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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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    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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    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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    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]
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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]

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    Therapeutic efficacy and tumor dose estimations in radioimmunotherapy of intraperitoneally growing OVCAR-3 cells in nude mice with (211)At-labeled monoclonal antibody MX35

    Elgqvist, Jörgen, Andersson, Håkan, Bäck, Tom, Hultborn, Ragnar, Jensen, Holger, Karlsson, Börje, Lindegren, Sture, Palm, Stig, Warnhammar, Elisabet, Jacobsson, Lars
    Journal of nuclear medicine : official publication, Society of Nuclear Medicine, November 2005, Vol.46(11), pp.1907-15 [Revue évaluée par les pairs]
    MEDLINE/PubMed (U.S. National Library of Medicine)
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    Titre: Therapeutic efficacy and tumor dose estimations in radioimmunotherapy of intraperitoneally growing OVCAR-3 cells in nude mice with (211)At-labeled monoclonal antibody MX35
    Auteur: Elgqvist, Jörgen; Andersson, Håkan; Bäck, Tom; Hultborn, Ragnar; Jensen, Holger; Karlsson, Börje; Lindegren, Sture; Palm, Stig; Warnhammar, Elisabet; Jacobsson, Lars
    Sujet: Antibodies, Monoclonal -- Pharmacokinetics ; Organometallic Compounds -- Pharmacokinetics ; Ovarian Neoplasms -- Metabolism ; Radiopharmaceuticals -- Pharmacokinetics
    Description: The purpose of this study was to investigate the therapeutic efficacy of-and to estimate the absorbed dose to-tumor cells from radioimmunotherapy (RIT) in an ovarian cancer model using the alpha-particle-emitting nuclide (211)At labeled to monoclonal antibody (mAb) MX35. Previous studies on mAb MOv18 did not allow for dosimetry because of antigen shedding in vitro. Five-week-old female nude BALB/c nu/nu mice were inoculated intraperitoneally with 1 x 10(7) cells of the human tumor cell line OVCAR-3. Three weeks later, the animals were given approximately 400, 800, or 1,200 kBq of (211)At-labeled mAb MX35 intraperitoneally. As controls, one group of animals was injected with unlabeled mAb and another group was injected with phosphate-buffered saline (PBS). Another group was given approximately 400 kBq of (211)At labeled to the previously investigated mAb MOv18 for efficacy comparison. Two months after treatment, the animals were sacrificed and the presence of macroscopic and microscopic tumors, as well as ascites, was determined. The absorbed dose to tumor cells on the peritoneal surface was estimated in terms of the sum of a specific and a nonspecific contribution. The specific contribution, arising from mAbs binding to the antigenic sites on the cell membrane, was calculated using a dynamic compartment model developed in-house and Monte Carlo software.... In the control groups given unlabeled MX35 or PBS, all 18 animals had ascites, 6 of 9 animals in each group had macroscopic tumors, and all animals had microscopic growth. In the 3 groups given different amounts of (211)At-MX35, only 3 of 25 animals developed ascites. None of these animals had any sign of macroscopic tumors, but 8 had microscopic growth. In the group given (211)At-MOv18, no animals had ascites or macroscopic tumors, but 3 of 10 animals had microscopic tumors. After injecting 400 kBq of (211)At-MX35, the absorbed dose due to specific binding, for a cell cluster with a radius of 50 microm, ranged from 413 to 223 Gy between 0- and 45-microm distance from the cluster center, assuming a homogeneous distribution of (211)At-MX35 in the cluster. The contribution from unbound (211)At-MX35 and (211)At-MX35 only distributed on the cluster surface, for this cluster size, ranged from 7 to 14 Gy and from 29 to 94 Gy, between 0- and 45-microm distance from the cluster center, respectively.... (211)At-MX35 injected intraperitoneally exhibits a high efficacy when treating micrometastatic growth of the ovarian cancer cell line OVCAR-3 on the peritoneum of nude mice.
    Fait partie de: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, November 2005, Vol.46(11), pp.1907-15
    Identifiant: 0161-5505 (ISSN); 16269606 Version (PMID)