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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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    Absorbed Doses and Risk Estimates of 211At-MX35 F(ab')2 in Intraperitoneal Therapy of Ovarian Cancer Patients

    Cederkrantz, Elin, Andersson, Håkan, Bernhardt, Peter, Bäck, Tom, Hultborn, Ragnar, Jacobsson, Lars, Jensen, Holger, Lindegren, Sture, Ljungberg, Michael, Magnander, Tobias, Palm, Stig, Albertsson, Per
    International journal of radiation oncology, biology, physics, 01 November 2015, Vol.93(3), pp.569-576 [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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    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]
    ScienceDirect Journals (Elsevier)
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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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    211At radioimmunotherapy of subcutaneous human ovarian cancer xenografts: evaluation of relative biologic effectiveness of an alpha-emitter in vivo

    Bäck, Tom, Andersson, Håkan, Divgi, Chaitanya R, Hultborn, Ragnar, Jensen, Holger, Lindegren, Sture, Palm, Stig, Jacobsson, Lars
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, December 2005, Vol.46(12), pp.2061-7 [Revue évaluée par les pairs]
    MEDLINE/PubMed (U.S. National Library of Medicine)
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    Titre: 211At radioimmunotherapy of subcutaneous human ovarian cancer xenografts: evaluation of relative biologic effectiveness of an alpha-emitter in vivo
    Auteur: Bäck, Tom; Andersson, Håkan; Divgi, Chaitanya R; Hultborn, Ragnar; Jensen, Holger; Lindegren, Sture; Palm, Stig; Jacobsson, Lars
    Sujet: Astatine -- Therapeutic Use ; Isotopes -- Therapeutic Use ; Ovarian Neoplasms -- Radiotherapy ; Radioimmunotherapy -- Methods ; Radioisotopes -- Pharmacology
    Description: The use of alpha-particle emitters in radioimmunotherapy (RIT) appears to be promising. We previously obtained convincing results in the treatment of microscopic intraperitoneal ovarian cancer in nude mice by using the alpha-emitter 211At. This study was performed to evaluate the relative biological effectiveness (RBE) of 211At compared with that of 60Co gamma-irradiation in an RIT model. Our endpoint was growth inhibition (GI) of subcutaneous xenografts. GI after irradiation was studied with subcutaneous xenografts of the human ovarian cancer cell line NIH:OVCAR-3 implanted in nude mice. The animals received an intravenous injection of 211At-labeled monoclonal antibody MX35 F(ab')2 at different levels of radioactivity (0.33, 0.65, and 0.90 MBq). Control mice received unlabeled MX35 F(ab')2 only. To calculate the mean absorbed dose to tumor, a separate biodistribution study established the uptake of 211At in tumors and organs at different times after injection. External irradiation of the tumors was performed with 60Co. Tumor growth was monitored, and the normalized tumor volume (NTV) was calculated for each tumor. GI was defined by dividing the NTV values by the fitted NTV curve obtained from the corresponding control mice. To compare the biologic effects of the 2 radiation qualities, the mean value for GI (from day 8 to day 23) was plotted for each tumor as a function of its corresponding absorbed dose. From exponential fits of these curves,... The biodistribution study showed the uptake of the immunoconjugate by the tumor (amount of injected radioactivity per gram) to be 14% after 7 h. At 40 h, the ratio of uptake in tumors to uptake in blood reached a maximum value of 6.2. The administered activities of 211At corresponded to doses absorbed by tumors of 1.35, 2.65, and 3.70 Gy. The value (mean+/-SEM) for D37 was 1.59+/-0.08 Gy. Tumor growth after 60Co external irradiation showed a value for D37 of 7.65+/-1.0 Gy. The corresponding RBE of 211At irradiation was 4.8+/-0.7. Using a tumor GI model in nude mice, we were able to derive an RBE of alpha-particle RIT with 211At. The RBE was found to be 4.8+/-0.7.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, December 2005, Vol.46(12), pp.2061-7
    Identifiant: 0161-5505 (ISSN); 16330571 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)

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    Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: Outcome related to measured tumor size and mean absorbed dose

    Elgqvist, Jörgen, Andersson, Håkan, Bäck, Tom, Claesson, Ingela, Hultborn, Ragnar, Jensen, Holger, Johansson, Bengt R, Lindegren, Sture, Olsson, Marita, Palm, Stig, Warnhammar, Elisabet, Jacobsson, Lars
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, August 2006, Vol.47(8), pp.1342-50 [Revue évaluée par les pairs]
    MEDLINE/PubMed (U.S. National Library of Medicine)
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    Titre: Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: Outcome related to measured tumor size and mean absorbed dose
    Auteur: Elgqvist, Jörgen; Andersson, Håkan; Bäck, Tom; Claesson, Ingela; Hultborn, Ragnar; Jensen, Holger; Johansson, Bengt R; Lindegren, Sture; Olsson, Marita; Palm, Stig; Warnhammar, Elisabet; Jacobsson, Lars
    Sujet: Ovarian Neoplasms -- Diagnostic Imaging ; Radioimmunotherapy -- Methods
    Description: The purpose of this work was to (a) investigate the efficacy of radioimmunotherapy using 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2 (nonspecific antibody) against differently advanced ovarian cancer in mice; (b) image the tumor growth on the peritoneum; and (c) calculate the specific energy and mean absorbed dose to tumors and critical organs. Two experiments with 5-wk-old nude mice (n = 100 + 93), intraperitoneally inoculated with approximately 1 x 10(7) NIH:OVCAR-3 cells, were done. At either 1, 3, 4, 5, or 7 wk after inoculation animals were intraperitoneally treated with approximately 400 kBq 211At-MX35 F(ab')2 (n = 50 + 45), approximately 400 kBq 211At-Rituximab F(ab')2 (n = 25 + 24), or unlabeled Rituximab F(ab')2 (n = 25 + 24). At the time of treatment 29 animals were sacrificed and biopsies were taken for determination of tumor sizes using scanning electron microscopy (SEM). Eight weeks after each treatment the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined. The specific energy and mean absorbed dose to tumors were calculated. The activity concentration was measured in critical organs and abdominal fluid. When given treatment 1, 3, 4, 5, or 7 wk after cell inoculation the tumor-free fraction (TFF) was 95%, 68%, 58%, 47%, 26%, and 100%, 80%, 20%, 20%, and 0% when treated with 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2, respectively. The SEM images revealed maximum tumor radius of approximately 30 mum 1 wk after cell inoculation, increasing to approximately 340 mum at 7 wk. Specific energy to cell nuclei varied between 0 and approximately 540 Gy, depending on assumptions regarding activity distribution and tumor size. The mean absorbed dose to thyroid, kidneys, and bone marrow was approximately 35, approximately 4, and approximately 0.3 Gy, respectively. Treatment with 211At-MX35 F(ab')2 or 211At-Rituximab F(ab')2 resulted in a TFF of 95%-100% when the tumor radius was 22 Gy) from the activity bound to the tumor surface and probably some contribution from penetrating activity.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, August 2006, Vol.47(8), pp.1342-50
    Identifiant: 0161-5505 (ISSN); 16883015 Version (PMID)

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    Fractionated radioimmunotherapy of intraperitoneally growing ovarian cancer in nude mice with 211At-MX35 F(ab′) 2: therapeutic efficacy and myelotoxicity

    Elgqvist, Jörgen, Andersson, Håkan, Bäck, Tom, Claesson, Ingela, Hultborn, Ragnar, Jensen, Holger, Lindegren, Sture, Olsson, Marita, Palm, Stig, Warnhammar, Elisabet, Jacobsson, Lars
    Nuclear medicine and biology, 2006, Vol.33(8), pp.1065-1072 [Revue évaluée par les pairs]