cells independent of glycosylation in Western blotting, flow cytometry, and immunohistochemical analysis. EMab-134 showed very high sensitivity (94.7% to oral squamous cell carcinomas in immunohistochemical analysis. In this study, we performed enzyme-linked immunosorbent assay (ELISA, flow cytometry, and immunohistochemical analysis to determine the epitope of EMab-134. A blocking peptide (375–394 amino acids of EGFR neutralized the EMab-134 reaction against oral cancer cells in flow cytometry and immunohistochemistry. The minimum epitope of EMab-134 was found to be the 377-RGDSFTHTPP−386 sequence. Our findings can be applied for the production of more functional anti-EGFR mAbs that in turn can be used for antitumor treatments.

Formulation, radiopharmaceutical kinetics and dosimetry of the {sup 188}Re(V)-DMSA complex; Formulacion, radiofarmacocinetica y dosimetria del complejo {sup 188}Re(V)-DMSA

Energy Technology Data Exchange (ETDEWEB)

Garcia S, L; Ferro F, G [Departamento de Materiales Radiactivos. Instituto Nacional de Investigaciones Nucleares, C.P. 52045 Salazar, Estado de Mexico (Mexico); Murphy, C.A. de; Pedraza L, M [Departamento de Medicina Nuclear, Instituto Nacional de la Nutricion, Salvador Zubiran, Mexico D.F. (Mexico); Azorin N, J [Departamento de Fisica, Universidad Autonoma Metropolitana Iztapalapa, Mexico D.F. (Mexico)

1999-07-01

It was developed through experimental design (ANOVA), a formulation to prepare the {sup 188} Re(V)-Dmsa complex. Likewise, there were realized studies of radiopharmaceutical kinetics and internal dosimetry in animals, its normal and with induced tumors, considering an open bi compartmental model using the MIRD methodology. The {sup 188} Re(V)-Dmsa complex was obtained with a radiochemical purity greater than 95% incubating 30 min at 90 Centigrade under the following formulation: [SnCl{sub 2}] = 1.4 mg/ml, [ascorbic acid] = 0.5 mg/ml, p H = 2.0 - 3.0. The stability test of the formulation, shows that after 48 h of its preparation, does not produce radiolytic degradation neither chemical decomposition. The radiopharmaceutical kinetics data show an average residence time 7.2h, velocity constant {alpha} = 0.6508h{sup -1} and {beta} = 0.1046 h{sup -1} with an apparent distribution volume 6.9 l. The main elimination via was renal and it was observed osseous caption with an accumulated activity 522.049 {+-} 62 MBq h (residence time 14.1094 {+-} 1.69h). In according with the dosimetric calculations, by each 37 MBq injected, the equivalent dose at the tumor was 9.67{+-} 0.33 Sv/g, for an effective dose 0.292 {+-} 0.0017 mSv/MBq. The images obtained in the gamma camera of the mice with induced tumors, show that do not have significant accumulation in the metabolic organs. The caption in bone and in tumors induced of the {sup 188} Re(V)-Dmsa complex, show its potential for be used as a palliative agent for pain in patients with osseous metastasis and in the treatment of tumors of soft tissue. (Author)

Development of radioactively labelled cancer seeking biomolecules for targeted therapy

International Nuclear Information System (INIS)

Pillai, M.R.A.

2000-01-01

The work done towards the development of bifunctional chelating agents, modified peptide and their radiolabelling studies with 90 Y and 188 Re are reported. Bifunctional chelating agents DOTA, TETA and DAHPES were synthesised. DOTA-Lanreotide (Mauritius) was synthesised from lanreotide. 90 Y and 188 Re used in the studies were obtained from 90 Sr- 90 Y and 188 W- 188 Re generators. Complexation studies of DOTA and Mauritius with 90 Y and that of DAHPES and EC with 188 Re were carried out. Cell labelling of 90 Y-DOTA-Lanreotide with a cell line expressing somatostatin receptors was also carried out

The Dresden in-stent restenosis radiation trial (DIRRT) with liquid-filled 188Re balloon

International Nuclear Information System (INIS)

Kropp, J.; Runge, R.R.; Reynen, K.; Koeckeritz, U.; Schmeisser, A.; Strasser, R.H.

2002-01-01

Full text: In some studies intracoronary radiation therapy (IRT) to minimize the restenosis rate after PTCA proved to be effective. We evaluated the performance, safety and effectiveness of IRT with 188 Re-perrhenate filled into a standard PTCA balloon. This kind of IRT allows a self-centering homogenous dose distribution to the vessel wall. 107 patients (pts) with a mean age of 63 years (81 m, 26 fin) with in-stent restenosis (type B in 39 %, type C in 61 %) and proven ischemia were included. After routine re-PTCA with or without additional stent implantation a second standard balloon was placed into the PTCA area and filled with β - -emitting liquid 188 Re at 3 atm. Irradiation time was 525 ± 167 sec to achieve a dose of 30 Gy at 0.5 mm depth of the vessel wall. In only one procedure there was a disconnection of the 188 Re containing system and the catheter but no contamination of the cath table or lab was measured. In 16 coronaries 21 stents were additionally implanted. In the follow-up 4 stent thromboses (1 day, 37 days, 2 x 6 months) with subsequent myocardial infarction were noticed, all in pts with additionally implanted stents. 57 pts had control angiography after 4 to 6 months after therapy and 41 after one year. Restenosis (stenosis > 50 % of luminal diameter) was shown in 9 out of 12 pts (75 %) with additionally implanted stents but only in 4 out of 24 pts (17 %) with PTCA alone. Reocclusion was noticed in 3 (25 %) pts with additional stent but only in 1 pt (4 %) without. No re-restenosis occurred in 20 patients which were without finding after 6 months. Intracoronary radiation therapy (IRT) with β - -emitting liquid-filled 188 Re balloon is a safe and effective therapy method which might be used routinely. Long-term results seem satisfactory in a patient group with in-stent restenosis and high risk of re-restenosis. But the positive effect of irradiation is abolished if an additional stent after PTCA is needed. (author)

Molecular biomarkers of resistance to anti-EGFR treatment in metastatic colorectal cancer, from classical to innovation.

Science.gov (United States)

Giampieri, Riccardo; Scartozzi, Mario; Del Prete, Michela; Maccaroni, Elena; Bittoni, Alessandro; Faloppi, Luca; Bianconi, Maristella; Cecchini, Luca; Cascinu, Stefano

2013-11-01

Systematic dissection of the EGFR pathway was considered as the best way to identify putative markers of resistance to anti-EGFR therapies. This kind of approach leaves other, less known but by no means less important, putative mechanisms of resistance. We tried to shed some light on these mechanisms of resistance. We performed a research through Pubmed database of all published articles highlighting mechanisms of resistance to Cetuximab and Panitumumab based therapies, published in 2000-2012 period. We reviewed the "classical" molecular factors, extensively analyzed as predictive factors for efficacy to anti-EGFR therapy, such as K-ras, B-raf, and PI3K-mTOR-Akt, focusing on their predictive or prognostic value and on the controversial aspects of the biomarker analysis for clinical practice. On the second part we will then move on to other less known molecular markers, for the future understanding of biological mechanisms underlying anti-EGFR therapy resistance, such as non-canonical heterodimer candidates, microRNA, IGF1-IGF1R, HGF-cMET and secondary mutations of EGFR. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Development of radioactively labelled cancer seeking biomolecules for targeted therapy. India

International Nuclear Information System (INIS)

Pillai, M.R.A.

2000-01-01

The work done towards the development of bifunctional chelating agents, modified peptide and their radiolabelling studies with 90 Y and 188 Re are reported. Bifunctional chelating agents DOTA, TETA and DAHPES were synthesised. DOTA-Lanreotide (Mauritius) was synthesised from Lanreotide. 90 Y and 188 Re used in the studies were obtained from 90 Sr- 90 Y and 188 W- 188 Re generators. Complexation studies of DOTA and Mauritius with 90 Y and that of DAHPES and EC with 188 Re were carried out. Cell labelling of 90 Y-DOTA-Lanreotide with a cell line expressing somatostatin receptors was also carried out

Dexamethasone-(C21-phosphoramide)-[anti-EGFR]: molecular design, synthetic organic chemistry reactions, and antineoplastic cytotoxic potency against pulmonary adenocarcinoma (A549).

Science.gov (United States)

Coyne, Cody P; Narayanan, Lakshmi

2016-01-01

Corticosteroids are effective in the management of a variety of disease states, such as several forms of neoplasia (leukemia and lymphoma), autoimmune conditions, and severe inflammatory responses. Molecular strategies that selectively "target" delivery of corticosteroids minimize or prevents large amounts of the pharmaceutical moiety from passively diffusing into normal healthy cell populations residing within tissues and organ systems. The covalent immunopharmaceutical, dexamethasone-(C21-phosphoramide)-[anti-EGFR] was synthesized by reacting dexamethasone-21-monophosphate with a carbodiimide reagent to form a dexamethasone phosphate carbodiimide ester that was subsequently reacted with imidazole to create an amine-reactive dexamethasone-(C21-phosphorylimidazolide) intermediate. Monoclonal anti-EGFR immunoglobulin was combined with the amine-reactive dexamethasone-(C21-phosphorylimidazolide) intermediate, resulting in the synthesis of the covalent immunopharmaceutical, dexamethasone-(C21-phosphoramide)-[anti-EGFR]. Following spectrophotometric analysis and validation of retained epidermal growth factor receptor type 1 (EGFR)-binding avidity by cell-ELISA, the selective anti-neoplasic cytotoxic potency of dexamethasone-(C21-phosphoramide)-[anti-EGFR] was established by MTT-based vitality stain methodology using adherent monolayer populations of human pulmonary adenocarcinoma (A549) known to overexpress the tropic membrane receptors EGFR and insulin-like growth factor receptor type 1. The dexamethasone:IgG molar-incorporation-index for dexamethasone-(C21-phosphoramide)-[anti-EGFR] was 6.95:1 following exhaustive serial microfiltration. Cytotoxicity analysis: covalent bonding of dexamethasone to monoclonal anti-EGFR immunoglobulin did not significantly modify the ex vivo antineoplastic cytotoxicity of dexamethasone against pulmonary adenocarcinoma at and between the standardized dexamethasone equivalent concentrations of 10(-9) M and 10(-5) M. Rapid increases in

Dexamethasone-(C21-phosphoramide-[anti-EGFR]: molecular design, synthetic organic chemistry reactions, and antineoplastic cytotoxic potency against pulmonary adenocarcinoma (A549

Directory of Open Access Journals (Sweden)

Coyne CP

2016-08-01

Full Text Available Cody P Coyne,1 Lakshmi Narayanan2 1Department of Basic Sciences, 2Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Starkville, MS, USA Purpose: Corticosteroids are effective in the management of a variety of disease states, such as several forms of neoplasia (leukemia and lymphoma, autoimmune conditions, and severe inflammatory responses. Molecular strategies that selectively “target” delivery of corticosteroids minimize or prevents large amounts of the pharmaceutical moiety from passively diffusing into normal healthy cell populations residing within tissues and organ systems. Materials and methods: The covalent immunopharmaceutical, dexamethasone-(C21-phosphoramide-[anti-EGFR] was synthesized by reacting dexamethasone-21-monophosphate with a carbodiimide reagent to form a dexamethasone phosphate carbodiimide ester that was subsequently reacted with imidazole to create an amine-reactive dexamethasone-(C21-phosphorylimidazolide intermediate. Monoclonal anti-EGFR immunoglobulin was combined with the amine-reactive dexamethasone-(C21-phosphorylimidazolide intermediate, resulting in the synthesis of the covalent immunopharmaceutical, dexamethasone-(C21-phosphoramide-[anti-EGFR]. Following spectrophotometric analysis and validation of retained epidermal growth factor receptor type 1 (EGFR-binding avidity by cell-ELISA, the selective anti-neoplasic cytotoxic potency of dexamethasone-(C21-phosphoramide-[anti-EGFR] was established by MTT-based vitality stain methodology using adherent monolayer populations of human pulmonary adenocarcinoma (A549 known to overexpress the tropic membrane receptors EGFR and insulin-like growth factor receptor type 1. Results: The dexamethasone:IgG molar-incorporation-index for dexamethasone-(C21-phosphoramide-[anti-EGFR] was 6.95:1 following exhaustive serial microfiltration. Cytotoxicity analysis: covalent bonding of dexamethasone to monoclonal anti-EGFR immunoglobulin

On the Magnetic Properties of the K=1 Rotational Band in {sup 188}Re

Energy Technology Data Exchange (ETDEWEB)

Malmskog, S G; Hoejeberg, M

1967-05-15

The transitions in the decay of the 18.6 min {sup 188}Re isomer have been studied with a Ge(Li) detector. Two new weak gamma ray transitions of 156 and 169 keV were found and interpreted as cross-over transitions. From a delayed coincidence experiment using a double lens electron-electron coincidence spectrometer the half-life of the first excited 63.6 keV level in Re was determined as T{sub 1/2} = 56 {+-} 7 psec. The half lives of the first excited 2{sup +} levels in {sup 186}Os and {sup 188}Os were also measured and found to be 0.81 {+-} 0.03 nsec and 0.68 {+-} 0.03 nsec respectively.

Locoregional Confinement and Major Clinical Benefit of 188Re-Loaded CXCR4-Targeted Nanocarriers in an Orthotopic Human to Mouse Model of Glioblastoma.

Science.gov (United States)

Séhédic, Delphine; Chourpa, Igor; Tétaud, Clément; Griveau, Audrey; Loussouarn, Claire; Avril, Sylvie; Legendre, Claire; Lepareur, Nicolas; Wion, Didier; Hindré, François; Davodeau, François; Garcion, Emmanuel

2017-01-01

Gold standard beam radiation for glioblastoma (GBM) treatment is challenged by resistance phenomena occurring in cellular populations well prepared to survive or to repair damage caused by radiation. Among signals that have been linked with radio-resistance, the SDF1/CXCR4 axis, associated with cancer stem-like cell, may be an opportune target. To avoid the problem of systemic toxicity and blood-brain barrier crossing, the relevance and efficacy of an original system of local brain internal radiation therapy combining a radiopharmaceutical with an immuno-nanoparticle was investigated. The nanocarrier combined lipophilic thiobenzoate complexes of rhenium-188 loaded in the core of a lipid nanocapsule (LNC 188 Re) with a function-blocking antibody, 12G5 directed at the CXCR4, on its surface. The efficiency of 12G5-LNC 188 Re was investigated in an orthotopic and xenogenic GBM model of CXCR4-positive U87MG cells implanted in the striatum of Scid mice. We demonstrated that 12G5-LNC 188 Re single infusion treatment by convection-enhanced delivery resulted in a major clinical improvement in median survival that was accompanied by locoregional effects on tumor development including hypovascularization and stimulation of the recruitment of bone marrow derived CD11b- or CD68-positive cells as confirmed by immunohistochemistry analysis. Interestingly, thorough analysis by spectral imaging in a chimeric U87MG GBM model containing CXCR4-positive/red fluorescent protein (RFP)-positive- and CXCR4-negative/RFP-negative-GBM cells revealed greater confinement of DiD-labeled 12G5-LNCs than control IgG2a-LNCs in RFP compartments. Main conclusion: These findings on locoregional impact and targeting of disseminated cancer cells in tumor margins suggest that intracerebral active targeting of nanocarriers loaded with radiopharmaceuticals may have considerable benefits in clinical applications.

{sup 188}Re-HDD/lipiodol therapy for hepatocellular carcinoma: an activity escalation study

Energy Technology Data Exchange (ETDEWEB)

Lambert, Bieke; Vos, Filip de; Wiele, Christophe van de [Ghent University Hospital, Nuclear Medicine Division, Gent (Belgium); Bacher, Klaus; Thierens, Hubert [Ghent University, Department of Medical Physics, Gent (Belgium); Defreyne, Luc [Ghent University Hospital, Division of Interventional Radiology, Gent (Belgium); Vlierberghe, Hans van [Ghent University Hospital, Division of Gastroenterology, Gent (Belgium); Jeong, Jae Min [Seoul National University College of Medicine, Department of Nuclear Medicine, Cancer Research Institute, Seoul (Korea); Wang, Rong Fu [Beijing University, Department of Nuclear Medicine, Beijing (China); Meerbeeck, Jan van [Ghent University Hospital, Department of Respiratory Diseases, Gent (Belgium); Smeets, Peter [Ghent University Hospital, Department of Radiology, Gent (Belgium); Troisi, Roberto [Ghent University Hospital, Division of Abdominal Surgery and Liver Transplantation, Gent (Belgium)

2006-03-15

The aim of this study was to investigate the feasibility of administering increasing activities of {sup 188}Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ({sup 188}Re-HDD/lipiodol) for the treatment of hepatocellular carcinoma (HCC) in patients with well-compensated cirrhosis. The activity levels were increased by 1.1 GBq/step after a 6-week interval without unacceptable adverse events in at least five consecutive patients. Absorbed doses to the various organs were calculated according to the MIRD formalism, based on three gamma-scintigraphic studies. Response was assessed by means of MRI and alpha-fetoprotein (AFP) monitoring. Thirty-five treatments were carried out in 28 patients. Activities from 4.8 to 7.0 GBq {sup 188}Re-HDD/lipiodol were administered via a transfemoral catheter. The mean absorbed dose to the liver (including tumour) was 7.6{+-}2.2, 9.8{+-}4.9 and 15.2{+-}4.9 Gy for the 4.8-, 5.9- and 7.0-GBq groups, respectively. Treatment was well tolerated at all activity levels. Further escalation of the administered activity was not feasible owing to limitations related to the radiolabelling procedure. Response assessment on MRI showed partial response, stable disease and disease progression in 1, 28 and 2 assessable treatments, respectively. In 8 of 17 treatment sessions with an initially elevated AFP, a reduction ranging from 19% to 97% was observed 6 weeks later. (orig.)

Upregulation of HLA Class I Expression on Tumor Cells by the Anti-EGFR Antibody Nimotuzumab

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Greta Garrido

2017-10-01

Full Text Available Defining how epidermal growth factor receptor (EGFR-targeting therapies influence the immune response is essential to increase their clinical efficacy. A growing emphasis is being placed on immune regulator genes that govern tumor – T cell interactions. Previous studies showed an increase in HLA class I cell surface expression in tumor cell lines treated with anti-EGFR agents. In particular, earlier studies of the anti-EGFR blocking antibody cetuximab, have suggested that increased tumor expression of HLA class I is associated with positive clinical response. We investigated the effect of another commercially available anti-EGFR antibody nimotuzumab on HLA class I expression in tumor cell lines. We observed, for the first time, that nimotuzumab increases HLA class I expression and its effect is associated with a coordinated increase in mRNA levels of the principal antigen processing and presentation components. Moreover, using 7A7 (a specific surrogate antibody against murine EGFR, we obtained results suggesting the importance of the increased MHC-I expression induced by EGFR-targeted therapies display higher in antitumor immune response. 7A7 therapy induced upregulation of tumor MHC-I expression in vivo and tumors treated with this antibody display higher susceptibility to CD8+ T cells-mediated lysis. Our results represent the first evidence suggesting the importance of the adaptive immunity in nimotuzumab-mediated antitumor activity. More experiments should be conducted in order to elucidate the relevance of this mechanism in cancer patients. This novel immune-related antitumor mechanism mediated by nimotuzumab opens new perspectives for its combination with various immunotherapeutic agents and cancer vaccines.

Formulation, radiopharmaceutical kinetics and dosimetry of the 188Re(V)-DMSA complex

International Nuclear Information System (INIS)

Garcia S, L.; Ferro F, G.; Murphy, C.A. de; Pedraza L, M.; Azorin N, J.

1999-01-01

It was developed through experimental design (ANOVA), a formulation to prepare the 188 Re(V)-Dmsa complex. Likewise, there were realized studies of radiopharmaceutical kinetics and internal dosimetry in animals, its normal and with induced tumors, considering an open bi compartmental model using the MIRD methodology. The 188 Re(V)-Dmsa complex was obtained with a radiochemical purity greater than 95% incubating 30 min at 90 Centigrade under the following formulation: [SnCl 2 ] = 1.4 mg/ml, [ascorbic acid] = 0.5 mg/ml, p H = 2.0 - 3.0. The stability test of the formulation, shows that after 48 h of its preparation, does not produce radiolytic degradation neither chemical decomposition. The radiopharmaceutical kinetics data show an average residence time 7.2h, velocity constant α = 0.6508h -1 and β = 0.1046 h -1 with an apparent distribution volume 6.9 l. The main elimination via was renal and it was observed osseous caption with an accumulated activity 522.049 ± 62 MBq h (residence time 14.1094 ± 1.69h). In according with the dosimetric calculations, by each 37 MBq injected, the equivalent dose at the tumor was 9.67± 0.33 Sv/g, for an effective dose 0.292 ± 0.0017 mSv/MBq. The images obtained in the gamma camera of the mice with induced tumors, show that do not have significant accumulation in the metabolic organs. The caption in bone and in tumors induced of the 188 Re(V)-Dmsa complex, show its potential for be used as a palliative agent for pain in patients with osseous metastasis and in the treatment of tumors of soft tissue. (Author)

Country report: Cuba. Local Production of 90Y And 188Re Radionuclides and Development of Radiopharmaceuticals for Therapy

International Nuclear Information System (INIS)

Xiques, Abmel; Hernández, Ignacio; Leyva, René; Pérez, Marylaine; Alonso, Luis Michel; Zamora, Minelys

2010-01-01

During the first period of this CRP we could test an efficient and reliable generator system based on ion-chromatography to obtain 90 Y from its parent radionuclide 90 Sr. This production scheme for 90 Y was outlined in the previous CRP related with the development of generator technologies. Quality parameters such as trace metals that can potentially interfere in the labeling of biomoléculas, 90 Y recovery, 90 Sr/ 90 Y ratio and radiation dose to bed matrix were evaluated. The results showed that high recovery and radionuclidic purity could be obtained for 90 Y during its repeated separation from the 90 Sr cow. No replacement or treatment of the cow were necessary and low waste generation and 90 Sr losses less that 0.1% after each run were also observed during the present study. A Fab’ fragment was enzimatically produced and purified from the monoclonal antibody h-R3 (Nimotuzumab®). The fragment and the parent antibody were successfully conjugated with DOTA and labeled with 90 Y. The radioinmunoconjugate thus obtained also exhibited a good 24 h in-vitro stability in an excess of DTPA. A 90 Y radiocoloid was prepared in a cromic phosphate particle for radiosynoviorthesis with promising results in animal models. Two alumina based 188 W/ 188 Re generators were prepared and their eluates were used in the labeling of hR3-DOTA conjugates. Quality control and in vivo evaluation in comparison with 99m Tc-hR3 showed very good results and similar pattern of distribution and pharmacokinetic and will be used in clinical trials for cancer patients. (author)

Quantum-Dot-Based Theranostic Micelles Conjugated with an Anti-EGFR Nanobody for Triple-Negative Breast Cancer Therapy.

Science.gov (United States)

Wang, Yuyuan; Wang, Yidan; Chen, Guojun; Li, Yitong; Xu, Wei; Gong, Shaoqin

2017-09-13

A quantum-dot (QD)-based micelle conjugated with an anti-epidermal growth factor receptor (EGFR) nanobody (Nb) and loaded with an anticancer drug, aminoflavone (AF), has been engineered for EGFR-overexpressing cancer theranostics. The near-infrared (NIR) fluorescence of the indium phosphate core/zinc sulfide shell QDs (InP/ZnS QDs) allowed for in vivo nanoparticle biodistribution studies. The anti-EGFR nanobody 7D12 conjugation improved the cellular uptake and cytotoxicity of the QD-based micelles in EGFR-overexpressing MDA-MB-468 triple-negative breast cancer (TNBC) cells. In comparison with the AF-encapsulated nontargeted (i.e., without Nb conjugation) micelles, the AF-encapsulated Nb-conjugated (i.e., targeted) micelles accumulated in tumors at higher concentrations, leading to more effective tumor regression in an orthotopic triple-negative breast cancer xenograft mouse model. Furthermore, there was no systemic toxicity observed with the treatments. Thus, this QD-based Nb-conjugated micelle may serve as an effective theranostic nanoplatform for EGFR-overexpressing cancers such as TNBCs.

Structural considerations for functional anti-EGFR × anti-CD3 bispecific diabodies in light of domain order and binding affinity.

Science.gov (United States)

Asano, Ryutaro; Nagai, Keisuke; Makabe, Koki; Takahashi, Kento; Kumagai, Takashi; Kawaguchi, Hiroko; Ogata, Hiromi; Arai, Kyoko; Umetsu, Mitsuo; Kumagai, Izumi

2018-03-02

We previously reported a functional humanized bispecific diabody (bsDb) that targeted EGFR and CD3 (hEx3-Db) and enhancement of its cytotoxicity by rearranging the domain order in the V domain. Here, we further dissected the effect of domain order in bsDbs on their cross-linking ability and binding kinetics to elucidate general rules regarding the design of functional bsDbs. Using Ex3-Db as a model system, we first classified the four possible domain orders as anti-parallel (where both chimeric single-chain components are variable heavy domain (VH)-variable light domain (VL) or VL-VH order) and parallel types (both chimeric single-chain components are mixed with VH-VL and VL-VH order). Although anti-parallel Ex3-Dbs could cross-link the soluble target antigens, their cross-linking ability between soluble targets had no correlation with their growth inhibitory effects. In contrast, the binding affinity of one of the two constructs with a parallel-arrangement V domain was particularly low, and structural modeling supported this phenomenon. Similar results were observed with E2x3-Dbs, in which the V region of the anti-EGFR antibody clone in hEx3 was replaced with that of another anti-EGFR clone. Only anti-parallel types showed affinity-dependent cancer inhibitory effects in each molecule, and E2x3-LH (both components in VL-VH order) showed the most intense anti-tumor activity in vitro and in vivo . Our results showed that, in addition to rearranging the domain order of bsDbs, increasing their binding affinity may be an ideal strategy for enhancing the cytotoxicity of anti-parallel constructs and that E2x3-LH is particularly attractive as a candidate next-generation anti-cancer drug.

Radiation absorbed doses in the event of balloon rupture (BR) during endovascular brachytherapy (EB) using 188Re-perrhenate

International Nuclear Information System (INIS)

Angelides, S.; Hetherington, E.; Karolis, C.; Walker, B.; Jackson, T.; Knittel, T.; Friend, C.; Pitney, M.; Jepson, N.; Milross, C.; Lonergan, D.

2000-01-01

Full text: endovascular brachytherapy (EB) using liquid or solid radiation sources, is an effective emerging therapy for coronary artery disease. Liquid sources provide uniform radiation dose to the vessel wall. However the radiation burden in the unlikely event of BR is not insignificant. The aims of this study were to determine i) absorbed dose for various 188 Re radiopharmaceuticals in the event of BR, and ii) effects of thyroid uptake blocking agent, Lugol's iodine (Ll) and/or bladder catheterisation (BC). Dose calculations were based on MIRDOSE 3.1 with dynamic bladder model and MIRD Dose Estimate Report No.8 for 99 Tc m -pertechnetate, which has similar biokinetic properties to 188 Re-perrhenate. Normal renal function and a bladder voiding interval of 4.8h (1 minute with catheter) were assumed. BR was simulated ex-vivo by puncturing a Solaris angioplasty balloon filled with normal saline at 4 atm. LI, MAG3 and DTPA substantially reduces the radiation dose following BR, particularly to the thyroid, and BC reduces the bladder wall dose. Only the contents of the balloon leaked; 0.4 ml of the total volume of 1.8ml. As binding of 188 Re to ligands is cumbersome, we opted to use LI. Twenty five patients with in-stent re-stenosis have been treated using 188 Re-perrhenate (8 GBq/ml), with no BR. Copyright (2000) The Australian and New Zealand Society of Nuclear Medicine Inc

18-FDG-PET in pretherapeutical determination of extra medullary involvement prior to Re-188-antibody guided myeloablative therapy

International Nuclear Information System (INIS)

Hofmann, M.; Boerner, A.R.; Otto, D.; Knapp, W.H.; Hertenstein, B.

2002-01-01

Full text: In relapsed or refractory leukemia it is highly desirable to intensify the conditioning prior to allogenic bone mamarrow transplantation (BMT). Application of the 188-Re-labelled antibody BW 250/183 has proved to be feasible for internal radiation therapy of the bone marrow. Because the number of granulocytes (which express the CD66b antigen targeted) in extramedullary manifestations are usually low, the treatment of extramkedullary lesions will be not effective. This study deals with the pretherapeutical identification of patients with extramedullary involvement via 18-F-FDG-PET. 1-2 weeks prior scheduled 188-Re-therapy 12 patients underwent 18-F-FDG PET (dedicated PET scanner Siemens ECAT EXACT 47). Non physiological tracer accumulations were evaluated by means of SUV and consecutive morphological imaging (CT/MRI). 3 of 11 patients did show non physiological enrichment. 1 patient had enrichment in the upper mediastine, which was confirmed as extramedullary leukemia involvement by cytology. In CT scan these lesions had been identified as small lymphnodes (1-2 cm diameter). 2 Patients did show small lesions in the lung. In one patient they were confirmed to be active fungous infection (pos. sputum culture) and in the other patient they were regarded as regenerative residuals of previous known pneumonic infection not active now (neg. sputum cultures and neg. inflammation markers). 18-F-FDG PET is helpful of identifying extramedullary involvement and gives in addition information on the inflammatory status of patients prior to BMT. (author)

Effect of a 188 Re-SSS lipiodol/131I-lipiodol mixture, 188 Re-SSS lipiodol alone or 131I-lipiodol alone on the survival of rats with hepatocellular carcinoma.

Science.gov (United States)

Garin, Elienne; Rakotonirina, Hervé; Lejeune, Florence; Denizot, Benoit; Roux, Jerome; Noiret, Nicolas; Mesbah, Habiba; Herry, Jean-Yues; Bourguet, Patrick; Lejeune, Jean-Jacques

2006-04-01

It has been shown that the use of a cocktail of isotopes of different ranges of action leads to an increase in the effectiveness of metabolic radiotherapy. The purpose of the present study was to compare with a control group the effectiveness of three different treatments in rats bearing hepatocellular carcinoma (HCC), using (1) a mixture of lipiodol labelled with both I and Re, (2) lipiodol labelled with I alone and (3) lipiodol labelled with Re alone. Four groups were made up, each containing 14 rats with the N1-S1 tumour cell line. Group 1 received a mixture composed of 22 MBq of Re-SSS lipiodol and 7 MBq I-lipiodol. Group 2 received 14 MBq I-lipiodol. Group 3 received 44 MBq of Re-SSS lipiodol and group 4 acted as the control. The survival of the various groups was compared by a non-parametric test of log-rank, after a follow-up of 60, 180 and 273 days. Compared with the controls, the rats treated with a mixture of Re-SSS lipiodol and I-lipiodol show an increase in survival, but only from day 60 onwards (P=0.05 at day 60 and 0.13 at days 180 and 273). For the rats treated with I-lipiodol, there was a highly significant increase in survival compared with the controls at day 60, day 180 and day 273 (P=0.03, 0.04 and 0.04, respectively). There is no significant increase in survival for the rats treated with Re-SSS lipiodol, irrespective of the follow-up duration (P=0.53 at day 60, 0.48 at day 180, and 0.59 at day 273). In this study, I-lipiodol is the most effective treatment in HCC-bearing rats, because this is the only method that leads to a prolonged improvement of survival. These results cannot necessarily be extrapolated to humans because of the relatively small size and unifocal nature of the lesions in this study. It appears necessary to carry out a study in humans with larger tumours in order to compare these three treatments, particularly with a view to replacing I-labelled lipiodol by Re-labelled lipiodol. However, this study clearly demonstrated that

Development of freeze-dried kit for direct 99mTc -labeling of nimotuzumab to diagnose human EGFR positive tumors

International Nuclear Information System (INIS)

Toledo, Darien; Figueiras, Jenneby; Rojas, Gertrudis; León, Kalet; Gongora Bravo, Magdiel; Miguel Martínez, Antonio; Michel Alonso, Luis; Hernández, Ignacio; León, Mariela; Leyva, René; Hernández, Gerardo Ramses

2016-01-01

Epidermal growth factor receptor (EGFR), a 170 kDa transmembrane tyrosine kinase receptor which specifically binds epidermal growth factor (EGF) and transforming growth factor-a (TGFa) that are crucial in signaling cell proliferation, differentiation, and survival1. Overexpression of EGFR has been observed in breast cancer2, colorectal cancer, ovarian cancer, squamous cell lung carcinoma3 head and neck cancer4 and bladder cancer. Molecular imaging using radiopharmaceuticals directed towards EGFR could characterize the receptor status of tumors and thereby predict response to anti-EGFR agents for the treatment of cancer. Nimotuzumab is a humanized anti-EGFR monoclonal antibody5 designed to reduce immunogenicity and rate of clearance from the body6. Radiolabelled formulations of nimotuzumab would have applications for non-invasive imaging in order to characterize EGFR-positive tumors and thus to select patient populations that could benefit from therapy7, 8. The studies described in this work were designed to develop and evaluate the in vitro and in vivo the properties of a radiolabeled freeze dried kit of nimotuzumab and to determine its potential for radio immunodiagnostic applications. (author)

Development of radioactively labelled cancer seeking biomolecules for targeted radiotherapy

International Nuclear Information System (INIS)

Varvarigou, A.D.; Archimandritis, S.C.

2000-01-01

Within the framework of the above project we are studying the labelling of biomolecules, peptides and antibodies, with radionuclides emitting β - and γ radiation. More specifically, for the time being, we have investigated the labelling of peptides with Re-188 and of antibodies with Sm-153 and Re-188. The radiolabelled derivatives are further evaluated in vivo for possible application in Oncology. For these radiobiological studies we are trying to apply ectopic and orthotopic tumour animal models and to develop, in collaboration with other national and foreign institutes, proper imaging devices for small animal imaging

Diagnostic of tumours of epithelial origin with the monoclonal antibody IOR EGF/R3 murino

International Nuclear Information System (INIS)

Ramos, M.

1997-01-01

Despite of the advantages on anti tumoral therapy, the cancer of epithelial origin constitutes one of the first causes of death worldwide. That kind of tumors have a 10-30-fold overexpression of the epidermal growth factor receptor (EGFr). Monoclonal antibody ior egf/r3 is a lgG2a, which recognizes the epidermal growth factor receptor. The aim of the present work was the evaluate the diagnostic efficacy of the 99m Tc-labelled ior egf/r3 for the detection of epithelial derived tumors, its metastasis and its recurrences

Liquid kit for preparation of 188rhenium-etidronate

International Nuclear Information System (INIS)

Marczewski, Barbara; Dias, Carla Roberta; Moraes, Vanessa; Osso Junior, Joao Alberto

2005-01-01

The aim of this study was the preparation of a liquid kit for radiolabeling of 188 Re-HEDP (hydroxyethylidene diphosphonate). 188 Re was obtained from alumina based 188 W/ 188 Re generators. This paper reports the efficacy of a cold kit stored for more than two weeks, determined by the dependence of the radiolabeling yields of 188 Re-HEDP on the incubation time, reducing agent concentration, the effects of concentration of ligand, the p H of the reaction and the temperature. The cold kits showed a good stability when carrie-free rhenium-188 was added in the reaction mixture. (author)

Preclinical evaluation of isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu for folate receptor-positive tumor targeting.

Science.gov (United States)

Kim, Woo Hyoung; Kim, Chang Guhn; Kim, Myoung Hyoun; Kim, Dae-Weung; Park, Cho Rong; Park, Ji Yong; Lee, Yun-Sang; Youn, Hyewon; Kang, Keon Wook; Jeong, Jae Min; Chung, June-Key

2016-06-01

The purpose of the present study was to prepare isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu (folate-GGCE), and to evaluate the feasibility of their use for folate receptor (FR)-targeted molecular imaging and as theranostic agents in a mouse tumor model. Folate-GGCE was synthesized using solid-phase peptide synthesis and radiolabeled with Tc-99m or Re-188. Radiochemical characterization was performed by radio-high-performance liquid chromatography. The biodistribution of Tc-99m-folate-GGCE was studied, with or without co-injection of excess free folate, in mice bearing both FR-positive (KB cell) and FR-negative (HT1080 cell) tumors. Biodistribution of Re-188-folate-GGCE was studied in mice bearing KB tumors. Serial planar scintigraphy was performed in the dual tumor mouse model after intravenous injection of Tc-99m-folate-GGCE. Serial micro-single photon emission computed tomography/computed tomography (SPECT/CT) studies were performed, with or without co-injection of excess free folate, in the mouse tumor model after injection of Tc-99m-folate-GGCE or Re-188-folate-GGCE. The radiolabeling efficiency and radiochemical stability of Tc-99m- and Re-188-folate-GGCE were more than 95 % for up to 4 h after radiolabeling. Uptake of Tc-99m-folate-GGCE at 1, 2, and 4 h after injection in KB tumor was 16.4, 23.2, and 17.6 % injected dose per gram (%ID/g), respectively. This uptake was suppressed by 97.4 % when excess free folate was co-administered. Tumor:normal organ ratios at 4 h for blood, liver, lung, muscle, and kidney were 54.3, 25.2, 38.3, 97.8, and 0.3, respectively. Tumor uptake of Re-188-folate-GGCE at 2, 4, 8, and 16 h after injection was 17.4, 21.7, 24.1, and 15.6 %ID/g, respectively. Tumor:normal organ ratios at 8 h for blood, liver, lung, muscle, and kidney were 126.8, 21.9, 54.8, 80.3, and 0.4, respectively. KB tumors were clearly visualized at a high intensity using serial scintigraphy and micro-SPECT/CT in mice injected with Tc-99m- or Re

S values at voxels level for 188Re and 90Y calculated with the MCNP-4C code

International Nuclear Information System (INIS)

Coca, M.A.; Torres, L.A.; Cornejo, N.; Martin, G.

2008-01-01

Full text: MIRD formalism at voxel level has been suggested as an optional methodology to perform internal radiation dosimetry calculation during internal radiation therapy in Nuclear Medicine. Voxel S values for Y 90 , 131 I, 32 P, 99m Tc and 89 Sr have been published to different sizes. Currently, 188 Re has been proposed as a promising radionuclide for therapy due to its physical features and availability from generators. The main objective of this work was to estimate the voxel S values for 188 Re at cubical geometry using the MCNP-4C code for the simulations of radiation transport and energy deposition. Mean absorbed dose to target voxels per radioactive decay in a source voxel were estimated and reported for 188 Re and Y 90 . A comparison of voxel S values computed with the MCNP code and the data reported in MIRD Pamphlet 17 for 90 Y was performed in order to evaluate our results. (author)

MAXIMIZATION OF DNA DAMAGE TO MGMT(+ EGFR(+ GBM CELLS USING OPTIMAL COMBINATION OF TEMOZOLOMIDE-ANTI EGFR MONOCLONAL ANTIBODY NIMOTUZUMAB

Directory of Open Access Journals (Sweden)

M. A. M. Inggas

2015-09-01

Full Text Available Background: Glioblastoma multiforme (GBM is the most aggressive primary brain tumor in adultswith dismal prognosis due to the unavailability of an effective therapy. Up to now, there had been no definitive studies published on EGFR inhibition therapy as a chemosensitizer for GBM therapy using Temozolomide (TMZ. This study aims to reveal the most effective method and timing to administer TMZ-anti EGFR targeted therapy which causes maximal DNA damage on GBM cells.Methods: Various regimens of anti EGFR monoclonal antibody Nimotuzumab (NMZ was administered in different combinations with TMZ, performed on U87MG MGMT(+ EGFR(+ cells. The effectiveness of the combinations were evaluated by measuring yH2AX levels which reflects the degree of DNA damage. One-way Anova and LSD tests were performed to determine the effects of each treatment with p<0.05. Results and discussion: the mean SD of yH2AX of each treatment was: 11,90±1,25 for the control group; 29.33±1.91 for NMZ alone; 28.13±1.58 for TMZ alone; 41.53±3.51 for concurrent use; 35.67 ±2.65 for NMZ after 24 hours TMZ; 31.87±2.94 for NMZ after 48 hours TMZ; 39.57±4.2 for TMZ after 24 hours NMZ; and 35.93 ±3.56 for TMZ after 48 hours NMZ. The administration of TMZ concurrent with or after 24 hours NMZ gives the highest amount of DNA damage to GBM cells. Conclusion: The administration of Nimotuzumab targeted therapy up to 24 hours before Temozolomide chemotherapy has been proven to be effective in maximizing the amount of DNA damage done to GBM cells in vitro. 

Development of radioactively labelled cancer seeking biomolecules for targeted radiotherapy. Greece

International Nuclear Information System (INIS)

Varvarigou, Alexandra D.; Archimandritis, Spyridon C.

2000-01-01

Within the framework of the above project we are studying the labelling of biomolecules, peptides and antibodies, with radionuclides emitting β - and γ radiation. More specifically, for the time being, we have investigated the labelling of peptides with Re-188 and of antibodies with Sm-153 and Re-188. The radiolabelled derivatives are further evaluated in vivo for possible application in Oncology. For these radiobiological studies we are trying to apply ectopic and orthotopic tumour animal models and to develop, in collaboration with other national and foreign institutes, proper imaging devices for small animal imaging

S values at voxels level for 188Re and 90Y calculated with the MCNP-4C code

International Nuclear Information System (INIS)

Coca Perez, Marco Antonio; Torres Aroche, Leonel Alberto; Cornejo, Nestor; Martin Hernandez, Guido

2003-01-01

The main objective of this work was estimate the voxels S values for 188 Re at cubical geometry using the MCNP-4C code for the simulation of radiation transport and energy deposition. Mean absorbed dose to target voxels per radioactive decay in a source voxels were estimated and reported for 188 Re and Y 90 . A comparison of voxels S values computed with the MCNP code the data reported in MIRD pamphlet 17 for 90 Y was performed in order to evaluate our results

Risk of fatigue in cancer patients receiving anti-EGFR monoclonal antibodies: results from a systematic review and meta-analysis of randomized controlled trial.

Science.gov (United States)

Zhu, Jianhong; Zhao, Wenxia; Liang, Dan; Li, Guocheng; Qiu, Kaifeng; Wu, Junyan; Li, Jianfang

2018-04-01

To evaluate the association between fatigue and anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MAbs), we conducted the first meta-analysis to access the incidence and risk of fatigue associated with anti-EGFR MAbs. Electronic databases were searched for randomized controlled trials (RCTs) published up to February 2017. Eligible studies were selected according to PRISMA statement. Incidence rates, risk ratio (RRs), and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models. Outcomes of quality were summarized in accordance with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology. Thirty-five RCTs (including 15,622 patients) were included; median follow-up ranged from 8.1 to 71.4 months, and the fatigue events were recorded and graded according to the Common Toxicity Criteria for Adverse Events version 2.0 or 3.0 in most of the included trials. For patients receiving anti-EGFR MAbs, the overall incidence of all-grade and high-grade fatigue was 54.1% and 10.5%, respectively. Compared with control, anti-EGFR MAbs significantly increased the risk of all-grade fatigue (RR 1.10, 95% CI, 1.05-1.14, moderate-quality evidence) and high-grade fatigue (RR 1.31, 95% CI, 1.19-1.45, moderate-quality evidence). No significant differences among subgroup analyses (anti-EGFR MAbs, tumor type, and median follow-up) on high-grade fatigue were observed. No evidence of publication bias was observed. The present study suggested that anti-EGFR MAbs may increase the risk of fatigue in cancer patients.

Liquid kit for preparation of {sup 188}rhenium-etidronate

Energy Technology Data Exchange (ETDEWEB)

Marczewski, Barbara; Dias, Carla Roberta; Moraes, Vanessa; Osso Junior, Joao Alberto [Instituto de Pesquisas Energeticas e Nucleares (IPEN-CNEN/SP), SP (Brazil). Centro de Radiofarmacia]. E-mail: baszot@gmail.com

2005-10-15

The aim of this study was the preparation of a liquid kit for radiolabeling of {sup 188} Re-HEDP (hydroxyethylidene diphosphonate). {sup 188} Re was obtained from alumina based {sup 188} W/{sup 188} Re generators. This paper reports the efficacy of a cold kit stored for more than two weeks, determined by the dependence of the radiolabeling yields of {sup 188} Re-HEDP on the incubation time, reducing agent concentration, the effects of concentration of ligand, the p H of the reaction and the temperature. The cold kits showed a good stability when carrie-free rhenium-188 was added in the reaction mixture. (author)

Role of 188Re(V)DMSA in the diagnosis and therapy of medullary thyroid carcinoma: a pilot study in an animal model

International Nuclear Information System (INIS)

Learoyd, D.L.; Roach, P.J.; Snowdon, G.M.; Dadachova, K.; Moreau, A.M.; Robinson, B.G.

1999-01-01

Full text: 99 Tc m (V)DMSA has been reported to be highly sensitive in the diagnosis of medullary thyroid cancer (MTC). Rhenium-188, a beta emitter, has potential for therapy of MTC. However, initial studies with 188 Re indicate high renal uptake which may interfere with potential therapeutic applications of this radiopharmaceutical. A modified radiolabelling method has been shown to reduced the renal uptake of 188 Re(V)DMSA in control animals. The aims of this study were to determine whether there is uptake of modified 188 Re(V)DMSA in nude mice injected with an MTC cell line and whether there is potential for MTC therapy. Two groups of mice were injected in the left flank (SC) with TT cell line, and in mice showing tumour growth a low-dose (400 kBq) of 188 Re(V)DMSA was injected via a tail vein 8 weeks later. Biodistribution was performed on several mice and several others were given 'therapy' injections (8 MBq) to determine whether tumour shrinkage could be objectively observed. Tracer uptake was highest in bone and kidneys but tumour uptake was relatively low. However, no new tumour growth was seen in any of the mice subsequent to therapy injections and 1 mouse showed complete remission within 5 weeks of injection. Further animal and human studies will need to be performed to determine the potential role of this modified 118 Re(V)DMSA in patients with MTC

Country report: Cuba. Local Production of {sup 90}Y And {sup 188}Re Radionuclides and Development of Radiopharmaceuticals for Therapy

Energy Technology Data Exchange (ETDEWEB)

Xiques, Abmel; Hernández, Ignacio; Leyva, René; Pérez, Marylaine; Alonso, Luis Michel; Zamora, Minelys [Centro de Isotopos (CENTIS) (Cuba)

2010-07-01

During the first period of this CRP we could test an efficient and reliable generator system based on ion-chromatography to obtain {sup 90}Y from its parent radionuclide {sup 90}Sr. This production scheme for {sup 90}Y was outlined in the previous CRP related with the development of generator technologies. Quality parameters such as trace metals that can potentially interfere in the labeling of biomoléculas, {sup 90}Y recovery, {sup 90}Sr/{sup 90}Y ratio and radiation dose to bed matrix were evaluated. The results showed that high recovery and radionuclidic purity could be obtained for {sup 90}Y during its repeated separation from the {sup 90}Sr cow. No replacement or treatment of the cow were necessary and low waste generation and {sup 90}Sr losses less that 0.1% after each run were also observed during the present study. A Fab’ fragment was enzimatically produced and purified from the monoclonal antibody h-R3 (Nimotuzumab®). The fragment and the parent antibody were successfully conjugated with DOTA and labeled with {sup 90}Y. The radioinmunoconjugate thus obtained also exhibited a good 24 h in-vitro stability in an excess of DTPA. A {sup 90}Y radiocoloid was prepared in a cromic phosphate particle for radiosynoviorthesis with promising results in animal models. Two alumina based {sup 188}W/{sup 188}Re generators were prepared and their eluates were used in the labeling of hR3-DOTA conjugates. Quality control and in vivo evaluation in comparison with {sup 99m}Tc-hR3 showed very good results and similar pattern of distribution and pharmacokinetic and will be used in clinical trials for cancer patients. (author)

Dual-Color Fluorescence Imaging of EpCAM and EGFR in Breast Cancer Cells with a Bull's Eye-Type Plasmonic Chip.

Science.gov (United States)

Izumi, Shota; Yamamura, Shohei; Hayashi, Naoko; Toma, Mana; Tawa, Keiko

2017-12-19

Surface plasmon field-enhanced fluorescence microscopic observation of a live breast cancer cell was performed with a plasmonic chip. Two cell lines, MDA-MB-231 and Michigan Cancer Foundation-7 (MCF-7), were selected as breast cancer cells, with two kinds of membrane protein, epithelial cell adhesion molecule (EpCAM) and epidermal growth factor receptor (EGFR), observed in both cells. The membrane proteins are surface markers used to differentiate and classify breast cancer cells. EGFR and EpCAM were detected with Alexa Fluor ® 488-labeled anti-EGFR antibody (488-EGFR) and allophycocyanin (APC)-labeled anti-EpCAM antibody (APC-EpCAM), respectively. In MDA-MB231 cells, three-fold plus or minus one and seven-fold plus or minus two brighter fluorescence of 488-EGFR were observed on the 480-nm pitch and the 400-nm pitch compared with that on a glass slide. Results show the 400-nm pitch is useful. Dual-color fluorescence of 488-EGFR and APC-EpCAM in MDA-MB231 was clearly observed with seven-fold plus or minus two and nine-fold plus or minus three, respectively, on the 400-nm pitch pattern of a plasmonic chip. Therefore, the 400-nm pitch contributed to the dual-color fluorescence enhancement for these wavelengths. An optimal grating pitch of a plasmonic chip improved a fluorescence image of membrane proteins with the help of the surface plasmon-enhanced field.

Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study.

Science.gov (United States)

Shinozaki, Eiji; Yoshino, Takayuki; Yamazaki, Kentaro; Muro, Kei; Yamaguchi, Kensei; Nishina, Tomohiro; Yuki, Satoshi; Shitara, Kohei; Bando, Hideaki; Mimaki, Sachiyo; Nakai, Chikako; Matsushima, Koutatsu; Suzuki, Yutaka; Akagi, Kiwamu; Yamanaka, Takeharu; Nomura, Shogo; Fujii, Satoshi; Esumi, Hiroyasu; Sugiyama, Masaya; Nishida, Nao; Mizokami, Masashi; Koh, Yasuhiro; Abe, Yukiko; Ohtsu, Atsushi; Tsuchihara, Katsuya

2017-11-07

Patients with BRAF V600E -mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAF V600E (BRAF non-V600E mutations) contribute to anti-EGFR antibody resistance. This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort. In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAF V600E (6.0%), and 7 patients with BRAF non-V600E mutations (4.7%), respectively. The response rates in RAS, BRAF V600E , and BRAF non-V600E were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAF non-V600E mutations was 2.4 months, similar to that in RAS or BRAF V600E mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months). Although BRAF non-V600E mutations identified were a rare and unestablished molecular subtype, certain BRAF non-V600E mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.

Nuclear EGFR as a molecular target in cancer

International Nuclear Information System (INIS)

Brand, Toni M.; Iida, Mari; Luthar, Neha; Starr, Megan M.; Huppert, Evan J.; Wheeler, Deric L.

2013-01-01

The epidermal growth factor receptor (EGFR) has been one of the most targeted receptors in the field of oncology. While anti-EGFR inhibitors have demonstrated clinical success in specific cancers, most patients demonstrate either intrinsic or acquired resistance within one year of treatment. Many mechanisms of resistance to EGFR inhibitors have been identified, one of these being attributed to alternatively localized EGFR from the cell membrane into the cell’s nucleus. Inside the nucleus, EGFR functions as a co-transcription factor for several genes involved in cell proliferation and angiogenesis, and as a tyrosine kinase to activate and stabilize proliferating cell nuclear antigen and DNA dependent protein kinase. Nuclear localized EGFR is highly associated with disease progression, worse overall survival in numerous cancers, and enhanced resistance to radiation, chemotherapy, and the anti-EGFR therapies gefitinib and cetuximab. In this review the current knowledge of how nuclear EGFR enhances resistance to cancer therapeutics is discussed, in addition to highlighting ways to target nuclear EGFR as an anti-cancer strategy in the future

(188)Re-SSS/Lipiodol: Development of a Potential Treatment for HCC from Bench to Bedside.

Science.gov (United States)

Lepareur, Nicolas; Ardisson, Valérie; Noiret, Nicolas; Garin, Etienne

2012-01-01

Hepatocellular carcinoma (HCC) is the 5th most common tumour worldwide and has a dark prognosis. For nonoperable cases, metabolic radiotherapy with Lipiodol labelled with β-emitters is a promising therapeutic option. The Comprehensive Cancer Centre Eugène Marquis and the National Graduate School of Chemistry of Rennes (ENSCR) have jointly developed a stable and efficient labelling of Lipiodol with rhenium-188 (E(βmax) = 2.1 MeV) for the treatment of HCC. The major "milestones" of this development, from the first syntheses to the recent first injection in man, are described.

Animal experiment on 188Re-radioactive nanometre particle esophageal stent

International Nuclear Information System (INIS)

Chu Jianjun; Yang Bo; Zhao Difei; Wang Mingzhi; Sun Liang; Jiang Wei

2004-01-01

Objective: To investigate the mechanism and clinical reliability of applying 188 Re-radioactive nanometre particle esophageal stent. Methods: An elastic meshed esophageal stent made of double membranous nickel-titanium alloy and loaded with 188 Re-radioactive nanometre particles was used . The stent was introduced into the esophagus of eight experimental pigs and fixed in place. Two pigs served as controls. With the pig aneasthetized, the stent with good expandability was placed in the proper position. Radioactive MBq was applied to the 8 experiment pigs while the two control pigs received only the stent without the radioactive material. Three hours after the insertion of the stent, the pigs were allowed to feed, without any choking observed. Results: Seven days after the treatment of pathologic experiment pigs showed infla mmatory celluar infilfration, congestion and edema in the mucosa and submucous layer. After 21 days, some parts of the esophageal mucosa showed thickening of the vascular layer of the blood vessels and scanty fibrous hyperplasia. Seven days after application of larger dose of 259 MBq stent, pathology examination carried out in the experiment pigs showed extensive infla mmatory cellular infilfration, edema and congestion in the muscles and submucosa, and patch-like necrosis. Twenty-one days after application, repairing fibrous hyperplasia appeared. In the control pigs, not even any traumatic damage was observed. Periodic checking of the stool did not show any leakage of radioactivity and there was no displacement of the stents as confirmed by X-ray exam. Conclusions: The stent is effective to maintain an unobstructed passage of food . The loaded radioactive particles can be concentrated in the target area and adjusted by a body surface magnetic modulation and inhibit the intraluminal epithelial growth of esophageal mucosa without any severe radiation reaction or damage. It is quite promising to resolve the obstruction of advanced esophageal

Interim report on intrathoracic radiotherapy of human small-cell lung carcinoma in nude mice with Re-188-RC-160, a radiolabeled somatostatin analogue

International Nuclear Information System (INIS)

Zamora, P.O.; Bender, H.; Biersack, H.J.; Knapp, F.F. Jr.

1995-01-01

The purpose of this study was to evaluate the therapeutic efficacy of Re-188-RC-160 in experimental models of human small cell lung carcinomas which mimic the clinical presentation. In the experimental model, cells from the human small cell lung carcinoma cell line NCI-H69 cells were inoculated into the thoracic cavity of athymic mice and rats. Subsequently, the biodistribution of Re-188-RC-160 after injection into the pleural cavity, a radiolabeled somatostatin analogue, was monitored as was the effect on the subsequent growth of tumors. The results presented here, and which are a part of a larger series of studies, suggest that Re-188-RC-160 can be effectively used in this animal model to restrict the growth of small cell lung carcinoma in the thoracic cavity

Nanobiopolymer for direct targeting and inhibition of EGFR expression in triple negative breast cancer.

Directory of Open Access Journals (Sweden)

Satoshi Inoue

Full Text Available Treatment options for triple negative breast cancer (TNBC are generally limited to cytotoxic chemotherapy. Recently, anti-epidermal growth factor receptor (EGFR therapy has been introduced for TNBC patients. We engineered a novel nanobioconjugate based on a poly(β-L-malic acid (PMLA nanoplatform for TNBC treatment. The nanobioconjugate carries anti-tumor nucleosome-specific monoclonal antibody (mAb 2C5 to target breast cancer cells, anti-mouse transferrin receptor (TfR antibody for drug delivery through the host endothelial system, and Morpholino antisense oligonucleotide (AON to inhibit EGFR synthesis. The nanobioconjugates variants were: (1 P (BioPolymer with AON, 2C5 and anti-TfR for tumor endothelial and cancer cell targeting, and EGFR suppression (P/AON/2C5/TfR, and (2 P with AON and 2C5 (P/AON/2C5. Controls included (3 P with 2C5 but without AON (P/2C5, (4 PBS, and (5 P with PEG and leucine ester (LOEt for endosomal escape (P/mPEG/LOEt. Drugs were injected intravenously to MDA-MB-468 TNBC bearing mice. Tissue accumulation of injected nanobioconjugates labeled with Alexa Fluor 680 was examined by Xenogen IVIS 200 (live imaging and confocal microscopy of tissue sections. Levels of EGFR, phosphorylated and total Akt in tumor samples were detected by western blotting. In vitro western blot showed that the leading nanobioconjugate P/AON/2C5/TfR inhibited EGFR synthesis significantly better than naked AON. In vivo imaging revealed that 2C5 increased drug-tumor accumulation. Significant tumor growth inhibition was observed in mice treated with the lead nanobioconjugate (1 [P = 0.03 vs. controls; P<0.05 vs. nanobioconjugate variant (2]. Lead nanobioconjugate (1 also showed stronger inhibition of EGFR expression and Akt phosphorylation than other treatments. Treatment of TNBC with the new nanobioconjugate results in tumor growth arrest by inhibiting EGFR and its downstream signaling intermediate, phosphorylated Akt. The nanobioconjugate

Fluorescent Affibody Molecule Administered In Vivo at a Microdose Level Labels EGFR Expressing Glioma Tumor Regions.

Science.gov (United States)

de Souza, Ana Luiza Ribeiro; Marra, Kayla; Gunn, Jason; Samkoe, Kimberley S; Hoopes, P Jack; Feldwisch, Joachim; Paulsen, Keith D; Pogue, Brian W

2017-02-01

Fluorescence guidance in surgical oncology provides the potential to realize enhanced molecular tumor contrast with dedicated targeted tracers, potentially with a microdose injection level. For most glioma tumors, the blood brain barrier is compromised allowing some exogenous drug/molecule delivery and accumulation for imaging. The aberrant overexpression and/or activation of epidermal growth factor receptor (EGFR) is associated with many types of cancers, including glioblastoma, and so the use of a near-infrared (NIR) fluorescent molecule targeted to the EGFR receptor provides the potential for improving tumor contrast during surgery. Fluorescently labeled affibody molecule (ABY-029) has high EGFR affinity and high potential specificity with reasonably fast plasma clearance. In this study, ABY-29 was evaluated in glioma versus normal brain uptake from intravenous injection at a range of doses, down to a microdose injection level. Nude rats were inoculated with the U251 human glioma cell line in the brain. Tumors were allowed to grow for 3-4 weeks. ABY-029 fluorescence ex vivo imaging of brain slices was acquired at different time points (1-48 h) and varying injection doses from 25 to 122 μg/kg (from human protein microdose equivalent to five times microdose levels). The tumor was most clearly visualized at 1-h post-injection with 8- to 16-fold average contrast relative to normal brain. However, the tumor still could be identified after 48 h. In all cases, the ABY-029 fluorescence appeared to localize preferentially in EGFR-positive regions. Increasing the injected dose from a microdose level to five times, a microdose level increased the signal by 10-fold, and the contrast was from 8 to 16, showing that there was value in doses slightly higher than the microdose restriction. Normal tissue uptake was found to be affected by the tumor size, indicating that edema was a likely factor affecting the expected tumor to normal tissue contrast. These results suggest

Beta Radiation exposure of medical personnel during vascular brachytherapy with Re-188

International Nuclear Information System (INIS)

Moka, D.; Baer, F.; Barth, I.; Rimpler, A.

2002-01-01

Intracoronary radiation is currently considered a promising breakthrough approach for preventing restenosis after angioplasty and stenting in patients with severe coronary artery disease. For the therapy of in-stent-restenosis vascular irradiation using balloon catheters filled with liquid radioisotopes provide excellent homogeneity due to the artery stenosis morphology. The radionuclide normally used is a Re-188 solutions (E β ,max=2,12 MeV). To achieve a sufficient dose in the stenosed artery wall (30 Gy in 0.5 mm wall depth) in a tolerable time-scale very high specific activities (>5-10 GBq/ml) of the isotope are necessary. During the preparation of the radioactive solution and the application at the patient very short distances between the source of the radiation and the skin of the doctors for cardiology / nuclear medicine are possible, especially when manipulations at the balloon catheter during the radiation are necessary. In addition, a severe risk of contamination exists. A further problem is that in hospitals often no or insufficient dosimeters for beta radiation are available. Occupational radiation exposure of the personnel was determined at the preparation of the Re-188 solution, the therapy itself and the waste management. The partial body exposure, i. e. the dose of the skin at the hands due to beta radiation, was determined with very sensitive thin-layer thermoluminescence dosimeters (TLD). During a preparation, intracoronary radiation and waste management of the Re-188-perrhenate solution using normal radiation shielding first measurements resulted din more than 500 mSv per working day at the fingertips. This extreme high radiation exposure of the personnel were mainly due to direct radiation by touching the evacuated balloon catheter (only residual radionuclides left). to reduced radiation we performed several additional radiation protection measures. The consequent use of plastic shielding of the source, the use of a semiautomatic preparation

3D dosimetry study of 188Re liquid balloon for intravascular brachytherapy using BANG polymer gel dosemeters

International Nuclear Information System (INIS)

Wuu, S.; Schiff, P.B.; Maryanski, M.; Liu, T.; Borzillary, S.; Weinberger, J.

2002-01-01

It has been suggested that the combination of intravascular brachytherapy and coronary stent implantation may result in further reduction of restenosis after percutaneous balloon angioplasty. The use of an angioplasty balloon filled with a P 188 Re liquid beta source for intravascular brachytherapy provides the advantage of accurate source positioning and uniform dose distribution to the coronary vessel wall. The effect of source edge and stent on the dose distribution of the target tissue may be clinically important. In BANG gels, the absorbed radiation produces free-radical chain polymerisation of acrylic monomers that are initially dissolved in the gel. The number of polymer particles is proportional to the absorbed dose. In this study, 3D dose distributions are presented for 188 Re balloons, with and without stents, using a prototype He-Ne laser CT scanner and the proprietary BANG polymer gel dosemeters. (author)

Country report: Serbia. Development, Preparing and Quality Assurance of Radiopharmaceuticals Based on 188Re and 90Y for Radionuclide Therapy: The Possibilities for their Production in Laboratory for Radioisotopes, Ins «Vinča»

International Nuclear Information System (INIS)

Djokić, Divna

2010-01-01

The main object of the research planed for this project was to optimize the procedures for the 90 Y and 188 Re labelling of different compounds as well as their in vitro and in vivo evaluation. The work has been involved setting up the facilities, standardization of preparing protocols, and improving existing quality assurance/quality control (QA/QC) procedures in order to supply reliable products to the national nuclear medicine community

Re-purification of labelled ferritin antigen with HPLC

International Nuclear Information System (INIS)

Zhang Haoyi; Jin Lichun

2002-01-01

Objective: To improve the quality of long-term stored labelled ferritin antigen with HPLC. Methods: The antigen was analyzed and purified with HPLC and again analyzed with RIA afterwards. Results: Ferritin antigen underwent significant polymerization after long-term (aggregation) storage. After re-purification with HPLC, its immuno-activity and labelled specific radioactivity were both significantly improved. Conclusion: Quality of stored ferritin RIA kit could be greatly improved after re-purification with HPLC

Active and passive vectorization of technetium99m and 188rhenium radiopharmaceuticals for medical imaging and radiotherapy

International Nuclear Information System (INIS)

Lepareur, N.

2003-11-01

Research for new molecules for nuclear medicine is a field in constant development. Over the past few years, development of new radiopharmaceuticals for radiotherapy has renewed interest for rhenium chemistry. Indeed, its two isotopes 186 Re and 188 Re, owing to their ideal properties and their similitude with 99m Tc, which is widely used as a radiotracer for diagnostic imaging, seem very promising for the preparation of radiopharmaceuticals. In the first part of this manuscript, the synthesis of rhenium and technetium-99 complexes, [M(RPhCS3)2(RPhCS2)] (M = Re, Tc), is described. The preparation of technetium 99m based radiopharmaceuticals, analogues to the pondered complexes, is also described. The stability/reactivity of these complexes has been studied by exchange reactions with potential ligands, specially dithiocarbamates, and also by UV-visible absorption spectroscopy and thermogravimetry. The reactivity of the complexes towards dithiocarbamates leads to the possibility to bind biomolecules to the metallic core, via the dithiocarbamate moiety. This method represents a potential alternative to current ones using the so-called bifunctional approach. In the second part of this manuscript, a new kit formulation for the 188 Re labeling of lipiodol is described, using a complex analogous to those described in the previous part. The labeled oil is a potential cure for hepatocellular carcinoma. The in vitro and in vivo stability of this 188 Re-SSS lipiodol and of its analogue 99m Tc-SSS lipiodol has been studied, and also their in vivo behavior in healthy pigs. This study has shown the quasi-exclusive hepatic fixation of the radiopharmaceutical, and has proven its good stability. Its selectivity for tumors remains to be shown before trying it on humans. (author)

Long-term survival after a favorable response to anti-EGFR antibody plus chemotherapy to treat bone marrow metastasis: a case report of KRAS-wildtype rectal cancer

Directory of Open Access Journals (Sweden)

Nakamura S

2017-02-01

Full Text Available Sho Nakamura, Tadahisa Fukui, Shuhei Suzuki, Hiroyuki Takeda, Kaname Watanabe, Takashi Yoshioka Department of Clinical Oncology, Yamagata University Faculty of Medicine, Yamagata, Japan Abstract: Bone marrow metastasis is a rare consequence of colorectal cancer that results in a poor prognosis; few reports describe a favorable response to doublet chemotherapy combined with targeted therapy, which is currently the standard treatment. We experienced a case where anti-epidermal growth factor receptor (EGFR antibody produced a marked anti-tumor response to bone marrow metastasis that led to long-term survival. A 51-year-old man was diagnosed with a primary KRAS-wildtype rectal cancer with multiple metastases, including the bone marrow. Disease control was achieved for 10.8 months following chemotherapy with a modified FOLFOX6 regimen combined with an anti-EGFR antibody. He died of cancer 22.7 and 16.6 months after disease onset and first-line chemotherapy, respectively. This case shows that early tumor shrinkage and deepness of response to the anti-EGFR antibody were observed even in a patient with bone marrow metastasis. Anti-EGFR antibody therapy should therefore be considered even when a patient’s medical condition appears to be poor owing to bone marrow metastasis. Moreover, tumors that are likely to be sensitive to chemotherapy, such as RAS-wildtype colorectal cancers, can be considered for anti-EGFR antibody therapy even if the patient is considered unfit for chemotherapy. Keywords: colorectal cancer, anti-epidermal growth factor receptor antibody, molecular targeted therapies, disseminated intravascular coagulation, standard of care

Active and passive vectorization of technetium{sup 99m} and {sup 188}rhenium radiopharmaceuticals for medical imaging and radiotherapy; Vectorisations active et passive de radiopharmaceutiques du technetium-99m et du rhenium-188 pour l'imagerie medicale et la therapie

Energy Technology Data Exchange (ETDEWEB)

Lepareur, N

2003-11-15

Research for new molecules for nuclear medicine is a field in constant development. Over the past few years, development of new radiopharmaceuticals for radiotherapy has renewed interest for rhenium chemistry. Indeed, its two isotopes {sup 186}Re and {sup 188}Re, owing to their ideal properties and their similitude with {sup 99m}Tc, which is widely used as a radiotracer for diagnostic imaging, seem very promising for the preparation of radiopharmaceuticals. In the first part of this manuscript, the synthesis of rhenium and technetium-99 complexes, [M(RPhCS3)2(RPhCS2)] (M = Re, Tc), is described. The preparation of technetium{sup 99m} based radiopharmaceuticals, analogues to the pondered complexes, is also described. The stability/reactivity of these complexes has been studied by exchange reactions with potential ligands, specially dithiocarbamates, and also by UV-visible absorption spectroscopy and thermogravimetry. The reactivity of the complexes towards dithiocarbamates leads to the possibility to bind biomolecules to the metallic core, via the dithiocarbamate moiety. This method represents a potential alternative to current ones using the so-called bifunctional approach. In the second part of this manuscript, a new kit formulation for the {sup 188}Re labeling of lipiodol is described, using a complex analogous to those described in the previous part. The labeled oil is a potential cure for hepatocellular carcinoma. The in vitro and in vivo stability of this {sup 188}Re-SSS lipiodol and of its analogue {sup 99m}Tc-SSS lipiodol has been studied, and also their in vivo behavior in healthy pigs. This study has shown the quasi-exclusive hepatic fixation of the radiopharmaceutical, and has proven its good stability. Its selectivity for tumors remains to be shown before trying it on humans. (author)

Active and passive vectorization of technetium{sup 99m} and {sup 188}rhenium radiopharmaceuticals for medical imaging and radiotherapy; Vectorisations active et passive de radiopharmaceutiques du technetium-99m et du rhenium-188 pour l'imagerie medicale et la therapie

Energy Technology Data Exchange (ETDEWEB)

Lepareur, N

2003-11-15

Research for new molecules for nuclear medicine is a field in constant development. Over the past few years, development of new radiopharmaceuticals for radiotherapy has renewed interest for rhenium chemistry. Indeed, its two isotopes {sup 186}Re and {sup 188}Re, owing to their ideal properties and their similitude with {sup 99m}Tc, which is widely used as a radiotracer for diagnostic imaging, seem very promising for the preparation of radiopharmaceuticals. In the first part of this manuscript, the synthesis of rhenium and technetium-99 complexes, [M(RPhCS3)2(RPhCS2)] (M = Re, Tc), is described. The preparation of technetium{sup 99m} based radiopharmaceuticals, analogues to the pondered complexes, is also described. The stability/reactivity of these complexes has been studied by exchange reactions with potential ligands, specially dithiocarbamates, and also by UV-visible absorption spectroscopy and thermogravimetry. The reactivity of the complexes towards dithiocarbamates leads to the possibility to bind biomolecules to the metallic core, via the dithiocarbamate moiety. This method represents a potential alternative to current ones using the so-called bifunctional approach. In the second part of this manuscript, a new kit formulation for the {sup 188}Re labeling of lipiodol is described, using a complex analogous to those described in the previous part. The labeled oil is a potential cure for hepatocellular carcinoma. The in vitro and in vivo stability of this {sup 188}Re-SSS lipiodol and of its analogue {sup 99m}Tc-SSS lipiodol has been studied, and also their in vivo behavior in healthy pigs. This study has shown the quasi-exclusive hepatic fixation of the radiopharmaceutical, and has proven its good stability. Its selectivity for tumors remains to be shown before trying it on humans. (author)

Anti-EGFR-iRGD recombinant protein conjugated silk fibroin nanoparticles for enhanced tumor targeting and antitumor efficiency

Directory of Open Access Journals (Sweden)

Bian X

2016-05-01

Full Text Available Xinyu Bian,* Puyuan Wu,* Huizi Sha, Hanqing Qian, Qing Wang, Lei Cheng, Yang Yang, Mi Yang, Baorui LiuComprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, Nanjing, People’s Republic of China*These authors contributed equally to this workAbstract: In this study, we report a novel kind of targeting with paclitaxel (PTX-loaded silk fibroin nanoparticles conjugated with iRGD–EGFR nanobody recombinant protein (anti-EGFR-iRGD. The new nanoparticles (called A-PTX-SF-NPs were prepared using the carbodiimide-mediated coupling procedure and their characteristics were evaluated. The cellular cytotoxicity and cellular uptake of A-PTX-SF-NPs were also investigated. The results in vivo suggested that NPs conjugated with the recombinant protein exhibited more targeting and anti-neoplastic property in cells with high EGFR expression. In the in vivo antitumor efficacy assay, the A-PTX-SF-NPs group showed slower tumor growth and smaller tumor volumes than PTX-SF-NPs in a HeLa xenograft mouse model. A real-time near-infrared fluorescence imaging study showed that A-PTX-SF-NPs could target the tumor more effectively. These results suggest that the anticancer activity and tumor targeting of A-PTX-SF-NPs were superior to those of PTX-SF-NPs and may have the potential to be used for targeted delivery for tumor therapies. Keywords: EGFR, nanobody, iRGD, recombinant protein, targeting drug carriers, antitumor efficiency

Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor-Resistant EGFR-Mutant Lung Cancer with and without T790M Mutations

NARCIS (Netherlands)

Janjigian, Yelena Y.; Smit, Egbert F.; Groen, Harry J. M.; Horn, Leora; Gettinger, Scott; Camidge, D. Ross; Riely, Gregory J.; Wang, Bushi; Fu, Yali; Chand, Vikram K.; Miller, Vincent A.; Pao, William

EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in >50% of cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes

The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer

DEFF Research Database (Denmark)

Therkildsen, Christina; Bergmann, Troels K; Henrichsen-Schnack, Tine

2014-01-01

BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS-RAF-MAPK a......BACKGROUND: In metastatic colorectal cancer, mutation testing for KRAS exon 2 is widely implemented to select patients with wild-type tumors for treatment with the monocloncal anti-EGFR antibodies cetuximab and panitumumab. The added predictive value of additional biomarkers in the RAS...

46 CFR 188.10-3 - Approved container.

Science.gov (United States)

2010-10-01

... 46 Shipping 7 2010-10-01 2010-10-01 false Approved container. 188.10-3 Section 188.10-3 Shipping... PROVISIONS Definition of Terms Used in This Subchapter § 188.10-3 Approved container. This term means a container which is properly labeled, marked and approved by DOT for the commodity which it contains. [CGFR...

Country report: Serbia. Development, Preparing and Quality Assurance of Radiopharmaceuticals Based on {sup 188}Re and {sup 90}Y for Radionuclide Therapy: The Possibilities for their Production in Laboratory for Radioisotopes, Ins «Vinča»

Energy Technology Data Exchange (ETDEWEB)

Djokić, Divna [Vinča Institute of Nuclear Sciences, Laboratory for Radioisotopes, Belgrade (Serbia)

2010-07-01

The main object of the research planed for this project was to optimize the procedures for the {sup 90}Y and {sup 188}Re labelling of different compounds as well as their in vitro and in vivo evaluation. The work has been involved setting up the facilities, standardization of preparing protocols, and improving existing quality assurance/quality control (QA/QC) procedures in order to supply reliable products to the national nuclear medicine community.

A view on EGFR-targeted therapies from the oncogene-addiction perspective.

Science.gov (United States)

Perez, Rolando; Crombet, Tania; de Leon, Joel; Moreno, Ernesto

2013-01-01

Tumor cell growth and survival can often be impaired by inactivating a single oncogen- a phenomenon that has been called as "oncogene addiction." It is in such scenarios that molecular targeted therapies may succeed. among known oncogenes, the epidermal growth factor receptor (EGFR) has become the target of different cancer therapies. So far, however, the clinical benefit from EGFR-targeted therapies has been rather limited. a critical review of the large amount of clinical data obtained with anti-EGFR agents, carried out from the perspective of the oncogene addiction concept, may help to understand the causes of the unsatisfactory results. In this article we intend to do such an exercise taking as basis for the analysis a few case studies of anti-EGFR agents that are currently in the clinic. There, the "EGFR addiction" phenomenon becomes apparent in high-responder patients. We further discuss how the concept of oncogene addiction needs to be interpreted on the light of emerging experimental evidences and ideas; in particular, that EGFR addiction may reflect the interconnection of several cellular pathways. In this regard we set forth several hypotheses; namely, that requirement of higher glucose uptake by hypoxic tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted antibodies in EGFR-addicted tumors would induce stable disease by reversing the malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T cell response. Finally, we discuss possible reasons for the failure of certain combinatorial therapies involving anti-EGFR agents, arguing that some of these agents might produce either a negative or a positive trans-modulation effect on other oncogenes. It becomes evident that we need operational definitions of EGFR addiction in order to determine which patient populations may benefit from treatment with anti-EGFR drugs, and to improve the design of these therapies.

A view on EGFR-targeted therapies from the oncogene-addiction perspective

Directory of Open Access Journals (Sweden)

Rolando ePerez

2013-04-01

Full Text Available Tumor cell growth and survival can often be impaired by inactivating a single oncogen – a phenomenon that has been called as 'oncogene addiction'. It is in such scenarios that molecular targeted therapies may succeed. Among known oncogenes, the epidermal growth factor receptor (EGFR has become the target of different cancer therapies. So far, however, the clinical benefit from EGFR-targeted therapies has been rather limited. A critical review of the large amount of clinical data obtained with anti-EGFR agents, carried out from the perspective of the oncogene addiction concept, may help to understand the causes of the unsatisfactory results. In this article we intend to do such an exercise taking as basis for the analysis a few case studies of anti-EGFR agents that are currently in the clinic. There, the 'EGFR addiction' phenomenon becomes apparent in high-responder patients. We further discuss how the concept of oncogene addiction needs to be interpreted on the light of emerging experimental evidences and ideas; in particular, that EGFR addiction may reflect the interconnection of several cellular pathways. In this regard we set forth several hypotheses; namely, that requirement of higher glucose uptake by hypoxic tumor cells may reinforce EGFR addiction; and that chronic use of EGFR-targeted antibodies in EGFR-addicted tumors would induce stable disease by reversing the malignant phenotype of cancer stem cells and also by sustaining an anti-tumor T cell response. Finally, we discuss possible reasons for the failure of certain combinatorial therapies involving anti-EGFR agents, arguing that some of these agents might produce either a negative or a positive trans-modulation effect on other oncogenes. It becomes evident that we need operational definitions of EGFR addiction in order to determine which patient populations may benefit from treatment with anti-EGFR drugs, and to improve the design of these therapies.

Preclinical models for an innovative glioblastoma therapeutical strategy by 188Re-SSS encapsulated in nano-tools: translational view

International Nuclear Information System (INIS)

Cikankowitz, A.; Belloche, C.; Verger, E.; Garcion, E.; Hindre, F.; Chassain, G.; Fellah, B.; Abadie, J.; Chouin, N.; Ibisch, C.; Davodeau, F.; Couez, D.; Lepareur, N.; Lacoeuille, F.; Menei, P.

2015-01-01

Full text of publication follows. Aim: Glioblastoma (GBM) is the most frequent cancer of the nervous system and therapies currently used cannot treat definitively this disease. By the way of NucSan (Nuclear for health) program which supports research development about the use of radio pharmaceutics in oncology, the aim of the proposed work is to provide evidences that internal radiotherapy through lipid nanocapsules loaded with Rhenium-188 (LNC 188 Re-SSS) is an alternative therapeutic strategy for GBM that can be translated to human medicine. Previous works have shown a remarkable efficiency of this tool among syngeneic rats linked with local and peripheral recruitments of the immune system's effectors. In this context, two animal models have been chosen to validate the feasibility of this new innovative therapy design (LNC 188 Re-SSS stereotactic injection). Materials and methods: the syngeneic six weeks old C57BL/6J female mice were treated 6 or 12 days after stereotactic GL261 cells implantation, by a single injection of increasing activities of LNC 188 Re-SSS (0,925; 1,85 and 2,7 MBq/5μl). MRI was used to follow tumor progression to determine the mass volume through the selection of regions of interest. The increased median survival time (IMST) was also assessed for treated mice versus control mice (stereotactic injection of saline solution). For long time survival animals (3 times the median survival time), they were rechallenged through the same procedure in the other hemisphere. The brachy-cephalic dog bearing spontaneous tumor will lead to additional evidences to specifically highlight the potential of this innovative technology for GBM treatment. In order to validate procedures of intracerebral injections, a stereotactic head frame specially designed for dog has been conceived which allow both images acquisition (MRI-SPECT and PET) and the achievement of biopsies. Results/Perspectives: as previously observed on rat models, the preliminary data show

Plant virus-resembling optical nano-materials conjugated with anti-EGFR for targeted cancer imaging

Science.gov (United States)

Gupta, Sharad; Wilder, Hailey; Rao, A. L. N.; Vullev, V. I.; Anvari, Bahman

2012-03-01

We recently reported the construction of a new type of optically active nano-particles composed of genome-depleted plant infecting brome mosaic virus (BMV) doped with indocyanine green (ICG), an FDA-approved chromophore . We refer to these constructs as optical viral ghosts (OVGs) since only the capsid protein (CP) subunits of BMV remain to encapsulate ICG. Herein, we covalently conjugated the surface of OVGs with anti-epidermal growth factor receptors (anti-EGFR) to target cancerous human bronchial epithelial cells (C-HBECs) in-vitro. Our preliminary results demonstrate the utility of conjugated OVGs for targeted imaging of cancer cells.

The Synthesis And Characterization Of Wolfram Phthalocyanine For The Target Material Of High Specific Activity Radioisotope Wolfram - 188 (188W)

International Nuclear Information System (INIS)

Setiawan, Duyeh

2000-01-01

The application of 188 Re radioisotope separation on aluminia column through elution solution has increased significantly since the last two decades. The 188 Re radioisotope has been done fram 188 Re beta-decay through a neutron capture radiation on wolfram -186 target. In trhe column separation, high specific activity of 188 W radioisotope is required to get sufficient activity in small quality 188 W radioisotope has been carried out in this research. Wolfram-phthalocyanine compound was prepared by refluxing a mixture of wolfram trioxyde, (WO 3 ) and phthalonitrile, (C 8 H 4 N 2 ) at 250 o C for two hours. The synthesis of wolfram phthalocyanine is 70% purity yield, the product are green crystals, have a 193,0-193,8 o C melting points, and has a molecular formula C 3 2H 1 6 N8 WO 2 . The infra red spectrum of wolfram-phthalocyanine was the absorption band at 964,3 cm - 1 was due to the vibration of W=O bond of the wolfram dioxy-phthalocyanine. The x-ray diffraction of the wolfram dioxy-phthalocyanine was similar with molybdenum dioxy-phthalocyanine compound. This fact showed that the product was wolfram dioxy-phthalocyanine

Safety, Pharmacokinetics, Immunogenicity, and Biodistribution of (186)Re-Labeled Humanized Monoclonal Antibody BIWA 4 (Bivatuzumab( in Patients with Early-Stage Breast Cancer.

NARCIS (Netherlands)

Koppe, M.; Schaijk, F. van; Roos, J.C.; Leeuwen, P.; Heider, K.H.; Kuthan, H.; Bleichrodt, R.P.

2004-01-01

The aim of this prospective study was to evaluate the safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized anti-CD44v6 monoclonal antibody (MAb( BIWA 4 (Bivatuzumab( in 9 patients with early-stage breast cancer. Radioimmunoscintigraphy (RIS( was performed within

Present status of research on Re-186 radiopharmaceuticals at Radioisotope Production Center

Energy Technology Data Exchange (ETDEWEB)

Mutalib, A [Radioisotope Production Center, National Atomic Energy Agency Kawasan PUSPIPTEK, Serpong (Indonesia)

1998-10-01

Rhenium shows a close chemical similarity to technetium and is suitable for radiotherapy because the {beta}-emitting radionuclides {sup 186}Re (t{sub 1/2} 90 h, E{sub {beta}} = 1.1 MeV, E{sub {gamma}} = 137 keV) and {sup 188}Re (t{sub 1/2} = 17 h, E{sub {beta}} = 2.1 MeV). The {gamma}-emission associated with decay of {sup 186}Re is also useful in scintigraphy. The research on {sup 186}Re radiopharmaceuticals at Radioisotope Production Center has been carried out since April 1997. Interest in radioimmunotherapy (RIT) led us to the development of labeling antibodies with rhenium isotopes. Although there are several methods for coupling radiometal to antibody, we prefer an indirect labeling method in which a bifunctional chelating agent is used for coupling of {sup 186}Re to monoclonal antibodies. In this report we outline the study on the preparation of {sup 186}Re DMSA-TFP as precursor for labeling with monoclonal antibody. (author)

Analysis of effectiveness of the palliative treatment of metastatic bone's pain with 188Re-HEDP

International Nuclear Information System (INIS)

Savio, E.; Zeledon, P.; Paolino, A.; De Marco, E.; Gaudino, J.

2003-01-01

The objective of the study was to evaluate the treatment effectiveness with 188Re-HEDP in a group of 27 patients, who had received 36 doses. A pharmaceutical care programme was also added in order to improve drug follow-up after treatment. Two levels of doses were administered: 30 or 60 mCi. Initially a trace dose was given in order to estimate the therapeutic dose, which was individualise according to bone uptake of the radiopharmaceutical. Bone uptake was determined measuring radioactivity in urine samples (0, 1, 2, 4 and 6 hs), because the radiopharmaceutical showed only renal elimination. Multiple dose schedules with with 3 months between both doses were also tried. Seventy two percent showed an algesic effect during the first week post-treatment, with was kept during one month, while seven tenn (17%) percent of the patients the effect was kept for two of more months. Opioid analgesic (third level of OMS scale) were diminished in eighty two percent of the patients and AINES drugs in seventy one percent. The pharmaceutical care programme also showed the importance of the radio pharmacist role to improve treatment outcomes. 188Re-HEDP effectiveness was achieved in 100% of the patients, but with different pain palliation response in time and/or drug intake, with a suitable radiological safety

PEGylated N-methyl-S-methyl dithiocarbazate as a new reagent for the high-yield preparation of nitrido Tc-99m and Re-188 radiopharmaceuticals

Energy Technology Data Exchange (ETDEWEB)

Boschi, Alessandra, E-mail: alessandra.boschi@unife.i [Laboratory of Nuclear Medicine, Department of Radiological Sciences, University of Ferrara, 44100 Ferrara (Italy); Massi, Alessandro [Department of Chemistry, University of Ferrara, 44100 Ferrara (Italy); Uccelli, Licia; Pasquali, Micol; Duatti, Adriano [Laboratory of Nuclear Medicine, Department of Radiological Sciences, University of Ferrara, 44100 Ferrara (Italy)

2010-11-15

A novel nitrido nitrogen atom donor for the preparation of {sup 99m}Tc and {sup 188}Re radiopharmaceuticals containing a metal-nitrogen multiple bond is presented. HO{sub 2}C-PEG{sub 600}-DTCZ was obtained by conjugation of N-methyl-S-methyl dithiocarbazate [H{sub 2}N-N(CH{sub 3})-C({identical_to}S)SCH{sub 3}, HDTCZ] with polyethylene glycol 600 (PEG{sub 600}). Asymmetrical heterocomplexes of the type [M(N)(PNP)(B)]{sup 0/+} (M={sup 99m}Tc, {sup 188}Re; PNP=diphosphine ligands, B=DBODC, DEDC, NSH, H{sub 2}OS, CysNAc, HDTCZ) and symmetrical nitride compounds of the type [M(N)(L){sub 2}] (L=DEDC, DPDC) have been prepared in high yield by using the newly designed nitride nitrogen atom donor HO{sub 2}C-PEG{sub 600}-DTCZ. A two-step procedure was applied for preparing the above symmetrical and asymmetrical complexes. The first step involved the preliminary formation of a mixture of nitride Tc-99m or Re-188 precursors, which contained the [M{identical_to}N]{sup 2+} core, through reduction of generator-eluted {sup 99m}Tc-pertechnetate or {sup 188}Re-perrhenate with thin (II) chloride in the presence of HO{sub 2}C-PEG{sub 600}-DTCZ. In the second step, the intermediate mixture was converted either in the final mixed asymmetrical complex by the simultaneous addition of diphosphine ligand and the suitable bidentate ligand B, or in the final symmetrical complex by the only addition of the bidentate ligand L. It was also demonstrated that the novel water-soluble nitride nitrogen atom donor HO{sub 2}C-PEG{sub 600}-DTCZ did not show coordinating properties toward the M{identical_to}N ({sup 99m}Tc, {sup 188}Re) core. Biodistribution studies in rats of the hitherto unreported [{sup 99m}Tc(N)(PNP{sub 3})DTCZ]{sup +} and [{sup 99m}Tc(N)(PNP{sub 5})DTCZ]{sup +} complexes showed that they selectively localize in the myocardium of rats with a favourable heart-to-lung and heart-to-liver uptake ratios. In particular, the heart-to-lung and heart-to-liver uptake ratios dramatically

Myeloablative radioimmunotherapy with {sup 188}Re-CD66mAb before stem cell transplantation. No increase of proinflammatory cytokine levels of TNF-{alpha}; Myeloablative Radioimmuntherapie mit {sup 188}Re-CD66mAb vor Stammzelltransplantation. Kein Anstieg proinflammatorischer Zytokinspiegel von TNF-{alpha}

Energy Technology Data Exchange (ETDEWEB)

Mutschler, J.; Reske, S.N. [Universitaetsklinik Ulm (Germany). Klinik fuer Nuklearmedizin; Steinbach, G. [Universitaetsklinik Ulm (Germany). Abt. Klinische Chemie; Bunjes, D. [Universitaetsklinik Ulm (Germany). Medizinische Klinik III; Buchmann, I. [Universitaetsklinik Heidelberg (Germany). Abt. fuer Nuklearmedizin

2009-07-01

Tumour necrosis factor-{alpha} (TNF-{alpha}) serum levels may increase due to intensive conditioning regimes with high-dose chemotherapy and total body irradiation (TBI) before stem cell transplantation. This increases the risk for developing acute graft versus host disease (aGvHD) after stem cell transplantation. In this prospective study we investigated the influence of radioimmunotherapy with {sup 188}Re-CD-66-mAb on changes on TNF-{alpha} serum levels. Patients, methods: In 18 patients we measured TNF-{alpha} before and up to 96 hours after radioimmunotherapy, in 2 patients in addition following TBI, in 9 patients also following chemotherapy. For measuring TNF-{alpha} we used an automated immunochemiluminescence assay (Immulite 1000 DPC Biermann, Bad Nauheim). The mean follow up period to record incidence of aGVHD was 100 days after stem cell transplantation. Compared to the basal levels before, the levels of TNF-{alpha} after conditioning with {sup 188}Re-CD-66-mAb did not increase significantly and remained in the physiological range. In contrast, these initial physiological cytokine levels increased and became pathological following 48 h after total body irradiation (13.2 {+-} 6.6 pg/ml) and chemotherapy (10.8 {+-} 15.7 pg/ml). In our study we found a low incidence of aGvHD (22.2%, n = 4/18). Conclusion: These results demonstrate that additional conditioning therapy with {sup 188}Re-CD-66-mAb does not increase proinflammatory cytokine levels of TNF-{alpha}. This finding may indicate that additive radioimmunotherapy may not be a significant factor for increasing the rate of conditioning- associated aGvHD. (orig.)

Development of radioactively labelled cancer seeking biomolecules for targeted radiotherapy

International Nuclear Information System (INIS)

Balter, H.; Verdera, S.

2000-01-01

The main objective of this project is the labelling and quality control of biomolecules with radionuclides beta emitters with high purity and stability. Techniques and methodology for labelling with 188 Re, 153 Sm, and 125 I as well as quality controls were done according the recommendations of the first research coordination meeting of this CRP. Also some useful chelators reported in the literature were synthesized in our laboratory

In vitro and in vivo comparison of binding of 99m-Tc-labeled anti-CEA MAb F33-104 with 99m-Tc-labeled anti-CEA MAb BW431/26

International Nuclear Information System (INIS)

Watanabe, N.; Gunma Univ. School of Medicine; Oriuchi, N.; Inoue, T.; Sugiyama, S.; Kuroki, M.; Matsuoka, Y.; Tanada, S.; Murata, H.; Sasaki, Y.

1999-01-01

Aim: The purpose of this study was to assess the potential for radioimmunodetection (RAID) of murine anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb) F33-104 labeled with technetium-99m (99m-Tc) by a reduction-mediated labeling method. Methods: The binding capacity of 99m-Tc-labeled anti-CEA MAb F33-104 with CEA by means of in vitro procedures such as immunoradiometric assay and cell binding assay and the biodistribution of 99m-Tc-labeled anti-CEA MAb F33-104 in normal nude mice and nude mice bearing human colon adenocarcinoma LS180 tumor were investigated and compared with 99m-Tc-labeled anti-CEA MAb BW431/26. Results: The in vitro binding rate of 99m-Tc-labeled anti-CEA MAb F33-104 with CEA in solution and attached to the cell membrane was significantly higher than 99m-Tc-labeled anti-CEA MAb BW431/261 (31.4 ± 0.95% vs. 11.9 ± 0.55% at 100 ng/mL of soluble CEA, 83.5 ± 2.84% vs. 54.0 ± 2.54% at 10 7 of LS 180 cells). In vivo, accumulation of 99m-Tc-labeled anti-CEA MAb F33-104 was higher at 18 h postinjection than 99m-Tc-labeled anti-CEA MAb BW431/26 (20.1 ± 3.50% ID/g vs. 14.4 ± 3.30% ID/g). 99m-Tc-activity in the kidneys of nude mice bearing tumor was higher at 18 h postinjection than at 3 h (12.8 ± 2.10% ID/g vs. 8.01 ± 2.40% ID/g of 99m-Tc-labeled anti-CEA MAb F33-104, 10.7 ± 1.70% ID/g vs. 8.10 ± 1.75% ID/g of 99m-Tc-labeled anti-CEA MAb BW431/26). Conclusion: 99m-Tc-labeled anti-CEA MAb F33-104 is a potential novel agent for RAID of recurrent colorectal cancer. (orig.) [de

Monoclonal anti-elastin antibody labelled with technetium-99m

International Nuclear Information System (INIS)

Oliveira, Marcia B.N. de; Silva, Claudia R. da; Araujo, Adriano C. de; Bernardo Filho, Mario; Porto, Luis Cristovao M.S.; Gutfilen, Bianca; Souza, J.E.Q.; Frier, Malcolm

1999-01-01

Technetium-99m ( 99m Tc) is widely employed in nuclear medicine due to its desirable physical, chemical and biological properties. Moreover, it is easily available and normally is inexpensive. A reducing agent is necessary to label cells and molecules with 99m Tc and stannous chloride (Sn C L 2 ) is usually employed. Elastin is the functional protein component of the elastic fiber and it is related with some diseases such as arteriosclerosis, pulmonary emphysema and others. The present study refers to the preparation of the 99m Tc labeled monoclonal anti-elastin antibody. The monoclonal antibody was incubated with an excess of 2-iminothiolane. The free thiol groups created, were capable of binding with the reduced technetium. Labeling was an exchange reaction with 99m Tc-glucoheptonate. The labeled preparation was left at 4 deg C for one hour. Then, it was passed through a Sephadex G50 column. Various fractions were collected and counted. A peak corresponding to the radiolabeled antibody was obtained. Stability studies of the labelled anti-elastin were performed at 0,3 6, 24 hours, at both 4 deg C or room temperature. The biodistribution pattern of the 99m Tc-anti-elastin was studied in healthy male Swiss mice. The immunoreactivity was also determined. An useful labeled-anti-elastin was obtained to future immunoscintigraphic investigations. (author)

EGFR-targeted anti-cancer drugs in radiotherapy: Preclinical evaluation of mechanisms

International Nuclear Information System (INIS)

Baumann, Michael; Krause, Mechthild; Dikomey, Ekkehard; Dittmann, Klaus; Doerr, Wolfgang; Kasten-Pisula, Ulla; Rodemann, H. Peter

2007-01-01

Preclinical and clinical results indicate that the EGFR can mediate radioresistance in different solid human tumours. Combination of radiotherapy and EGFR inhibitors can improve local tumour control compared to irradiation alone and has been introduced into clinical radiotherapy practice. So far several mechanisms have been identified in preclinical studies to contribute to improved local tumour control after radiation combined with EGFR inhibitors. These include direct kill of cancer stem cells by EGFR inhibitors, cellular radiosensitization through modified signal transduction, inhibition of repair of DNA damage, reduced repopulation and improved reoxygenation during fractionated radiotherapy. Effects and mechanisms may differ for different classes of EGFR inhibitors, for different tumours and for normal tissues. The mechanisms underlying this heterogeneity are currently poorly understood, and predictive assays are not available yet. Importantly, mechanisms and predictors for the combined effects of radiation with EGFR inhibitors appear to be considerably different to those for application of EGFR inhibitors alone or in combination with chemotherapy. Therefore to further evaluate the efficacy and mechanisms of EGFR-inhibition in combined treatments, radiotherapy-specific preclinical research strategies, which include in vivo experiments using local tumour control as an endpoint, as well as animal studies on normal tissue toxicity are needed

Development of radioactively labelled cancer seeking biomolecules for targeted radiotherapy. Uruguay

International Nuclear Information System (INIS)

Balter, H.; Verdera, S.

2000-01-01

The main objective of this project is the labelling and quality control of biomolecules with radionuclides beta emitters with high purity and stability. Techniques and methodology for labelling with 188 Re, 153 Sm, and 125 I as well as quality controls were done according to the recommendations of the first research coordination meeting of this CRP. Also some useful chelators reported in the literature were synthesized in our laboratory)

Characterization of 7A7, an anti-mouse EGFR monoclonal antibody proposed to be the mouse equivalent of cetuximab.

Science.gov (United States)

He, Xuzhi; Cruz, Jazmina L; Joseph, Shannon; Pett, Nicola; Chew, Hui Yi; Tuong, Zewen K; Okano, Satomi; Kelly, Gabrielle; Veitch, Margaret; Simpson, Fiona; Wells, James W

2018-02-23

The Epidermal Growth Factor Receptor (EGFR) is selectively expressed on the surface of numerous tumours, such as non-small cell lung, ovarian, colorectal and head and neck carcinomas. EGFR has therefore become a target for cancer therapy. Cetuximab is a chimeric human/mouse monoclonal antibody (mAb) that binds to EGFR, where it both inhibits signaling and induces cell death by antibody-dependent cell mediated cytotoxicity (ADCC). Cetuximab has been approved for clinical use in patients with head and neck squamous cell carcinoma (HNSCC) and colorectal cancer. However, only 15-20% patients benefit from this drug, thus new strategies to improve cetuximab efficiency are required. We aimed to develop a reliable and easy preclinical mouse model to evaluate the efficacy of EGFR-targeted antibodies and examine the immune mechanisms involved in tumour regression. We selected an anti-mouse EGFR mAb, 7A7, which has been reported to be "mouse cetuximab" and to exhibit similar properties to its human counterpart. Unfortunately, we were unable to reproduce previous results obtained with the 7A7 mAb. In our hands, 7A7 failed to recognize mouse EGFR, both in native and reducing conditions. Moreover, in vivo administration of 7A7 in an EGFR-expressing HPV38 tumour model did not have any impact on tumour regression or animal survival. We conclude that 7A7 does not recognize mouse EGFR and therefore cannot be used as the mouse equivalent of cetuximab use in humans. As a number of groups have spent effort and resources with similar issues we feel that publication is a responsible approach.

Protein labelling with avidin-biotin systems

International Nuclear Information System (INIS)

Hernandez B, B.E.

1998-01-01

The stability of connection in avidin-biotin system is very important due to the quadruple connections with avidin established with the same number of biotin molecules, which can amplify damage on cancer cells and increase specific activity of radio immuno conjugate in white cell. If between the first and second step (Ac Mo-biotin + avidin) enough time is left so that the monoclonal antibody accumulates in a therapeutic concentration required for the tumor or cancerous cells, then upon application of the third step (biotin-DTPA- 153 Sm) it is hoped that in the first 30 minutes after application, only radioactivity remains with tumor. However, so that the amount radioactivity is enough to destroy a tumor, it would be necessary to use 153 Sm with an activity of approximately 370 GBq (10 Ci)/ (mg). Since 99m Tc has similar chemistry to that of the 188 Re, it is possible to propose their conjugates with biotin-avidin-Ac Mo- 188 Re as a powerful option for therapeutic applications, this is, recommending the use of biotinylated labelled monoclonal antibody and the further injection of avidin to decrease of desirable effects on several other organs and bone marrow and high specific and selective action on tumor. On the other hand, we postulate the hypothesis in the sense that 188 Re complexes tend to be more stable than those of 99m Tc, probably due to their metabolism, in which radioactivity of 188 Re, not captured by tumor, is cleared easily from blood stream which results in a decrease of total and liver total dose in patient. (Author)

The Use of EGFR Tyrosine Kinase Inhibitors in EGFR Wild-Type Non-Small-Cell Lung Cancer.

Science.gov (United States)

Stinchcombe, Thomas E

2016-04-01

The objective response rate and progression-free survival observed with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with metastatic epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) are modest. The adverse events associated with EGFR TKIs are manageable but they must be considered in the context of the limited efficacy. The development of anti-PD-1 immunotherapy as second-line therapy has reduced the role of EGFR TKIs in EGFR wild-type NSCLC. Recently, there has been increased recognition of the benefit of the earlier integration of palliative care and symptom management, and this is reasonable alternative to treatment with an EGFR TKI for many patients. My practice pattern for patients with EGFR wild-type NSCLC is platinum-based chemotherapy as first-line therapy, immunotherapy as second-line therapy, and single-agent chemotherapy as third-line therapy for patients with preserved performance status who want to pursue further therapy. Only a small proportion of patients are eligible for fourth-line therapy, and I prefer to enroll them in clinical trials rather than use EGFR TKIs. I suspect that the use of EGFR TKIs in clinical use and as a comparator arm for clinical trials will continue to decline over the next several years.

Treatment of liver cancer with Rhenium-188 Lipiodol: Colombian experience

International Nuclear Information System (INIS)

Bernal, P.; Osorio, M.; Mendoza, M.; Esguerra, R.; Ucros, G.; Gutierrez, C.; Velez, O.; Cerquera, A.M.; Padhy, A.K.

2002-01-01

Aim:Trans-arterial Radio-conjugate therapy plays an important role in the palliative treatment of inoperable liver cancer. It also helps in reduction of the tumor to an operable state from an inoperable one. As a part of an IAEA sponsored coordinated research project, a new radiopharmaceutical, Rhenium-188 Lipiodol has been developed. The aim of this study was to establish the safety of the radiopharmaceutical and to find out the efficacy of treatment. Materials and Methods: Eight patients suffering from various forms of liver cancer (Hepatocellular carcinoma-4, Metastases from carcinoma of colon-3 and Carcinoid- 1) were treated with Rhenium -188 Lipiodol. Seven out of the eight patients were classified as ECOG- 1 and one as ECOG- 3. Labelling of Rhenium-188 with Lipiodol was carried out according to a protocol developed under the CRP and standardized in our service. Rhenium-188 Lipiodol was administered through the trans-arterial route by either selective (75%) or ultra selective (25%) hepatic arteriography. Administered therapeutic doses ranged between 170 MBq and 4181 MBq. Dosimetric evaluations were made using the IAEA developed dosimetry spreadsheet. All patients were followed up (1-5 months, average = 2 months) after treatment by clinical examination, liver function tests, haematological examinations and CT scans of liver to determine the size of hepatic tumor. Results: Rhenium-188 Lipiodol treatment was well tolerated by all patients. No immediate systemic complications were noted in any of the patients within 72 hrs. following therapy. Only two patients had mild rise in temperature in the immediate post-therapy period, which subsided subsequently. One patient who was classified as Child B and ECOG 3, developed encephalopathy on the seventh day after treatment. He died of hepatic failure. Another one present depressive syndrome, didn't accept food and died Follow-up CT scans in all the surviving (6/8) patients revealed significant reduction of the tumours

Country report: United Kingdom. Bifunctional bisphosphonate complexes with {sup 99m}Tc and {sup 188}Re for the diagnosis and therapy of bone metastases

Energy Technology Data Exchange (ETDEWEB)

Torres Martin de Rosales, Rafael; Blower, P.J., E-mail: rafael.torres@kcl.ac.uk, E-mail: philip.blower@kcl.ac.uk [Division of Imaging Sciences, King' s College London, 4th Floor, Lambeth Wing, St. Thomas Hospital, London (United Kingdom)

2010-07-01

1,1-Bisphosphonates (BPs) are a family of compounds extensively used in the management of disorders of bone metabolism.{sup 1} They accumulate in areas of high bone metabolism, such as bone metastases, and consequently have been receiving increasing attention as molecular imaging probes and pain palliation treatments.{sup 2} Imaging bone metastases with BPs using single photon emission computed tomography (SPECT) or planar scintigraphy is one of the most often-performed clinical imaging procedures. Beta-emitting analogues capable of producing a therapeutic effect have also been developed.{sup 3} In particular, the rhenium compounds {sup 186/188}Re-hydroxyethylidene-1,1-diphosphonate ({sup 186/188}Re-HEDP) have shown promise as palliative agents for bone metastases in recent clinical trials.{sup 4} The radiochemicals consist of a complex of a BP (e.g. methylene diphosphonate, MDP) with gamma- ({sup 99m}Tc) or beta- ({sup 186/186}Re) emitters.

Labelling techniques of biomolecules for targeted radiotherapy. Final report of a co-ordinated research project 1998-2002

International Nuclear Information System (INIS)

2003-07-01

optimization of radiolabelling techniques with beta emitting radioisotopes, including quality control procedures and evaluation of the labelled products in in vitro and in vivo models. Biomolecule carriers that were considered for investigation included somatostatin analogues like lanreotide, Tyr-octreotide, ior-P1394 and vasointestinal peptide (VIP), as well as anti-CEA monoclonal antibody. Using either the bifunctional chelate approach or direct reductive exposure of -SH groups, labelling of these biomolecules with therapeutic radionuclides was pursued. Through these attempts it was expected to identify one or two agents with high radiochemical purity and labelling efficiency for further evaluation. Promising agents would be selected for further investigation using biodistribution studies in animals and uptake in tumour bearing animals. Fifteen selected research institutes from Argentina, Austria, Brazil, Cuba, Greece, Finland, Hungary, India, Italy, Mexico, Pakistan, Peoples Republic of China, Romania, Thailand and Uruguay with recognized expertise in the field of therapeutic radionuclides and radiopharmaceutical research were selected to participate in the CRP. The first research co-ordination meeting to plan the work and define the research protocols to be investigated was held in Milan, Italy in July 1998. At this meeting it was decided to concentrate the efforts on two radionuclides, 188Re and 90Y, which are produced by generator systems and result in carrier free products; lanreotide was selected as a model peptide. Synthesis of the bifunctional chelating agent DOTA was also recommended for the labelling of biomolecules with 90Y. The development of the corresponding coupling techniques, optimization of protocols for direct and indirect labelling of lanreotide and anti-carcino embryonic antigen (CEA) monoclonal antibody and in vitro evaluation in cell lines and membrane receptors were also included in the work plan for the following period. IgG labelled with 131I and

Labelling techniques of biomolecules for targeted radiotherapy. Final report of a co-ordinated research project 1998-2002

Energy Technology Data Exchange (ETDEWEB)

NONE

2003-07-01

optimization of radiolabelling techniques with beta emitting radioisotopes, including quality control procedures and evaluation of the labelled products in in vitro and in vivo models. Biomolecule carriers that were considered for investigation included somatostatin analogues like lanreotide, Tyr-octreotide, ior-P1394 and vasointestinal peptide (VIP), as well as anti-CEA monoclonal antibody. Using either the bifunctional chelate approach or direct reductive exposure of -SH groups, labelling of these biomolecules with therapeutic radionuclides was pursued. Through these attempts it was expected to identify one or two agents with high radiochemical purity and labelling efficiency for further evaluation. Promising agents would be selected for further investigation using biodistribution studies in animals and uptake in tumour bearing animals. Fifteen selected research institutes from Argentina, Austria, Brazil, Cuba, Greece, Finland, Hungary, India, Italy, Mexico, Pakistan, Peoples Republic of China, Romania, Thailand and Uruguay with recognized expertise in the field of therapeutic radionuclides and radiopharmaceutical research were selected to participate in the CRP. The first research co-ordination meeting to plan the work and define the research protocols to be investigated was held in Milan, Italy in July 1998. At this meeting it was decided to concentrate the efforts on two radionuclides, 188Re and 90Y, which are produced by generator systems and result in carrier free products; lanreotide was selected as a model peptide. Synthesis of the bifunctional chelating agent DOTA was also recommended for the labelling of biomolecules with 90Y. The development of the corresponding coupling techniques, optimization of protocols for direct and indirect labelling of lanreotide and anti-carcino embryonic antigen (CEA) monoclonal antibody and in vitro evaluation in cell lines and membrane receptors were also included in the work plan for the following period. IgG labelled with 131I and

Cellular Immunotherapy for Carcinoma Using Genetically Modified EGFR-Specific T Lymphocytes

Directory of Open Access Journals (Sweden)

Xikun Zhou

2013-05-01

Full Text Available Epidermal growth factor receptor (EGFR is overexpressed in a variety of human malignancies, including pancreatic cancer, breast cancer, colon cancer, and non-small cell lung cancer. Overexpression of EGFR is a predictive marker of therapeutic response and several lines of evidence suggest that EGFR is an excellent target for tumor therapy. However, the effective antitumor capacity of EGFR-specific T cells against EGFR-overexpressing tumor cells has not been fully elucidated. In our previous study, we identified an anti-EGFR single-chain variable fragment (scFv with specific and high affinity after screening by ribosome display. In this study, the anticancer potential of anti-EGFR scFv was investigated on the basis of cell-targeted therapy. A chimeric antigen receptor (CAR targeting EGFR was constructed and expressed on the cell membrane of T lymphocytes. These CAR-modified T cells demonstrated antitumor efficacy both in vitro and in vivo. In addition, the safety evaluation showed that CAR-modified lymphocytes have no or very minimal acute systemic toxicity. Taken together, our study provided the experimental basis for clinical application of genetically engineered lymphocytes; moreover, we also evaluate a new and interesting cell therapy protocol.

TP53, STK11 and EGFR Mutations Predict Tumor Immune Profile and the Response to anti-PD-1 in Lung Adenocarcinoma.

Science.gov (United States)

Biton, Jerome; Mansuet-Lupo, Audrey; Pécuchet, Nicolas; Alifano, Marco; Ouakrim, Hanane; Arrondeau, Jennifer; Boudou-Rouquette, Pascaline; Goldwasser, Francois; Leroy, Karen; Goc, Jeremy; Wislez, Marie; Germain, Claire; Laurent-Puig, Pierre; Dieu-Nosjean, Marie-Caroline; Cremer, Isabelle; Herbst, Ronald; Blons, Hélène F; Damotte, Diane

2018-05-15

By unlocking anti-tumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed. We performed in depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and to PD-L1 expression, and a public clinical database was used to validate the results obtained. We showed that distinct combinations of STK11 , EGFR and TP53 mutations, were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of TP53 mutations without co-occurring STK11 or EGFR alterations ( TP53 -mut/ STK11 - EGFR -WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T cell density and PD-L1 expression. In this tumor subtype, pathways related to T cell chemotaxis, immune cell cytotoxicity, and antigen processing were up-regulated. Finally, a prolonged progression-free survival (PFS: HR=0.32; 95% CI, 0.16-0.63, p <0.001) was observed in anti-PD-1 treated patients harboring TP53 -mut/ STK11 - EGFR -WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression. Our study reveals that different combinations of TP53 , EGFR and STK11 mutations , together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. Copyright ©2018, American Association for Cancer Research.

Myeloablative radioimmunotherapy with 188Re-CD66mAb before stem cell transplantation. No increase of proinflammatory cytokine levels of TNF-α

International Nuclear Information System (INIS)

Mutschler, J.; Reske, S.N.; Steinbach, G.; Bunjes, D.; Buchmann, I.

2009-01-01

Tumour necrosis factor-α (TNF-α) serum levels may increase due to intensive conditioning regimes with high-dose chemotherapy and total body irradiation (TBI) before stem cell transplantation. This increases the risk for developing acute graft versus host disease (aGvHD) after stem cell transplantation. In this prospective study we investigated the influence of radioimmunotherapy with 188 Re-CD-66-mAb on changes on TNF-α serum levels. Patients, methods: In 18 patients we measured TNF-α before and up to 96 hours after radioimmunotherapy, in 2 patients in addition following TBI, in 9 patients also following chemotherapy. For measuring TNF-α we used an automated immunochemiluminescence assay (Immulite 1000 DPC Biermann, Bad Nauheim). The mean follow up period to record incidence of aGVHD was 100 days after stem cell transplantation. Compared to the basal levels before, the levels of TNF-α after conditioning with 188 Re-CD-66-mAb did not increase significantly and remained in the physiological range. In contrast, these initial physiological cytokine levels increased and became pathological following 48 h after total body irradiation (13.2 ± 6.6 pg/ml) and chemotherapy (10.8 ± 15.7 pg/ml). In our study we found a low incidence of aGvHD (22.2%, n = 4/18). Conclusion: These results demonstrate that additional conditioning therapy with 188 Re-CD-66-mAb does not increase proinflammatory cytokine levels of TNF-α. This finding may indicate that additive radioimmunotherapy may not be a significant factor for increasing the rate of conditioning- associated aGvHD. (orig.)

EGFR T790M mutation after chemotherapy for small cell lung cancer transformation of EGFR-positive non-small cell lung cancer

Directory of Open Access Journals (Sweden)

Tomoaki Sonoda

Full Text Available In non-small cell lung cancer (NSCLC with an epidermal growth factor receptor (EGFR mutation, 50%–65% of cases acquire resistance after treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs because of an EGFR T790M point mutation and 3%–14% of these cases transformed to small cell lung cancer (SCLC. Generally, the EGFR T790M secondary mutation develops with ongoing ATP competitive inhibition. We present a case of a 76-year-old woman with lung adenocarcinoma harboring an EGFR-L858R mutation who received first-line gefitinib and developed SCLC transformation. She was administered several chemotherapy agents, including a platinum doublet. The primary lesion that showed SCLC transformation had reconverted to adenocarcinoma with EGFR L858R and T790M mutations at the time of a second re-biopsy. Therefore, she was administered osimertinib, which resulted in clinical remission. This case suggested that serial biopsies are necessary even after SCLC transformation. Keywords: NSCLC, EGFR mutation, SCLC transformation, T790M, Osimertinib

Anti-HER2 antibody and ScFvEGFR-conjugated antifouling magnetic iron oxide nanoparticles for targeting and magnetic resonance imaging of breast cancer

Directory of Open Access Journals (Sweden)

Chen H

2013-10-01

Full Text Available Hongwei Chen,1,* Liya Wang,1,2,* Qiqi Yu,1,2 Weiping Qian,3 Diana Tiwari,1 Hong Yi,4 Andrew Y Wang,5 Jing Huang,1,2 Lily Yang,3 Hui Mao1,2 1Department of Radiology and Imaging Sciences, 2Center for Systems Imaging, 3Department of Surgery, Emory University School of Medicine, 4Robert Apkarian Electron Microscopy Core, Emory University, Atlanta, GA, 5Ocean NanoTech LLC, Springdale, AK, USA *These authors contributed equally to this work Abstract: Antifouling magnetic iron oxide nanoparticles (IONPs coated with block copolymer poly(ethylene oxide-block-poly(γ-methacryloxypropyltrimethoxysilane (PEO-b-PγMPS were investigated for improving cell targeting by reducing nonspecific uptake. Conjugation of a HER2 antibody, Herceptin®, or a single chain fragment (ScFv of antibody against epidermal growth factor receptor (ScFvEGFR to PEO-b-PγMPS-coated IONPs resulted in HER2-targeted or EGFR-targeted IONPs (anti-HER2-IONPs or ScFvEGFR-IONPs. The anti-HER2-IONPs bound specifically to SK-BR-3, a HER2-overexpressing breast cancer cell line, but not to MDA-MB-231, a HER2-underexpressing cell line. On the other hand, the ScFvEGFR-IONPs showed strong reactivity with MDA-MB-231, an EGFR-positive human breast cancer cell line, but not with MDA-MB-453, an EGFR-negative human breast cancer cell line. Transmission electron microscopy revealed internalization of the receptor-targeted nanoparticles by the targeted cancer cells. In addition, both antibody-conjugated and non-antibody-conjugated IONPs showed reduced nonspecific uptake by RAW264.7 mouse macrophages in vitro. The developed IONPs showed a long blood circulation time (serum half-life 11.6 hours in mice and low accumulation in both the liver and spleen. At 24 hours after systemic administration of ScFvEGFR-IONPs into mice bearing EGFR-positive breast cancer 4T1 mouse mammary tumors, magnetic resonance imaging revealed signal reduction in the tumor as a result of the accumulation of the targeted IONPs

EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages

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Gu, Da-min [Department of Anesthesiology, Affiliated Yixing People' s Hospital, Jiangsu University, Yixing (China); Lu, Pei-Hua, E-mail: lphty1_1@163.com [Department of Medical Oncology, Wuxi People' s Hospital Affiliated to Nanjing Medical University, Wuxi (China); Zhang, Ke; Wang, Xiang [Department of Anesthesiology, Affiliated Yixing People' s Hospital, Jiangsu University, Yixing (China); Sun, Min [Department of General Surgery, Affiliated Yixing People' s Hospital, Jiangsu University, Yixing (China); Chen, Guo-Qian [Department of Clinical Laboratory, Wuxi People' s Hospital Affiliated to Nanjing Medical University, Wuxi (China); Wang, Qiong, E-mail: WangQiongprof1@126.com [Department of Clinical Laboratory, Wuxi People' s Hospital Affiliated to Nanjing Medical University, Wuxi (China)

2015-02-13

In this study, we tested the potential role of astragaloside IV (AS-IV) against oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damages in murine cortical neurons, and studied the associated signaling mechanisms. AS-IV exerted significant neuroprotective effects against OGD/R by reducing reactive oxygen species (ROS) accumulation, thereby attenuating oxidative stress and neuronal cell death. We found that AS-IV treatment in cortical neurons resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by Nrf2 Ser-40 phosphorylation, and its nuclear localization, as well as transcription of antioxidant-responsive element (ARE)-regulated genes: heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1) and sulphiredoxin 1 (SRXN-1). Knockdown of Nrf2 through lentiviral shRNAs prevented AS-IV-induced ARE genes transcription, and abolished its anti-oxidant and neuroprotective activities. Further, we discovered that AS-IV stimulated heparin-binding-epidermal growth factor (HB-EGF) release to trans-activate epidermal growth factor receptor (EGFR) in cortical neurons. Blockage or silencing EGFR prevented Nrf2 activation by AS-IV, thus inhibiting AS-IV-mediated anti-oxidant and neuroprotective activities against OGD/R. In summary, AS-IV protects cortical neurons against OGD/R damages through activating of EGFR-Nrf2 signaling. - Highlights: • Pre-treatment of astragaloside IV (AS-IV) protects murine cortical neurons from OGD/R. • AS-IV activates Nrf2-ARE signaling in murine cortical neurons. • Nrf2 is required for AS-IV-mediated anti-oxidant and neuroprotective activities. • AS-IV stimulates HB-EGF release to trans-activate EGFR in murine cortical neurons. • EGFR mediates AS-IV-induced Nrf2 activation and neuroprotection against OGD/R.

EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages

International Nuclear Information System (INIS)

Gu, Da-min; Lu, Pei-Hua; Zhang, Ke; Wang, Xiang; Sun, Min; Chen, Guo-Qian; Wang, Qiong

2015-01-01

In this study, we tested the potential role of astragaloside IV (AS-IV) against oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damages in murine cortical neurons, and studied the associated signaling mechanisms. AS-IV exerted significant neuroprotective effects against OGD/R by reducing reactive oxygen species (ROS) accumulation, thereby attenuating oxidative stress and neuronal cell death. We found that AS-IV treatment in cortical neurons resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by Nrf2 Ser-40 phosphorylation, and its nuclear localization, as well as transcription of antioxidant-responsive element (ARE)-regulated genes: heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1) and sulphiredoxin 1 (SRXN-1). Knockdown of Nrf2 through lentiviral shRNAs prevented AS-IV-induced ARE genes transcription, and abolished its anti-oxidant and neuroprotective activities. Further, we discovered that AS-IV stimulated heparin-binding-epidermal growth factor (HB-EGF) release to trans-activate epidermal growth factor receptor (EGFR) in cortical neurons. Blockage or silencing EGFR prevented Nrf2 activation by AS-IV, thus inhibiting AS-IV-mediated anti-oxidant and neuroprotective activities against OGD/R. In summary, AS-IV protects cortical neurons against OGD/R damages through activating of EGFR-Nrf2 signaling. - Highlights: • Pre-treatment of astragaloside IV (AS-IV) protects murine cortical neurons from OGD/R. • AS-IV activates Nrf2-ARE signaling in murine cortical neurons. • Nrf2 is required for AS-IV-mediated anti-oxidant and neuroprotective activities. • AS-IV stimulates HB-EGF release to trans-activate EGFR in murine cortical neurons. • EGFR mediates AS-IV-induced Nrf2 activation and neuroprotection against OGD/R

99m Tc-anti-epidermal growth factor receptor nanobody for tumor imaging.

Science.gov (United States)

Piramoon, Majid; Hosseinimehr, Seyed Jalal; Omidfar, Kobra; Noaparast, Zohreh; Abedi, Seyed Mohammad

2017-04-01

Nanobodies are important biomolecules for tumor targeting. In this study, we synthesized and labeled anti-epidermal growth factor receptor (EGFR) nanobody OA-cb6 with 99m Tc(CO) 3 + and evaluated its characteristics for targeting the EGFR in the A431 human epidermal carcinoma cell line. Nanobody radiolabeling was achieved with high yield and radiochemical purity, and the radioconjugate was stable. Biodistribution results in nude mice exhibited a favorable tumor-to-muscle ratio at 4-hr postinjection, and tumor location was visualized at 4 hr after injection of radiolabeled nanobody. Our result showed that the OA-cb6- 99m Tc-tricarbonyl radiolabeled nanobody is a promising radiolabeled biomolecule for tumor imaging in cancers with high EGFR overexpression. © 2016 John Wiley & Sons A/S.

HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.

Science.gov (United States)

Ingthorsson, S; Andersen, K; Hilmarsdottir, B; Maelandsmo, G M; Magnusson, M K; Gudjonsson, T

2016-08-11

The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492(HER2)) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492(HER2) (D492(HER2/EGFR)) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492(HER2/EGFR) xenografts grow slower than the D492(HER2) tumors, while overexpression of EGFR alone (D492(EGFR)) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492(HER2) xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492

Radiosynthesis and biological evaluation of 18F-labeled 4-anilinoquinazoline derivative (18F-FEA-Erlotinib) as a potential EGFR PET agent.

Science.gov (United States)

Huang, Shun; Han, Yanjiang; Chen, Min; Hu, Kongzhen; Qi, Yongshuai; Sun, Penghui; Wang, Men; Wu, Hubing; Li, Guiping; Wang, Quanshi; Du, Zhiyun; Zhang, Kun; Zhao, Suqing; Zheng, Xi

2018-04-01

Epidermal growth factor receptor (EGFR) has gained significant attention as a therapeutic target. Several EGFR targeting drugs (Gefitinib and Erlotinib) have been approved by US Food and Drug Administration (FDA) and have received high approval in clinical treatment. Nevertheless, the curative effect of these medicines varied in many solid tumors because of the different levels of expression and mutations of EGFR. Therefore, several PET radiotracers have been developed for the selective treatment of responsive patients who undergo PET/CT imaging for tyrosine kinase inhibitor (TKI) therapy. In this study, a novel fluorine-18 labeled 4-anilinoquinazoline based PET tracer, 1N-(3-(1-(2- 18 F-fluoroethyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine ( 18 F-FEA-Erlotinib), was synthesized and biological evaluation was performed in vitro and in vivo. 18 F-FEA-Erlotinib was achieved within 50min with over 88% radiochemical yield (decay corrected RCY), an average specific activity over 50GBq/μmol, and over 99% radiochemical purity. In vitro stability study showed no decomposition of 18 F-FEA-Erlotinib after incubated in PBS and FBS for 2h. Cellular uptake and efflux experiment results indicated the specific binding of 18 F-FEA-Erlotinib to HCC827 cell line with EGFR exon 19 deletions. In vivo, Biodistribution studies revealed that 18 F-FEA-Erlotinib exhibited rapid blood clearance both through hepatobiliary and renal excretion. The tumor uptake of 18 F-FEA-Erlotinib in HepG2, HCC827, and A431 tumor xenografts, with different EGFR expression and mutations, was visualized in PET images. Our results demonstrate the feasibility of using 18 F-FEA-Erlotinib as a PET tracer for screening EGFR TKIs sensitive patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acrolein and thiol-reactive electrophiles suppress allergen-induced innate airway epithelial responses by inhibition of DUOX1 and EGFR.

Science.gov (United States)

Danyal, Karamatullah; de Jong, Willem; O'Brien, Edmund; Bauer, Robert A; Heppner, David E; Little, Andrew C; Hristova, Milena; Habibovic, Aida; van der Vliet, Albert

2016-11-01

Acrolein is a major thiol-reactive component of cigarette smoke (CS) that is thought to contribute to increased asthma incidence associated with smoking. Here, we explored the effects of acute acrolein exposure on innate airway responses to two common airborne allergens, house dust mite and Alternaria alternata, and observed that acrolein exposure of C57BL/6 mice (5 ppm, 4 h) dramatically inhibited innate airway responses to subsequent allergen challenge, demonstrated by attenuated release of the epithelial-derived cytokines IL-33, IL-25, and IL-1α. Acrolein and other anti-inflammatory thiol-reactive electrophiles, cinnamaldehyde, curcumin, and sulforaphane, similarly inhibited allergen-induced production of these cytokines from human or murine airway epithelial cells in vitro. Based on our previous observations indicating the importance of Ca 2+ -dependent signaling, activation of the NADPH oxidase DUOX1, and Src/EGFR-dependent signaling in allergen-induced epithelial secretion of these cytokines, we explored the impact of acrolein on these pathways. Acrolein and other thiol-reactive electrophiles were found to dramatically prevent allergen-induced activation of DUOX1 as well as EGFR, and acrolein was capable of inhibiting EGFR tyrosine kinase activity via modification of C797. Biotin-labeling strategies indicated increased cysteine modification and carbonylation of Src, EGFR, as well as DUOX1, in response to acrolein exposure in vitro and in vivo, suggesting that direct alkylation of these proteins on accessible cysteine residues may be responsible for their inhibition. Collectively, our findings indicate a novel anti-inflammatory mechanism of CS-derived acrolein and other thiol-reactive electrophiles, by directly inhibiting DUOX1- and EGFR-mediated airway epithelial responses to airborne allergens. Copyright © 2016 the American Physiological Society.

64Cu-Labeled Trastuzumab Fab-PEG24-EGF Radioimmunoconjugates Bispecific for HER2 and EGFR: Pharmacokinetics, Biodistribution, and Tumor Imaging by PET in Comparison to Monospecific Agents.

Science.gov (United States)

Kwon, Luke Yongkyu; Scollard, Deborah A; Reilly, Raymond M

2017-02-06

Heterodimerization of EGFR with HER2 coexpressed in breast cancer (BC) promotes tumor growth, and increased EGFR expression is associated with trastuzumab resistance. Our aim was to construct 64 Cu-labeled bispecific radioimmunoconjugates (bsRIC) composed of trastuzumab Fab, which binds HER2 linked through a polyethylene glycol (PEG 24 ) spacer to EGF, and to compare their pharmacokinetic, biodistribution, and tumor imaging characteristics by positron-emission tomography (PET). bsRICs were generated by linking maleimide modified trastuzumab Fab with thiolated EGF through a thioether bond. HER2 and EGFR binding were assessed in vitro in MDA-MB-231 (EGFR mod /HER2 low ), MDA-MB-468 (EGFR high /HER2 neg ), MDA-MB-231-H2N (EGFR mod /HER2 mod ), and SKOV3 (EGFR low /HER2 high ) cells by competition and saturation cell binding assays to estimate the dissociation constant (K d ). The elimination of the 64 Cu-NOTA-trastuzumab Fab-PEG 24 -EGF bsRICs from the blood of Balb/c mice was compared to monospecific 64 Cu-NOTA-trastuzumab Fab and 64 Cu-NOTA-EGF. MicroPET/CT imaging was performed in NOD/SCID mice bearing subcutaneous MDA-MB-468, MDA-MB-231/H2N, or SKOV3 human BC xenografts at 24 and 48 h postinjection (p.i.) of bsRICs. Tumor and normal tissue uptake were quantified by biodistribution studies and compared to monospecific agents. The binding of bsRICs to MDA-MB-231 cells was decreased to 24.5 ± 5.2% by excess EGF, while the binding of bsRICs to SKOV3 cells was decreased to 38.6 ± 5.4% by excess trastuzumab Fab, demonstrating specific binding to both EGFR and HER2. 64 Cu-labeled bsRICs incorporating the PEG 24 spacer were eliminated more slowly from the blood than 64 Cu-bsRICs without the PEG spacer and were cleared much more slowly than 64 Cu-NOTA-Fab or 64 Cu-NOTA-EGF. All three tumor xenografts were visualized by microPET/CT at 24 and 48 h p.i. of bsRICs. Biodistribution studies at 48 h p.i. in NOD/SCID mice with MDA-MB-231/H2N tumors demonstrated significantly

BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition

International Nuclear Information System (INIS)

Brunetto de Farias, Caroline; Heinen, Tiago Elias; Pereira dos Santos, Rafael; Abujamra, Ana Lucia; Schwartsmann, Gilberto

2012-01-01

Highlights: ► BDNF protected HT-29 colorectal cancer cells from the antitumor effect of cetuximab. ► TrkB inhibition potentiated the antitumor effect of cetuximab. ► BDNF/TrkB signaling might be involved in resistance to anti-EGFR therapy. -- Abstract: The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling can protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy.

A camelid nanobody against EGFR was easily obtained through refolding of inclusion body expressed in Escherichia coli.

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Xu, Li; Song, Xiaoyu; Jia, Lingyun

2017-11-01

Using anti-EGFR (epidermal growth factor receptor) nanobody is a good choice for diagnoses and therapeutics for high EGFR expression diseases. In the present study, the percentage composition of anti-EGFR nanobody attained 25% of the total cell protein expressed in Escherichia coli BL21 (DE3). However, almost all nanobodies were expressed as inclusion bodies. To acquire active nanobodies, a series of dilution refolding procedures were optimized after inclusion bodies were dissolved into 6 M urea and purified with immobilized metal affinity chromatography. The results showed the refolding rate of the anti-EGFR nanobodies attained to 73%, and about 100 mg nanobodies were refolded from 1 L cells under the conditions that the initial nanobody concentration was 0.3 mg/mL, the dilution speed was 2.5 mL/Min, the dilution buffer was Tris-HCl at pH 8.0, the additives were 0.2 M Arg, 5 mM reduced glutathione (GSH), and 1 mM oxidized glutathione (GSSG). Then the activity of the refolded nanobodies was confirmed. The results showed that the refolded anti-EGFR nanobodies, in a dose-dependent manner, bounded to the tumor cell surface of A431 and MCF-7 and significantly inhibited the proliferation of A431 caused by the epidermal growth factor. Our study provides a facile method to rapidly, efficiently, and massively prepare anti-EGFR antibodies and promotes anti-EGFR-based recognition in cancer diagnoses and therapeutics. © 2016 International Union of Biochemistry and Molecular Biology, Inc.

Immunoassay of serum polypeptide hormones by using 125I-labelled anti(-immunoglobulin G) antibodies.

Science.gov (United States)

Beck, P; Nicholas, H

1975-03-01

1. A technique for indirectly labelling antibodies to polypeptide hormones, by combining them with radioactively labelled anti-(immunoglobulin G) is described. (a) 125I-labelled anti-(rabbit immunoglobulin G) and anti-(guinea-pig immunoglobulin G) antibodies with high specific radioactivity were prepared after purification of the antibodies on immunoadsorbents containing the respective antigens. (b) Rabbit immunoglobulin G antibodies to human growth hormone, porcine glucagon and guinea-pig immunoglobulin G antibodies to bovine insulin and bovine parathyroid hormone were combined with immunoadsorbents containing the respective polypeptide hormone antigen. (c) The immunoglobulin G antibodies to the polypeptide hormones were reacted with 125-I-labelled anti-(immunoglobulin G) antibodies directed against the appropriate species of immunoglobulin G,and the anti-hormone antibodies were combined with the hormone-containing immunoadsorbent. (d) 125I-labelled anti-(immunoglobulin G) antibodies and anti-hormone antibodies were simultaneously eluted from the hormone-containing immunoadsorbent by dilute HCl, pH 2.0. After elution the anti-(immunoglobulin G) antibodies and antihormone antibodies were allowed to recombine at pH 8.0 and 4 degrees C. 2. The resultant immunoglobulin G-anti-immunoglobulin G complex was used in immunoradiometric (labelled antibody) and two-site assays of the respective polypeptide hormone. 3. By using these immunoassays, concentrations down to 90pg of human growth hormone/ml, 100 pg of bovine insulin/ml, 80 pg of bovine parathyroid hormone/ml and 150 pg of glucagon/ml were readily detected. Assays of human plasma for growth hormone and insulin by these methods showed good agreement with results obtained by using a directly 125I-labelled anti-hormone antibody in an immunoradiometric assay of human growth hormone or by radioimmunoassay of human insulin. 4. The method described allows immunoradiometric or two-site assays to be performed starting with as

Spheroid Culture of Head and Neck Cancer Cells Reveals an Important Role of EGFR Signalling in Anchorage Independent Survival.

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Braunholz, Diana; Saki, Mohammad; Niehr, Franziska; Öztürk, Merve; Borràs Puértolas, Berta; Konschak, Robert; Budach, Volker; Tinhofer, Ingeborg

2016-01-01

In solid tumours millions of cells are shed into the blood circulation each day. Only a subset of these circulating tumour cells (CTCs) survive, many of them presumable because of their potential to form multi-cellular clusters also named spheroids. Tumour cells within these spheroids are protected from anoikis, which allows them to metastasize to distant organs or re-seed at the primary site. We used spheroid cultures of head and neck squamous cell carcinoma (HNSCC) cell lines as a model for such CTC clusters for determining the role of the epidermal growth factor receptor (EGFR) in cluster formation ability and cell survival after detachment from the extra-cellular matrix. The HNSCC cell lines FaDu, SCC-9 and UT-SCC-9 (UT-SCC-9P) as well as its cetuximab (CTX)-resistant sub-clone (UT-SCC-9R) were forced to grow in an anchorage-independent manner by coating culture dishes with the anti-adhesive polymer poly-2-hydroxyethylmethacrylate (poly-HEMA). The extent of apoptosis, clonogenic survival and EGFR signalling under such culture conditions was evaluated. The potential of spheroid formation in suspension culture was found to be positively correlated with the proliferation rate of HNSCC cell lines as well as their basal EGFR expression levels. CTX and gefitinib blocked, whereas the addition of EGFR ligands promoted anchorage-independent cell survival and spheroid formation. Increased spheroid formation and growth were associated with persistent activation of EGFR and its downstream signalling component (MAPK/ERK). Importantly, HNSCC cells derived from spheroid cultures retained their clonogenic potential in the absence of cell-matrix contact. Addition of CTX under these conditions strongly inhibited colony formation in CTX-sensitive cell lines but not their resistant subclones. Altogether, EGFR activation was identified as crucial factor for anchorage-independent survival of HNSCC cells. Targeting EGFR in CTC cluster formation might represent an attractive anti

BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition

Energy Technology Data Exchange (ETDEWEB)

Brunetto de Farias, Caroline [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); Children' s Cancer Institute, 90420-140 Porto Alegre, RS (Brazil); Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Heinen, Tiago Elias; Pereira dos Santos, Rafael [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); Laboratory of Neuropharmacology and Neural Tumor Biology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90050-170 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Abujamra, Ana Lucia [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); Children' s Cancer Institute, 90420-140 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Schwartsmann, Gilberto [Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS (Brazil); Department of Internal Medicine, School of Medicine, Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS (Brazil); and others

2012-08-24

Highlights: Black-Right-Pointing-Pointer BDNF protected HT-29 colorectal cancer cells from the antitumor effect of cetuximab. Black-Right-Pointing-Pointer TrkB inhibition potentiated the antitumor effect of cetuximab. Black-Right-Pointing-Pointer BDNF/TrkB signaling might be involved in resistance to anti-EGFR therapy. -- Abstract: The clinical success of targeted treatment of colorectal cancer (CRC) is often limited by resistance to anti-epidermal growth factor receptor (EGFR) therapy. The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB have recently emerged as anticancer targets, and we have previously shown increased BDNF levels in CRC tumor samples. Here we report the findings from in vitro experiments suggesting that BDNF/TrkB signaling can protect CRC cells from the antitumor effects of EGFR blockade. The anti-EGFR monoclonal antibody cetuximab reduced both cell proliferation and the mRNA expression of BDNF and TrkB in human HT-29 CRC cells. The inhibitory effect of cetuximab on cell proliferation and survival was counteracted by the addition of human recombinant BDNF. Finally, the Trk inhibitor K252a synergistically enhanced the effect of cetuximab on cell proliferation, and this effect was blocked by BDNF. These results provide the first evidence that increased BDNF/TrkB signaling might play a role in resistance to EGFR blockade. Moreover, it is possible that targeting TrkB could potentiate the anticancer effects of anti-EGFR therapy.

Anti-EGFR-Targeted Therapy for Esophageal and Gastric Cancers: An Evolving Concept

Directory of Open Access Journals (Sweden)

Tomislav Dragovich

2009-01-01

Full Text Available Cancers of the esophagus and stomach present a major health burden worldwide. In the past 30 years we have witnessed some interesting shifts in terms of epidemiology of esophago gastric cancers. Regardless of a world region, the majority of patients diagnosed with esophageal or gastric cancers die from progression or recurrence of their disease. While there are many active cytotoxic agents for esophageal and stomach cancers, their impact on the disease course has been modest at best. Median survival for patients with advanced gastroesophageal cancer is still less than a year. Therefore, novel strategies, based on our understanding of biology and genetics, are desperately needed. Epidermal growth factor receptor (EGFR pathway has been implicated in pathophysiology of many epithelial malignancies, including esophageal and stomach cancers. EGFR inhibitors, small molecule tyrosine kinase inhibitors and monoclonal antibodies, have been explored in patients with esophageal and gastric cancers. It appears that tumors of the distal esophagus and gastroesophageal junction (GEJ may be more sensitive to EGFR blockade than distal gastric adenocarcinomas. Investigations looking into potential molecular predictors of sensitivity to EGFR inhibitors for patients with esophageal and GEJ cancers are ongoing. While we are still searching for those predictors, it is clear that they will be different from ones identified in lung and colorectal cancers. Further development of EGFR inhibitors for esophageal and GEJ cancers should be driven by better understanding of EGFR pathway disregulation that drives cancer progression in a sensitive patient population.

Synthesis of novel '4+1' Tc(III)/Re(III) mixed-ligand complexes with dendritically modified ligands

International Nuclear Information System (INIS)

Gniazdowska, E.; Kuenstler, J.U.; Stephan, H.; Pietzsch, H.J.

2006-01-01

Coordination chemistry of technetium and rhenium attracts a considerable interest due to the nuclear medicine applications of their radionuclides. Inert, so-called '3+1' or '4+1' technetium/rhenium mixed-ligand complexes open a new way to application of 99 mTc/ 188 Re labeled compounds in tumor diagnosis and therapy. In the presented paper, authors describe the synthesis and study of novel 99 mTc/ 188 Re complexes with dendritically functionalized tetradentate (tripodal chelator 2,2',2''-nitrilotris(ethanethiol), NS 3 and carboxyl group-bearing ligand, NS 3 (COOH) 3 ) and monodentate (dendritically modified isocyanide, CN-R(COOMe) 3 and isocyanide-modified peptide, CN-GGY) ligands. To verify the identity of the prepared n.c.a. complexes, non-radioactive analogous '4+1' Re compounds were synthesized. The experimental data show that a dendritic modification of the tetradentate/monodentate ligands changes the complex lipophilicity and does not influence its stability

Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting

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Sander A. A. Kooijmans

2016-03-01

Full Text Available Background: Extracellular vesicles (EVs are attractive candidate drug delivery systems due to their ability to functionally transport biological cargo to recipient cells. However, the apparent lack of target cell specificity of exogenously administered EVs limits their therapeutic applicability. In this study, we propose a novel method to equip EVs with targeting properties, in order to improve their interaction with tumour cells. Methods: EV producing cells were transfected with vectors encoding for anti-epidermal growth factor receptor (EGFR nanobodies, which served as targeting ligands for tumour cells, fused to glycosylphosphatidylinositol (GPI anchor signal peptides derived from decay-accelerating factor (DAF. EVs were isolated using ultrafiltration/size-exclusion liquid chromatography and characterized using western blotting, Nanoparticle Tracking Analysis, and electron microscopy. EV–tumour cell interactions were analyzed under static conditions using flow cytometry and under flow conditions using a live-cell fluorescence microscopy-coupled perfusion system. Results: V analysis showed that GPI-linked nanobodies were successfully displayed on EV surfaces and were highly enriched in EVs compared with parent cells. Display of GPI-linked nanobodies on EVs did not alter general EV characteristics (i.e. morphology, size distribution and protein marker expression, but greatly improved EV binding to tumour cells dependent on EGFR density under static conditions. Moreover, nanobody-displaying EVs showed a significantly improved cell association to EGFR-expressing tumour cells under flow conditions. Conclusions: We show that nanobodies can be anchored on the surface of EVs via GPI, which alters their cell targeting behaviour. Furthermore, this study highlights GPI-anchoring as a new tool in the EV toolbox, which may be applied for EV display of a variety of proteins, such as antibodies, reporter proteins and signaling molecules.

Development of Cu-64 labeled EGF for In Vivo PET Imaging of EGFR Expression

Energy Technology Data Exchange (ETDEWEB)

Backer, Joseph M.

2009-07-12

In this project we proposed to establish feasibility of the development of targeted tracers for radionuclide imaging of epidermal growth factor receptors (EGFR) in cancer patients. The significance and impact of the proposed radiotracers are determined by the crucial role that EGFR plays in many cancers and by the rapid entrance of EGFR-inhibiting drugs into clinic. Clinical experience, however, revealed that only 10-25% of patients that are defined as EGFR-positive by immunohistochemical analysis respond to EGFR-directed therapeutics and there is poor correlation between EGFR immunohistochemistry and treatment. Therefore, for more efficacious use of EGFR-targeting therapeutics, there is a need for information about EGFR activity in patients. We hypothesized that radionuclide imaging of functionally active EGFR will provide such information and would allow for 1) rational patient stratification, 2) rapid monitoring of responses to therapy, and 3) development of personalized treatment regimens. We hypothesized that tracers based epidermal growth factor (EGF), a natural EGFR ligand, as a targeting vector would be particularly advantageous. First, only functionally active and therefore critical for disease progression EGFRs will bind and internalize an EGF-based tracer. Second, continuous internalization of EGF-based tracers by recyclable EGFR would lead to intracellular accumulation of radionuclide and improved signal-to-background ratio. Third, small size of EGF relative to antibodies would facilitate tumor penetration with vastly better non-specific soft tissue and blood clearance rates. Fourth, as a human protein, EGF is not expected to be immunogenic. Finally, at the beginning of this project, we have already engineered and expressed functionally active EGF with an N-terminal Cys-tag for site-specific conjugation of various payloads, including radionuclide chelators. In the Phase I of this project, in collaboration with Dr. Blankenberg’s group at Stanford

Development of Cu-64 labeled EGF for In Vivo PET Imaging of EGFR Expression

International Nuclear Information System (INIS)

Backer, Joseph M.

2009-01-01

In this project we proposed to establish feasibility of the development of targeted tracers for radionuclide imaging of epidermal growth factor receptors (EGFR) in cancer patients. The significance and impact of the proposed radiotracers are determined by the crucial role that EGFR plays in many cancers and by the rapid entrance of EGFR-inhibiting drugs into clinic. Clinical experience, however, revealed that only 10-25% of patients that are defined as EGFR-positive by immunohistochemical analysis respond to EGFR-directed therapeutics and there is poor correlation between EGFR immunohistochemistry and treatment. Therefore, for more efficacious use of EGFR-targeting therapeutics, there is a need for information about EGFR activity in patients. We hypothesized that radionuclide imaging of functionally active EGFR will provide such information and would allow for (1) rational patient stratification, (2) rapid monitoring of responses to therapy, and (3) development of personalized treatment regimens. We hypothesized that tracers based epidermal growth factor (EGF), a natural EGFR ligand, as a targeting vector would be particularly advantageous. First, only functionally active and therefore critical for disease progression EGFRs will bind and internalize an EGF-based tracer. Second, continuous internalization of EGF-based tracers by recyclable EGFR would lead to intracellular accumulation of radionuclide and improved signal-to-background ratio. Third, small size of EGF relative to antibodies would facilitate tumor penetration with vastly better non-specific soft tissue and blood clearance rates. Fourth, as a human protein, EGF is not expected to be immunogenic. Finally, at the beginning of this project, we have already engineered and expressed functionally active EGF with an N-terminal Cys-tag for site-specific conjugation of various payloads, including radionuclide chelators. In the Phase I of this project, in collaboration with Dr. Blankenberg's group at Stanford

Negative hyper-selection of metastatic colorectal cancer patients for anti-EGFR monoclonal antibodies: the PRESSING case-control study.

Science.gov (United States)

Cremolini, C; Morano, F; Moretto, R; Berenato, R; Tamborini, E; Perrone, F; Rossini, D; Gloghini, A; Busico, A; Zucchelli, G; Baratelli, C; Tamburini, E; Tampellini, M; Sensi, E; Fucà, G; Volpi, C; Milione, M; Di Maio, M; Fontanini, G; De Braud, F; Falcone, A; Pietrantonio, F

2017-12-01

Refining the selection of metastatic colorectal cancer patients candidates for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies beyond RAS and BRAF testing is a challenge of precision oncology. Several uncommon genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than EGFR or downstream signalling pathways, have been suggested by preclinical and retrospective studies. We conducted this multicentre, prospective, case-control study to demonstrate the negative predictive impact of a panel of rare genomic alterations [PRESSING (PRimary rESiStance IN RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-eGfr monoclonal antibodies) panel], including HER2/MET amplifications, ALK/ROS1/NTRK1-3/RET fusions and PIK3CA mutations. Hypothesizing a prevalence of candidate alterations of 15% and 0% in resistant and sensitive RAS and BRAF wild-type patients, respectively, with two-sided α and β errors of 0.05 and 0.20, 47 patients per group were needed. Forty-seven patients per group were included. PRESSING panel alterations were significantly more frequent in resistant (24 out of 47, 51.1%) than in sensitive (1 out of 47, 2.1%) patients (P < 0.001) and in right- (12 out of 29, 41.4%) than left-sided (13 out of 65, 20.0%) tumours (P = 0.03). The predictive accuracy of PRESSING panel and sidedness was 75.3% and 70.2%, respectively. Among hyper-selected patients, right-sidedness was still associated with resistance (P = 0.002). The predictive accuracy of the combined evaluation of PRESSING panel and sidedness was 80.4%. As a secondary analysis, 8 (17.0%) resistant and 0 sensitive patients showed microsatellite instability (P < 0.001). The investigated panel of genomic alterations allows refining the selection of RAS and BRAF wild-type metastatic colorectal cancer patients candidates for anti-EGFRs, partially explaining and further corroborating the predictive ability of primary

Manufacture of anti-bogus label by track-etching technique

International Nuclear Information System (INIS)

He Xiangming; Wan Chunrong

2006-01-01

Anti-bogus label is manufactured by the track-etching technique. The apparent pattern on the label consists of track-etched pores on the membrane. The manufacture of the label depends on the intricate technology and the state strictly controls the sensitive nuclear facilities, ensuring that the label is not copied. The pattern on the label is specially characterized by permeability of liquid in order to distinguish it from a forged one. A genuine label can be distinguished from a sham one by a transparent liquid (e.g. water) or a colorful pen. Nowadays, the products of more than 100 famous brands (trade mark) have been protected from forgery by this technology in the market of China. This is a new method for the utilization of a research reactor

PCR-based assays versus direct sequencing for evaluating the effect of KRAS status on anti-EGFR treatment response in colorectal cancer patients: a systematic review and meta-analysis.

Directory of Open Access Journals (Sweden)

Lianfeng Shan

Full Text Available The survival rate of colorectal cancer (CRC patients carrying wild-type KRAS is significantly increased by combining anti-EGFR monoclonal antibody (mAb with standard chemotherapy. However, conflicting data exist in both the wild-type KRAS and mutant KRAS groups, which strongly challenge CRC anti-EGFR treatment. Here we conducted a meta-analysis in an effort to provide more reliable information regarding anti-EGFR treatment in CRC patients.We searched full reports of randomized clinical trials using Medline, the American Society of Clinical Oncology (ASCO, and the European Society for Medical Oncology (ESMO. Two investigators independently screened the published literature according to our inclusive and exclusive criteria and the relative data were extracted. We used Review Manager 5.2 software to analyze the data.The addition of anti-EGFR mAb to standard chemotherapy significantly improved both progression-free survival (PFS and median overall survival (mOS in the wild-type KRAS group; hazard ratios (HRs for PFS and mOS were 0.70 [95% confidence interval (CI, 0.58-0.84] and 0.83 [95% CI, 0.75-0.91], respectively. In sub-analyses of the wild-type KRAS group, when PCR-based assays are employed, PFS and mOS notably increase: the HRs were 0.74 [95% CI, 0.62-0.88] and 0.87 [95% CI, 0.78-0.96], respectively. In sub-analyses of the mutant KRAS group, neither PCR-based assays nor direct sequencing enhance PFS or mOS.Our data suggest that PCR-based assays with high sensitivity and specificity allow accurate identification of patients with wild-type KRAS and thus increase PFS and mOS. Furthermore, such assays liberate patients with mutant KRAS from unnecessary drug side effects, and provide them an opportunity to receive appropriate treatment. Thus, establishing a precise standard reference test will substantially optimize CRC-targeted therapies.

Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion.

Science.gov (United States)

Potthoff, K; Hofheinz, R; Hassel, J C; Volkenandt, M; Lordick, F; Hartmann, J T; Karthaus, M; Riess, H; Lipp, H P; Hauschild, A; Trarbach, T; Wollenberg, A

2011-03-01

Anti-epidermal growth factor receptor treatment strategies, i.e. monoclonal antibodies such as cetuximab and panitumumab, or epidermal growth factor receptor (EGFR) small molecule tyrosine kinase inhibitors, such as erlotinib and gefitinib, have expanded the treatment options for different tumor types. Dermatologic toxic effects are the most common side-effects of EGFR inhibitor therapy. They can profoundly affect the patient's quality of life. The aim of this study was to provide interdisciplinary expert recommendations on how to treat patients with skin reactions undergoing anti-EGFR treatment. An expert panel from Germany with expertise in medical oncology, dermatology or clinical pharmacology was convened to develop expert recommendations based on published peer-reviewed literature. The expert recommendations for the state-of-the-art treatment of skin reactions induced by EGFR inhibitor therapy include recommendations for diagnostics and grading as well as grade-specific and stage-adapted treatment approaches and preventive measures. It was concluded that EGFR-inhibitor-related dermatologic reactions should always be treated combining basic care of the skin and a specific therapy adapted to stage and grade of skin reaction. For grade 2 and above, specific treatment recommendations for early- and later-stage skin reactions induced by EGFR-inhibitor therapy were proposed. This paper presents a German national expert opinion for the treatment of skin reactions in patients receiving EGFR inhibitor therapy.

Investigation of SP94 Peptide as a Specific Probe for Hepatocellular Carcinoma Imaging and Therapy

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Li, Yanli; Hu, Yan; Xiao, Jie; Liu, Guobing; Li, Xiao; Zhao, Yanzhao; Tan, Hui; Shi, Hongcheng; Cheng, Dengfeng

2016-01-01

SP94 (SFSIIHTPILPL), a novel peptide, has shown specific binding to hepatocellular carcinoma (HCC) cells. We aimed to investigate the capability of SP94 as a targeting probe for HCC imaging and therapy following labeling with technetium-99m (99mTc) and rhenium-188 (188Re). HYNIC-SP94 was prepared by solid phase synthesis and then labeled with 99mTc. Cell competitive binding, internalization assay, in vitro and in vivo stability, biodistribution and micro-single photon emission computed tomography /computed tomography (SPECT/CT) imaging studies were performed to investigate the capability of 99mTc tricine-EDDA/HYNIC-SP94 as a specific HCC imaging probe. Initial promising targeting results inspired evaluation of its therapeutic effect when labeled by 188Re. HYNIC-SP94 was then labeled again with 188Re to perform cell apoptosis, microSPECT/CT imaging evaluation and immunohistochemistry. Huh-7 cells exhibited typical apoptotic changes after 188Re irradiation. According to 99mTc tricine-EDDA/HYNIC-SP94 microSPECT/CT imaging, tumor uptake was significantly decreased compared with that of pre-treatment with 188Re-HYNIC-SP94. The immunohistochemistry also displayed obvious necrosis and apoptosis as well as inhibition of proliferation in the 188Re-HYNIC-SP94 treatment group. The results supported that 99mTc tricine-EDDA/HYNIC-SP94 is able to target HCC cells and 188Re-HYNIC- SP94 holds potential as a therapeutic agent for HCC, making 99mTc/188Re-HYNIC-SP94 a promising targeting probe for HCC imaging and therapy. PMID:27649935

Vorinostat and metformin sensitize EGFR-TKI resistant NSCLC cells via BIM-dependent apoptosis induction.

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Chen, Hengyi; Wang, Yubo; Lin, Caiyu; Lu, Conghua; Han, Rui; Jiao, Lin; Li, Li; He, Yong

2017-11-07

There is a close relationship between low expression of BIM and resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Vorinostat is a pan-histone deacetylase inhibitor (HDACi) that augments BIM expression in various types of tumor cells, however, this effect is attenuated by the high expression of anti-apoptotic proteins in EGFR-TKI resistant non-small cell lung cancer (NSCLC) cells. Vorinostat in combination with metformin - a compound that can inhibit anti-apoptotic proteins expression, might cooperate to activate apoptotic signaling and overcome EGFR-TKI resistance. This study aimed to investigate the cooperative effect and evaluate possible molecular mechanisms. The results showed that vorinostat combined with gefitinib augmented BIM expression and increased the sensitivity of EGFR-TKI resistant NSCLC cells to gefitinib, adding metformin simultaneously could obviously inhibit the expression of anti-apoptotic proteins, and further increased expression levels of BIM and BAX, and as a result, further improved the sensitivity of gefitinib both on the NSCLC cells with intrinsic and acquired resistance to EGFR-TKI. In addition, autophagy induced by gefitinib and vorinostat could be significantly suppressed by metformin, which might also contribute to enhance apoptosis and improve sensitivity of gefitinib. These results suggested that the combination of vorinostat and metformin might represent a novel strategy to overcome EGFR-TKI resistance associated with BIM-dependent apoptosis in larger heterogeneous populations.

A critical quantum chemical and experimental study of the potentiality of direct labeling of the CN group with [99mTc(CO)3]+ or [186/188Re(CO)3]+ in CN containing biomolecules

International Nuclear Information System (INIS)

Safi, Benasser; Mertens, John; Kersemans, Ken; Geerlings, Paul

2008-01-01

Introduction: It was determined recently that [ 99m Tc(OH 2 ) 2 (X - )(CO 3 ) 3 ] could strongly bind to the CN group, allowing direct labeling of CN in vitamin B 12 despite the presence of a benzimidazole group. The aim of this paper was to perform a critical study of this potentiality, coupling quantum chemical calculations to experimental evidence. Methods: Computational methods: Within the density functional theory calculations, the 6-31+G** basis set (C, H, O, N atoms) and the LANL2DZ basis set (Tc,Re) were used. Stability calculations of the [RCNM(CO) 3 ] + ) (M=Tc,Re) complexes were performed with the Gaussian 03 suite of programs, while for the evaluation of relative stability substitution reactions were used. Radiochemistry: Vitamin B 12 , 4-hydroxy-benzylcyanide and 4-methoxy-benzonitrile were labeled at 100 deg. C during 30 min. High-performance liquid chromatography analysis was performed using radioactive and UV detection. Results: Computational methods: The influence of different ligands on the stability yielded a sequence: imidazole>tBuCN>NH 3 ∼CH 3 CN>HCN (mimicking the best CoCN)>H 2 O. The transmetalation reaction indicates that all ligands prefer Re to Tc. The preference for the nitrogen atom of imidazole to the cyanide nitrogen atom for complex formation with [Tc(CO) 3 (H 2 O) 3 ] + is interpreted in terms of the hard and soft acid and base properties principle. Radiochemistry: 4-Hydroxy-benzylcyanide and 4-methoxy-benzonitrile did not show any labeling. An excess of acetonitrile did not inhibit the labeling of vitamin B 12 as expected if the CN group should be involved, indicating that the labeling occurs on a stronger complexing group present like benzimidazole. Conclusion: Both theory and experiments prove that [CN-Tc(CO) 3 (H 2 O) (2-x) L x ] + complexes are weak and that in vitamin B 12 most probably the benzimidazole group is involved

Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy

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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.

Physico-chemical characterisation and biological evaluation of 188-Rhenium colloids for radiosynovectomy

International Nuclear Information System (INIS)

Ures, Ma Cristina; Savio, Eduardo; Malanga, Antonio; Fernández, Marcelo; Paolino, Andrea; Gaudiano, Javier

2002-01-01

Radiosynovectomy is a type of radiotherapy used to relieve pain and inflammation from rheumatoid arthritis. In this study, 188-Rhenium ( 188 Re) colloids were characterized by physical and biological methodologies. This was used to assess which parameters of the kit formulation would be the basis in the development of a more effective radiopharmaceutical for synovectomy. Intraarticular injection in knees of rabbits assessed cavity leakage of activity. The physical characteristics of tin (Sn) and sulphur (S) colloids were determined to assess the formulation with suitable properties. Particles were grouped in three ranges for analyzing their distribution according to their number, volume and surface. The ideal particle size range was considered to be from 2 to 10 microns. Membrane filtration and laser diffraction characterization methodologies were used. While membrane filtration could give misleading data, laser diffraction proportions more reliable results. The Sn colloid showed a better distribution of particle volume and surface than S colloid, in the 2 to 10 microns range. The 188 Re-Sn colloid was obtained with a radiochemical purity higher than 95% after 30 minutes of autoclaving. While Sn colloid kit stability was verified for 60 days, the 188 Re-Sn preparation was stable in the first 24 hrs. No significant intrabatch variability (n = 3) was detected. Biodistribution and scintigraphic studies in rabbits after intraarticular injection showed relevant activity only in knee, being 90% at 48 hours. The 188 Re-Sn colloid is easy to prepare, is stable for 24 hours and shows minimal cavity leakage after intraarticular injection into rabbit knees, suggesting this radiotherapeutical agent has suitable physical properties for evaluation for joint treatment in humans

The effect of dimethyl sulfoxide on the induction of DNA strand breaks in plasmid DNA and colony formation of PC Cl3 mammalian cells by alpha-, beta-, and Auger electron emitters (223)Ra, (188)Re, and (99m)Tc.

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Runge, Roswitha; Oehme, Liane; Kotzerke, Jörg; Freudenberg, Robert

2016-12-01

DNA damage occurs as a consequence of both direct and indirect effects of ionizing radiation. The severity of DNA damage depends on the physical characteristics of the radiation quality, e.g., the linear energy transfer (LET). There are still contrary findings regarding direct or indirect interactions of high-LET emitters with DNA. Our aim is to determine DNA damage and the effect on cellular survival induced by (223)Ra compared to (188)Re and (99m)Tc modulated by the radical scavenger dimethyl sulfoxide (DMSO). Radioactive solutions of (223)Ra, (188)Re, or (99m)Tc were added to either plasmid DNA or to PC Cl3 cells in the absence or presence of DMSO. Following irradiation, single strand breaks (SSB) and double strand breaks (DSB) in plasmid DNA were analyzed by gel electrophoresis. To determine the radiosensitivity of the rat thyroid cell line (PC Cl3), survival curves were performed using the colony formation assay. Exposure to 120 Gy of (223)Ra, (188)Re, or (99m)Tc leads to maximal yields of SSB (80 %) in plasmid DNA. Irradiation with 540 Gy (223)Ra and 500 Gy (188)Re or (99m)Tc induced 40, 28, and 64 % linear plasmid conformations, respectively. DMSO prevented the SSB and DSB in a similar way for all radionuclides. However, with the α-emitter (223)Ra, a low level of DSB could not be prevented by DMSO. Irradiation of PC Cl3 cells with (223)Ra, (188)Re, and (99m)Tc pre-incubated with DMSO revealed enhanced survival fractions (SF) in comparison to treatment without DMSO. Protection factors (PF) were calculated using the fitted survival curves. These factors are 1.23 ± 0.04, 1.20 ± 0.19, and 1.34 ± 0.05 for (223)Ra, (188)Re, and (99m)Tc, respectively. For (223)Ra, as well as for (188)Re and (99m)Tc, dose-dependent radiation effects were found applicable for plasmid DNA and PC Cl3 cells. The radioprotection by DMSO was in the same range for high- and low-LET emitter. Overall, the results indicate the contribution of mainly indirect radiation

Antitumor efficacy of triple monoclonal antibody inhibition of epidermal growth factor receptor (EGFR) with MM151 in EGFR-dependent and in cetuximab-resistant human colorectal cancer cells

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Napolitano, Stefania; Martini, Giulia; Martinelli, Erika; Della Corte, Carminia Maria; Morgillo, Floriana; Belli, Valentina; Cardone, Claudia; Matrone, Nunzia; Ciardiello, Fortunato; Troiani, Teresa

2017-01-01

Purpose We investigated the effect of triple monoclonal antibody inhibition of EGFR to overcome acquired resistance to first generation of anti-EGFR inhibitors. Experimental design MM151 is a mixture of three different monoclonal IgG1 antibodies directed toward three different, non-overlapping, epitopes of the EGFR. We performed an in vivo study by using human CRC cell lines (SW48, LIM 1215 and CACO2) which are sensitive to EGFR inhibitors, in order to evaluate the activity of MM151 as compared to standard anti-EGFR mAbs, such as cetuximab, as single agent or in a sequential strategy of combination MM151 with irinotecan (induction therapy) followed by MM151 with a selective MEK1/2 inhibitor (MEKi) (maintenance therapy). Furthermore, the ability of MM151 to overcome acquired resistance to cetuximab has been also evaluated in cetuximab-refractory CRC models. Results MM151 shown stronger antitumor activity as compared to cetuximab. The maintenance treatment with MM151 plus MEKi resulted the most effective therapeutic modality. In fact, this combination caused an almost complete suppression of tumor growth in SW48, LIM 1215 and CACO2 xenografts model at 30 week. Moreover, in this treatment group, mice with no evidence of tumor were more than double as compared to single agent treated mice. Its superior activity has also been demonstrated, in cetuximab-refractory CRC models. Conclusions These results provide experimental evidence that more efficient and complete EGFR blockade may determine better antitumor activity and could contribute to prevent and/or overcome acquired resistance to EGFR inhibitors. PMID:29137301

The therapeutic threesome, Iodine 131, Lutetium-111 and Rhenium-188 Radionuclide Trifecta

International Nuclear Information System (INIS)

Turner, J.H.

2007-01-01

Full text: Affordable, available, cost-effective, safe, efficacious therapeutic radiopharmaceuticals are required for clinical application throughout the world. In-house preparation of non-proprietary therapeutic radiopharmaceuticals at tertiary referral hospitals in all countries following appropriate technology transfer and training at key research and development centres can potentially supply this need. Illustrative examples of novel therapeutic radiopharmaceuticals currently under development in physician sponsored phase II clinical trials and candidates for contemplation of translation to developing countries include: (1) I-131 Rituximab radioimmunotherapy of relapsed/refractory and first-line treatment of non- Hodgkin's lymphoma; (2) Lu-177 octreotate radiopeptide therapy of neuroendocrine malignancy with capecitabine tumour radiosensitization; (3) Re-188 lipiodol intrahepatic arterial therapy of hepatocellular carcinoma. In addition to presentation of preliminary clinical results, the logistics and techniques of preparation, quality control and administration of each of these therapeutic radiopharmaceuticals will be described and the calculation of individual patient dosimetry and issues of radiation safety will also be addressed. 1. Iodine-131 rituximab: I-131 rituximab may be prepared in a hospital department of nuclear medicine equipped with a shielded fume cupboard, using commercially available single-use sterile pyrogen-free labelling kits (Go Medical Industries Pty Ltd, Subiaco, Australia) (1). Individualized prospective dosimetry is performed on each patient by quantitative whole body gamma imaging, to determine the therapeutic administered activity, to provide a maximum safe whole body radiation absorbed dose of 0.75 Gy, which equates to less than 2 Gy to red marrow (2). More than 200 patients with relapsed/refractory non-Hodgkin's lymphoma have been treated at Fremantle Hospital without infection or haemorrhagic incident. Myelosuppression is self

Protein labelling with avidin-biotin systems; Radiomarcado de proteinas con sistemas avidina-biotina

Energy Technology Data Exchange (ETDEWEB)

Hernandez B, B E

1998-06-01

The stability of connection in avidin-biotin system is very important due to the quadruple connections with avidin established with the same number of biotin molecules, which can amplify damage on cancer cells and increase specific activity of radio immuno conjugate in white cell. If between the first and second step (Ac Mo-biotin + avidin) enough time is left so that the monoclonal antibody accumulates in a therapeutic concentration required for the tumor or cancerous cells, then upon application of the third step (biotin-DTPA-{sup 153} Sm) it is hoped that in the first 30 minutes after application, only radioactivity remains with tumor. However, so that the amount radioactivity is enough to destroy a tumor, it would be necessary to use {sup 153} Sm with an activity of approximately 370 GBq (10 Ci)/ (mg). Since {sup 99m} Tc has similar chemistry to that of the {sup 188} Re, it is possible to propose their conjugates with biotin-avidin-Ac Mo-{sup 188} Re as a powerful option for therapeutic applications, this is, recommending the use of biotinylated labelled monoclonal antibody and the further injection of avidin to decrease of desirable effects on several other organs and bone marrow and high specific and selective action on tumor. On the other hand, we postulate the hypothesis in the sense that {sup 188} Re complexes tend to be more stable than those of {sup 99m} Tc, probably due to their metabolism, in which radioactivity of {sup 188} Re, not captured by tumor, is cleared easily from blood stream which results in a decrease of total and liver total dose in patient. (Author).

Therapeutic value of EGFR inhibition in CRC and NSCLC: 15 years of clinical evidence.

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Troiani, Teresa; Napolitano, Stefania; Della Corte, Carminia Maria; Martini, Giulia; Martinelli, Erika; Morgillo, Floriana; Ciardiello, Fortunato

2016-01-01

Epidermal growth factor receptor (EGFR) plays a key role in tumour evolution, proliferation and immune evasion, and is one of the most important targets for biological therapy, especially for non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). In the past 15 years, several EGFR antagonists have been approved for the treatment of NSCLC and metastatic CRC (mCRC). To optimise the use of anti-EGFR agents in clinical practice, various clinical and molecular biomarkers have been investigated, thus moving their indication from unselected to selected populations. Nowadays, anti-EGFR drugs represent a gold-standard therapy for metastatic NSCLC harbouring EGFR activating mutation and for RAS wild-type mCRC. Their clinical efficacy is limited by the presence of intrinsic resistance or the onset of acquired resistance. In this review, we provide an overview of the antitumour activity of EGFR inhibitors in NSCLC and CRC and of mechanisms of resistance, focusing on the development of a personalised approach through 15 years of preclinical and clinical research.

Evaluation of safe use of 188Re-HEDP comparing urine data and whole body counting in gamma camera

International Nuclear Information System (INIS)

Paolino, Andrea; Teran, Mariella; Savio, Eduardo; Coppe, Fatima; Lopez, Andrea; Hermida, Juan C.; Gaudiano, Javier

2008-01-01

Cancer is the second more frequent cause of death, after cardiovascular disease, in developing countries. Most of adult patients with neoplasms will develop skeletal metastases that can lead to progressive pain. 188 Re emits both beta particles suitable for therapy and a gamma ray (155 keV), adequate for diagnostic imaging in order to verify localization in the pain areas associated to metastatic process. The aim of this work was to correlate 188 Re-HEDP dose estimations using biological samples and direct measures. All the patients had breast or prostate cancer, with bone metastases. Each patient received a tracer dose of 185 MBq of radiopharmaceutical. Urine samples were collected at 0-1, 1-2, 2-4 and, 4-6 hours post administration, and measured in dose calibrator. Whole body counts were acquired using a camera without collimator, window centered at 155 KeV, matrix 256 x 256, during 60 seconds. Data were obtained at 1 and 6 hours post administration with the patient in sitting position at 2 meter from the detector. Percentage of injected dose was calculated both for urine samples and image for each patient. The number of disintegrations was determined for organs in which higher concentration of activity was observed: those involved in the excretion, red marrow and the reminder of the body. Total doses were estimated using OLINDA/EXM software. Conclusions: Data showed that the organs chosen as more compromised during the tracer dose procedure received very low effective doses. A good correlation between calculations performed both for image and urine samples was obtained. Safety of the radiopharmaceutical was also verified using this method. (author)

Application and evolution of several therapy nuclides labelled antibody in tumour therapy

International Nuclear Information System (INIS)

He Jiaheng; Luo Shunzhong; Wang Guanquan

2004-12-01

Radiolabeled Monoclonal antibody had a lot of merits, such as decreasing the lesion because of the external exposure to normal tissue and the whole body, destroying cancer cells which McAb could not reach, and little ornamentation effect by Antigen. Therefor, it gradually became a kind of guiding therapy method which endowed with practical value. Up to now, the radionuclides which be used for tumour radioimmunotherapy included mostly 131 I, 90 Y, 188 Re, 186 Re, 153 Sm, 211 At, et al. The application and evolution of several therapy nuclides labelled antibody in tumour therapy are in troduced. (authors)

Kinetics of EGFR expression during fractionated irradiation varies between different human squamous cell carcinoma lines in nude mice

International Nuclear Information System (INIS)

Eicheler, Wolfgang; Krause, Mechthild; Hessel, Franziska; Zips, Daniel; Baumann, Michael

2005-01-01

Background and purpose: Preclinical and clinical data indicate that high pretherapeutic EGFR expression is associated with poor local tumour control, possibly caused by a high repopulation rate of clonogenic cells during radiotherapy in these tumours. Previous data reported from our laboratory showed a correlation between EGFR expression and acceleration of repopulation in poorly differentiated FaDu human squamous cell carcinoma (SCC) during fractionated irradiation. To test whether this is a general phenomenon, two further SCC were investigated in the present study. Patients and methods: GL and UT-SCC-14, two moderately well differentiated and keratinising hSCC, were grown as xenografts in nude mice. Functional data on the repopulation kinetics during fractionated irradiation for these tumour models have been previously determined. The expression of EGFR during fractionation was analysed by immunohistochemistry. Endpoints were the membrane-staining score and the proportion of EGFR-positive cells (EGFR labelling index). Results: Different kinetics of EGFR expression during fractionated RT were found. In UT-SCC-14, EGFR staining score and labelling index increased significantly during radiotherapy. In GL SCC, the EGFR expression was unchanged. Both tumours are characterized by a small but significant repopulation rate during radiotherapy. Conclusions: The expression of EGFR may change significantly during fractionated irradiation. No clear correlation between EGFR expression and the repopulation kinetics of clonogenic tumour cells during fractionated irradiation was found. The changes in EGFR expression during irradiation warrant further investigation on their prognostic implications and on their importance for therapeutic interventions

Radiolabeled Cetuximab Conjugates for EGFR Targeted Cancer Diagnostics and Therapy †

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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

Anti-tumor activity of high-dose EGFR tyrosine kinase inhibitor and sequential docetaxel in wild type EGFR non-small cell lung cancer cell nude mouse xenografts

OpenAIRE

Tang, Ning; Zhang, Qianqian; Fang, Shu; Han, Xiao; Wang, Zhehai

2016-01-01

Treatment of non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is still a challenge. This study explored antitumor activity of high-dose icotinib (an EGFR tyrosine kinase inhibitor) plus sequential docetaxel against wild-type EGFR NSCLC cells-generated nude mouse xenografts. Nude mice were subcutaneously injected with wild-type EGFR NSCLC A549 cells and divided into different groups for 3-week treatment. Tumor xenograft volumes were monitored and record...

Pyrosequencing, a method approved to detect the two major EGFR mutations for anti EGFR therapy in NSCLC

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Richard Marie-Jeanne

2011-05-01

Full Text Available Abstract Background Epidermal Growth Factor Receptor (EGFR mutations, especially in-frame deletions in exon 19 (ΔLRE and a point mutation in exon 21 (L858R predict gefitinib sensitivity in patients with non-small cell lung cancer. Several methods are currently described for their detection but the gold standard for tissue samples remains direct DNA sequencing, which requires samples containing at least 50% of tumor cells. Methods We designed a pyrosequencing assay based on nested PCR for the characterization of theses mutations on formalin-fixed and paraffin-embedded tumor tissue. Results This method is highly specific and permits precise characterization of all the exon 19 deletions. Its sensitivity is higher than that of "BigDye terminator" sequencing and enabled detection of 3 additional mutations in the 58 NSCLC tested. The concordance between the two methods was very good (97.4%. In the prospective analysis of 213 samples, 7 (3.3% samples were not analyzed and EGFR mutations were detected in 18 (8.7% patients. However, we observed a deficit of mutation detection when the samples were very poor in tumor cells. Conclusions pyrosequencing is then a highly accurate method for detecting ΔLRE and L858R EGFR mutations in patients with NSCLC when the samples contain at least 20% of tumor cells.

Biodistribution of Yttrium-90-Labeled Anti-CD45 Antibody in a Nonhuman Primate Model

International Nuclear Information System (INIS)

Nemecek, Eneida; Hamlin, Donald K.; Fisher, Darrell R.; Krohn, Kenneth A.; Pagel, John M.; Applebaum, F. R.; Press, Oliver W.; Matthews, Dana C.

2005-01-01

Radioimmunotherapy may improve the outcome of hematopoietic cell transplantation for hematologic malignancies by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the organ localization of yttrium-90-labeled anti-CD45 (90Y-anti-CD45) antibody in macaques, a model that had previously predicted iodine-131-labeled anti-CD-45 (131I-anti-CD45) antibody biodistribution in humans. Experimental Design: Twelve Macaca nemestrina primates received anti-CD45 antibody labeled with 1 to 2 mCi of 90Y followed by serial blood sampling and marrow and lymph node biopsies, and necropsy. The content of 90Y per gram of tissue was determined by liquid scintillation spectrometry. Time-activity curves were constructed using average isotope concentrations in each tissue at measured time points to yield the fractional residence time and estimate radiation absorbed doses for each organ per unit of administered activity. The biodistribution of 90Y-anti-CD45 antibody was then compared with that previously obtained with 131I-anti-CD45 antibody in macaques. Results: The spleen received 2,120, marrow 1,060, and lymph nodes 315 cGy/mCi of 90Y injected. The liver and lungs were the nontarget organs receiving the highest radiation absorbed doses (440 and 285 cGy/mCi, respectively). Ytrrium-90-labeled anti-CD45 antibody delivered 2.5- and 3.7-fold more radiation to marrow than to liver and lungs, respectively. The ratios previously observed with 131I-antiCD45 antibody were 2.5-and 2.2-fold more radiation to marrow than to liver and lungs, respectively. Conclusions: This study shows that 90Y-anti-CD45 antibody can deliver relatively selective radiation to hematopoietic tissues, with similar ratios of radiation delivered to target versus nontarget organs, as compared with the 131I immunoconjugate in the same animal model

EGFR gene amplification is relatively common and associates with outcome in intestinal adenocarcinoma of the stomach, gastro-oesophageal junction and distal oesophagus

International Nuclear Information System (INIS)

Birkman, Eva-Maria; Ålgars, Annika; Lintunen, Minnamaija; Ristamäki, Raija; Sundström, Jari; Carpén, Olli

2016-01-01

Approximately 50 % of gastric adenocarcinomas belong to a molecular subgroup characterised by chromosomal instability and a strong association with the intestinal histological subtype. This subgroup typically contains alterations in the receptor tyrosine kinase–RAS pathway, for example EGFR or HER2 gene amplifications leading to protein overexpression. In clinical practice, HER2 overexpressing metastatic gastric cancer is known to respond to treatment with anti-HER2 antibodies. By contrast, anti-EGFR antibodies have not been able to provide survival benefit in clinical trials, which, however, have not included patient selection based on the histological subtype or EGFR gene copy number analysis of the tumours. To examine the role of EGFR as a potential biomarker, we studied the prevalence, clinicopathological associations as well as prognostic role of EGFR and HER2 expression and gene amplification in intestinal adenocarcinomas of the stomach, gastro-oesophageal junction and distal oesophagus. Tissue samples from 220 patients were analysed with EGFR and HER2 immunohistochemistry. Those samples with moderate/strong staining intensity were further analysed with silver in situ hybridization to quantify gene copy numbers. The results were associated with clinical patient characteristics and survival. Moderate/strong EGFR protein expression was found in 72/220 (32.7 %) and EGFR gene amplification in 31/220 (14.1 %) of the tumours, while moderate/strong HER2 protein expression was detected in 31/220 (14.1 %) and HER2 gene amplification in 29/220 (13.2 %) of the tumours. EGFR and HER2 genes were co-amplified in eight tumours (3.6 %). EGFR gene amplification was more common in tumours of distal oesophagus/gastro-oesophageal junction/cardia than in those of gastric corpus (p = 0.013). It was associated with shortened time to cancer recurrence (p = 0.026) and cancer specific survival (p = 0.033). EGFR gene amplification is relatively common in intestinal adenocarcinomas

EGFR and Bcl-2 in gastric mucosa of children infected with Helicobacter pylori

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Ewa Ryszczuk

2016-03-01

Full Text Available Aim: The aim of the study was to evaluate the expression of EGFR and Bcl-2 proteins as inhibitory markers of apoptosis in surface epithelial cells and gland cells of antral gastric mucosa in children infected with Helicobacter pylori according to the severity and activity of antral gastritis and to assess the correlation between the number of cells expressing EGFR and the number of cells expressing Bcl-2 in H. pylori infected children.Materials and methods: The study included 44 children: 68.2% with chronic gastritis and positive IgG against H. pylori, and 31.8% with functional disorders of the gastrointestinal tract and with normal IgG against H. pylori. The evaluation of EGFR expression in gastric mucosa was performed immunohistochemically using monoclonal mouse anti-EGFR antibody. The polyclonal antibody was used to determine the expression of anti-Bcl-2.Results: A significant increase in the number of cells expressing EGFR and Bcl-2 protein was found in the epithelial cells in severe as well as mild and moderate gastritis in the group of children infected with H. pylori. An increase in the number of cells expressing EGFR and Bcl-2 protein was also found in the epithelial cells in group I according to the activity of gastritis. There was a statistically significant positive correlation between the numbers of cells expressing EGFR and Bcl-2 in H. pylori infected children.Conclusion: Increased expression of EGFR and Bcl-2 proteins in the epithelial cells and a statistically significant positive correlation between the numbers of cells expressing EGFR and Bcl-2 in H. pylori infected children could suggest increased regeneration abilities of gastric mucosa.

Determination of radiochemical yields of 186Re-labelled complexes using thin layer chromatography

International Nuclear Information System (INIS)

Konirova, R.; Kohlickova, M.; Jedinakova-Krizova, V.

1999-01-01

The reaction conditions for synthesis of three rhenium complexes 186 Re-methylendiphosphonate (MDP), 186 Re-hydroxyethylidendiphosphonate (HEDP) and 186 Re-citrate have been investigated. Radiochemical yield of complexation has been determined by thin layer chromatography and paper chromatography. The rhenium complexation with corresponding ligand is dependent on pH values of reaction mixture, concentration of studied ligand (MDP, HEDP and sodium citrate) and concentration of reducing agent. Stannous chloride with ascorbic acid (as antioxidant) was used for reduction of perrhenate. The labeling yield of 186 Re-MDP was about 90 %, of 186 Re-HEDP more than 80 % and more than 75 % for 186 Re-citrate under optimum conditions. Besides, the possibility of application of porphyrins as organic ligands for complexation with rhenium isotopes is examined. (authors)

Rhenium-188 as an alternative to Iodine-131 for treatment of breast tumors expressing the sodium/iodide symporter (NIS)

International Nuclear Information System (INIS)

Dadachova, E.; Bouzahzah, B.; Zuckier, L.S.; Pestell, R.G.

2002-01-01

The sodium-iodide symporter (NIS), which transports iodine into the cell, is expressed in thyroid tissue and was recently found to be expressed in approximately 80% of human breast cancers but not in healthy breast tissue. These findings raised the possibility that therapeutics targeting uptake by NIS may be used for breast cancer treatment. To increase the efficacy of such therapy it would be ideal to identify a radioactive therapy with enhanced local emission. The feasibility of using the powerful beta-emitting radiometal 188 Re in the form of 188 Re-perrhenate was therefore compared with 131 I for treatment of NIS-expressing mammary tumors. In the current studies, using a xenografted breast cancer model induced by the ErbB2 oncogene in nude mice, 188 Re-perrhenate exhibited NIS-dependent uptake into the mammary tumor. Dosimetry calculations in the mammary tumor demonstrate that 188 Re-perrhenate is able to deliver a dose 4.5 times higher than 131 I suggesting it may provide enhanced therapeutic efficacy

Iodine-131 labeled anti-CEA polyclonal antibody detection of gastrointestinal cancer

International Nuclear Information System (INIS)

Nabi, H.A.; Hinkle, G.H.; Olsen, J.O.; Haagensen, D.A.; Thurston, M.O.; Mojzisik, C.; Houchens, D.; Martin, E.W. Jr.

1984-01-01

To localize gastrointestinal tumor, 31 patients were injected with 1.7-2.1 mCi I-131 anti-CEA baboon polyclonal antibody. Whole body imaging at 48, 72, and occasionally 96 hrs was performed with a Signa Camera (Technicare) peaked at 364 keV with 20% window. Additional spot views were usually obtained. No subtraction methods were used. All patients had surgical and pathological confirmation of the nuclear medicine studies. Labeled antibody images were positive in 15 (8 recurrent or metastatic colorectal, 2 gastric, 1 pancreatic, 1 primary colon, and 1 breast metastatic to chest wall). In 1, antibody images were positive for metastatic deposits in para-aortic lymph nodes, but negative for primary rectal tumor. True negative images were observed in 6; false negative images in 9 (4 liver metastases, 2 rectal, 1 pancreatic, 1 mesenteric lymph node metastasis, 1 bone metastasis). In all cases, no correlation existed between preoperative CEA serum levels and imaging. I-131 labeled anti-CEA polyclonal antibody imaging proved highly efficient in detecting gastric cancer (2/2) and moderately efficient in detecting recurrent colorectal cancer (8/15). On the other hand, the I-131 labeled polyclonal anti-CEA antibody imaging was of limited value in detecting colon cancer (1/9), pancreatic cancer (1/4) and metastatic liver disease

Humanized versus murine anti-human epidermal growth factor receptor monoclonal antibodies for immunoscintigraphic studies

Energy Technology Data Exchange (ETDEWEB)

Morales, Alejo A. Morales; Duconge, Jorge; Alvarez-Ruiz, Daniel; Becquer-Viart, Maria de Los Angeles; Nunez-Gandolff, Gilda; Fernandez, Eduardo; Caballero-Torres, Idania; Iznaga-Escobar, Normando

2000-02-01

The anti-human epidermal growth factor receptor (EGF-R) humanized antibody h-R3 (IgG{sub 1}), which binds to an extracellular domain of EGF-R, was used to evaluate the biodistribution on nude mice xenografted with A431 epidermoid carcinoma cell line. Results are compared with its murine version ior egf/r3 monoclonal antibody (mAb). Twenty-one athymic female 4NMRI nu/nu mice were injected intravenously with 10 {mu}g/100 {mu}Ci of {sup 99m}Tc-labeled mAbs. The mAb ior C5 that recognizes an antigen expressed preferentially on the surface of malignant and cytoplasm of normal colorectal cells was used as negative control. Immunoreactivity of {sup 99m}Tc-labeled mAbs was measured by enzyme linked immunosorbent assay on A431 cell line and the immunoreactive fractions determined by Lindmo method. Among all organs significant accumulation was found in tumor (6.14{+-}2.50 %ID/g, 5.06{+-}2.61 %ID/g for murine and humanized mAbs, respectively) 4 h after injection. The immunoreactive fractions were found to be 0.88 and 0.81 for murine and humanized mAb, respectively. Thus, we expect better results using the humanized mAb h-R3 for diagnostic immunoscintigraphy.

Humanized versus murine anti-human epidermal growth factor receptor monoclonal antibodies for immunoscintigraphic studies

International Nuclear Information System (INIS)

Morales, Alejo A. Morales; Duconge, Jorge; Alvarez-Ruiz, Daniel; Becquer-Viart, Maria de Los Angeles; Nunez-Gandolff, Gilda; Fernandez, Eduardo; Caballero-Torres, Idania; Iznaga-Escobar, Normando

2000-01-01

The anti-human epidermal growth factor receptor (EGF-R) humanized antibody h-R3 (IgG 1 ), which binds to an extracellular domain of EGF-R, was used to evaluate the biodistribution on nude mice xenografted with A431 epidermoid carcinoma cell line. Results are compared with its murine version ior egf/r3 monoclonal antibody (mAb). Twenty-one athymic female 4NMRI nu/nu mice were injected intravenously with 10 μg/100 μCi of 99m Tc-labeled mAbs. The mAb ior C5 that recognizes an antigen expressed preferentially on the surface of malignant and cytoplasm of normal colorectal cells was used as negative control. Immunoreactivity of 99m Tc-labeled mAbs was measured by enzyme linked immunosorbent assay on A431 cell line and the immunoreactive fractions determined by Lindmo method. Among all organs significant accumulation was found in tumor (6.14±2.50 %ID/g, 5.06±2.61 %ID/g for murine and humanized mAbs, respectively) 4 h after injection. The immunoreactive fractions were found to be 0.88 and 0.81 for murine and humanized mAb, respectively. Thus, we expect better results using the humanized mAb h-R3 for diagnostic immunoscintigraphy

Radioimmunotherapy of Nude Mice Bearing Human Colon Carcinoma with I-131 Labeled Anti-carcinoembryonic Antigen

International Nuclear Information System (INIS)

Kim, Byung Tae; Lee, Kyung Han; Kim, Sang Eun; Choi, Yong; Chi, Dae Yoon; Chung, June Key; Lee, Myung Chul; Koh, Chang Soon; Chung, Hong Keun

1995-01-01

This study was designed to evaluate the effects of various factors on the therapeutic effect of the I-l3l labeled anti-carcinoembryonic antigen monoclonal antibody(anti-CEA antibody). Tetrazolium-based colorimetric assay (MTT) was used to compare in vitro cytotoxicity of 3 Korean colon cancer cell lines (SNU-C2A, SNU-C4, SNU-C5) for selection of proper 2 cell lines in this study. The changes of the size of tumor which was xenografted to nude mice (balb/c nu/nu) were compared in 4 groups (group treated I-131 labeled anti-CEA antibody, group treated with non-radiolabeled anti-CEA antibody, group treated with I-131. labeled anti-human chorionic gonadotropin monoclonal antibody (anti-hCG antibody) as nonspecific antibody, and group injected with normal saline as a control). Immunohistochemical staining and in vivo autoradiography were performed after excision of the xenografted tumor. The results were as below mentioned. The in vitro cytotoxic effect of I-131 labeled anti-CEA antibody is most prominent in SNU-C5 cell line between 3 cancer cell lines. The changes of xenografted tumor size in both SNU-C4 and SNU-C5 cell tumors at the thirteenth day after injection of the antibodies were smallest in the group treated with I-131 labeled anti-CEA antibody (SNU-C4/SNU-C5; 324/342%) comparing with other groups, group treated with anti-CEA antibody (622/660%), group treated with I-131 anti-hCG antibody (538/546%), and control group(1030/724%) (p<0.02 in SNU-C4 and p<0.1in SNU-C5 at the 13th day after injection of antibodies). On the thirteenth day after injection of the antibodies nude mice were sacreficed to count the radiouptake of tumor and to check the changes of tumor size. Correlations between radiouptake and change of tumor size were calculated in each groups and significant negative correlation was only obtained in the group treated with I-131 anti-CEA antibody (p<0.05). There were no correlations between antigenic expression of carcinoembryonic antigen and

Nimotuzumab enhances temozolomide?induced growth suppression of glioma cells expressing mutant EGFR in vivo

OpenAIRE

Nitta, Yusuke; Shimizu, Saki; Shishido?Hara, Yukiko; Suzuki, Kaori; Shiokawa, Yoshiaki; Nagane, Motoo

2016-01-01

Abstract A mutant form of epidermal growth factor receptor (EGFR), EGFRvIII, is common in glioblastoma (GBM) and confers enhanced tumorigenic activity and drug resistance. Nimotuzumab, an anti?EGFR antibody, has shown preclinical and clinical activity to GBM, but its specific activity against EGFRvIII has not been fully investigated. Human glioma U87MG or LNZ308 cells overexpressing either wild?type (wt) EGFR or EGFRvIII were treated with nimotuzumab, temozolomide, or both. Expression and pho...

Anti-sense suppression of epidermal growth factor receptor expression alters cellular proliferation, cell-adhesion and tumorigenicity in ovarian cancer cells.

Science.gov (United States)

Alper, O; De Santis, M L; Stromberg, K; Hacker, N F; Cho-Chung, Y S; Salomon, D S

2000-11-15

Over-expression of epidermal growth factor receptor (EGFR) in ovarian cancer has been well documented. Human NIH:OVCAR-8 ovarian carcinoma cells were transfected with an expression vector containing the anti-sense orientation of truncated human EGFR cDNA. EGFR anti-sense over-expression resulted in decreased EGFR protein and mRNA expression, cell proliferation and tumor formation in nude mice. In accordance with the reduced levels of EGFR in EGFR anti-sense-expressing cells, tyrosine phosphorylation of EGFR was decreased compared to untransfected parental cells treated with EGF. In EGFR anti-sense-transfected cells, expression of erbB-3, but not erbB-2, was increased. In addition, basal and heregulin-beta 1-stimulated tyrosine phosphorylation of erbB-3 was higher in EGFR anti-sense vector-transfected cells. A morphological alteration in EGFR anti-sense gene-expressing cells was correlated with a decrease in the expression of E-cadherin, alpha-catenin and, to a lesser extent, beta-catenin. Changes in the expression of these proteins were associated with a reduction in complex formation among E-cadherin, beta-catenin and alpha-catenin and between beta-catenin and EGFR in EGFR anti-sense-expressing cells compared to sense-transfected control cells. These results demonstrate that EGFR expression in ovarian carcinoma cells regulates expression of cell adhesion proteins that may enhance cell growth and invasiveness. Copyright 2000 Wiley-Liss, Inc.

[Anti-EGFR Antibody Combination Chemotherapy Was Effective against Locally Advanced Ascending Colon Cancer as Well as a Recurrent Lesion - A Case Report].

Science.gov (United States)

Yamada, Yasufumi; Yokomizo, Hajime; Yano, Yuki; Okayama, Sachiyo; Satake, Masaya; Ida, Arika; Usui, Takebumi; Yamaguchi, Kentaro; Shiozawa, Shunichi; Yoshimatsu, Kazuhiko; Shimakawa, Takeshi; Katsube, Takao; Naritaka, Yoshihiko; Kato, Hiroyuki

2017-10-01

Here we report a case in which a locally advanced ascending colon cancer was successfully treated with anti-EGFR immunotherapy combined with chemotherapy and curative resection, and recurrent cancer was treated with the same chemotherapy. A 71-year-old man was diagnosed with ascending colon cancer in our department. No distant metastasis was observed, but curative resection was considered impossible because of extensive local cancer invasion. Because a genetic analysis revealed the presence of the wild-type KRAS gene, 6 courses of mFOLFOX6 plus cetuximab were administered. A cPR was obtained and curative resection was performed. The final diagnosis was ypT3N1M0, ypStage III a colon cancer, and chemotherapy improved the cancer stage to Grade 1b. Six courses of FOLFOX6 were then administered, followed by observation. After 2 years 6 months, a tumor of approximately 5 cm in size was noted in the right buttock using surveillance CT and was diagnosed as recurrent colon cancer. We considered further curative resection difficult and therefore 6 courses of mFOLFOX6 plus panitumumab were administered, a cPR was obtained, and right hip tumor extirpation surgery was performed. These results suggest that chemotherapy combined with anti-EGFR antibody immunotherapy is effective in treating recurrent colon cancer.

Phosphorylated EGFR expression may predict outcome of EGFR-TKIs therapy for the advanced NSCLC patients with wild-type EGFR

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Wang Fen

2012-08-01

Full Text Available Abstract Background EGFR mutation is a strong predictive factor of EGFR-TKIs therapy. However, at least 10% of patients with EGFR wild-type are responsive to TKIs, suggesting that other determinants of outcome besides EGFR mutation might exist. We hypothesized that activation of phosphorylated EGFR could be a potential predictive biomarker to EGFR-TKIs treatment among patients in wild-type EGFR. Method Total of 205 stage IIIb and IV NSCLC patients, tissue samples of whom were available for molecular analysis, were enrolled in this study. The phosphorylation of EGFR at tyrosine 1068 (pTyr1068 and 1173 (pTyr1173 were assessed by immunohistochemistry, and EGFR mutations were detected by denaturing high performance liquid chromatograph (DHPLC. Results Among 205 patients assessable for EGFR mutation and phosphorylation analysis, 92 (44.9% were EGFR mutant and 165 patients (57.6% had pTyr1173 expression. Superior progression-free survival (PFS was seen after EGFR-TKIs therapy in patients with pTyr1068 expression compared to pTyr1068 negative ones (median PFS 7.0 months vs. 1.2 months, P P = 0.016. In subgroup of patients with wild-type EGFR, pTyr1068 expression positive ones had a significantly prolonged PFS (4.2 months vs.1.2 months P  Conclusion pTyr1068 may be a predictive biomarker for screening the population for clinical response to EGFR-TKIs treatment; especially for patients with wild-type EGFR.

Treatment of diffuse in-stent restenosis with rotational atherectomy followed by radiation therapy with a 188Re-MAG3-filled balloon: six-month clinical and angiographic results of R4 registry

International Nuclear Information System (INIS)

Moon, D. H.; Oh, S. J.; Park, S. W.; Hong, M. K.; Lee, C. H.; Kim, J. Z.; Park, S. J.; Lee, H. K.

2000-01-01

Intracoronary β-irradiation after rotational atherectomy may be a reasonable approach to prevent recurrent in-stent restenosis (ISR). This study was done to evaluate the feasibility and efficacy of β-radiation therapy with a 188 Re-MAG3-filled balloon following rotational atherectomy for ISR. Fifty consecutive patients with diffuse ISR (length >10 mm) in native coronary arteries underwent rotational atherectomy and adjunctive balloon angioplasty followed by β-irradiation using 188 Re-MAG3-filled balloon catheter. The radiation doses was 15 Gy at 1.0 mm deep into vessel wall. Mean length of the lesion and irradiated segment was 25.6±12.7 mm and 37.6±11.2 mm, respectively. The radiation was delivered successfully to all patients, with a mean irradiation time of 20.1±61 7 sec. No adverse event including myocardial infarction, death, or stent thrombosis occurred during the follow-up period (mean 10.3±3.7 mon) and non-target vessel revascularization was needed in one patient. Six-month binary angiographic restenosis rate was 10.4% (2 focal ISR and 3 edge restenosis) and loss index was 0.17±0.31. Irradiation using 188 Re-MAG3-filled balloon following rotational atherectomy for patients with diffuse ISR may improve the clinical and angiographic outcomes. Further prospective randomized trials are warranted to evaluate the synergistic effect of debulking and irradiation in patients with diffuse ISR

An indirect antibody assay using haptenated antigen and 125I-labelled anti-hapten antibody

International Nuclear Information System (INIS)

Aalberse, R.C.; Amsterdam Univ.

1978-01-01

Hapten (trinitrophenyl) was coupled to antigen (ovalbumin). The haptenated antigen was bound by anti-ovalbumin antibody and binding was quantitated with 125 I-labelled anti-hapten antibodies. Thus, with a single radioactive reagent, antibodies against a variety of antigens can be detected while the problems inherent in a labelled antiglobulin binding test are avoided. In the ovalbumin system, the haptenated antigen binding test proved to be approximately 20 times as sensitive as the iodinated ovalbumin binding test

Inhibition of radiation-induced EGFR nuclear import by C225 (Cetuximab) suppresses DNA-PK activity

International Nuclear Information System (INIS)

Dittmann, Klaus; Mayer, Claus; Rodemann, Hans-Peter

2005-01-01

Background and purpose: Inhibition of EGFR-function can induce radiosensitization in tumor cells. Purpose of our investigation was to identify the possible molecular mechanism of radiosensitization following treatment with anti-EGFR-antibody C225 (Cetuximab). Materials and methods: The effect of C225 on radiation response was determined in human cell lines of bronchial carcinoma (A549) and breast adenoma cells (MDA MB 231). The molecular effects of C225 on EGFR-function after irradiation were analyzed applying western blotting, immune-precipitation and kinase assays. Effects on DNA-repair were detected by quantification of γ-H2AX positive foci 24 h after irradiation. Results: The EGFR specific antibody C225 induced radiosensitization in A549 and also in MDA MB 231 cells. Radiosensitization in A549 was associated with blockage of radiation-induced EGFR transport into the nucleus, and immobilized the complex of EGFR with DNA-dependent protein kinase (DNA-PK) in the cytoplasm. As a consequence radiation-induced DNA-PK activation was abolished, a process that is essential for DNA-repair after radiation exposure. Likewise C225 treatment increased the residual amount of γ-H2AX-positive foci 24 h after irradiation in A549 and in MDA MB 231 cells. Conclusions: Our results suggest that irradiation induced DNA-PK activation-essential for DNA repair-may be hampered specifically by use of the anti-EGFR-antibody C225. This process is associated with radiosensitization

Evaluation of epidermal growth factor receptor (EGFR) by chromogenic in situ hybridization (CISH) and immunohistochemistry (IHC) in archival gliomas using bright-field microscopy.

Science.gov (United States)

Marquez, Abbey; Wu, Rina; Zhao, Jianxin; Tao, Jianhua; Shi, Zuorong

2004-03-01

Overexpression of EGFR secondary to EGFR gene amplification is a common feature in primary malignant gliomas. To correctly assess EGFR protein and gene level as possible prognostic and predictive markers in gliomas, straightforward assays, which can be used routinely in the pathology laboratory to evaluate EGFR status, becomes critical. EGFR gene amplification and chromosome 7 aneuploidy was detected in 34 formalin-fixed, paraffin-embedded benign and malignant gliomas by chromogenic in situ hybridization (CISH) using digoxigenin-labeled EGFR and biotin-labeled chromosome 7 centromeric probes. The results were evaluated by bright-field microscopy under a 40x objective lens. EGFR protein level was detected by immunohistochemistry (IHC) using monoclonal antibody 31G7. Five cases, 3 astrocytoma grade III (33%) and 2 glioblastoma multiforme (GBM) (33%), had EGFR amplification displayed as diaminobenzidine-stained multiple dots suggesting the pattern of double-minute chromosomes. Chromosome 7 polysomy was found in 68% gliomas, 100% GBM, 67% astrocytoma grade III, 42% astrocytoma grade II, 50% astrocytoma grade I, 100% ependymoma, and the 1 case of mixed glioma III. High expression of EGFR protein was present in 62% gliomas and displayed membrane and cytoplasmic staining. All tumors with EGFR gene amplification showed EGFR high expression. High expression of EGFR without gene amplification was observed in all grades of gliomas. Simultaneous detection of EGFR gene copies or chromosome 7 centromere signals along with tissue morphology allows us to compare CISH results easily with IHC results. Our results show that CISH is an objective, practical, and accurate assay to screen for EGFR gene status in gliomas.

Development and utilization of the inorganic polymer materials for {sup 99}Mo-{sup 99m}Tc and {sup 188}W-{sup 188}Re generator based on (n, gamma) method

Energy Technology Data Exchange (ETDEWEB)

Yoshida, Kosuke; Ishikawa, Koji; Terunuma, Hitoshi; Hasegawa, Yoshio; Tatenuma, Katsuyoshi [KAKEN Co., Mito, Ibaraki (Japan)

2003-03-01

A molybdenum (Mo) adsorbent called PZC (Poly Zirconium Compound) with high efficiency of Mo adsorption has been developed in order to generate {sup 99m}Tc from {sup 99}Mo produced from natural Mo by (n, gamma) method. The {sup 99m}Tc generator using PZC has cleared mostly the technical subjects. By the results of many experiments, cold and hot test with {sup 99}Mo activity from low level (10{sup 5} Bq) to high level (10{sup 10} Bq), it has been confirmed that the PZC method can be practically applied for the (n, gamma) {sup 99}Mo-{sup 99m}Tc generator. From the reasons that PZC has the ability and many merits such as high adsorption capacity (>250 mg-Mo/g-PZC) of Mo, high elution yield (av. 80%) of {sup 99m}Tc, the low breakthrough (<0.05 kBq-{sup 99m}Mo/MBq-{sup 99m}Tc) of {sup 99}Mo and others, the current (n, fission) {sup 99m}Tc generator utilizing {sup 99}Mo produced from enriched uranium will be taken the place by PZC method. In this paper, the practicability of PZC and a newly developed functional material PTC(Poly Titanium Compound) as the (n, gamma) {sup 99}Mo-{sup 99m}Tc generator, and an ability of PZC as the {sup 188}W-{sup 188}Re generator will be shown. (author)

Treatment of diffuse in-stent restenosis with rotational atherectomy followed by radiation therapy with a {sup 188}Re-MAG3-filled balloon: six-month clinical and angiographic results of R4 registry

Energy Technology Data Exchange (ETDEWEB)

Moon, D. H.; Oh, S. J.; Park, S. W.; Hong, M. K.; Lee, C. H.; Kim, J. Z.; Park, S. J.; Lee, H. K. [College of Medicine, Ulsan Univ., Seoul (Korea, Republic of)

2000-07-01

Intracoronary {beta}-irradiation after rotational atherectomy may be a reasonable approach to prevent recurrent in-stent restenosis (ISR). This study was done to evaluate the feasibility and efficacy of {beta}-radiation therapy with a {sup 188}Re-MAG3-filled balloon following rotational atherectomy for ISR. Fifty consecutive patients with diffuse ISR (length >10 mm) in native coronary arteries underwent rotational atherectomy and adjunctive balloon angioplasty followed by {beta}-irradiation using {sup 188}Re-MAG3-filled balloon catheter. The radiation doses was 15 Gy at 1.0 mm deep into vessel wall. Mean length of the lesion and irradiated segment was 25.6{+-}12.7 mm and 37.6{+-}11.2 mm, respectively. The radiation was delivered successfully to all patients, with a mean irradiation time of 20.1{+-}61 7 sec. No adverse event including myocardial infarction, death, or stent thrombosis occurred during the follow-up period (mean 10.3{+-}3.7 mon) and non-target vessel revascularization was needed in one patient. Six-month binary angiographic restenosis rate was 10.4% (2 focal ISR and 3 edge restenosis) and loss index was 0.17{+-}0.31. Irradiation using {sup 188}Re-MAG3-filled balloon following rotational atherectomy for patients with diffuse ISR may improve the clinical and angiographic outcomes. Further prospective randomized trials are warranted to evaluate the synergistic effect of debulking and irradiation in patients with diffuse ISR.

EGFR signaling in colorectal cancer: a clinical perspective

Directory of Open Access Journals (Sweden)

Saletti P

2015-01-01

Full Text Available Piercarlo Saletti,1 Francesca Molinari,2 Sara De Dosso,1 Milo Frattini2 1Oncology Institute of Southern Switzerland, Bellinzona, 2Laboratory of Molecular Pathology, Institute of Pathology, Locarno, Switzerland Abstract: Colorectal cancer (CRC remains a formidable health burden worldwide, with up to 50% of patients developing metastases during the course of their disease. This group of CRC patients, characterized by the worst prognosis, has been extensively investigated to improve their life expectancy. Main efforts, focused on the epidermal growth-factor receptor (EGFR, which plays a pivotal role in CRC pathogenesis, have led to the development and introduction in clinical practice of specific targeted therapies (ie, monoclonal antibodies. Subsequently, the scientific community has tried to identify molecular predictors of the efficacy of such therapies. However, it has become clear that EGFR alterations occurring in CRC are difficult to investigate, and therefore their predictive role is unclear. In contrast, the clinical role of two downstream members (KRAS and NRAS has been clearly demonstrated. Currently, EGFR-targeted therapies can be administered only to patients with wild-type KRAS and NRAS genes. Our review addresses the medical management of metastatic CRC. Specifically, we describe in detail the molecular biology of metastatic CRC, focusing on the EGFR signaling pathway, and we discuss the role of current and emerging related biomarkers and therapies in this field. We also summarize the clinical evidence regarding anti-EGFR monoclonal antibodies and examine potential future perspectives. Keywords: colorectal cancer, EGFR, gene mutations, cetuximab, panitumumab

Report on the 2nd Research Coordination Meeting on The Development of Therapeutic Radiopharmaceuticals Based on 188Re and 90Y for Radionuclide. Working Document

International Nuclear Information System (INIS)

2010-01-01

Radionuclide therapy is practiced for the treatment of malignant disorders of various organs and tissues as well as for treating certain other diseases such as rheumatoid arthritis. Advances in understanding tumor biology as well as developments in peptide chemistry and monoclonal antibody technology are opening new opportunities for the development of therapeutic radiopharmaceuticals, thereby widening the scope of radionuclide therapy. In addition, particulate based radiopharmaceuticals are useful for treating hepatocarcinoma as well as in radiation synovectomy. With the establishment of new products the demand and application of therapeutic nuclear medicine is expected to grow rapidly. While there are a large number of radioisotopes proposed for targeted therapy, practical considerations had been limiting the number of usable isotopes. Generator-produced radionuclides are an attractive option for the large scale on-site availability of therapeutic isotopes. The IAEA’s CRP on the ‘Development of generator technologies for therapeutic radionuclides’ (2004-2007) was successful in developing technologies for the preparation of 188 W/ 188 Re and 90 Sr/ 90 Y generators for eluting 188 Re and 90 Y of high radionuclidic and chemical purity usable for research applications in the development of therapeutic radiopharmaceuticals. The IAEA’s CRP on ‘The development of therapeutic radiopharmaceuticals based on 188 Re and 90 Y for radionuclide therapy’ was formulated to focus on enhancing the capacity of the 90 Sr/ 90 Y generator; to develop and validate quality control methods for the generator eluate; and to develop therapeutic radiopharmaceuticals based on 188 Re and 90 Y. The first RCM of the CRP was held in Polatom, Warsaw, Poland from 30 June to 4 July 2008. The meeting reviewed the work going on in the different participating laboratories, and the facilities, expertise and capabilities of the different participating groups, and formulated the work plan of

Clearance of 131I-labeled murine monoclonal antibody from patients' blood by intravenous human anti-murine immunoglobulin antibody

International Nuclear Information System (INIS)

Stewart, J.S.; Sivolapenko, G.B.; Hird, V.; Davies, K.A.; Walport, M.; Ritter, M.A.; Epenetos, A.A.

1990-01-01

Five patients treated with intraperitoneal 131I-labeled mouse monoclonal antibody for ovarian cancer also received i.v. exogenous polyclonal human anti-murine immunoglobulin antibody. The pharmacokinetics of 131I-labeled monoclonal antibody in these patients were compared with those of 28 other patients receiving i.p.-radiolabeled monoclonal antibody for the first time without exogenous human anti-murine immunoglobulin, and who had no preexisting endogenous human anti-murine immunoglobulin antibody. Patients receiving i.v. human anti-murine immunoglobulin antibody demonstrated a rapid clearance of 131I-labeled monoclonal antibody from their circulation. The (mean) maximum 131I blood content was 11.4% of the injected activity in patients receiving human anti-murine immunoglobulin antibody compared to 23.3% in patients not given human anti-murine immunoglobulin antibody. Intravenous human anti-murine immunoglobulin antibody decreased the radiation dose to bone marrow (from 131I-labeled monoclonal antibody in the vascular compartment) 4-fold. Following the injection of human anti-murine immunoglobulin antibody, 131I-monoclonal/human anti-murine immunoglobulin antibody immune complexes were rapidly transported to the liver. Antibody dehalogenation in the liver was rapid, with 87% of the injected 131I excreted in 5 days. Despite the efficient hepatic uptake of immune complexes, dehalogenation of monoclonal antibody was so rapid that the radiation dose to liver parenchyma from circulating 131I was decreased 4-fold rather than increased. All patients developed endogenous human anti-murine immunoglobulin antibody 2 to 3 weeks after treatment

Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3

Directory of Open Access Journals (Sweden)

Zhao Lei

2012-12-01

Full Text Available Abstract Background Epidermal growth factor receptor (EGFR is suggested to predict the radiosensitivity and/or prognosis of human esophageal squamous cell carcinoma (ESCC. The objective of this study was to investigate the efficacy of Nimotuzumab (an anti-EGFR monoclonal antibody on ESCC radiotherapy (RT and underlying mechanisms. Methods Nimotuzumab was administrated to 2 ESCC cell lines KYSE30 and TE-1 treated with RT. Cell growth, colony formation and apoptosis were used to measure anti-proliferation effects. The method of RNA interference was used to investigate the role of insulin-like growth factor binding protein-3 (IGFBP-3 in ESCC cells radiosensitivity treated with Nimotuzumab. In vivo effect of Nimotuzumab on ESCC radiotherapy was done using a mouse xenograft model. Results Nimotuzumab enhanced radiation response of KYSE30 cells (with high EGFR expression in vitro, as evidenced by increased radiation-inhibited cell growth and colony formation and radiation-mediated apoptosis. Mechanism study revealed that Nimotuzumab inhibited phosphorylated EGFR (p-EGFR induced by EGF in KYSE30 cells. In addition, knockdown of IGFBP-3 by short hairpin RNA significantly reduced KYSE30 cells radiosensitivity (PP>0.05. In KYSE30 cell xenografts, Nimotuzumab combined with radiation led to significant tumor growth delay, compared with that of radiation alone (P=0.029, and also with IGFBP-3 up-regulation in tumor tissue. Conclusions Nimotuzumab could enhance the RT effect of ESCC cells with a functional active EGFR pathway. In particular, the increased ESCC radiosensitivity by Nimotuzumab might be dependent on the up-regulation of IGFBP-3 through EGFR-dependent pathway.

Anti-EGFR therapy radiosensitizes human lung adenocarcinoma xenograft in nude mouse

International Nuclear Information System (INIS)

Wang Hui; Li Tianran; Tian Jiahe; Qu Baolin; Zhu Hui

2008-01-01

Objective: To investigate the effect of Gefitinib on radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. Methods: Human lung adenocarcinoma cell line A549 was used to establish nude mouse xenograft tumor model. The mice were derided into 4 groups: control, irradiation alone, Gefinitib alone and radiation combined with Genifitib. Radiation schedule was 3 fractions of 5 Gy, once daily. Gefitinib was daily administered by gavage at 100 mg/(kg·day -1 ) for 14 days. In the combination group, radiotherapy was performed 2 hours after Gefitinib administration. Tumor diameter was measured every other day. Percentage of tumor growth inhibition, growth delay time and regrowth delay time were evaluated. Results: For A549 xenografts in radiation alone, gefitinib alone and combination therapy groups, the percentage of tumor growth inhibition was 22.7%, 12.4% and 38.2%, respectively (F=25.75, P=0.000). Tumor growth delay time was 6.0, 7.8 and 21.6 days, respectively (F=70.49, P=0.000). Tumor regrowth delay time in combination therapy and irradiation alone groups was 23.4 and 10.2 days. (F=174.24, P= 0.000). Sensitizing enhancement ratio of combination group was 1.5 in growth and 1.7 in regrowth. Conclusions: Anti-EGFR therapy enhances the radiosensitivity of human lung adenocarcinoma xenograft in nude mouse. (authors)

Treatment with rhenium-188-perrhenate and iodine-131 of NIS-expressing mammary cancer in a mouse model remarkably inhibited tumor growth

International Nuclear Information System (INIS)

Dadachova, Ekaterina; Nguyen, Andrew; Lin, Elaine Y.; Gnatovskiy, Leo; Lu, Ping; Pollard, Jeffrey W.

2005-01-01

Introduction: Novel therapeutic modalities are needed for breast cancer patients in whom standard treatments are not effective. Mammary gland sodium/iodide symporter has been identified as a molecular target in breast cancers in humans and in some transgenic mouse models. We report the results of a therapy study with 131 I - and 188 ReO 4 - of breast cancer in polyoma middle T oncoprotein (PyMT) transgenic mice endogenously expressing the Na + /I - symporter (NIS). Methods: PyMT mice (12-13 weeks old) with one palpable tumor of 0.5-0.8 cm in diameter were used. For the therapy studies, PyMT mice were (1) treated with two intraperitoneal injections of 1.5 mCi of 188 ReO 4 - 1 week apart, (2) pretreated for 1 week with 5 μg of triiodothyronine (T3) followed by two intraperitoneal injections of 1.5 mCi of 131 I - 1 week apart or (3) left untreated. The tumor and normal organ uptakes were assessed by scintigraphic imaging. The thyroid function of treated and control animals was evaluated at the completion of the study by measuring the T3/thyroxine (T4) ratio in their blood. Results: There was significant uptake of 131 I - and 188 ReO 4 - in the primary palpable tumors as well as in nonpalpable tumors, stomachs and thyroids. The tumor uptake after the second injection was 10 times lower in comparison with the first injection. Tumor growth was significantly inhibited in both the 131 I - and 188 ReO 4 - groups in comparison with the control group, and tumors in the 188 ReO 4 - group increased in size significantly less than in the 131 I - group. The T3/T4 ratios were calculated to be 27 and 25 for the control group and the 188 ReO 4 - group, respectively; for 131 I - , both the T3 and T4 levels were below detection limit, demonstrating much less effect on the thyroids of treatment with 188 ReO 4 - than with 131 I - . Conclusions: These results prove that NIS expression in breast tumors in animal models allows specific, efficient and safe treatment with a variety of

Preparation of 99''m technitium labelled erythrocytes coated with anti-rhesus-D immunoglobulin (anti-Rho-D IgG) for defective spleen diagnosis

International Nuclear Information System (INIS)

Nanny Kartini, H.; Karnama, S.; Ahmad Muhtadi; Karna Awangga

1999-01-01

Preparation of 99m technetium-red blood cells coated with anti-rhesus-D IgG has been carried out and evaluated. Some factors such as the concentration of Sn(II) and incubation time which can influence the labelling yield are discussed. A labelling efficiency of greater than 90% (93.1 ±1.4% ) was obtained. Biological studies in normal human volunteers, showed that 99m Tc-red blood cell coated with anti-rhesus-D IgG accumulated in the spleen and may become a spleen imaging agent. (author)

Clinical efficacy of icotinib in lung cancer patients with different EGFR mutation status: a meta-analysis.

Science.gov (United States)

Qu, Jian; Wang, Ya-Nan; Xu, Ping; Xiang, Da-Xiong; Yang, Rui; Wei, Wei; Qu, Qiang

2017-05-16

Icotinib is a novel and the third listed epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), which exerts a good anti-tumor efficacy on non-small cell lung cancer (NSCLC). The efficacy of EGFR-TKIs has been shown to be associated with the EGFR mutation status, especially exon 19 deletion (19Del) and exon 21 L858R mutation. Therefore, a meta-analysis was performed to assess the efficacy of icotinib in NSCLC patients harboring EGFR mutations (19Del or L858R) and wild type (19Del and L858R loci wild type). A total of 24 studies were included for comparing the objective response rate (ORR) in the EGFR wild type and mutant patients treated with icotinib. The ORRs of EGFR mutant patients (19Del or L858R) are better than those of EGFR wild type patients (OR = 7.03(5.09-9.71), P icotinib treatment; EGFR 19Del patients treated with icotinib have better ORRs than EGFR L858R patients. EGFR mutation status is a useful biomarker for the evaluation of icotinib efficacy in NSCLC patients.

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling.

Science.gov (United States)

Qing, Xiaoping; Chinenov, Yurii; Redecha, Patricia; Madaio, Michael; Roelofs, Joris Jth; Farber, Gregory; Issuree, Priya D; Donlin, Laura; Mcllwain, David R; Mak, Tak W; Blobel, Carl P; Salmon, Jane E

2018-04-02

Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney diseases. Here, we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double-stranded DNA (anti-dsDNA) Ab production by simultaneously blocking HB-EGF/EGFR and TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice, alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a target for selective and simultaneous dual inhibition of 2 major pathological pathways in the effector arm of the disease.

Anti-tumor activity of high-dose EGFR tyrosine kinase inhibitor and sequential docetaxel in wild type EGFR non-small cell lung cancer cell nude mouse xenografts

Science.gov (United States)

Tang, Ning; Zhang, Qianqian; Fang, Shu; Han, Xiao; Wang, Zhehai

2017-01-01

Treatment of non-small-cell lung cancer (NSCLC) with wild-type epidermal growth factor receptor (EGFR) is still a challenge. This study explored antitumor activity of high-dose icotinib (an EGFR tyrosine kinase inhibitor) plus sequential docetaxel against wild-type EGFR NSCLC cells-generated nude mouse xenografts. Nude mice were subcutaneously injected with wild-type EGFR NSCLC A549 cells and divided into different groups for 3-week treatment. Tumor xenograft volumes were monitored and recorded, and at the end of experiments, tumor xenografts were removed for Western blot and immunohistochemical analyses. Compared to control groups (negative control, regular-dose icotinib [IcoR], high-dose icotinib [IcoH], and docetaxel [DTX]) and regular icotinib dose (60 mg/kg) with docetaxel, treatment of mice with a high-dose (1200 mg/kg) of icotinib plus sequential docetaxel for 3 weeks (IcoH-DTX) had an additive effect on suppression of tumor xenograft size and volume (P Icotinib-containing treatments markedly reduced phosphorylation of EGFR, mitogen activated protein kinase (MAPK), and protein kinase B (Akt), but only the high-dose icotinib-containing treatments showed an additive effect on CD34 inhibition (P icotinib plus docetaxel had a similar effect on mouse weight loss (a common way to measure adverse reactions in mice), compared to the other treatment combinations. The study indicate that the high dose of icotinib plus sequential docetaxel (IcoH-DTX) have an additive effect on suppressing the growth of wild-type EGFR NSCLC cell nude mouse xenografts, possibly through microvessel density reduction. Future clinical trials are needed to confirm the findings of this study. PMID:27852073

Preliminary studies with 188Rhenium-tin colloid for radiation synovectomy: preparation, size determination, in vivo distribution, effects and dosimetry studies

International Nuclear Information System (INIS)

Mathe, D.; Balogh, L.; Polyak, A.; Kiraly, R.; Andocs, G.; Janoki, G. A.; Chaudhari, P.R.; Perge, E.; Glavits, R.

2002-01-01

Generator-produced beta-emitting radionuclides such 188R e are gaining in importance for radiosynoviorthesis because of their availability on a regular basis. We prepared a 188 Re-tin colloid in reaction carried out either at 100 o C or at room temperature (RT). The size of the colloid particles was measured with a laser light-scattering method, and their biodistribution, dosimetric aspects and therapeutic effects were studied in an antigen-induced arthritis (AIA) model in rabbits. 188R e-tin colloid solution was injected intraarticularly into the knee joints of rabbits with AIA and imaging studies were performed. Blood samples were collected post injection for estimation of the blood residence time. We also injected 2 intact rabbits in the same manner with 188R e perrhenate solution in order to observe its effects and distribution in the body. All the treated rabbit knees were subjected to histopathology.The colloid particle size distribution was different after preparation at the different reaction temperatures, with a more suitable mean of 4.53 μm in the RT preparation. The dose delivered to the synovial surface was between 3.51 and 4.21 Gy and that to the bone surface was between 0.70 and 0.84 Gy. Histopathologic examination revealed the development of fibrous connective tissue in the AIA knees 4 weeks after treatment, but not in the control group. The 188R e-tin colloid preparation used in study was suitable for radiation synovectomy application. It requires modifications in the preparation protocol so as to increase the labelling efficiency in correlation with an appropriate particle size. (author)

Safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized monoclonal antibody BIWA 4 (Bivatuzumab) in patients with early-stage breast cancer.

Science.gov (United States)

Koppe, Manuel; Schaijk, Frank van; Roos, Jan; Leeuwen, Paul van; Heider, Karl-Heinz; Kuthan, Hartmut; Bleichrodt, Robert

2004-12-01

The aim of this prospective study was to evaluate the safety, pharmacokinetics, immunogenicity, and biodistribution of (186)Re-labeled humanized anti-CD44v6 monoclonal antibody (MAb( BIWA 4 (Bivatuzumab( in 9 patients with early-stage breast cancer. Radioimmunoscintigraphy (RIS( was performed within 1, 24, and 72 hours after administration. BIWA 4 concentration in plasma (ELISA and radioactivity measurements( and the development of human antihuman antibody (HAHA( responses was determined. The biodistribution of (186)Re-BIWA 4 was determined by radioactivity measurements in tumor and normal tissue biopsies obtained during surgery 1 week after administration. Administration of (186)Re-BIWA 4 was well tolerated by all patients and no HAHA responses were observed. The mean t(1/2) in plasma of BIWA 4 (ELISA( was 81 hours (range, 67-97(, whereas the mean radioactivity t(1/2) tended to be longer, at 105 hours (range, 90-114(. RIS unmistakably showed the tumor in 3 patients. Less clear identifications were established in 3 additional patients. In 2 patients, the tumor was wrongly identified in the contralateral breast. Median tumor CD44v6 expression, as determined by immunohistochemistry, was 70% (range, 10-90%). Mean tumor uptake was 2.96% ID/kg (range, 0.92-6.27(, with no apparent correlation with either tumor CD44v6 expression, tumor-cell cellularity, or tumor diameter. Tumor-to-nontumor ratios were unfavorable for blood, bone marrow, mammary gland tissue, and skin. The (186)Re-labeled humanized MAb BIWA 4 can safely be administered to patients with early-stage breast cancer. Tumorto- nontumor ratios were unfavorable, with no apparent correlation with CD44v6 expression, tumor-cell cellularity, or tumor diameter. BIWA 4, therefore, appears to have limitations as a vehicle for radioimmunotherapy in patients with breast cancer.

Internal radiation dosimetry, pharmacokinetics and biodistribution of the 99mTc labeled ior egf/r3 monoclonal antibody

International Nuclear Information System (INIS)

Torres, L.A.; Perera, A.; Ramos, M.; Hernandez, A.; Iznaga, N.; Solano, M.E.; Alvarez, I.; Rodriguez, J.L.

2001-01-01

The aim of this work was to assess the internal radiation dosimetry, human pharmacokinetics and biodistribution of the 99m Tc-labeled murine monoclonal antibody (MAb) ior egf/r3, used for diagnosis of epithelial tumors. Five patients were included in this study. Multiple blood and urine samples were collected and sequential anterior and posterior whole-body scintigraphies up to 24 hr post-injection were acquired from all patients. The internal radiation dosimetry was estimated using the methods developed by the Medical Internal Radiation Dosimetry (MIRD) committee. Raw data were computed from operations between scintigraphic images and regions of interest (ROI). The residence times of the activity on the source organs were computed to assess the absorbed dose by 24 target organs. The dosimetric results showed that liver, gallbladder and spleen received the higher absorbed dose. The computed mean values were 0.69 mGy/MBq, 0.19mGy/MBq and 0.37 mGy/MBq, respectively. The mean value of effective dose was 1,2E-01 mSv/MBq and the effective equivalent dose was 9,2E-02 mSv/MBq. The pharmacokinetics and biodistribution results showed that this compound has a biexponential plasmatic and blood clearance with a rapid biodistribution phase and a slower elimination phase. This compound was excreted by the urinary and hepatobiliary systems. Liver was the principal target organ of this product showing a great retention of the MAb. These dosimetric results have allowed to use the ior egf/r3 kit in a safe and controlled way. (author)

Preparation and in vivo evaluation of linkers for 211At labeling of humanized anti-Tac

International Nuclear Information System (INIS)

Yordanov, A.T.; Garmestani, K.; Zhang, M.; Zhang, Z.; Yao, Z.; Phillips, K.E.; Herring, B.; Horak, E.; Beitzel, M.P.; Schwarz, U.P.; Gansow, O.A.; Plascjak, P.S.; Eckelman, W.C.; Waldmann, T.A.; Brechbiel, M.W.

2001-01-01

The syntheses, radiolabeling, antibody conjugation, and in vivo evaluation of new linkers for 211 At labeling of humanized anti-Tac (Hu-anti-Tac), an antibody to the α-chain of the IL-2 receptor (IL-2Rα) shown to be a useful target for radioimmunotherapy are described. Synthesis of the organometallic linker precursors is accomplished by reaction of the corresponding bromo- or iodoaryl esters with bis(tributyltin) in the presence of a palladium catalyst. Subsequent conversion to the corresponding N-succinimidyl ester and labeling with 211 At of two new linkers, N-succinimidyl 4-[ 211 At]astato-3-methylbenzoate and N-succinimidyl N-(4-[ 211 At]astatophenethyl)succinamate (SAPS), together with the previously reported N-succinimidyl 4-[ 211 At]astatobenzoate and N-succinimidyl 3-[ 211 At]astato-4-methylbenzoate, are each conjugated to Hu-anti-Tac. The plasma survival times of these conjugates are compared to those of directly iodinated ( 125 I) Hu-anti-Tac. The N-succinimidyl N-(4-[ 211 At]astatophenethyl)succinamate compound (SAPS) emerged from this assay as the most viable candidate for 211 At-labeling of Hu-anti-Tac. SAPS, along with the directly analogous radio-iodinated reagent, N-succinimidyl N-(4-[ 125 I]astatophenethyl)succinamate (SIPS), are evaluated in a biodistribution study along with directly iodinated ( 125 I) Hu-anti-Tac. Blood clearance and biological accretion results indicate that SAPS is a viable candidate for further evaluation for radioimmunotherapy of cancer

Therapeutic efficacy and dosimetric aspects of Rhenium-188-HEDP in bone pain palliation

International Nuclear Information System (INIS)

Liepe, Knut

2005-01-01

Full text: Bone metastases are a frequent complication of cancer, occurring in up 70% of patients suffering from advanced breast or prostate cancer and often present with severe bone pain. In this purpose the radionuclide therapy is a useful option for cancer patients. Different radionuclides are described, such as 89 Sr, 32 P, 153 Sm-EDTMP, 186 Re-HEDP, 131 I-BDP3, 90 Y, 117mSn-DTPA, 188 Re-HEDP and 188 Re-DMSA. The most experiences are available for 89 Sr. An indication for the treatment are patients with osteoblastic metastases, bone pain, sufficient bone marrow function and at least of three bone metastases visualized in bone scan. A bisphosphonate therapy, a chemotherapy with lower bone marrow toxicity or a local field external beam radiotherapy represent no contraindications, especially because the reported synergistic effects to the systemic radionuclide therapy. In 33 treated patients (breast and prostate cancer) we investigated the effect of 188 Re-HEDP on pain relief, analgesic intake and impairment of bone marrow function. There were an improvement on the Karnofsky performance scale from 74 7% to 85 9% 12 weeks after therapy (p= 0.001). The pain score showed a maximum decrease from 44 ± 18% to 27 ± 20% in the 3rd to the 8th week after therapy (p = .009) and 76% had a pain relief (20% were pain free). The maximal differences between the values of platelets and leukocytes before and after therapy were not statistically significant (p = 0.021 and p = 0.094). In 105 investigated patients treated with different radionuclides ( 89 Sr, 153 Sm-EDTMP, 186 Re-HEDP, 188 Re-HEDP and 89 Sr in combination with chemotherapy) no different therapeutic efficacy of the treatments were observed. In dose calculation of 188 Re-HEDP a radiation dose of 3.83 ± 2.01 mGy/MBq (12.6 Gy for 3300 MBq) for bone metastases and 0.61 ± 0.21 mGy/MBq (2 Gy for 3300 MBq) were found. With the introducing of radionuclide treatments with chemotherapy and repeated treatments, the

Technetium-99m labeling anti-amastigote polyclonal antibodies of Leishmania amazonensis

International Nuclear Information System (INIS)

Araujo, J.G.V.C.; Toledo, V.P.C.P.; Guimaraes, T.M.P.D.; Bernardo-Filho, M.; Simal, C.J.R.; Mota, L.G.; Diniz, S.O.F.; Cardoso, V.N.

2002-01-01

Anti-amastigote polyclonal antibody (IgG) was incubated with solutions of stannous chloride and sodium borohidride. After that, 3.7 MBq of technetium-99m ( 99m Tc) was added. A labeling yield of the antibody about 84% was obtained. After filtration of 99m Tc-IgG, the radiochemical purity increased from 84 to 95%. The labeling of IgG with 99m Tc did not modify the immunoreactivity of the antibody, since it was able to identify in vitro and in vivo the specific antigen of Leishmania amazonensis

Biodistribution, pharmacokinetic, and imaging studies with 186Re-labeled NR-LU-10 whole antibody in LS174T colonic tumor-bearing mice

International Nuclear Information System (INIS)

Goldrosen, M.H.; Biddle, W.C.; Pancook, J.; Bakshi, S.; Vanderheyden, J.L.; Fritzberg, A.R.; Morgan, A.C. Jr.; Foon, K.A.

1990-01-01

Biodistribution, pharmacokinetic, and radioimaging studies were performed with 186Re-labeled NR-LU-10 whole antibody in athymic nude mice bearing the LS174T tumor growing either s.c. or in an experimental hepatic metastasis model. NR-LU-10 is an IgG2b murine monoclonal antibody (MAb) that reacts with virtually all human tumors of epithelial origin. NR-BC-1, a IgG2b murine MAb that reacts with normal human B-cell and B malignancies, was used as an isotype-matched control. These MAbs were radiolabeled with 186Re by a preformed chelate approach by using the triamide thiolate ligand system. 186Re-labeled NR-LU-10 (50 microCi) was injected into nude mice bearing LS174T tumors growing s.c. Biodistribution studies revealed that the LS174T tumor retained the highest concentration of 186Re-labeled NR-LU-10 at day 6. The tumor:blood ratio ranged from 0.1:1 to 10.8:1 by day 6, the last day of analysis. In contrast the tumor:blood ratio of 186Re-labeled NR-BC-1, the isotype-matched MAb control, was 1:1 on day 6. Pharmacokinetic analysis indicated that the t1/2 beta of NR-LU-10 for blood and other tissues ranged from 21 to 25 h, while the t1/2 beta for the LS174T tumor averaged 52 h. The area under the curve for tumor compared to blood was 2.8- to 5.7-fold higher than the area under the curve for all other tissues and organs. The mean residence time for NR-LU-10 in blood and all other organs ranged from 23 to 26 h, while the mean residence time for NR-LU-10 in the LS174T tumor was 72 h. Scintigraphic images revealed selective uptake of the 186Re-labeled NR-LU-10, but not of the 186Re-labeled NR-BC-1, at the LS174T tumor site. Studies in an experimental model of hepatic metastasis revealed a similar selective pattern of 186Re-labeled NR-LU-10 accumulation. Scintigraphic images of the LS174T tumor growing within the athymic nude mouse liver were obtained

Spin-labelling study of interactions of ovalbumin with multilamellar liposomes and specific anti-ovalbumin antibodies.

Science.gov (United States)

Brgles, Marija; Mirosavljević, Krunoslav; Noethig-Laslo, Vesna; Frkanec, Ruza; Tomasić, Jelka

2007-03-10

Ovalbumin (OVA) has been used continuously as the model antigen in numerous studies of immune reactions and antigen processing, very often encapsulated into liposomes. The purpose of this work was to study the possible interactions of spin-labelled OVA and lipids in liposomal membranes using electron spin resonance (ESR) spectroscopy. OVA was covalently spin-labelled with 4-maleimido-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO-maleimide), characterized and encapsulated into multilamellar, negatively charged liposomes. ESR spectra of this liposomal preparation gave evidence for the interaction of OVA with the lipid bilayers. Such an interaction was also evidenced by the ESR spectra of liposomal preparation containing OVA, where liposomes were spin-labelled with n-doxyl stearic acids. The spin-labelled OVA retains its property to bind specific anti-OVA antibodies, as shown by ESR spectroscopy, but also in ELISA for specific anti-OVA IgG.

The labelling of antibody anti-PBP2a with 99mTc

International Nuclear Information System (INIS)

Mororo, Janio da Silva

2012-01-01

Staphylococcus aureus is a major cause of life-threatening infections such as bacteraemia and endocarditis. Unfortunately, many strains of this bacterial species have become resistant to certain antibiotics, including methicillin and amoxicillin. These strains are known as methicillin-resistant S. aureus (MRSA). The penicillin binding protein 2a (PBP2a) is the enzyme responsible for conferring resistance p-lactams antibiotics for MRSA, being one promising molecule for therapy with mAb. However, besides the therapy, the methods of diagnosis are also inefficient because the diagnosis currently takes several days to produce a reliable result. Taking into account, the objective of this research was radiolabeling one anti-PBP2a mAb developed by Bio-Manguinhos/FioCruz-RJ, utilizing 99m Tc, for in situ diagnostic of the infectious caused by MRSA. First, anti-PBP2a mAb was reduced utilizing 2-mecaptoethanol (2-ME) for generate sulphydryl groups (-SH) and after to be labeled with 99m Tc. In this work, were utilized two techniques of direct method: Method 1, using tartrate and gentisic acid reagents, acting like transchelant and stabilizer agents, respectively; and Method 2, using one commercial kit of MDP. Besides the radiolabeling, the mAb reduced and mAb labeled with 99m Tc were submitted to immunoreactivity analysis, with SDS-PAGE non-reducing, Immunoblotting, ELISA and neutralization assay in vitro methods. The quantity produced of sulphydryl groups by mAb was satisfactory, approximately 5 per mAb, utilizing 6.500:1 of 2-ME:mAb molar ratio. The better labeling method was Method 2, with labeling yield of 73.5%, and showed a good stability after 2 hours (73.2%). The better formulation was: 0.5 mg of mAb anti- PBP2a, 10 μU of MDP kit, after resuspended with 5 mL of saline, and 75.48 MBq (2.04 mCi) of 99m Tc, reacting by 15 minutes. The labeled mAb maintained the immunoreactivity, utilizing immunologic and in vitro experiments. (author)

EGFR kinase-dependent and kinase-independent roles in clear cell renal cell carcinoma.

Science.gov (United States)

Cossu-Rocca, Paolo; Muroni, Maria R; Sanges, Francesca; Sotgiu, Giovanni; Asunis, Anna; Tanca, Luciana; Onnis, Daniela; Pira, Giovanna; Manca, Alessandra; Dore, Simone; Uras, Maria G; Ena, Sara; De Miglio, Maria R

2016-01-01

-dependent and kinase-independent functions, both potentially involved in CCRCC progression. These results might have important implications on therapeutic approaches to CCRCC, since the disruption of the interaction between EGFR/SGLT1, mediated by anti-EGFR antibodies and/or SGLT1 inhibitors, might constitute a novel therapeutic target for CCRCC treatment, and new clinical trials should be evaluated on the basis of this therapeutic proposal.

Molecular docking, MM/GBSA and 3D-QSAR studies on EGFR ...

Indian Academy of Sciences (India)

Abstract. Epidermal growth factor receptor (EGFR) is the first growth factor receptor proposed as a target ... Information rendered from 3D-QSAR model and sitemap analysis was used to ... skin making it a key target for anti-tumor strategy. ∗.

Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest

International Nuclear Information System (INIS)

Kriegs, Malte; Gurtner, Kristin; Can, Yildiz; Brammer, Ingo; Rieckmann, Thorsten; Oertel, Reinhard; Wysocki, Marek; Dorniok, Franziska; Gal, Andreas; Grob, Tobias J.; Laban, Simon; Kasten-Pisula, Ulla; Petersen, Cordula; Baumann, Michael; Krause, Mechthild; Dikomey, Ekkehard

2015-01-01

Purpose: How EGF receptor (EGFR) inhibition induces cellular radiosensitization and with that increase in tumor control is still a matter of discussion. Since EGFR predominantly regulates cell cycle and proliferation, we studied whether a G1-arrest caused by EGFR inhibition may contribute to these effects. Materials and methods: We analyzed human non-small cell lung cancer (NSCLC) cell lines either wild type (wt) or mutated in p53 (A549, H460, vs. H1299, H3122) and HCT116 cells (p21 wt and negative). EGFR was inhibited by BIBX1382BS, erlotinib or cetuximab; p21 was knocked down by siRNA. Functional endpoints analyzed were cell signaling, proliferation, G1-arrest, cell survival as well as tumor control using an A549 tumor model. Results: When combined with IR, EGFR inhibition enhances the radiation-induced permanent G1 arrest, though solely in cells with intact p53/p21 signaling. This increase in G1-arrest was always associated with enhanced cellular radiosensitivity. Strikingly, this effect was abrogated when cells were re-stimulated, suggesting the initiation of dormancy. In line with this, only a small non-significant increase in tumor control was observed for A549 tumors treated with fractionated RT and EGFR inhibition. Conclusion: For NSCLC cells increase in radiosensitivity by EGFR inhibition results from enhanced G1-arrest. However, this effect does not lead to improved tumor control because cells can be released from this arrest by re-stimulation

Preliminary results of transarterial Rhenium-188 HDD Lipiodol in treatment of inoperable primary hepatocellular carcinoma

International Nuclear Information System (INIS)

Sundram, Felix

2004-01-01

Full text: In this paper we present our early experience with a new radio-conjugate, namely rhenium-188 HDD Lipiodol (Re-188 lipiodol). Imported radiopharmaceuticals are generally expensive, particularly for developing countries. A Tungsten (W-188-Re 188) generator obtained from ORNL (Oak Ridge National Laboratory, Tennessee, USA) allows us on-site production of a beta emitting therapeutic isotope (Re-188) for up to 6 months from a single generator. The objectives of this study were to establish the safety of trans-arterial Re-188 lipiodol in patients with inoperable HCC, and determine the adverse effects and efficacy for this radio-conjugate treatment in a multi-center study of patients with advanced HCC. A multi-center study was sponsored by the International Atomic Energy Agency (Vienna) to assess the safety and efficacy of trans-arterial Re-188 HDD conjugated lipiodol (radio-conjugate) in the treatment of patients with inoperable hepatocellular carcinoma (HCC), The radio-conjugate was prepared by using a HDD (4-hexadecyl 1-2, 9, 9-tetramethyl-4, 7-diaza-1, 10-decanethiol) kit developed in Korea, and lipiodol. Over a period of eighteen months seventy patients received at least one treatment of radio-conjugate. Some patients were re-treated if there was no evidence of disease progression. The level of radio-conjugate administered was based on radiation-absorbed dose to critical normal organs, calculated following a 'scout' dose of radio-conjugate. The organs at greatest risk for radiation toxicity are the normal liver, the lung and the bone marrow. A specially designed spreadsheet was used to determine maximum tolerated activity (MTA), defined as the amount of radioactivity calculated to deliver no more than 12 Gray (Gy) to lungs, or 30 Gy to liver, or 1.5 Gy to bone marrow. These doses have been found to be safe in multiple trials using external beam therapy and systemically administered radiopharmaceuticals. Patients were followed for at least twelve weeks

Treatment with rhenium-188-perrhenate and iodine-131 of NIS-expressing mammary cancer in a mouse model remarkably inhibited tumor growth

Energy Technology Data Exchange (ETDEWEB)

Dadachova, Ekaterina [Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461 (United States)]. E-mail: edadacho@aecom.yu.edu; Nguyen, Andrew [Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461 (United States); Lin, Elaine Y. [Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461 (United States); Gnatovskiy, Leo [Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461 (United States); Lu, Ping [Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461 (United States); Pollard, Jeffrey W. [Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461 (United States)

2005-10-01

Introduction: Novel therapeutic modalities are needed for breast cancer patients in whom standard treatments are not effective. Mammary gland sodium/iodide symporter has been identified as a molecular target in breast cancers in humans and in some transgenic mouse models. We report the results of a therapy study with {sup 131}I{sup -} and {sup 188}ReO{sub 4} {sup -} of breast cancer in polyoma middle T oncoprotein (PyMT) transgenic mice endogenously expressing the Na{sup +}/I{sup -} symporter (NIS). Methods: PyMT mice (12-13 weeks old) with one palpable tumor of 0.5-0.8 cm in diameter were used. For the therapy studies, PyMT mice were (1) treated with two intraperitoneal injections of 1.5 mCi of {sup 188}ReO{sub 4} {sup -} 1 week apart, (2) pretreated for 1 week with 5 {mu}g of triiodothyronine (T3) followed by two intraperitoneal injections of 1.5 mCi of {sup 131}I{sup -} 1 week apart or (3) left untreated. The tumor and normal organ uptakes were assessed by scintigraphic imaging. The thyroid function of treated and control animals was evaluated at the completion of the study by measuring the T3/thyroxine (T4) ratio in their blood. Results: There was significant uptake of {sup 131}I{sup -} and {sup 188}ReO{sub 4} {sup -} in the primary palpable tumors as well as in nonpalpable tumors, stomachs and thyroids. The tumor uptake after the second injection was 10 times lower in comparison with the first injection. Tumor growth was significantly inhibited in both the {sup 131}I{sup -} and {sup 188}ReO{sub 4} {sup -} groups in comparison with the control group, and tumors in the {sup 188}ReO{sub 4} {sup -} group increased in size significantly less than in the {sup 131}I{sup -} group. The T3/T4 ratios were calculated to be 27 and 25 for the control group and the {sup 188}ReO{sub 4} {sup -} group, respectively; for {sup 131}I{sup -}, both the T3 and T4 levels were below detection limit, demonstrating much less effect on the thyroids of treatment with {sup 188}ReO{sub 4

EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: a systematic review and meta analysis.

Directory of Open Access Journals (Sweden)

Zheng Jiang

Full Text Available The epidermal growth factor receptor (EGFR gene copy number (GCN has been previously demonstrated to correlate with the clinical outcome of colorectal cancer (CRC treated with anti-EGFR monoclonal antibodies (mAbs, although it remains controversial. We conducted a systematic review and meta-analysis to assess EGFR GCN as a potential biomarker of survival for patients with advanced CRC receiving treatment with anti-EGFR mAbs.We systematically identified articles investigating EGFR GCN by fluorescent or chromogenic in situ hybridization or other detection techniques in patients with metastatic CRC treated with panitumumab or cetuximab, (last search: 10 August 2012. Eligible studies had to report on overall survival (OS, progression-free survival (PFS or time-to-progression (TTP, stratified by EGFR GCN. Summary hazard ratios (HRs were calculated using random-effects models.Among 13 identified studies, 10 (776 patients, 302 with increased GCN, 8 (893 patients, 282 with increased GCN and 3 (149 patients, 66 with increased GCN were eligible for the OS, PFS and TTP meta-analyses, respectively. Increased EGFR GCN was associated with increased OS (HR = 0.62; 95% CI 0.50-0.77; P<0.001, PFS (HR = 0.65; 95% CI 0.47-0.89; P = 0.008 but not TTP (HR = 0.71; 95% CI 0.44-1.14; P = 0.157. It was also shown that EGFR GCN is independent of other factors such as KRAS status. Among those populations received second-line or higher treatment, increased EGFR GCN was strongly associated with improved survival (for OS, HR = 0.60; 95% CI 0.47-0.75; P<0.001; for PFS, HR = 0.59; 95% CI 0.47-0.75; P<0.001, whereas it did not influence survival in patients that received first-line therapy.Among the anti-EGFR-treated patients, increased EGFR GCN appears to be associated with improved survival outcomes. The effect on survival appears to be related to patients receiving the line of treatment.

Anti-epidermal or anti-vascular endothelial growth factor as first-line metastatic colorectal cancer in modified Glasgow prognostic score 2' patients

Science.gov (United States)

Dréanic, Johann; Dhooge, Marion; Barret, Maximilien; Brezault, Catherine; Mir, Olivier; Chaussade, Stanislas; Coriat, Romain

2015-01-01

Background In metastatic colorectal cancer, the modified Glasgow prognostic score (mGPS) has been approved as an independent prognostic indicator of survival. No data existed on poor prognosis patients treated with molecular-targeted agents. Methods From January 2007 to February 2012, patients with metastatic colorectal cancer and poor predictive survival score (mGPS = 2), treated with 5-fluorouracil-based chemotherapy in addition to an anti-epidermal growth factor receptor (EGFR) or anti-vascular epidermal growth factor (VEGF) therapy, were included to assess the interest of targeted therapy within mGPS = 2' patients. Results A total of 27 mGPS = 2' patients were included and received a 5-fluorouracil-based systemic chemotherapy in addition to an anti-EGFR treatment (cetuximab; n = 18) or an anti-VEGF treatment (bevacizumab; n = 9). Median follow-up was 12.1 months (interquartile range 4.9–22). Patients were Eastern Cooperative Oncology Group (ECOG) Performance Status 1, 2, and 3 in 66% (n = 18), 26% (n = 7), and 8% (n = 2), respectively. Comparing anti-EGFR and anti-VEGF groups, median progression-free survival was 3.9 and 15.4 months, respectively, and was significantly different (P = 0.046). Conversely, the median overall survival was not significantly different between the two groups (P = 0.15). Conclusion Our study confirmed the poor survival of patients with mGPS = 2 despite the use of targeted therapy and identified the superiority of an anti-VEGF treatment in progression-free survival, without a significant benefit in the overall survival compared with the anti-EGFR therapy. Our results deserved confirmation by a prospective clinical trial. PMID:26401469

Tuning a Protein-Labeling Reaction to Achieve Highly Site Selective Lysine Conjugation.

Science.gov (United States)

Pham, Grace H; Ou, Weijia; Bursulaya, Badry; DiDonato, Michael; Herath, Ananda; Jin, Yunho; Hao, Xueshi; Loren, Jon; Spraggon, Glen; Brock, Ansgar; Uno, Tetsuo; Geierstanger, Bernhard H; Cellitti, Susan E

2018-04-16

Activated esters are widely used to label proteins at lysine side chains and N termini. These reagents are useful for labeling virtually any protein, but robust reactivity toward primary amines generally precludes site-selective modification. In a unique case, fluorophenyl esters are shown to preferentially label human kappa antibodies at a single lysine (Lys188) within the light-chain constant domain. Neighboring residues His189 and Asp151 contribute to the accelerated rate of labeling at Lys188 relative to the ≈40 other lysine sites. Enriched Lys188 labeling can be enhanced from 50-70 % to >95 % by any of these approaches: lowering reaction temperature, applying flow chemistry, or mutagenesis of specific residues in the surrounding protein environment. Our results demonstrated that activated esters with fluoro-substituted aromatic leaving groups, including a fluoronaphthyl ester, can be generally useful reagents for site-selective lysine labeling of antibodies and other immunoglobulin-type proteins. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of EGFR, KRAS and BRAF gene mutations in renal cell carcinoma

Directory of Open Access Journals (Sweden)

Omer Bayrak

2014-08-01

Full Text Available A subset of renal cell carcinoma (RCC patients has been shown to respond to anti-EGFR therapy. As KRAS and BRAF mutations are associated with poor response to anti-EGFR therapy in some cancers, it has been suggested that screening for KRAS and BRAF mutations in RCC may be a promising strategy to identify patients who might respond to EGFR-targeted therapy. The aim of this study was to investigate the mutation status of EGFR, KRAS and BRAF in RCC patients. Renal tumors and normal renal samples from forty-eight patients who underwent radical or partial nephrectomy for kidney cancer were used in this study. Histological classification of the tumors was performed according to International Union against Cancer (UICC / American Joint Committee on Cancer (AJCC classification. Seventeen patients (48% had clear-cell RCC, 7 (20% had chromophobe RCC, and 11 patients (32% had papillary RCC. DNA isolated from the samples was subjected to melting curve mutation analysis for EGFR, BRAF and KRAS using ABI-3130 DNA sequencer. DNA sequencing analysis of RCC samples, when compared with morphologically normal matched regions, did not show any exon mutations. Our results do not support the notion that EGFR, KRAS and BRAF might be mutated in RCC. Normal 0 false false false TR X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0cm; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-ansi-language:TR; mso-fareast-language:EN-US;}

Prognostic value of plasma EGFR ctDNA in NSCLC patients treated with EGFR-TKIs.

Directory of Open Access Journals (Sweden)

Chengjuan Zhang

Full Text Available Epidermal growth factor receptor (EGFR specific mutations have been known to improve survival of patients with non-small-cell lung carcinoma (NSCLC. However, whether there are any changes of EGFR mutations after targeted therapy and its clinical significance is unclear. This study was to identify the status of EGFR mutations after targeted therapy and predict the prognostic significance for NSCLC patients.A total of forty-five (45 NSCLC patients who received EGFR-TKI therapy were enrolled. We identified the changes of EGFR mutations in plasma ctDNA by Amplification Refractory Mutation System (ARMS PCR technology.In the 45 cases of NSCLC with EGFR mutations, the EGFR mutation status changed in 26 cases, in which, 12 cases (26.7% from positive to negative, and 14 cases (31.1% from T790M mutation negative to positive after TKI targeted therapy. The T790M occurance group had a shorter Progression -Free-Survival (PFS than the groups of EGFR mutation undetected and EGFR mutation turned out to have no change after EGFR-TKI therapy (p < 0.05.According to this study, it's necessary to closely monitor EGFR mutations during follow-up to predict the prognosis of NSCLC patients who are to receive the TKI targeted therapy.

Matching the Decay Half-Life with the Biological Half-Life: ImmunoPET Imaging with 44Sc-Labeled Cetuximab Fab Fragment

Science.gov (United States)

2015-01-01

Scandium-44 (t1/2 = 3.9 h) is a relatively new radioisotope of potential interest for use in clinical positron emission tomography (PET). Herein, we report, for the first time, the room-temperature radiolabeling of proteins with 44Sc for in vivo PET imaging. For this purpose, the Fab fragment of Cetuximab, a monoclonal antibody that binds with high affinity to epidermal growth factor receptor (EGFR), was generated and conjugated with N-[(R)-2-amino-3-(para-isothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N′,N″,N″-pentaacetic acid (CHX-A″-DTPA). The high purity of Cetuximab-Fab was confirmed by SDS-PAGE and mass spectrometry. The potential of the bioconjugate for PET imaging of EGFR expression in human glioblastoma (U87MG) tumor-bearing mice was investigated after 44Sc labeling. PET imaging revealed rapid tumor uptake (maximum uptake of ∼12% ID/g at 4 h postinjection) of 44Sc–CHX-A″-DTPA–Cetuximab-Fab with excellent tumor-to-background ratio, which might allow for same day PET imaging in future clinical studies. Immunofluorescence staining was conducted to correlate tracer uptake in the tumor and normal tissues with EGFR expression. This successful strategy for immunoPET imaging of EGFR expression using 44Sc–CHX-A″-DTPA–Cetuximab-Fab can make clinically translatable advances to select the right population of patients for EGFR-targeted therapy and also to monitor the therapeutic efficacy of anti-EGFR treatments. PMID:25389697

Report on the 2{sup nd} Research Coordination Meeting on The Development of Therapeutic Radiopharmaceuticals Based on {sup 188}Re and {sup 90}Y for Radionuclide. Working Document

Energy Technology Data Exchange (ETDEWEB)

NONE

2010-07-01

Radionuclide therapy is practiced for the treatment of malignant disorders of various organs and tissues as well as for treating certain other diseases such as rheumatoid arthritis. Advances in understanding tumor biology as well as developments in peptide chemistry and monoclonal antibody technology are opening new opportunities for the development of therapeutic radiopharmaceuticals, thereby widening the scope of radionuclide therapy. In addition, particulate based radiopharmaceuticals are useful for treating hepatocarcinoma as well as in radiation synovectomy. With the establishment of new products the demand and application of therapeutic nuclear medicine is expected to grow rapidly. While there are a large number of radioisotopes proposed for targeted therapy, practical considerations had been limiting the number of usable isotopes. Generator-produced radionuclides are an attractive option for the large scale on-site availability of therapeutic isotopes. The IAEA’s CRP on the ‘Development of generator technologies for therapeutic radionuclides’ (2004-2007) was successful in developing technologies for the preparation of {sup 188}W/{sup 188}Re and {sup 90}Sr/{sup 90}Y generators for eluting {sup 188}Re and {sup 90}Y of high radionuclidic and chemical purity usable for research applications in the development of therapeutic radiopharmaceuticals. The IAEA’s CRP on ‘The development of therapeutic radiopharmaceuticals based on {sup 188}Re and {sup 90}Y for radionuclide therapy’ was formulated to focus on enhancing the capacity of the {sup 90}Sr/{sup 90}Y generator; to develop and validate quality control methods for the generator eluate; and to develop therapeutic radiopharmaceuticals based on {sup 188}Re and {sup 90}Y. The first RCM of the CRP was held in Polatom, Warsaw, Poland from 30 June to 4 July 2008. The meeting reviewed the work going on in the different participating laboratories, and the facilities, expertise and capabilities of the different

Tc-99m direct radiolabeling of monoclonal antibody ior egf/r3: quality control and image studies in mice

International Nuclear Information System (INIS)

Dias, Carla Roberta; Marczewski, Barbara; Moraes, Vanessa; Barboza, Marycel Figols de; Osso Junior, Joao Alberto

2005-01-01

Monoclonal antibodies (Mabs) have been useful for immunoscintigraphic applications in clinical diagnosis since they were introduced in the practice of nuclear medicine. The ior egf/r3 (Centis, Cuba) is a murine monoclonal antibody against epidermal growth factor receptor (EGF-R) and has been widely used in the radioimmunodiagnosis of tumors of epithelial origin. Labeled with 99m Tc, its main application in Nuclear Medicine is the follow up, detection and evaluation of tumor recurrences. The objective of this work is to describe the preparation of a lyophilized formulation (kit) for radiolabeling the Mab ior egf/r3 with 99m Tc for immunoscintigraphic applications. Radiolabeling efficiency, effects on immunoreactivity, image studies and stability of the formulation are reported. The study demonstrated that the kit formulation can be labeled with 99m Tc at high yields and can be used to visualize in vivo human tumors of epithelial origin by immunoscintigraphy studies.(author)

The combined status of estrogen receptor (ER) and epidermal growth factor (EGFR) predicts a poor outcome in primary breast cancer

International Nuclear Information System (INIS)

Artagaveytia, N.; Román, E.; Alonso, I.; Sabini, G.; Garófalo, E.

2004-01-01

The aim of this study was to investigate retrospectively the presence of ER, PR, Db Receptor and Epidermal Growth Factor (EGFR) in 678 patients carrying primary breast cancer, its correlation with clinic pathological parameters and evolution. the determination of ER, PR and EGFR was performed by Scatchard biochemical technique, based cutoff 10 fmoles / mg of protein. The RE-b detection performed by RT-PCR from total RNA, using the GAPDH gene as a control. Statistical analyzes were applied the Chi2 tests, Spearman and Kruskal-Wallis. The disease-free survival (SVLE) and survival overall (SVG) were analyzed using Kaplan Meier / Log Rank Test and analysis Cox regression. Median follow-up was 28 months (range 1-218 months). sixty Four percent of the patients were post-menopausal and 83% occurred in stages Early disease (I-II, pTNM UICC). The receptor positivity was 68%, 47%, 23% and 58% for ER, PR, EGFR and ER-b-mRNA, respectively. A correlation was found positive between the content of ER and PR (p = 1.10-5) and negative between these receptors and EGFR (n = 359, p = 0.014 and p = 0.018, respectively). We observed a trend to increased expression ER-b when ER, PR or both receptors were negative comparable to that observed with EGFR. Also, a gradual decrease in the content of ER and PR was observed with the progression to more advanced stages (p = 0.04 and p = 0.03). Of a total of 501 evaluable patients 23% relapsed and 12% died. ER positivity was associated with a greater SVLE and SVG 24 and 60 months follow up (p = 0.06). A major impact did the RE content, levels less than 45 fmol / mg protein were associated with disease recurrence (p = 0.03 and p = 0.006 for 24 and 60 months). Although less significant EGFR status influenced SVLE and SVG. In particular, the presence of EGFR in ER + group affected the evolution tripling relapses and deaths (p = 0.058). The presence of ER-b also had a negative impact on this patient group. In Cox regression analysis, N + and T> 2cm

KRAS Testing for Anti-EGFR Therapy in Advanced Colorectal Cancer: An Evidence-Based and Economic Analysis.

Science.gov (United States)

2010-01-01

In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenomics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER: An Evidence-Based and Economic AnalysisEpidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based and Economic AnalysisK-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based and Economic Analysis. The objective of this systematic review is to determine the predictive value of KRAS testing in the treatment of metastatic colorectal cancer (mCRC) with two anti-EGFR agents, cetuximab and panitumumab. Economic analyses are also being conducted to evaluate the cost-effectiveness of KRAS testing. CONDITION AND TARGET POPULATION Metastatic colorectal cancer (mCRC) is usually defined as stage IV disease according to the American Joint Committee on Cancer tumour node metastasis (TNM) system or stage D in

Fluorescein isothiocyanate labeled, magnetic nanoparticles conjugated D-penicillamine-anti-metadherin and in vitro evaluation on breast cancer cells

International Nuclear Information System (INIS)

Akca, Ozlet; Unak, Perihan; Medine, E. Ylker; Sakarya, Serhan; Ozdemir, Caglar; Timur, Suna

2011-01-01

Silane modified magnetic nanoparticles were prepared after capped with silica generated from the hydrolyzation of tetraethyl orthosilicate (TEOS). Amino silane (SG-Si900) was added to this solution for surface modification of silica coated magnetic particles. Finally, D-penicillamine (D-PA)-antimetadherin (anti-MTDH) was covalently linked to the amine group using glutaraldehyde as cross-linker. Magnetic nanoparticles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), vibrating sample magnetometer (VSM), and atomic force microscopy (AFM). AFM results showed that particles are nearly monodisperse, and the average size of particles was 40 to 50 nm. An amino acid derivative D-PA was conjugated anti-MTDH, which results the increase of uptaking potential of a conjugated agent, labelled fluorescein isothiocyanate (FITC) and then conjugated to the magnetic nanoparticles. In vitro evaluation of the conjugated D-PA-anti-MTDH-FITC to magnetic nanoparticle was studied on MCF-7 breast cancer cell lines. Fluorescence microscopy images of cells after incubation of the sample were obtained to monitor the interaction of the sample with the cancerous cells. Incorporation on cells of FITC labeled and magnetic nanoparticles conjugated D-PA-anti-MTDH was found higher than FITC labeled D-PA-anti-MTDH. The results show that magnetic properties and application of magnetic field increased incorporation rates. The obtained D-PA-anti-MTDH-magnetic nanoparticles-FITC complex has been used for in vitro imaging of breast cancer cells. FITC labeled and magnetic nanoparticles conjugated D-PA-anti-MTDH may be useful as a new class of scintigraphic agents. Results of this study are sufficiently encouraging to bring about further evaluation of this and related compounds for ultraviolet magnetic resonance (UV-MR) dual imaging. (author)

Tc-{sup 99m} direct radiolabeling of monoclonal antibody ior egf/r3: quality control and image studies in mice

Energy Technology Data Exchange (ETDEWEB)

Dias, Carla Roberta; Marczewski, Barbara; Moraes, Vanessa; Barboza, Marycel Figols de; Osso Junior, Joao Alberto [Instituto de Pesquisas Energeticas e Nucleares (IPEN-CNEN/SP), SP (Brazil). Centro de Radiofarmacia]. E-mail: crdias@ipen.br

2005-10-15

Monoclonal antibodies (Mabs) have been useful for immunoscintigraphic applications in clinical diagnosis since they were introduced in the practice of nuclear medicine. The ior egf/r3 (Centis, Cuba) is a murine monoclonal antibody against epidermal growth factor receptor (EGF-R) and has been widely used in the radioimmunodiagnosis of tumors of epithelial origin. Labeled with 99m Tc, its main application in Nuclear Medicine is the follow up, detection and evaluation of tumor recurrences. The objective of this work is to describe the preparation of a lyophilized formulation (kit) for radiolabeling the Mab ior egf/r3 with 99m Tc for immunoscintigraphic applications. Radiolabeling efficiency, effects on immunoreactivity, image studies and stability of the formulation are reported. The study demonstrated that the kit formulation can be labeled with 99m Tc at high yields and can be used to visualize in vivo human tumors of epithelial origin by immunoscintigraphy studies.(author)

In Vivo Imaging of Xenograft Tumors Using an Epidermal Growth Factor Receptor-Specific Affibody Molecule Labeled with a Near-infrared Fluorophore

Directory of Open Access Journals (Sweden)

Haibiao Gong

2010-02-01

Full Text Available Overexpression of epidermal growth factor receptor (EGFR is associated with many types of cancers. It is of great interest to noninvasively image the EGFR expression in vivo. In this study, we labeled an EGFR-specific Affibody molecule (Eaff with a near-infrared (NIR dye IRDye800CW maleimide and tested the binding of this labeled molecule (Eaff800 in cell culture and xenograft mouse tumor models. Unlike EGF, Eaff did not activate the EGFR signaling pathway. Results showed that Eaff800 was bound and taken up specifically by EGFR-overexpressing A431 cells. When Eaff800 was intravenously injected into nude mice bearing A431 xenograft tumors, the tumor could be identified 1 hour after injection and it became most prominent after 1 day. Images of dissected tissue sections demonstrated that the accumulation of Eaff800 was highest in the liver, followed by the tumor and kidney. Moreover, in combination with a human EGFR type 2 (HER2-specific probe Haff682, Eaff800 could be used to distinguish between EGFR- and HER2-overexpressing tumors. Interestingly, the organ distribution pattern and the clearance rate of Eaff800 were different from those of Haff682. In conclusion, Eaff molecule labeled with a NIR fluorophore is a promising molecular imaging agent for EGFR-overexpressing tumors.

Cuban Monoclonal Antibodies for Radioimmunodiagnosis and Radioimmunotherapy of Cancer Diseases

International Nuclear Information System (INIS)

Casaco, A.

2009-01-01

The Centre of Molecular Immunology produces monoclonal antibodies for treating cancer diseases. We are mainly focus on two target systems; one is the epidermal growth factor receptor (EGF-R) because there is a tremendous relationship between the EGF/EGF-R system and several human tumours such as lung, head and neck, ovarian breast and brain cancers; the second one is the ganglioside system, the relevance of certain gangliosides in tumour growth and metastatic dissemination has been well documented, GM3(NeuGc) ganglioside is particularly interesting due to its restrictive expression in normal human tissues. Nimotuzumab (h-R3) is a humanized monoclonal antibody (mAb) that was obtained by complementarity-determining regions grafting of a murine mAb (ior egf/r3) to a human framework having remarkable antiproliferative, pro-apoptotic, and antiangiogenic effects. A Phase I clinical trial was performed to evaluate the toxicity and clinical effect of an intracavitary (intracerebral) administration of a single dose of nimotuzumab (h-R3) labelled with increasing doses of 188Re. All patients bearing astrocytomas grade III/IV should be treated previously with conventional therapies and have an EGF-R overexpression in the tumour, demonstrated by immunohistochemical study. Maximal tolerated dose was 3 mg of the h-R3 labelled with 10 mCi of 188 Re. The radioimmunoconjugate showed a high retention in the surgical created resection cavity and the brain adjacent tissues with a mean value of 85.5% of the injected dose one hour post-administration. This radioimmunoconjugate may be relatively safe and a promising therapeutic approach for treating high grade gliomas. GM3(NeuGc) ganglioside is particularly interesting due to its restrictive expression in normal human tissues according to immunohistochemical studies, using either polyclonal or monoclonal antibodies. But both immunohistochemical and biochemical methods have strongly suggested its over-expression in human breast and colon

Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD/UPRT-armed oncolytic measles virus.

Science.gov (United States)

Zaoui, K; Bossow, S; Grossardt, C; Leber, M F; Springfeld, C; Plinkert, P K; Kalle, C von; Ungerechts, G

2012-03-01

First-line treatment of recurrent and/or refractory head and neck squamous cell carcinoma (HNSCC) is based on platinum, 5-fluorouracil (5-FU) and the monoclonal antiEGFR antibody cetuximab. However, in most cases this chemoimmunotherapy does not cure the disease, and more than 50% of HNSCC patients are dying because of local recurrence of the tumors. In the majority of cases, HNSCC overexpress the epidermal growth factor receptor (EGFR), and its presence is associated with a poor outcome. In this study, we engineered an EGFR-targeted oncolytic measles virus (MV), armed with the bifunctional enzyme cytosine deaminase/uracil phosphoribosyltransferase (CD/UPRT). CD/UPRT converts 5-fluorocytosine (5-FC) into the chemotherapeutic 5-FU, a mainstay of HNSCC chemotherapy. This virus efficiently replicates in and lyses primary HNSCC cells in vitro. Arming with CD/UPRT mediates efficient prodrug activation with high bystander killing of non-infected tumor cells. In mice bearing primary HNSCC xenografts, intratumoral administration of MV-antiEGFR resulted in statistically significant tumor growth delay and prolongation of survival. Importantly, combination with 5-FC is superior to virus-only treatment leading to significant tumor growth inhibition. Thus, chemovirotherapy with EGFR-targeted and CD/UPRT-armed MV is highly efficacious in preclinical settings with direct translational implications for a planned Phase I clinical trial of MV for locoregional treatment of HNSCC.

Design and Synthesis of 11C-Labelled Compound Libraries for the Molecular Imaging of EGFr, VEGFr-2, AT1 and AT2 Receptors: Transition-Metal Mediated Carbonylations Using [11C]Carbon Monoxide

International Nuclear Information System (INIS)

Aaberg, Ola

2009-01-01

This work deals with radiochemistry and new approaches to develop novel PET tracers labelled with the radionuclide 11 C. Two methods for the synthesis of 11 C-labelled acrylamides have been explored. First, [1- 11 C]-acrylic acid was obtained from a palladium(0)-mediated 11 C-carboxylation of acetylene with [ 11 C]carbon monoxide; this could be converted to the corresponding acyl chloride and then combined with benzylamine to form N-benzyl[carbonyl- 11 C]acrylamide. In the second method, the palladium(0)-mediated carbonylation of vinyl halides with [ 11 C]carbon monoxide was explored. This latter method, yielded labelled acrylamides in a single step with retention of configuration at the C=C double bond, and required less amine compared to the acetylene method. The vinyl halide method was used to synthesize a library of 11 C-labelled EGFr-inhibitors in 7-61% decay corrected radiochemical yield via a combinatorial approach. The compounds were designed to target either the active or the inactive form of EGFr, following computational docking studies. The rhodium(I)-mediated carbonylative cross-coupling of an azide and an amine was shown to be a very general reaction and was used to synthesize a library of dual VEGFr-2/PDGFrβ inhibitors that were 11 C-labelled at the urea position in 38-78% dc rcy. The angiotensin II AT 1 receptor antagonist eprosartan was 11 C-labelled at one of the carboxyl groups in one step using a palladium(0)-mediated carboxylation. Autoradiography shows specific binding in rat kidney, lung and adrenal cortex, and organ distribution shows a high accumulation in the intestines, kidneys and liver. Specific binding in frozen sections of human adrenal incidentalomas warrants further investigations of this tracer. Three angiotensin II AT 2 ligands were 11 C-labelled at the amide group in a palladium(0)-mediated aminocarbonylation in 16-36% dc rcy. One of the compounds was evaluated using in vitro using autoradiography, and in vivo using organ

{sup 99m}Tc-labeled chimeric anti-NCA 95 antigranulocyte monoclonal antibody for bone marrow imaging

Energy Technology Data Exchange (ETDEWEB)

Sarwar, M.; Higuchi, Tetsuya; Tomiyoshi, Katsumi [Gunma Univ., Maebashi (Japan). School of Medicine] [and others

1998-09-01

Chimeric mouse-human antigranulocyte monoclonal antibody (ch MAb) against non-specific cross-reacting antigen (NCA-95) was labeled with {sup 99m}Tc (using a direct method) and {sup 125}I (using the chloramine T method), and its binding to human granulocytes and LS-180 colorectal carcinoma cells expressing carcinoembryonic antigen on their surfaces, cross-reactive with anti-NCA-95 chimeric monoclonal antibody, increased in proportion to the number of cells added and reached more than 80% and 90%, respectively. In biodistribution studies, {sup 99m}Tc and {sup 125}I-labeled ch anti-NCA-95 MAb revealed high tumor uptake, and the tumor-to-blood ratio was 2.9 after 24 hours. The tumor-to-normal-organ ratio was also more than 3.0 in all organs except for the tumor-to-kidney ratio. Scintigrams of athymic nude mice confirmed the results of biodistribution studies that showed higher radioactivity in tumor and kidney of the mice administered with {sup 99m}Tc-labeled ch MAb. A normal volunteer injected with {sup 99m}Tc-labeled ch anti-NCA-95 antigranulocyte MAb showed clear bone marrow images, and a patient with aplastic anemia revealed irregular uptake in his lumbar spine, suggesting its utility for bone marrow scintigraphy and for the detection of hematological disorders, infections, and bone metastasis. (author)

sup 99m Tc-labelled anti NCA-95 antibodies in prosthetic heart valve endocarditis

Energy Technology Data Exchange (ETDEWEB)

Bair, H J; Becker, W; Wolf, F [Dept. of Nuclear Medicine, Univ. Erlangen-Nuernberg, Erlangen (Germany); Volkholz, H J [Dept. of Internal Medicine 1, Univ. of Erlangen-Nuernberg, Erlangen (Germany)

1991-08-01

A 54-y old women with earlier replacement of the mitral and aortic valves and clinical signs of localized endocarditis was studied with {sup 99m}Tc-labelled anti NCA-95 antibody. Whereas echocardiographic findings were negative, increased radionuclide uptake was observed left parasternal over the mitral valve as a sign of prosthetic valve endocarditis. This result could be confirmed by a similar study with leukocytes labelled in vitro with {sup 111}In-oxine. (orig.).

Gallic acid induces apoptosis in EGFR-mutant non-small cell lung cancers by accelerating EGFR turnover.

Science.gov (United States)

Nam, Boas; Rho, Jin Kyung; Shin, Dong-Myung; Son, Jaekyoung

2016-10-01

Gallic acid is a common botanic phenolic compound, which is present in plants and foods worldwide. Gallic acid is implicated in various biological processes such as cell growth and apoptosis. Indeed, gallic acid has been shown to induce apoptosis in many cancer types. However, the molecular mechanisms of gallic acid-induced apoptosis in cancer, particularly lung cancer, are still unclear. Here, we report that gallic acid induces apoptosis in EGFR-mutant non-small cell lung cancer (NSCLC) cells, but not in EGFR-WT NSCLC cells. Treatment with gallic acid resulted in a significant reduction in proliferation and induction of apoptosis, only in EGFR-mutant NSCLC cells. Interestingly, treatment with gallic acid led to a robust decrease in EGFR levels, which is critical for NSCLC survival. Treatment with gallic acid had no significant effect on transcription, but induced EGFR turnover. Indeed, treatment with a proteasome inhibitor dramatically reversed gallic acid-induced EGFR downregulation. Moreover, treatment with gallic acid induced EGFR turnover leading to apoptosis in EGFR-TKI (tyrosine kinase inhibitor)-resistant cell lines, which are dependent on EGFR signaling for survival. Thus, these studies suggest that gallic acid can induce apoptosis in EGFR-dependent lung cancers that are dependent on EGFR for growth and survival via acceleration of EGFR turnover. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cellular Plasticity and Heterogeneity of EGFR Mutant Lung Cancer

Science.gov (United States)

2016-11-01

Department of the Army position, policy or decision unless so designated by other documentation. REPORT DOCUMENTATION PAGE Form Approved OMB No...Growth Factor Receptor (EGFR) is altered in 10-15% of lung adenocarcinomas, a subtype of lung cancer. Patients with tumors that have this alteration...presence of a viral infection in the colony of the donating lab. We were able to obtain these mice by purchasing and having them re- derived from Jackson

The biodistribution study of 99mTc labelled anti-CEA monoclonal antibody in tumor bearing nude mice

International Nuclear Information System (INIS)

Lou Zongxin

1992-01-01

The author report the optimal condition of 99m Tc labelling with anti-CEA monoclonal antibody using chelating of 99m Tc with dimethylformamide. The labelling rate of this method is 60%-80%, the radiochemical purity of labelling antibody over 90% and maintain its better immuno activity. The biodistribution of the tumor bearing nude mice demonstrates that as compared with the control group, 24 hours after the intraperitoneal injection the injected labelled antibody has its specific concentration in tumor tissue

Bio-imaging of colorectal cancer models using near infrared labeled epidermal growth factor.

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Gadi Cohen

Full Text Available Novel strategies that target the epidermal growth factor receptor (EGFR have led to the clinical development of monoclonal antibodies, which treat metastatic colorectal cancer (mCRC but only subgroups of patients with increased wild type KRAS and EGFR gene copy, respond to these agents. Furthermore, resistance to EGFR blockade inevitably occurred, making future therapy difficult. Novel bio-imaging (BOI methods may assist in quantization of EGFR in mCRC tissue thus complementing the immunohistochemistry methodology, in guiding the future treatment of these patients. The aim of the present study was to explore the usefulness of near infrared-labeled EGF (EGF-NIR for bio-imaging of CRC using in vitro and in vivo orthotopic tumor CRC models and ex vivo human CRC tissues. We describe the preparation and characterization of EGF-NIR and investigate binding, using BOI of a panel of CRC cell culture models resembling heterogeneity of human CRC tissues. EGF-NIR was specifically and selectively bound by EGFR expressing CRC cells, the intensity of EGF-NIR signal to background ratio (SBR reflected EGFR levels, dose-response and time course imaging experiments provided optimal conditions for quantization of EGFR levels by BOI. EGF-NIR imaging of mice with HT-29 orthotopic CRC tumor indicated that EGF-NIR is more slowly cleared from the tumor and the highest SBR between tumor and normal adjacent tissue was achieved two days post-injection. Furthermore, images of dissected tissues demonstrated accumulation of EGF-NIR in the tumor and liver. EGF-NIR specifically and strongly labeled EGFR positive human CRC tissues while adjacent CRC tissue and EGFR negative tissues expressed weak NIR signals. This study emphasizes the use of EGF-NIR for preclinical studies. Combined with other methods, EGF-NIR could provide an additional bio-imaging specific tool in the standardization of measurements of EGFR expression in CRC tissues.

Immunohistochemical expression of the epidermal growth factor receptor (EGFR in colorectal carcinoma: relation with clinicopathological parameters

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Maurício Andrade Azevedo

2011-09-01

Full Text Available Introduction: The study of tissue immunostaining of the epidermal growth factor receptor (EGFR may contribute with the understanding of its role in the prognosis of colorectal carcinoma. Objective: To analyze the immunohistochemical expression of EGFR in colorectal carcinoma tissues and transitional tumor-mucosa and mucosa adjacent to neoplasia, and its relation with cancer. Method: The study was conducted with 40 patients with colorectal carcinoma who had surgery with curative intent in order to analyze the immunoexpression of EGFR with anti-EGFR. We used parametric and nonparametric tests. Results: The immunohistochemical expression of EGFR in tumor samples showed a significant difference as to the level of immunostaining in tissue specimens of transitional tumor-mucosa (p=0.01 and the level of immunoreactivity in tissues of the adjacent mucosa (p=0, 04. The immunoexpression of EGFR showed no significant relation with the size of the tumor, angiolymphatic invasion, neural invasion, cellular differentiation, level of carcinoma infiltration in the intestinal wall, lymph node metastases and liver metastases. Conclusions: The EGFR showed a more intense expression in the mucosa of colorectal carcinoma than in the transitional epithelium and adjacent non-neoplastic mucosa. The immunoexpression of EGFR did not correlate with pathological parameters of colorectal carcinoma and liver metastases.Introdução: O estudo da imunoexpressão tecidual do receptor do fator de crescimento epitelial (EGFR pode contribuir para o entendimento de seu papel no prognóstico do carcinoma colorretal. Objetivo: Analisar a expressão imuno-histoquímica do EGFR no carcinoma colorretal e nos tecidos da transição tumor-mucosa e da mucosa adjacente à neoplasia, e avaliar a relação com os aspectos anatomopatológicos da neoplasia. Método: Em 40 doentes com carcinoma colorretal operados com intenção curativa, estudou-se a imunoexpressão do EGFR com anticorpo anti-EGFR

Cetuximab in combination with anti-human IgG antibodies efficiently down-regulates the EGF receptor by macropinocytosis

International Nuclear Information System (INIS)

Berger, Christian; Madshus, Inger Helene; Stang, Espen

2012-01-01

The monoclonal antibody C225 (Cetuximab) blocks binding of ligand to the epidermal growth factor receptor (EGFR). In addition, it is known that incubation with C225 induces endocytosis of the EGFR. This endocytosis has previously been shown to be increased when C225 is combined with an additional monoclonal anti-EGFR antibody. However, the effects of antibody combinations on EGFR activation, endocytosis, trafficking and degradation have been unclear. By binding a secondary antibody to the C225-EGFR complex, we here demonstrate that a combination of antibodies can efficiently internalize and degrade the EGFR. Although the combination of antibodies activated the EGFR kinase and induced ubiquitination of the EGFR, the kinase activity was not required for internalization of the EGFR. In contrast to EGF-induced EGFR down-regulation, the antibody combination efficiently degraded the EGFR without initiating downstream proliferative signaling. The antibody-induced internalization of EGFR was found not to depend on clathrin and/or dynamin, but depended on actin polymerization, suggesting induction of macropinocytosis. Macropinocytosis may cause internalization of large membrane areas, and this could explain the highly efficient internalization of the EGFR induced by combination of antibodies. -- Highlight: ► Cetuximab induced endocytosis of EGFR increases upon combination with anti-human IgG. ► Antibody combination causes internalization of EGFR by macropinocytosis. ► Antibody-induced internalization of EGFR is independent of EGFR kinase activity. ► Antibody combination may have a zipper effect and cross-link EGFRs on neighboring cells.