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    • Plusieurs versions

    Comparison of therapeutic efficacy and biodistribution of 213Bi- and 211At-labeled monoclonal antibody MX35 in an ovarian cancer model

    Gustafsson, Anna M.E, Bäck, Tom, Elgqvist, Jörgen, Jacobsson, Lars, Hultborn, Ragnar, Albertsson, Per, Morgenstern, Alfred, Bruchertseifer, Frank, Jensen, Holger, Lindegren, Sture
    Nuclear medicine and biology, 2012, Vol.39(1), pp.15-22 [Revue évaluée par les pairs]

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    Intraperitoneal Alpha-Radioimmunotherapy of Advanced Ovarian Cancer in Nude Mice Using Different High Specific Activities

    Elgqvist, Jorgen, Ahlberg, Daniel, Andersson, Hakan, Jensen, Holger, Johansson, Bengt R, Kahu, Helena, Olsson, Marita, Lindegren, Sture
    World journal of oncology, June 2010, Vol.1(3), pp.101-110 [Revue évaluée par les pairs]

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    Repeated Intraperitoneal alpha-Radioimmunotherapy of Ovarian Cancer in Mice

    Elgqvist, Jörgen, Andersson, Håkan, Jensen, Holger, Kahu, Helena, Lindegren, Sture, Warnhammar, Elisabet, Hultborn, Ragnar
    Journal of oncology, 2010, Vol.2010, pp.394913 [Revue évaluée par les pairs]

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    Therapeutic Efficacy of Astatine-211–Labeled Trastuzumab on Radioresistant SKOV-3 Tumors in Nude Mice

    Palm, Stig, Bäck, Tom, Claesson, Ingela, Danielsson, Anna, Elgqvist, Jörgen, Frost, Sofia, Hultborn, Ragnar, Jensen, Holger, Lindegren, Sture, Jacobsson, Lars
    International journal of radiation oncology, biology, physics, 2007, Vol.69(2), pp.572-579 [Revue évaluée par les pairs]

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    Astatine-211-labeled antibodies for treatment of disseminated ovarian cancer: an overview of results in an ovarian tumor model

    Andersson, Håkan, Elgqvist, Jörgen, Horvath, György, Hultborn, Ragnar, Jacobsson, Lars, Jensen, Holger, Karlsson, Börje, Lindegren, Sture, Palm, Stig
    Clinical cancer research : an official journal of the American Association for Cancer Research, 01 September 2003, Vol.9(10 Pt 2), pp.3914S-21S [Revue évaluée par les pairs]
    MEDLINE/PubMed (U.S. National Library of Medicine)
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    Titre: Astatine-211-labeled antibodies for treatment of disseminated ovarian cancer: an overview of results in an ovarian tumor model
    Auteur: Andersson, Håkan; Elgqvist, Jörgen; Horvath, György; Hultborn, Ragnar; Jacobsson, Lars; Jensen, Holger; Karlsson, Börje; Lindegren, Sture; Palm, Stig
    Sujet: Astatine -- Therapeutic Use ; Isotopes -- Therapeutic Use ; Ovarian Neoplasms -- Radiotherapy ; Radioimmunotherapy -- Methods
    Description: The aim of the study was to establish and refine a preclinical model to alpha-immunoradiotherapy of ovarian cancer. At-211 was produced by cyclotron irradiation of a bismuth-209 target and isolated using a novel dry distillation procedure. Monoclonal antibodies were radiohalogenated with the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate and characterized in terms of radiochemical yield and in vitro binding properties. In vitro OVCAR-3 cells were irradiated using an external Cobalt-60 beam, as reference, or At-211-albumin and labeled antibody. Growth assays were used to establish cell survival. A Monte Carlo program was developed to simulate the energy imparted and the track length distribution. Nude mice were used for studies of WBC depression, with various activities of Tc-99m antibodies, as reference, and At-211 antibodies. In efficacy studies, OVCAR-3 cells were inoculated i.p., and animals were treated 2 weeks later. The animals were either dissected 6 weeks later or followed-up for long-term survival. A rapid distillation procedure, as well as a rapid and high-yield, single-pot labeling procedure, was achieved. From growth inhibition data, the relative biological effectiveness of the alpha-emission for OVCAR-3 cells was estimated to be approximately 5, which is in the same range as found in vivo for hematological toxicity. At-211 MOv18 was found to effectively inhibit the development of tumors and ascites, also resulting in long-term survival without significant toxic effect. Use of the short-range, high-linear energy transfer alpha-emitter At-211 conjugated to a surface epitope-recognizing monoclonal antibody appears to be highly efficient without significant toxicity in a mouse peritoneal tumor model, urging a Phase I clinical trial.
    Fait partie de: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 September 2003, Vol.9(10 Pt 2), pp.3914S-21S
    Identifiant: 1078-0432 (ISSN); 14506189 Version (PMID)

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    Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with {sup 211}At-MX35 F(ab'){sub 2}

    Elgqvist, Joergen, Andersson, Hakan, Bernhardt, Peter, Baeck, Tom, Claesson, Ingela, Hultborn, Ragnar, Jensen, Holger, Johansson, Bengt R, Lindegren, Sture, Olsson, Marita, Palm, Stig, Warnhammar, Elisabet, Jacobsson, Lars
    International Journal of Radiation Oncology, Biology and Physics, 15 November 2006, Vol.66(4) [Revue évaluée par les pairs]

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    Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35 F(ab′) 2

    Elgqvist, Jörgen, Andersson, Håkan, Bernhardt, Peter, Bäck, Tom, Claesson, Ingela, Hultborn, Ragnar, Jensen, Holger, Johansson, Bengt R, Lindegren, Sture, Olsson, Marita, Palm, Stig, Warnhammar, Elisabet, Jacobsson, Lars
    International journal of radiation oncology, biology, physics, 2006, Vol.66(4), pp.1228-1237 [Revue évaluée par les pairs]
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    Titre: Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35 F(ab′) 2
    Auteur: Elgqvist, Jörgen; Andersson, Håkan; Bernhardt, Peter; Bäck, Tom; Claesson, Ingela; Hultborn, Ragnar; Jensen, Holger; Johansson, Bengt R; Lindegren, Sture; Olsson, Marita; Palm, Stig; Warnhammar, Elisabet; Jacobsson, Lars
    Sujet: Ovarian Cancer ; Radioimmunotherapy ; Dosimetry ; Mx35 ; Astatine ; Ovarian Cancer ; Radioimmunotherapy ; Dosimetry ; Mx35 ; Astatine ; Medicine
    Description: Purpose: To elucidate the therapeutic efficacy of α-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the α-particle emitter Astatine-211 ( 211At) labeled to the mAb MX35 F(ab′) 2. Methods and Materials: Animals were inoculated intraperitoneally with ∼1 × 10 7 cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100, or 200 kBq 211At-MX35 F(ab′) 2 ( n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq 211At-Rituximab F(ab′) 2 ( n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors...
    Fait partie de: International journal of radiation oncology, biology, physics, 2006, Vol.66(4), pp.1228-1237
    Identifiant: 0360-3016 (ISSN); 1879-355X (E-ISSN); 10.1016/j.ijrobp.2006.07.003 (DOI)

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    Direct procedure for the production of 211At-labeled antibodies with an epsilon-lysyl-3-(trimethylstannyl)benzamide immunoconjugate

    Lindegren, Sture, Frost, Sofia, Bäck, Tom, Haglund, Elin, Elgqvist, Jörgen, Jensen, Holger
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, September 2008, Vol.49(9), pp.1537-45 [Revue évaluée par les pairs]
    MEDLINE/PubMed (U.S. National Library of Medicine)
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    Titre: Direct procedure for the production of 211At-labeled antibodies with an epsilon-lysyl-3-(trimethylstannyl)benzamide immunoconjugate
    Auteur: Lindegren, Sture; Frost, Sofia; Bäck, Tom; Haglund, Elin; Elgqvist, Jörgen; Jensen, Holger
    Sujet: Antibodies, Monoclonal -- Chemistry ; Astatine -- Chemistry ; Benzamides -- Chemistry
    Description: (211)At-labeled tumor-specific antibodies have long been considered for the treatment of disseminated cancer. However, the limited availability of the nuclide and the poor efficacy of labeling procedures at clinical activity levels present major obstacles to their use. This study evaluated a procedure for the direct astatination of antibodies for the production of clinical activity levels. The monoclonal antibody trastuzumab was conjugated with the reagent N-succinimidyl-3-(trimethylstannyl)benzoate, and the immunoconjugate was labeled with astatine. Before astatination of the conjugated antibody, the nuclide was activated with N-iodosuccinimide. The labeling reaction was evaluated in terms of reaction time, volume of reaction solvent, immunoconjugate concentration, and applied activity. The quality of the astatinated antibodies was determined by in vitro analysis and biodistribution studies in nude mice. The reaction proceeded almost instantaneously, and the results indicated a low dependence on immunoconjugate concentration and applied activity. Radiochemical labeling yields were in the range of 68%-81%, and a specific radioactivity of up to 1 GBq/mg could be achieved. Stability and radiochemical purity were equal to or better than those attained with a conventional 2-step procedure. Dissociation constants for directly astatinated, conventionally astatinated, and radioiodinated trastuzumab were 1.0+/-0.06 (mean+/-SD), 0.44+/-0.06, and 0.29+/-0.02 nM, respectively. The tissue distribution in non-tumor-bearing nude mice revealed only minor differences in organ uptake relative to that obtained with the conventional method. The direct astatination procedure enables the high-yield production of astatinated antibodies with radioactivity in the amounts required for clinical applications.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, September 2008, Vol.49(9), pp.1537-45
    Identifiant: 0161-5505 (ISSN); 18703591 Version (PMID); 10.2967/jnumed.107.049833 (DOI)

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    Myelotoxicity and RBE of 211At-conjugated monoclonal antibodies compared with 99mTc-conjugated monoclonal antibodies and 60Co irradiation in nude mice

    Elgqvist, Jörgen, Bernhardt, Peter, Hultborn, Ragnar, Jensen, Holger, Karlsson, Börje, Lindegren, Sture, Warnhammar, Elisabet, Jacobsson, Lars
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, March 2005, Vol.46(3), pp.464-71 [Revue évaluée par les pairs]
    MEDLINE/PubMed (U.S. National Library of Medicine)
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    Titre: Myelotoxicity and RBE of 211At-conjugated monoclonal antibodies compared with 99mTc-conjugated monoclonal antibodies and 60Co irradiation in nude mice
    Auteur: Elgqvist, Jörgen; Bernhardt, Peter; Hultborn, Ragnar; Jensen, Holger; Karlsson, Börje; Lindegren, Sture; Warnhammar, Elisabet; Jacobsson, Lars
    Sujet: Relative Biological Effectiveness ; Astatine -- Adverse Effects ; Bone Marrow -- Radiation Effects ; Radiometry -- Methods ; Technetium -- Adverse Effects
    Description: The rationale of this study was to determine the myelotoxicity in nude mice of the alpha-emitter 211At conjugated to monoclonal antibodies (mAbs) and to compare the effect with an electron emitter, (99m)Tc, and external irradiation from a 60Co source, for estimation of the relative biological effectiveness (RBE). 211At and (99m)Tc were conjugated to the IgG1 mAbs MX35 and 88BV59. Nude female BALB/c mice, 8- to 12-wk old, were injected intraperitoneally or intravenously. The biodistribution was determined 3, 6, and 18 h after injection. The bone-to-blood and bone marrow-to-blood activity concentration ratios (BBLR and BMBLR, respectively) were determined for simultaneously injected 211At- and (99m)Tc-mAbs. Bone marrow samples were taken from the femur. For each mouse, the whole-body retention was measured as well as the blood activity by repeated blood samples from the tail vein (0), 1, 3, 6, 12, and 18 h after injection. External-beam irradiation from a 60Co source was also performed at 3 different dose levels. White blood cell (WBC) counts, red blood cell counts, platelet counts, and hemoglobin were determined for each mouse initially and on days 1, 4, 5, 7, 15, 22, and 27 after injection. The calculations of the absorbed dose to the bone marrow were based on the BBLR, BMBLR, the cumulated activities,... The BMBLR was 0.58 +/- 0.06 and 0.56 +/- 0.06 for the 211At- and (99m)Tc-mAbs, respectively. No significant variation in BMBLR with time was found. The absorbed fractions for alpha-particles and electrons in the bone marrow were 0.88 and 0.75, respectively. The mean absorbed fractions of the photons from (99m)Tc were 0.033 and 0.52 for 140 and 18.3 keV, respectively. When different amounts of 211At- and (99m)Tc-mAbs (0.09-1.3 and 250-1,300 MBq, respectively) were administered intraperitoneally or intravenously, corresponding to absorbed doses to the bone marrow of 0.01-0.60 and 0.39-1.92 Gy, respectively, the WBC counts was suppressed by 1%-90% and 23%-89%, respectively. When external-beam irradiation with a 60Co source was performed to absorbed doses of 1.4, 1.9, and 2.4 Gy, the WBC counts was suppressed by 47%-90%. These results indicate a myelotoxic in vivo RBE of 3.4 +/- 0.6 for alpha-particles compared with (99m)Tc and 5.0 +/- 0.9 compared with 60Co irradiation. The effect on the WBC counts from bone marrow irradiation with 211At-mAbs indicates an in vivo RBE of 3.4 +/- 0.6 in comparison with (99m)Tc-mAbs. The RBE value compared with external irradiation is 5.0 +/- 0.9.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, March 2005, Vol.46(3), pp.464-71
    Identifiant: 0161-5505 (ISSN); 15750160 Version (PMID)

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    Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab')2--a phase I study

    Andersson, Håkan, Cederkrantz, Elin, Bäck, Tom, Divgi, Chaitanya, Elgqvist, Jörgen, Himmelman, Jakob, Horvath, György, Jacobsson, Lars, Jensen, Holger, Lindegren, Sture, Palm, Stig, Hultborn, Ragnar
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, July 2009, Vol.50(7), pp.1153-60 [Revue évaluée par les pairs]
    MEDLINE/PubMed (U.S. National Library of Medicine)
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    Titre: Intraperitoneal alpha-particle radioimmunotherapy of ovarian cancer patients: pharmacokinetics and dosimetry of (211)At-MX35 F(ab')2--a phase I study
    Auteur: Andersson, Håkan; Cederkrantz, Elin; Bäck, Tom; Divgi, Chaitanya; Elgqvist, Jörgen; Himmelman, Jakob; Horvath, György; Jacobsson, Lars; Jensen, Holger; Lindegren, Sture; Palm, Stig; Hultborn, Ragnar
    Sujet: Body Burden ; Radiometry ; Radiotherapy Dosage ; Antibodies, Monoclonal -- Therapeutic Use ; Astatine -- Therapeutic Use ; Ovarian Neoplasms -- Metabolism
    Description: The alpha-emitter (211)At labeled to a monoclonal antibody has proven safe and effective in treating microscopic ovarian cancer in the abdominal cavity of mice. Women in complete clinical remission after second-line chemotherapy for recurrent ovarian carcinoma were enrolled in a phase I study. The aim was to determine the pharmacokinetics for assessing absorbed dose to normal tissues and investigating toxicity. Nine patients underwent laparoscopy 2-5 d before the therapy; a peritoneal catheter was inserted, and the abdominal cavity was inspected to exclude the presence of macroscopic tumor growth or major adhesions. (211)At was labeled to MX35 F(ab')(2) using the reagent N-succinimidyl-3-(trimethylstannyl)-benzoate. Patients were infused with (211)At-MX35 F(ab')(2) (22.4-101 MBq/L) in dialysis solution via the peritoneal catheter. gamma-Camera scans were acquired on 3-5 occasions after infusion, and a SPECT scan was acquired at 6 h. Samples of blood, urine, and peritoneal fluid were collected at 1-48 h. Hematology and renal and thyroid function were followed for a median of 23 mo. Pharmacokinetics and dosimetric results were related to the initial activity concentration (IC) of the infused solution. The decay-corrected activity concentration decreased with time in the peritoneal fluid to 50% IC at 24 h, increased in serum to 6% IC at 45 h, and increased in the thyroid to 127% +/- 63% IC at 20 h without blocking and less than 20% IC with blocking. No other organ uptakes could be detected. The cumulative urinary excretion was 40 kBq/(MBq/L) at 24 h. The estimated absorbed dose to the peritoneum was 15.6 +/- 1.0 mGy/(MBq/L), to red bone marrow it was 0.14 +/- 0.04 mGy/(MBq/L), to the urinary bladder wall it was 0.77 +/- 0.19 mGy/(MBq/L), to the unblocked thyroid it was 24.7 +/- 11.1 mGy/(MBq/L), and to the blocked thyroid it was 1.4 +/- 1.6 mGy/(MBq/L) (mean +/- SD). No adverse effects were observed either subjectively or in laboratory parameters. This study indicates that by intraperitoneal administration of (211)At-MX35 F(ab')(2) it is possible to achieve therapeutic absorbed doses in microscopic tumor clusters without significant toxicity.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, July 2009, Vol.50(7), pp.1153-60
    Identifiant: 0161-5505 (ISSN); 19525452 Version (PMID); 10.2967/jnumed.109.062604 (DOI)