| 1. |
- Abou, Diane S., et al.
(författare)
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Preclinical Single Photon Emission Computed Tomography of Alpha Particle-Emitting Radium-223
- 2020
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 35:7, s. 520-529
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Dose optimization and pharmacokinetic evaluation of α-particle emitting radium-223 dichloride (223RaCl2) by planar γ-camera or single photon emission computed tomography (SPECT) imaging are hampered by the low photon abundance and injected activities. In this study, we demonstrate SPECT of 223Ra using phantoms and small animal in vivo models. Methods: Line phantoms and mice bearing 223Ra were imaged using a dedicated small animal SPECT by detecting the low-energy photon emissions from 223Ra. Localization of the therapeutic agent was verified by whole-body and whole-limb autoradiography and its radiobiological effect confirmed by immunofluorescence. Results: A state-of-the-art commercial small animal SPECT system equipped with a highly sensitive collimator enables collection of sufficient counts for three-dimensional reconstruction at reasonable administered activities and acquisition times. Line sources of 223Ra in both air and in a water scattering phantom gave a line spread function with a full-width-at-half-maximum of 1.45 mm. Early and late-phase imaging of the pharmacokinetics of the radiopharmaceutical were captured. Uptake at sites of active bone remodeling was correlated with DNA damage from the α particle emissions. Conclusions: This work demonstrates the capability to noninvasively define the distribution of 223RaCl2, a recently approved α-particle-emitting radionuclide. This approach allows quantitative assessment of 223Ra distribution and may assist radiation-dose optimization strategies to improve therapeutic response and ultimately to enable personalized treatment planning.
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| 2. |
- Almqvist, Ylva, et al.
(författare)
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Biodistribution of At-211-Labeled humanized monoclonal antibody A33
- 2007
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 22:4, s. 480-487
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Tidskriftsartikel (refereegranskat)abstract
- Radioimmunotherapy (RIT) could be a possible adjuvant treatment method for patients with colorectal carcinoma. The A33 antigen is a promising RIT target, as it is highly and homogenously expressed in 95% of all colorectal carcinomas. In this study, the humanized monoclonal antibody A33 (huA33), targeting the A33 antigen, was labeled with the therapeutic nuclide 211At, and the biodistribution and in vivo targeting ability of the conjugate was investigated in an athymic mouse xenograft model. There was an accumulation of 211At in tumor tissue over time, but no substantial accumulation was seen in any organ apart from the skin and thyroid, indicating no major release of free 211At in vivo. At all time points, the uptake of 211At-huA33 was higher in tumor tissue than in most organs, and at 8 hours postinjection (p.i.), no organ had a higher uptake than tumor tissue. The tumor-to-blood ratio of 211At-huA33 increased with time, reaching 2.5 after 21 hours p.i. The highest absorbed dose was found in the blood, but the tumor received a higher dose than any organ other than the thyroid. An in vivo blocking experiment showed that 211At-huA33 binds specifically to human tumor xenografts in athymic mice. In conclusion, the favorable biodistribution and specific in vivo targeting ability of 211At-huA33 makes it a potential therapeutic agent for the RIT of metastatic colorectal carcinoma.
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| 3. |
- Almqvist, Ylva, et al.
(författare)
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In vitro characterization of 211 At-labeled antibody A33 : a potential therapeutic agent against metastatic colorectal carcinoma
- 2005
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 20:5, s. 514-523
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Tidskriftsartikel (refereegranskat)abstract
- The humanized antibody A33 binds to the A33 antigen, expressed in 95% of primary and metastatic colorectal carcinomas. The restricted pattern of expression in normal tissue makes this antigen a possible target for radioimmunotherapy of colorectal micrometastases. In this study, the A33 antibody was labeled with the therapeutic nuclide 211At using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB). The in vitro characteristics of the 211At-benzoate-A33 conjugate (211At-A33) were investigated and found to be similar to those of 125I-benzoate-A33 (125I-A33) in different assays. Both conjugates bound with high affinity to SW1222 cells (Kd = 1.7 ± 0.2 nM, and 1.8 ± 0.1 nM for 211At-A33 and 125I-A33, respectively), and both showed good intracellular retention (70% of the radioactivity was still cell associated after 20 hours). The cytotoxic effect of 211At-A33 was also confirmed. After incubation with 211At-A33, SW1222 cells had a survival of approximately 0.3% when exposed to some 150 decays per cell (DPC). The cytotoxic effect was found to be dose-dependent, as cells exposed to only 56 DPC had a survival of approximately 5%. The 211At-A33 conjugate shows promise as a potential radioimmunotherapy agent for treatment of micrometastases originating from colorectal carcinoma.
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| 4. |
- Altai, Mohamed, et al.
(författare)
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In Vivo and In Vitro Studies on Renal Uptake of Radiolabeled Affibody Molecules for Imaging of HER2 Expression in Tumors
- 2013
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 28:3, s. 187-195
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules (6-7 kDa) are a new class of small robust three-helical scaffold proteins. Radiolabeled subnanomolar anti-HER2 affibody Z(HER2:342) was developed for imaging of HER2 expression in tumors, and a clinical study has demonstrated that the In-111- and Ga-68-labeled affibody molecules can efficiently detect HER2 expressing metastases in breast cancer patients. However, a significant renal accumulation of radioactivity after systemic injection of a radiolabeled anti-HER2 affibody conjugate is observed. The aim of this study was to investigate the mechanism of renal reabsorption of anti-HER2 affibody at the molecular level. Renal accumulation of radiolabeled anti-HER2 affibody molecules was studied in a murine model and in vitro using opossum-derived proximal tubule (OK) cells. It was found that kidney reabsorption of affibody molecule was not driven by megalin/cubilin. Amino acids in the target-binding side of affibody molecule were involved in binding to OK cells. On OK cells, two types of receptors for anti-HER2 affibody molecule were found: K-D1 = 0.8 nM, B-max1 = 71,500 and K-D2 = 9.2 nM, B-max2 = 367,000. The results of the present study indicate that affibody molecule and other scaffold-based targeting proteins with a relatively low kidney uptake can be selected using in vitro studies with tubular kidney cells.
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| 5. |
- Aneheim, Emma, 1982, et al.
(författare)
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Shelf-Life of e-Lysyl-3-(Trimethylstannyl)Benzamide Immunoconjugates, Precursors for At-211 Labeling of Antibodies
- 2015
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 30:1, s. 41-45
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Tidskriftsartikel (refereegranskat)abstract
- Astatine-211 is possibly the most promising radionuclide for targeted alpha-particle therapy when it comes to the treatment of occult disseminated cancer. Preclinical research has proven effective, and patient studies have been initiated based on these results. However, a lack of production capacity and the complex radiochemistry of At-211 are major obstacles for research and prospective clinical applications. In the present study, astatination of immunoconjugates, already prepared well in advance before radiolabeling, was performed to investigate the possibility of formulating a kit-like reagent for the production of At-211 radiopharmaceuticals. The shelf-life of e-lysyl-3-(trimethylstannyl)benzamide immunoconjugates was evaluated, that is, the effect of different storage times on the quality of the immunoconjugates. The quality being referred to is the capacity to maintain a good radiochemical yield and good cell-binding property after labeling with At-211. The stability of the conjugates was found to be pH dependent with high stability at pH >= 7 and less stability at pH <= 5.5. The immunoconjugates (based on trastuzumab) could be kept for more than 3 months in a phosphate buffered saline solution (pH 7.4) at 4 degrees C before labeling, without compromising the quality of the labeled product. The conjugates are also unaffected by storage at -20 degrees C. Conjugates with a good shelf-life compatible with distant shipping as well as improved radiochemistry are important steps to facilitate further clinical progress with At-211.
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| 6. |
- Back, Tom, et al.
(författare)
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Glomerular Filtration Rate After Alpha-Radioimmunotherapy with At-211-MX35-F(ab ')(2): A Long-Term Study of Renal Function in Nude Mice
- 2009
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 24:6, s. 649-658
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Tidskriftsartikel (refereegranskat)abstract
- Besides bone marrow, the kidneys are often dose-limiting organs in internal radiotherapy. The effects of high-linear energy transfer (LET) radiation on the kidneys after alpha-radioimmunotherapy (alpha-RIT) with the alpha-particle emitter, At-211, were studied in nude mice by serial measurements of the glomerular filtration rate (GFR). The renal toxicity was evaluated at levels close to the dose limit for the bone marrow and well within the range for therapeutic efficacy on tumors. Astatinated MX35-F(ab ')(2) monoclonal antibodies were administered intravenously to nude mice. Both non-tumor-bearing animals and animals bearing subcutaneous xenografts of the human ovarian cancer cell line, OVCAR-3, were used. The animals received approximately 0.4, 0.8, or 1.2MBq in one, two, or three fractions. The mean absorbed doses to the kidneys ranged from 1.5 to 15 Gy. The renal function was studied by serial GFR measurements, using plasma clearance of Cr-51-EDTA, up to 67 weeks after the first astatine injection. A dose-dependent effect on GFR was found and at the time interval 8-30 weeks after the first administration of astatine, the absorbed doses causing a 50% decrease in GFR were 16.4 +/- 3.3 and 14.0 +/- 4.1 Gy (mean +/- SEM), tumor-and non-tumor-bearing animals, respectively. The reduction in GFR progressed with time, and at the later time interval, (31-67 weeks) the corresponding absorbed doses were 7.5 +/- 2.4 and 11.3 +/- 2.3 Gy, respectively, suggesting that the effects of radiation on the kidneys were manifested late. Examination of the kidney sections showed histologic changes that were overall subdued. Following a-RIT with 211 At-MX35-F(ab')(2) at levels close to the dose limit of severe myelotoxicity, the effects found on renal function were relatively small, with only minor to moderate reductions in GFR. These results suggest that a mean absorbed dose to the kidneys of approximately 10Gy is acceptable, and that the kidneys would not be the primary dose-limiting organ in systemic a-RIT when using At-211-MX35-F(ab')(2).
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| 7. |
- Bading, James R., et al.
(författare)
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Quantitative serial imaging of an I-124 anti-CEA monoclonal antibody in tumor-bearing mice
- 2008
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 23:4, s. 399-409
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The 4.2-day half-life I-124 favors its use for positron emission tomography (PET) of monoclonal antibodies (mAbs). However, high positron energy and beta(+)-associated cascade gamma rays pose image resolution and background noise problems for I-124. This study evaluated quantitative PET of an I-124 mAb in tumor-bearing mice. Methods: An R4 microPET (TM) (Siemens/CTIMI, Knoxville, TN) was used with standard energy and coincidence timing windows (350-750 keV and 6 ns, respectively), delayed random coincidence subtraction, iterative image reconstruction, and no attenuation or scatter correction. Image resolution, contrast, and response linearity were compared for I-124 and F-18, using phantoms. Nude mice bearing human colon tumors (LS-174T) were injected intravenously with a chimeric I-124 anti-CEA mAb (cT84.66) and imaged serially 1 hour to 7 clays postinjection. Venous blood was sampled to validate image-derived blood curves. Mice were sacrificed after the final scan, and the biodistribution of I-124 was measured by direct tissue assay. Images were converted to units of kBq/g for each tissue of interest by comparing the final scans with the direct assays. Results: Measured resolution (FWHM) 0-16 mm from? the scanner axis was. 2.3-2.7 mm for I-124 versus 1.9-2.0 mm for F-18. Due to true coincidence e vents between annihilation photons and cascade gamma rays, background was greater for I-124 than F-18, but the signal-to-background ratio was still more than 20, and I-124 image intensities varied linearly with activity concentration. Tissue-based calibration worked well (i.e., PET blood curves agreed with direct measurements within 12% at all time points), while calibration, based on a cylindrical phantom approximating the mouse body, yielded tumor quantitation that was 46%-66% low, compared with direct assay. Conclusions: Images of quantitative accuracy sufficient for biodistribution. measurements can be obtained from tumor-bearing mice by using I-124 anti-CEA mAbs with standard. microPET acquisition and processing techniques, provided the calibration is based on the direct assay of excised tissue samples.
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| 8. |
- Bernhardt, Peter, 1966, et al.
(författare)
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Effects of treatment with (177)Lu-DOTA-Tyr(3)-octreotate on uptake of subsequent injection in carcinoid-bearing nude mice.
- 2007
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 22:5, s. 644-53
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to analyze the effect therapeutic injections of (177)Lu-DOTA(0)-Tyr(3)]-octreotate (DOTATATE) had on the tumor uptake of a subsequent injection with (111)In-DOTATATE in GOT1-bearing nude mice. METHODS AND MATERIALS: Nude mice, xenografted with the human midgut carcinoid, GOT1, were first intravenously injected with a curative (30 MBq) or a suboptimal (7.5 MBq) amount of (177)Lu-DOTATATE. At various intervals thereafter (4-13 days), a second injection with (111)In-DOTATATE (0.5 MBq) was given. One (1) day after the second injection, the animals were sacrificed, tumor tissues collected, the tumor (111)In and (177)Lu activity concentration determined, and tumor regression/cell density was recorded. RESULTS: In animals given curative amounts, the uptake of (111)In was lower than in untreated animals. On the other hand, a second late injection (3-13 days) after suboptimal amounts resulted in a twofold higher tumor activity concentration versus untreated animals. When the uptake of the curative injection was corrected for tumor cell density, which decreased from 66% to 4% over 2 weeks, an enhanced uptake per tumor cell was observed. The curative and suboptimal amounts resulted in a different uptake and retention of (177)Lu in tumors. The suboptimal amount resulted in a constant activity concentration, while the curative amount resulted in an increased activity concentration over time. CONCLUSIONS: Our results, as presented in this paper, describe how the second injection in a fractionation protocol will be affected by the first therapeutic amount. This new information might be useful in the optimization of radionuclide therapy.
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| 9. |
- Bjurberg, Maria, et al.
(författare)
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Early changes in 2-deoxy-2-[18F]fluoro-D-glucose metabolism in squamous-cell carcinoma during chemotherapy in vivo and in vitro.
- 2009
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 24:3, s. 327-332
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The aim of this study was to investigate early changes in uptake of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) in vivo and in vitro in a squamous-cell carcinoma (SCC) cell line originating from a human head and neck SCC during cytotoxic therapy with respect to metabolism in tumor cells and in surrounding stromal tissue. MATERIALS AND METHODS: In 60 nude mice with xenografted SCC, 50 animals were treated with cisplatin. Early changes in the tumor FDG uptake following therapy were evaluated sequentially with phosphor imaging. Using this technique, areas with focal hypermetabolism were detected. The cells creating the focal hypermetabolism were then identified histopathologically on the corresponding sections. In addition, early FDG uptake versus the number of viable tumor cells was measured in vitro following cisplatin treatment. RESULTS: An early transient increase in FDG uptake in tumor cells was seen on day 1 in treated tumors, followed by a rapid decrease confirmed by subsequent tumor regression. This metabolic flare was present in all treated tumors but not in the controls. In vitro, an increase in FDG uptake per cell was observed. CONCLUSIONS: Our results provide new insights into the early metabolic changes in squamous-cell carcinomas subjected to cytotoxic therapy and thus contribute to the discussion on the feasibility of early predictive PET studies.
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| 10. |
- Bäck, Tom, 1964, et al.
(författare)
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A Novel Method for Real-Time Quantification of Radioligand Binding to Living Tumor Cells In Vitro
- 2024
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Ingår i: CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS. - 1084-9785 .- 1557-8852. ; 39:1, s. 75-81
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Tidskriftsartikel (refereegranskat)abstract
- Background: Real-time quantification of radioligand binding to cells under in vivo-like conditions improves evaluation of clinical potential.Materials and Methods: SKOV-3 tumor cells were grown in a monolayer on a thin glass plate placed in a sealable shallow chamber with a continuous flow of 125I-trastuzumab solution. The time-dependent cell binding was measured using a NaI detector, and the binding parameters were derived by computational analysis.Results: The detection efficiency of 125I was 65 cps/kBq for radioligand bound to the cells. Experiments were analyzed to find the values of kon and koff. The resulting kon was 3.2-7.9 x 10(4) M-1 s(-1) and koff was 0.11-4.2 x 10(-5) s(-1).Conclusions: Radioligands can be rapidly evaluated by binding to living cells for selection and optimization of radioconjugates for diagnostic and therapeutic purposes.
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| 11. |
- Bäck, Tom, 1964, et al.
(författare)
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Glomerular filtration rate after alpha-radioimmunotherapy with 211At-MX35-F(ab')2: a long-term study of renal function in nude mice.
- 2009
-
Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 24:6, s. 649-58
-
Tidskriftsartikel (refereegranskat)abstract
- Besides bone marrow, the kidneys are often dose-limiting organs in internal radiotherapy. The effects of high-linear energy transfer (LET) radiation on the kidneys after alpha-radioimmunotherapy (alpha-RIT) with the alpha-particle emitter, (211)At, were studied in nude mice by serial measurements of the glomerular filtration rate (GFR). The renal toxicity was evaluated at levels close to the dose limit for the bone marrow and well within the range for therapeutic efficacy on tumors. Astatinated MX35-F(ab')(2) monoclonal antibodies were administered intravenously to nude mice. Both non-tumor-bearing animals and animals bearing subcutaneous xenografts of the human ovarian cancer cell line, OVCAR-3, were used. The animals received approximately 0.4, 0.8, or 1.2 MBq in one, two, or three fractions. The mean absorbed doses to the kidneys ranged from 1.5 to 15 Gy. The renal function was studied by serial GFR measurements, using plasma clearance of (51)Cr-EDTA, up to 67 weeks after the first astatine injection. A dose-dependent effect on GFR was found and at the time interval 8-30 weeks after the first administration of astatine, the absorbed doses causing a 50% decrease in GFR were 16.4 +/- 3.3 and 14.0 +/- 4.1 Gy (mean +/- SEM), tumor- and non-tumor-bearing animals, respectively. The reduction in GFR progressed with time, and at the later time interval, (31-67 weeks) the corresponding absorbed doses were 7.5 +/- 2.4 and 11.3 +/- 2.3 Gy, respectively, suggesting that the effects of radiation on the kidneys were manifested late. Examination of the kidney sections showed histologic changes that were overall subdued. Following alpha-RIT with (211)At-MX35-F(ab')(2) at levels close to the dose limit of severe myelotoxicity, the effects found on renal function were relatively small, with only minor to moderate reductions in GFR. These results suggest that a mean absorbed dose to the kidneys of approximately 10 Gy is acceptable, and that the kidneys would not be the primary dose-limiting organ in systemic alpha-RIT when using (211)At-MX35-F(ab')(2).
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| 12. |
- Cederkrantz, Elin, et al.
(författare)
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Evaluation of Effects on the Peritoneum After Intraperitoneal α-Radioimmunotherapy with (211)At.
- 2012
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 27:6, s. 353-364
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Tidskriftsartikel (refereegranskat)abstract
- Abstract The introduction of the short-lived α-emitter (211)At to intraperitoneal radioimmunotherapy has raised the issue of the tolerance dose of the peritoneum. The short range of the α-particles (70μm) and the short half-life (7.21h) of the nuclide yield a dose distribution in which the peritoneum is highly irradiated compared with other normal tissues. To address this issue, mice were injected with (211)At-trastuzumab to irradiate the peritoneum to absorbed doses ranging between 0 and 50 Gy and followed for up to 34 weeks. The peritoneum-to-plasma clearance of a small tracer, (51)Cr-ethylenediamine tetraacetic acid, was measured for evaluation of the small solute transport capacity of the peritoneal membrane. The macroscopic status of the peritoneum and the mesenteric windows was documented when the mice were sacrificed. Biopsies of the peritoneum were taken for morphology and immunohistochemical staining against plasminogen activator inhibitor-1 and calprotectin. Peritoneum-to-plasma clearance measurements indicated a dose-dependent decrease in peritoneal transport capacity in irradiated mice. However, macroscopic and microscopic evaluations of the peritoneal membrane showed no difference between irradiated mice versus controls. The results imply that the peritoneal membrane tolerates absorbed doses as high as 30-50 Gy from α-particle irradiation with limited response.
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| 13. |
- Edgren, Maliha, et al.
(författare)
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[111In-DPTA-D-Phe1] - Octreotide Scintigraphy in the Management of Patients with Advanced Renal Cell Carcinoma
- 1999
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 14:1, s. 59-64
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Somatostatin receptor scintigraphy using the 111In-labelled somatostatin analogue octreotide (Octreoscan) was performed in 9 patients with metastatic renal cell carcinoma. In total 11 scintigraphies were performed. Positive tumor uptakes were observed in 9 patients. The results of the octreotide scans were correlated to diagnostic CT and/or X-ray images. Forty (59%) out of 68 known tumor localizations were visualized with the octreotide scan. A second scan following therapy was performed in two patients. These patients showed progressive disease despite treatment and also exhibited intensified uptakes at octreotide scintigraphy. One false positive lesion was observed in the 40 lesions visualized in scintigraphy.It was concluded that renal cell carcinoma expresses somatostatin receptors, as could be visualized with Octreoscan scintigraphy. The scintigraphic technique can be used as an instrument for in vivo characterization of the disease. The data could also form a basis for future investigations regarding the possible therapeutic effect of octreotide in the management of renal cell cancer.
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| 14. |
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| 15. |
- Elgqvist, Jörgen, 1963, et al.
(författare)
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Intraperitoneal alpha-radioimmunotherapy in mice using different specific activities.
- 2009
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 24:4, s. 509-13
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to investigate the therapeutic efficacy of the alpha-radioimmunotherapy of ovarian cancer in mice, using different specific activities. This study was performed by using the monoclonal antibody, MX35 F(ab')(2), labeled with the alpha-particle-emitter, 211At. METHODS: Animals were intraperitoneally inoculated with approximately 1 x 10(7) cells of the cell line, NIH:OVCAR-3. Four (4) weeks later, five groups of animals were given 400 kBq of 211At-MX35 F(ab')(2) with specific activities equal to 130, 65, 32, 16, or 4 kBq/microg, respectively (n = 18 in each group). As controls, animals were given unlabeled MX35 F(ab')(2) (n = 12). Eight (8) weeks after treatment, the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined. RESULTS: The tumor-free fractions (TFFs) of the animals, defined as the fraction of animals with no macro- and microtumors and no ascites, were 0.67, 0.73, 0.50, 0.50, and 0.17 when treated as above. Only the TFF of 0.17, for the specific activity of 4 kBq/microg, was significantly less, compared to that of the specific activity of 130 kBq/microg. The TFF for the specific activity of 4 kBq/microg showed a significant lowering, compared to the specific activity of 130 kBq/microg (p < 0.05). Treatment with unlabeled MX35 F(ab')(2) resulted in a TFF of zero. CONCLUSIONS: A specific activity-dependent therapeutic outcome could not be shown in the interval of 130- to 16 kBq/mug. For lower specific activities (i.e., 4 kBq/microg), the therapeutic efficacy was significantly lowered.
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| 16. |
- Elgström, Erika, et al.
(författare)
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Change in Cell Death Markers During (177)Lu-mAb Radioimmunotherapy-Induced Rejection of Syngeneic Rat Colon Carcinoma.
- 2014
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 29:4, s. 143-152
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Purpose: To monitor cell death in tumors during the rejection process after treatment with an antibody radiolabeled with a β-emitter. Methods: Tumors during rejection after treatment with (177)Lu-labeled antibody BR96 and after administration of unlabeled BR96 were compared with untreated tumors from the same immunocompetent syngeneic rat tumor model. Cell death was monitored with the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunohistochemical staining of activated caspase-3 and γH2AX. These data were evaluated together with histopathological morphology, BR96-binding antigen expression, and (177)Lu radioactivity distribution imaged by digital autoradiography. Results: The untreated tumors showed staining for all the markers, mainly in and around the necrotic areas. One to 2 days p.i. large areas were stained with anti-γH2AX, followed by a slight decrease. Staining of activated caspase-3 was intense and extensive 1-2 days p.i., while found in and around necrotic areas 3-8 days p.i. TUNEL staining was similar to activated caspase-3 staining 1-2 days p.i. but more extensive than activated caspase-3 staining 3-4 days p.i. Digital autoradiography revealed activity concentration in granulation tissue from 1 day p.i. Conclusion: Following radioimmunotherapy in an immunocompetent syngeneic colon carcinoma model, tumor cells did not only die through caspase-3-dependent apoptosis, but also by other mechanisms.
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| 17. |
- Eriksson, David, et al.
(författare)
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Iodine-131 induces mitotic catastrophes and activates apoptotic pathways in HeLa Hep2 cells
- 2008
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 23:5, s. 541-549
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Tidskriftsartikel (refereegranskat)abstract
- Iodine-131 (131I) has been used both in unconjugated form and conjugated to antibody derivates (i.e., radioimmunotherapy; RIT) to treat malignant diseases. The mechanisms by which 131I-irradiation causes growth retardation are, however, inadequately understood. The aim of this study was to elucidate the sequential molecular and cellular events that initiate cell death in HeLa Hep2 cells exposed to 131I. In this paper, HeLa Hep2 cells were found to display a transient G2-M arrest following irradiation, but then reentered the cell cycle still containing unrepaired cellular damage. An increase of multipolar mitotic spindles, as well as a significant increase in centrosome numbers from 8.8% +/- 1.9% in controls to 54.7% +/- 2.2% in irradiated cells, was observed (p < 0.0001). A subsequent failure of cytokinesis caused the cells to progress into mitotic catastrophe. This was accompanied by the formation of giant cells with multiple nuclei, multilobulated nuclei, and an increased frequency of polyploidy cells. A fraction of the cells also displayed apoptotic features, including the activation of initiator caspases-2, -8, -9, and effector caspase-3, as well as cleavage of poly(ADP-ribose) polymerase, a cell-death substrate for active caspase-3. These findings demonstrate that mitotic catastrophes and the activation of a delayed type of apoptosis might be important mechanisms involved in cell death following the RIT of solid tumors with -emitting radionuclides, such as 131I.
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| 18. |
- Eriksson, Sophie, et al.
(författare)
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Repeated Radioimmunotherapy with (177)Lu-DOTA-BR96 in a Syngeneic Rat Colon Carcinoma Model.
- 2012
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 27:2, s. 134-140
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Aim: Fractionation is generally used as a mean to improve radioimmunotherapy (RIT). Since RIT is considered suitable for small-volume disease, the aim of the current study was to investigate whether repeated administration of (177)Lu-labeled mAb BR96 was tolerated and could delay or prevent metastatic disease after complete remission of the tumor obtained by the first administration. Methods: Immunocompetent rats bearing a syngeneic colon carcinoma were first treated with 400 MBq/kg (177)Lu-DOTA-BR96, an activity resulting in complete response in 29 of 30 animals. On day 21, two groups of rats were given an additional activity of 150 or 350 MBq/kg resulting in total administered activities corresponding to 0.9 and 1.3 times the maximal tolerated dose. Results: The additional treatment resulted in tolerable myelotoxicity; however, the frequency of metastatic disease and survival were not affected. Immunohistochemistry demonstrated binding of the BR96 antibody to tissue sections of analyzed metastases. Conclusions: In our model, development of metastatic disease after treatment of the manifest tumor was not prevented by an additional treatment with the same radioimmunoconjugate. Therefore, the antibody should be labeled with a more suitable radionuclide for treatment of metastases. The repeated targeted therapy was well tolerated in aspects of myelotoxicity.
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| 19. |
- Eriksson, Sophie, et al.
(författare)
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Sequential Radioimmunotherapy with (177)Lu- and (211)At-Labeled Monoclonal Antibody BR96 in a Syngeneic Rat Colon Carcinoma Model.
- 2014
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 29:6, s. 238-246
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Alpha-particle emitters, such as astatine-211 ((211)At), are generally considered suitable for the treatment of small cell clusters due to their short path length, while beta-particle emitters, for example, Lutetium-177 ((177)Lu), have a longer path length and are considered better for small, established tumors. A combination of such radionuclides may be successful in regimens of radioimmunotherapy. In this study, rats were treated by sequential administration of first a (177)Lu-labeled antibody, followed by a (211)At-labeled antibody 25 days later. Methods: Rats bearing solid colon carcinoma tumors were treated with 400MBq/kg body weight (177)Lu-BR96. After 25 days, three groups of animals were given either 5 or 10MBq/kg body weight of (211)At-BR96 simultaneously with or without a blocking agent reducing halogen uptake in normal tissues. Control animals were not given any (211)At-BR96. Myelotoxicity, body weight, tumor size, and development of metastases were monitored for 120 days. Results: Tumors were undetectable in 90% of the animals on day 25, independent of treatment. Additional treatment with (211)At-labeled antibodies did not reduce the proportion of animals developing metastases. The rats suffered from reversible myelotoxicity after treatment. Conclusions: Sequential administration of (177)Lu-BR96 and (211)At-BR96 resulted in tolerable toxicity providing halogen blocking but did not enhance the therapeutic effect.
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| 20. |
- Eriksson, Sophie, et al.
(författare)
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Treatment with Unlabeled mAb BR96 After Radioimmunotherapy with (177)Lu-DOTA-BR96 in a Syngeneic Rat Colon Carcinoma Model.
- 2012
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 27:3, s. 175-182
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic disease after successful treatment of the primary tumor continues to be a therapeutic challenge. Enhancement of therapeutic effects by the administration of unlabeled monoclonal antibodies (mAbs) after radioimmunotherapy (RIT) may provide a means of preventing or delaying the development of metastatic disease. In the present study, Brown Norway rats with syngeneic grafted colon carcinomas were administered the minimal effective therapeutic dose of 400 MBq/kg lutetium-177 ((177)Lu)-DOTA-BR96. After 2 weeks, half of the animals were given 15 mg/kg unlabeled mAb BR96 as consolidation therapy. Treatment response and toxicity were monitored 100 days after the treatment with unlabeled BR96. The treatment with unlabeled mAb after RIT resulted in a complete response (CR) in 19 of 19 animals, while RIT alone resulted in a CR in 17 of 19 animals. The additional treatment did not affect the number of animals with metastatic disease or the time to clinical symptoms of metastases. RIT resulted in reversible myelotoxicity. The unlabeled mAb BR96 did not cause any additional toxicity, making it possible to repeat the consolidation therapy.
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| 21. |
- Evans Axelsson, Susan, et al.
(författare)
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Targeting free prostate-specific antigen for in vivo imaging of prostate cancer using a monoclonal antibody specific for unique epitopes accessible on free prostate-specific antigen alone
- 2012
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 27:4, s. 243-251
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the feasibility of targeting the free, unbound forms of prostate-specific antigen (fPSA) for in vivo imaging of prostate adenocarcinomas (PCa), as PSA is produced and secreted at abundance during every clinical stage and grade of PCa, including castration-resistant disease. We injected 125I-labeled monoclonal antibody PSA30 (specific for an epitope uniquely accessible on fPSA alone) intravenously in male nude mice carrying subcutaneous xenografts of LNCaP tumors (n=36). Mice were sacrificed over a time course from 4 hours to 13 days after injecting 125I-labeled PSA30. Tissue uptake of 125I-PSA30 at 48 and 168 hours after intravenous injection was compared with two clinically used positron emission tomography radiopharmaceuticals, 18F-fluoro-deoxy-glucose (18F-FDG) or 18F-choline, in cryosections using Digital AutoRadiography (DAR) and also compared with immunohistochemical staining of PSA and histopathology. On DAR, the areas with high 125I-PSA30 uptake corresponded mainly to morphologically intact and PSA-producing LNCaP cells, but did not associate with the areas of high uptake of either 18F-FDG or 18F-choline. Biodistribution of 125I-PSA30 measured in dissected organs ex vivo during 4 to 312 hours after intravenous injection demonstrated maximum selective tumor uptake 24–48 hours after antibody injection. Our data showed selective uptake in vivo of a monoclonal antibody highly specific for fPSA in LNCaP cells. Hence, in vivo imaging of fPSA may be feasible with putative usefulness in disseminated PCa.
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| 22. |
- Frost, Sofia, 1981, et al.
(författare)
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Comparison of (211)At-PRIT and (211)At-RIT of Ovarian Microtumors in a Nude Mouse Model.
- 2013
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 28:2, s. 108-14
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Purpose: Pretargeted radioimmunotherapy (PRIT) against intraperitoneal (i.p.) ovarian microtumors using avidin-conjugated monoclonal antibody MX35 (avidin-MX35) and (211)At-labeled, biotinylated, succinylated poly-l-lysine ((211)At-B-PL(suc)) was compared with conventional radioimmunotherapy (RIT) using (211)At-labeled MX35 in a nude mouse model. Methods: Mice were inoculated i.p. with 1×10(7) NIH:OVCAR-3 cells. After 3 weeks, they received PRIT (1.0 or 1.5MBq), RIT (0.9MBq), or no treatment. Concurrently, 10 additional animals were sacrificed and examined to determine disease progression at the start of therapy. Treated animals were analyzed with regard to presence of tumors and ascites (tumor-free fraction; TFF), 8 weeks after therapy. Results: Tumor status at baseline was advanced: 70% of sacrificed animals exhibited ascites. The TFFs were 0.35 (PRIT 1.0MBq), 0.45 (PRIT 1.5MBq), and 0.45 (RIT). The 1.5-MBq PRIT group exhibited lower incidence of ascites and fewer tumors >1mm than RIT-treated animals. Conclusions: PRIT was as effective as RIT with regard to TFF; however, the size distribution of tumors and presence of ascites indicated that 1.5-MBq PRIT was more efficient. Despite advanced disease in many animals at the time of treatment, PRIT demonstrated good potential to treat disseminated ovarian cancer.
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| 23. |
- Frost, Sofia, 1981, et al.
(författare)
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In Vivo Distribution of Avidin-Conjugated MX35 and (211)At-Labeled, Biotinylated Poly-l-Lysine for Pretargeted Intraperitoneal ?-Radioimmunotherapy.
- 2011
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 26:6
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Purpose: Avidin-coupled monoclonal antibody MX35 (avidin-MX35) and astatine-211?labeled, biotinylated, succinylated poly-l-lysine ((211)At-B-PL(suc)) were administered in mice to assess potential efficacy as an intraperitoneal (i.p.) therapy for microscopic tumors. We aimed to establish a timeline for pretargeted radioimmunotherapy using these substances, and estimate the maximum tolerable activity. Methods: (125)I-avidin-MX35 and (211)At-B-PL(suc) were administered i.p. in nude mice. Tissue distributions were studied at various time points and mean absorbed doses were estimated from organ uptake of (211)At-B-PL(suc). Studies of myelotoxicity were performed after administration of different activities of (211)At-B-PL(suc). Results: We observed low blood content of both (125)I-avidin-MX35 and (211)At-B-PL(suc), indicating fast clearance. After sodium perchlorate blocking, the highest (211)At uptake was found in kidneys. Red bone marrow (RBM) accumulated some (211)At activity. Mean absorbed doses of special interest were 2.3 Gy/MBq for kidneys, 0.4 Gy/MBq for blood, and 0.9 Gy/MBq for RBM. An absorbed dose of 0.9 Gy to the RBM was found to be safe. These values suggested that RBM would be the key dose-limiting organ in the proposed pretargeting scheme, and that blood data alone was not sufficient for predicting its absorbed dose. Conclusions: To attain a favorable distribution of activity and avoid major toxicities, at least 1.0?MBq of (211)At-B-PL(suc) can be administered 24 hours after an i.p. injection of avidin-MX35. These results provide a basis for future i.p. therapy studies in mice of microscopic ovarian cancer.
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| 24. |
- Grafström, Gustav, et al.
(författare)
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(99m)Tc-DTPA Uptake and Electrical Impedance Measurements in Verification of In Vivo Electropermeabilization Efficiency in Rat Muscle.
- 2006
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 21:6, s. 623-635
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Tidskriftsartikel (refereegranskat)abstract
- Objective: In vivo electropermeabilization of cell membranes in rat muscle tissue cause a significant decrease of the electrical impedance, in the frequency region of 1-10 kHz. We aimed to study how the Tc-99m-DTPA uptake in the electropermeabilized region correlates to the change of admittance Y = 1/absZ, where Z is the measured impedance. Methods: The electropermeabilization was performed in vivo by applying high-voltage (0.5-2 kV) short (0.1-2 ms) pulses through gold-plated needle electrodes in skeletal muscle. The impedance was measured before and after each electropermeabilization pulse. The uptake of Tc-99m-DTPA uptake in the electropermeabilized region was measured after 6 and 24 hours with a gamma camera. Results: The pulse shape (square and exponential), duration, and amplitude of the applied electric field were varied, and electropermeabilization efficiency was evaluated using the various measurement modalities. Good correlations were found (correlation coefficient approximate to 0.9) between the Tc-99m-DTPA uptake in the electropermeabilized and control "region of interest" the admittance ratio Y (post-treatment)/Y (pretreatment), and charge displacement parameter Q. Conclusion: The electrical impedance measurements method can be utilized in clinical settings to verify the efficiency of electropermeabilization applied to chemotherapy and to power RNAi (RNA-interference) and DNA-plasmid transfection in vaccination, immunization, and gene-therapy.
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| 25. |
- Gunnarsson, Mikael, et al.
(författare)
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Long-term biokinetics and radiation exposure of patients undergoing 14C-glycocholic acid and 14C-xylose breath tests.
- 2007
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 22:6, s. 762-771
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Tidskriftsartikel (refereegranskat)abstract
- The (14)C-glycocholic acid and (14)C-xylose breath tests are clinically used for the diagnosis of intestinal diseases, such as bacterial overgrowth in the small intestine. The two tests have in earlier studies been thoroughly evaluated regarding their clinical value, but due to the long physical half-life of (14)C and the limited biokinetic and dosimetric data, which are available for humans, several hospitals have been restrictive in their use. The aim of this study was to investigate the long-term biokinetics and dosimetry of the two (14)C compounds in patients and volunteers, using the highly sensitive accelerator mass spectrometry (AMS) technique. Eighteen (18) subjects were included, 9 for each compound. The (14)C content in samples from exhaled air, urine, and, for some subjects, also feces were analyzed with both liquid scintillation counting (LSC) and AMS. The results from the glycocholic acid study showed that, up to 1 year after the administration, 67%+/-6% (mean+/-standard deviation) of the administered activity was recovered in exhaled air, 2.4%+/-0.4% was found in urine, and 7.6% (1 subject) in feces. In the xylose study, the major part was found in the urine (66%+/-2%). A significant part was exhaled (28%+/-5%), and the result from an initial 72-hour stool collection from 2 of the subjects showed that the excretion by feces was insignificant. The absorbed dose to various organs and tissues and the effective dose were calculated by using biokinetic models, based on a combination of experimental data from the present study and from earlier reports. In the glycocholic acid study, the highest absorbed dose was received by the colon (1.2 mGy/MBq). In the xylose study, the adipose tissue received 0.8 mGy/MBq. The effective dose was estimated to 0.5 (glycocholic acid) and 0.07 mSv/MBq (xylose). Thus, from a radiation protection point of view, we see no need for restrictions in using the two (14)C-labeled radiopharmaceuticals on adults with the activities normally administered (0.07-0.4 MBq).
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| 26. |
- Hagmarker, Linn, et al.
(författare)
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Segmentation of Whole-Body Images into Two Compartments in Model for Bone Marrow Dosimetry Increases the Correlation with Hematological Response in Lu-177-DOTATATE Treatments
- 2017
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 32:9, s. 335-343
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Tidskriftsartikel (refereegranskat)abstract
- Background: In Lu-177-DOTATATE treatments, bone marrow (BM) is one of the most important organs at risk. The authors previously developed an image-based two-compartment method for BM dosimetry, showing a significant correlation between absorbed dose to BM and hematological toxicity in Lu-177-DOTATATE treatments. In the present study, they aimed to further evaluate this BM dosimetry method by finding optimal settings for dividing the whole body into two compartments; in terms of minimizing the coefficient of variation (CV) for the individual absorbed doses and studying its correlation to the BM response. The authors have also added specific absorbed fractions for male and female. Finally, they compare this two-compartment method with whole-body dosimetry. Methods: This study included 46 patients with advanced neuroendocrine tumors treated with Lu-177-DOTATATE on two to five occasions at Sahlgrenska University Hospital. Planar gamma camera images were collected at four time points postinjection, and a segmentation tool using a normalized number of uptake foci (nNUF) to divide the whole body into high- and low-uptake compartments was used. The authors characterized the two-compartment model and compared it with whole-body dosimetry. Results and Conclusion: The dosimetry method was robust, with an optimal nNUF value of 0.1-0.2. Using an nNUF value of 0.15, the absorbed BM dose was estimated as 0.20Gy/7.4GBq, and the CV as 8.4%. Compared to whole-body dosimetry, stronger correlation was found between absorbed dose to BM and hematological response using the two-compartment method. The two-compartment method has potential as a valuable image-based alternative to blood-based BM dosimetry.
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| 27. |
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| 28. |
- Hindorf, Cecilia, et al.
(författare)
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Single-cell dosimetry for radioimmunotherapy of B-cell lymphoma patients with special reference to leukemic spread
- 2007
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 22:3, s. 357-366
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Many lymphoma patients have both macroscopic tumors and single-cell manifestations of their disease. Treatment efficacy could, therefore, depend on the radionuclide used. The aim of this study was to investigate dosimetry at a cellular level for three isotopes of radioiodine. Methods: Cells were assumed to be spherical with radii of 6.35, 7.7, and 9.05 mu m corresponding to the dimensions of the Raji cells. The radius of the nucleus was assumed to be 75% of the cellular radius. The electron energies were 18, 28, and 190 keV, corresponding to the mean electron energy per decay for I-125, I-123, and I-131, respectively. S-values for different activity distributions were simulated using Monte Carlo and dose-volume histograms as well as absorbed doses, and absorbed dose rates were calculated. Results: I-125 gives the highest absorbed dose (similar to 4-40 times that of I-131), whereas I-123 Will give the highest absorbed dose rate (similar to 100 times that of I-131). Under the given assumptions, the absorbed dose at this level is more dependent on the Size of the cells than on whether the radioimmunoconjugate is internalized. Conclusions: This enquiry showed that both I-123 and I-125 have greater potential than I-131 for the treatment of leukemic spread in patients With lymphoma.
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| 29. |
- Holstensson, Maria, et al.
(författare)
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Optimization of energy-window settings for scatter correction in quantitative In-111 imaging: Comparison of measurements and Monte Carlo simulations
- 2007
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 22:1, s. 136-142
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Tidskriftsartikel (refereegranskat)abstract
- Activity quantification in nuclear medicine imaging is highly desirable, particularly for dosimetry and biodistribution studies of radiopharmaceuticals. Quantitative In-111 imaging is increasingly important with the current interest in therapy using Y-90 radiolabeled antibodies. One of the major problems in quantification is scatter in the images, which leads to degradation of image quality. The aim of this study was to optimize the energy-window settings for quantitative In-111 imaging with a camera that enabled acquisition in three energy windows. Experimental measurements and Monte Carlo simulations, using the SI-MIND code, were conducted to investigate parameters such as sensitivity, image contrast, and image resolution. Estimated scatter-to-total ratios and distributions, as obtained by the different window settings, were compared with corresponding simulations. Results showed positive agreement between experimental measurements and results from simulations, both quantitatively and qualitatively. We conclude that of the investigated methods, the optimal energy-window setting was two windows centered at 171 and 245 keV, together with a broad scatter window located between the photopeaks.
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| 30. |
- Horti, József, et al.
(författare)
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A randomized, double-blind, placebo-controlled phase II study of vandetanib plus docetaxel/prednisolone in patients with hormone-refractory prostate cancer.
- 2009
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 24:2, s. 175-80
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Tidskriftsartikel (refereegranskat)abstract
- Vandetanib (ZACTIMA) is a once-daily oral anticancer drug that selectively inhibits vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection signaling. This randomized (1:1), double-blind study evaluated vandetanib (100 mg/day) or placebo in combination with docetaxel (D; 75 mg/m(2) every 3 weeks) and prednisolone (P; 2 x 5 mg/day) in 86 patients with metastatic hormone-refractory prostate cancer (mHRPC). The primary assessment was prostate-specific antigen (PSA) response (confirmed reduction of >or=50% from baseline) and a greater number of patients showed a PSA response with placebo + DP (67%) versus vandetanib + DP (40%); hazard ratio = 2.23 (one-sided 80% confidence limit = 2.90; one-sided p = 0.99). More patients experienced progression events (disease progression or death from any cause) with vandetanib + DP (65%) versus placebo + DP (60%); hazard ratio = 1.13 (one-sided 80% confidence limit = 1.44; one-sided p = 0.67). The overall incidence of adverse events was similar in both groups, although more patients experienced adverse events, leading to permanent discontinuation with vandetanib + DP (28%) versus placebo + DP (12%). However, the safety and tolerability profile for vandetanib was similar to that previously reported; adverse events that occurred more frequently in the vandetanib + DP arm were hypertension (14% vs. 2%), erythematous rash (14% vs. 2%), and exfoliative rash (12% vs. 2%). In this study of patients with mHRPC, vandetanib + DP did not demonstrate any efficacy benefit, compared with placebo + DP.
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| 31. |
- Hosseinimehr, Seyed Jalal, et al.
(författare)
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(125)I-Labeled Quercetin as a Novel DNA-Targeted Radiotracer
- 2011
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 26:4, s. 469-475
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Tidskriftsartikel (refereegranskat)abstract
- Quercetin is a major flavonoid that is found in most plants; it can intercalate with DNA. The purpose of this study was to investigate radiolabeling of qurecetin with (125)I, DNA binding and cellular process. In this work, quercetin was labeled with Auger emitting nuclide (125)I using chloramine-T. DNA binding of (125)I-quercetin ((125)I-Q) was investigated using cell-free in vitro assay with naked human genomic DNA in agarose plugs. Cellular uptake and nuclei accumulation were evaluated in human prostate cancer cell lines (DU 145). The internalization of (125)I-Q was evaluated with fluorescence microscopy. Cellular damage was monitored by using apoptosis assay. Quercetin was successfully labeled with (125)I, and it was taken up rapidly with cells and accumulated in the cellular nuclei. (125)I-Q-DNA binding was tight with long retention time, and it potentially induced DNA damage. These findings provide for using of (125)I-labeled quercetin as a carrier of Auger electron emitting radionuclide to the cell nuclei for targeted radiotherapy.
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| 32. |
- Jafari, Rozbeh, 1977-, et al.
(författare)
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Localization of complexed anticytokeratin 8 scFv TS1-218 to HeLa HEp-2 multicellular tumor spheroids and experimental tumors
- 2010
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 25:4, s. 455-463
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Tidskriftsartikel (refereegranskat)abstract
- Recombinant single-chain fragment variable (scFv) antibodies with specificity to tumor antigens can be used to target tumors in vivo. The approach to use administration of complexes of idiotypic-anti-idiotypic scFvs when targeting tumors has not been tested earlier, and from a theoretical point it could contribute to longer in vivo circulation and improved targeting efficiency by dissociation, when in contact with the target antigen. In this study two models to evaluate the targeting efficiency of such complexes were used. HeLa HEp-2 tumor cells were grown as multicellular tumor spheroids (MCTS) and exposed to the antibody constructs in vitro. The behavior in vivo was tested in an in vivo tumor xenograft model. To increase the size of the anticytokeratin 8 scFv, TS1-218, complexes were formed between TS1-218 and its anti-idiotype, alphaTS1 scFv. The functionality of (125)I-labeled TS1-218 alone and in complex was studied in both models. The uptake patterns were similar in both models. The idiotypic TS1-218 was able to localize to the MCTS and xenografted tumors, both alone and in complex with alphaTS1 scFv. TS1-218 in complex, however, demonstrated a significantly higher uptake than the monomeric TS1-218 in both models (p < 0.0005 and p < 0.0089, respectively). When complexes were administered in vivo, a slower clearance and an increased tumor half-life could be observed. The present investigation indicates that administration of targeting antibodies, with initially blocked antigen-binding sites by complex formation with their anti-idiotypes, may improve targeting efficiency.
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| 33. |
- Johansson, L, et al.
(författare)
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Biokinetics of iodide in man: Refinement of current ICRP dosimetry models
- 2003
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 18:3, s. 445-450
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Tidskriftsartikel (refereegranskat)abstract
- A compartmental model describing the distribution and retention of radioactive iodide in thyroid and other organs is presented. The model is developed from published ICRP models. It is designed primarily for radiation dosimetry of iodine radionuclides used in nuclear medicine, but may also be useful for occupational radiation protection. In the proposed model, the distribution of iodide to the thyroid is assumed to be more rapid than in earlier models. Uptakes in stomach wall and salivary glands are considered, and the absorbed doses to these organs calculated. The partitioning of iodide between stomach wall and content is also discussed. Recirculation of organic iodine is also taken into account. Age-dependent half-times for iodide in the thyroid, as well as for organically-bound iodine are presented. The proposed model is applicable for dose estimations with different uptakes in the thyroid as well as for the situation when the thyroid is blocked, completely or incompletely.
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Larsson, Erik, et al.
(författare)
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Mouse S-factors based on monte carlo simulations in the anatomical realistic Moby phantom for internal dosimetry
- 2007
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 22:3, s. 438-442
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Biokinetic and dosimetry studies in small animals often precede clinical radionuclide therapies. As in human studies, a reliable evaluation of therapeutic efficacy is essential and must be based on accurate dosimetry, which must be based on a realistic dosimetry model. The aim of this study was to evaluate the differences in the results when using a more anatomic realistic mouse phantom, as compared to previously mathematically described phantoms, based mainly on ellipsoids and cylinders. The difference in results from the two Monte Carlo codes, EGS4 and MCNPX 2.6a, was also evaluated. Methods: An anatomical correct mouse phantom (Moby) was developed by Segars et al. for the evaluation and optimization of the in vivo imaging of mice. The Moby phantom is based on surfaces, which allows for an easy and flexible definition of organ sizes. It includes respiratory movements and a beating heart. It also allows for a redefinition of the location of several internal organs. The execution of he Moby program generates a three-dimensional voxel-based phantom of a specified size, which was modified and used as input for Monte Carlo simulations of absorbed fractions and S-factors. The radiation transport was simulated both with the EGS4 system and the MCNPX 2.6a code. Calculations were done,for the radionuclides F-18, I-124, I-131, In-111, Lu-177, and Y-90. S-factors were calculated using in-house-developed IDL programs and compared with results from previously published models. Results: The comparison of S-factors obtained by the Moby model and mathematical phantoms showed that these, in many cases, were within the same range, whereas for some organs, they were underestimated in the mathematical phantoms. The results were closer to the more anatomically realistic phantom than to the mathematical phantoms, with some exceptions. When investing differences between MCNPX 2.6a and EGS4 using the Moby phantom, results indicated some differences in absorbed fractions for electrons. This reason may be owing to differences in the codes regarding the theory for which electron transport are simulated. Conclusions: It is possible to calculate S-factors that are specific for small animals, such as mice. The Moby phantom is useful as a dosimetry model because it is anatomically realistic, but still very flexible, with 35 accurately segmented regions.
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| 38. |
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| 39. |
- Lindegren, Sture, 1960, et al.
(författare)
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Realizing Clinical Trials with Astatine-211: The Chemistry Infrastructure
- 2020
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 35:6, s. 425-436
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Tidskriftsartikel (refereegranskat)abstract
- Despite the consensus around the clinical potential of the alpha-emitting radionuclide astatine-211 (At-211), there are only a limited number of research facilities that work with this nuclide. There are three main reasons for this: (1) Scarce availability of the nuclide. Despite a relatively large number of globally existing cyclotrons capable of producing(211)At, few cyclotron facilities produce the nuclide on a regular basis. (2) Lack of a chemical infrastructure, that is, isolation of(211)At from irradiated targets and the subsequent synthesis of an astatinated product. At present, the research groups that work with(211)At depend on custom systems for recovering(211)At from the irradiated targets. Setting up and implementing such custom units require long lead times to provide a proper working system. (3) The chemistry of(211)At. Compared with radiometals there are no well-established and generally accepted synthesis methods for forming sufficiently stable bonds between(211)At and the tumor-specific vector to allow for systemic applications. Herein we present an overview of the infrastructure of producing(211)At radiopharmaceuticals, from target to radiolabeled product including chemical strategies to overcome hurdles for advancement into clinical trials with(211)At.
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| 40. |
- Ljungberg, Michael, et al.
(författare)
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3D absorbed dose calculations based on SPECT: Evaluation for 111-In/90-Y therapy using Monte Carlo simulations.
- 2003
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 18:1, s. 99-107
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Tidskriftsartikel (refereegranskat)abstract
- A general method is presented for patient-specific three-dimensional (3D) absorbed dose calculations based on quantitative SPECT activity measurements. The computational scheme includes a method for registration of the CT study to the SPECT image, and compensation for attenuation, scatter, and collimator-detector response including septal penetration, performed as part of an iterative reconstruction method. From SPECT images, the absorbed dose rate is calculated using an EGS4 Monte Carlo code, which converts the activity distribution to an absorbed dose rate distribution. Evaluation of the accuracy in the activity quantification and the absorbed dose calculation is based on realistic Monte Carlo simulated SPECT data of a voxel-computer phantom and In-111 and Y-90. Septal penetration was not included in this study. The SPECT-based activity concentrations and absorbed dose distributions are compared to the actual values; the results imply that the corrections for attenuation and scatter yield results of high accuracy. The presented method includes compensation for most parameters deteriorating the quantitative image information. Inaccuracies are, however, introduced by the limited spatial resolution of the SPECT system, which are not fully compensated by the collimator-response correction. The proposed evaluation methodology may be used as a basis for future inter-comparison of different dosimetry calculation schemes.
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| 41. |
- Lundh, Charlotta, 1977, et al.
(författare)
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Biodistribution of free 211At and 125I- in nude mice bearing tumors derived from anaplastic thyroid carcinoma cell lines.
- 2006
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 21:6, s. 591-600
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Tidskriftsartikel (refereegranskat)abstract
- Free 211At has been proposed for therapy of anaplastic thyroid carcinoma (ATC). However, no extensive biodistribution study comparing tumor-bearing and nontumor-bearing mice has previously been performed. The aim of this study was to perform a complete evaluation of the biodistribution of 211At, both for normal and ATC-bearing mice. For comparison, the biodistribution of 125I- was simultaneously studied. Dosimetric evaluations were performed to investigate if (211)At can be used for therapy of ATC. METHODS: Athymic nude mice were subcutaneously injected with either of two human ATC cell lines, HTh83 and KAT-4. Tumor-bearing and nontumor-bearing mice were injected intravenously with 0.3 MBq 211At and 0.3 MBq 125I- simultaneously. The mice were sacrificed 4-24 hours after injection, and the activity concentrations in tissues were determined. RESULTS: Except for the thyroid, the concentration of 211At was higher than that of 125I- in the tissues. The uptake of 211At was primarily high in NIS-expressing organs. Furthermore, the absorbed doses to these organs were higher than both tumor types. CONCLUSIONS: The biodistribution of 211At and 125I- differed in this animal model. The higher mean absorbed dose from 211At in several organs than in tumor tissue restricts the possibility of using free 211At for therapy of ATC.
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| 42. |
- Madru, Renata, et al.
(författare)
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Simultaneous Preclinical Positron Emission Tomography-Magnetic Resonance Imaging Study of Lymphatic Drainage of Chelator-Free Cu-Labeled Nanoparticles
- 2018
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 33:6, s. 213-220
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hybrid positron emission tomography (PET)-magnetic resonance imaging (MRI) systems have been taken in use as new clinical diagnostic tools including detection and therapy planning of cancer. To reduce the amount of contrast agents injected in patients while fully benefitting both modalities, dual-modality probes are required.MATERIAL AND METHODS: This study was first aimed at developing a hybrid PET-MRI probe by labeling superparamagnetic iron oxide nanoparticles (SPIONs) with 64Cu using a fast and chelator-free conjugation method, and second, to demonstrate the ability of the agent to target sentinel lymph nodes (SLNs) in vivo using simultaneous PET-MRI imaging.RESULTS: High labeling efficiency of 97% produced within 10-15 min was demonstrated at room temperature. 64Cu-SPIONs were chemically stable in mouse serum for 24 h and after intradermal injection in the hind paw of C57BL/6J mice, demonstrated specific accumulation in the SLN. Simultaneous PET-MRI clearly demonstrated visualization of 64Cu-SPIONs, in dynamic and static imaging sequences up to 24 h after administration.CONCLUSION: The use of a single hybrid probe and simultaneous hybrid imaging provides an efficient, complementary integration of quantitation and is expected to improve preoperative planning and intraoperative guidance of cancer treatments.
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| 43. |
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| 44. |
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| 45. |
- Nickel, Mattias, et al.
(författare)
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Development and evaluation of a pharmacokinetic model for prediction of radioimmunotherapy based on pretherapy data.
- 2009
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Ingår i: Cancer Biotherapy & Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 24:1, s. 111-121
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this work was to develop a pharmacokinetic model for the analysis of the pharmacokinetics of (111)Inlabeled monoclonal antibodies (mAbs) in B-cell lymphoma patients and to evaluate the model's ability to predict a subsequent radioimmunotherapy by (90)Y-labeled mAbs. Data from quantified scintillation camera images and blood samples were used to fit a compartment model. The modeling included two steps: 1) a two-compartment model describing the total-body kinetics for the estimation of a set of global parameters and 2) a multicompartment model for estimating the model parameters for organs. In both steps, a correction for radiochemical impurity in the form of (111)In-DTPA (diethylene triamine pentaacetic acid) was included. The model was found to describe all patient data with good accuracy. From the model, the time-activity data of all organs could be separated into extravascular and vascular components, where the estimates of the regional vascular volumes were found to be in close agreement with literature data. A significant improvement of the model fit to total-body activity data was obtained by correcting for radiochemical impurity. The therapy kinetics area under the curves (AUCs) predicted from pretherapy data were in good agreement with the measured therapy AUCs. The good correlation between the model estimates and measured data, the accurate prediction of the therapy kinetics, and the good estimates of regional vascular volumes demonstrates the reliability of the model. These findings also indicate that the model can be useful for individual optimization of the amount of activity to be administered with respect to patient dosimetry.
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| 46. |
- Nilsson, Jenny, et al.
(författare)
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Cancer Cell Radiobiological Studies Using In-House-Developed α-Particle Irradiator.
- 2015
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 30:9, s. 386-94
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Tidskriftsartikel (refereegranskat)abstract
- An α-particle irradiator, enabling high-precision irradiation of cells for in vitro studies, has been constructed. The irradiation source was a (241)Am source, on which well inserts containing cancer cells growing in monolayer were placed. The total radioactivity, uniformity, and α-particle spectrum were determined by use of HPGe detector, Gafchromic™ dosimetry film, and PIPS(®) detector measurements, respectively. Monte Carlo simulations were used for dosimetry. Three prostate cancer (LNCaP, DU145, PC3) and three pancreatic cancer (Capan-1, Panc-1, BxPC-3) cell lines were irradiated by α-particles to the absorbed doses 0, 0.5, 1, and 2Gy. For reference, cells were irradiated using (137)Cs to the absorbed doses 0, 1, 2, 4, 6, 8, and 10Gy. Radiation sensitivity was estimated using a tetrazolium salt-based colorimetric assay with absorbance measurements at 450nm. The relative biological effectiveness for α-particles relative to γ-irradiation at 37% cell survival for the LNCaP, DU145, PC3, Capan-1, Panc-1, and BxPC-3 cells was 7.9±1.7, 8.0±0.8, 7.0±1.1, 12.5±1.6, 9.4±0.9, and 6.2±0.7, respectively. The results show the feasibility of constructing a desktop α-particle irradiator as well as indicate that both prostate and pancreatic cancers are good candidates for further studies of α-particle radioimmunotherapy.
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| 47. |
- Norrgren, Kristina, et al.
(författare)
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Comparative renal, hepatic, and bone marrow toxicity of Cisplatin and radioactive Cisplatin (191Pt) in Wistar rats
- 2006
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 21:5, s. 528-534
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to investigate the possibility to increase the therapeutic gain of the cytotoxic agent, cisplatin, by incorporation of radioactive platinum. In this study, we investigated how organs at risk (i.e., kidneys, bone marrow, and liver) are affected by treatment with 191Pt-cisplatin, compared to treatment with conventional cisplatin. Rats (total, n = 69) were divided into three groups and given 5 mg/kg 191Pt-cisplatin and 5 mg/kg nonradioactive cisplatin or saline. The weight of the animals and blood samples, including analysis of creatinine, bilirubin, alanine and aspartate aminotransferases and platelet count, was followed for 6 weeks after treatment. Histopathology examinations of kidney and liver tissues were performed. An initial decrease in weight gain was seen from 3 days after treatment with cisplatin and 191Pt-cisplatin and for 1 week onward; thereafter, the weight gain continued, following the same pattern as for the control group. Concentration of plasma creatinine was increased for both cisplatin groups but with no significant difference between treatment groups. No other significant differences in effect parameters were found. There was no increase in toxicity for radioactive cisplatin on liver, kidneys, and bone marrow, compared to conventional cisplatin. Further experimental and clinical studies on preparations of this type are thus warranted.
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| 48. |
- Oddstig, Jenny, 1978, et al.
(författare)
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A novel photon radiation detector system for in vitro biokinetic measurements.
- 2005
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 20:6, s. 629-38
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: This study evaluates a novel photon radiation detector system for in vitro biokinetic measurements. METHODS: A cell-culture well can be considered to consist of two different compartments: the cells and the medium. By placing the well on a lead-collimated scintillation (NaI(T1)) detector, changes in activity distribution between the compartments will result in changes in count rates owing to the efficiency ratio (ER) between the cells and the medium. The ER depends on differences in detection solid angles for the compartments and differences in attenuation of photons emitted from the compartments. Evaluation of the optimal measuring geometries for the detector system was done by Monte Carlo (MC) simulations. The detector system was tested in two different in vitro situations. RESULTS: The MC simulations showed that the most optimal detector system was obtained by using a lead-collimated well crystal. Both the MC simulations and the experiments have proven the usability of the system. CONCLUSIONS: The detector system was demonstrated to be of value for biokinetic studies. The cellular binding of radiolabeled substances can be determined with high precision, and real-time measurements can be performed on a cell culture without harvesting the cells.
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| 49. |
- Oddstig, Jenny, 1978, et al.
(författare)
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Radiation Induces Up-Regulation of Somatostatin Receptors 1, 2, and 5 in Small Cell Lung Cancer In Vitro Also at Low Absorbed Doses.
- 2011
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Ingår i: Cancer biotherapy & radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1557-8852 .- 1084-9785. ; 26:6
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background: Radiation can be used to up-regulate the expression of the somatostatin receptor (sstr) subtype 2 in small cell lung cancer (SCLC) cells at absorbed doses of 2?8 Gy. Increased sstr expression results in increased binding of radiolabeled somatostatin analogs to the tumor cell, which enhances the efficacy of systemic radionuclide therapy. The aim of this study was to determine if lower absorbed doses could up-regulate sstr2 expression, and possibly influence other sstr subtypes. Methods: Human H69 SCLC cells were irradiated with an absorbed dose of 0.12?6.0 Gy and the sstr mRNA expression 3 days after irradiation was measured by quantitative real-time polymerase chain reaction for sstr1?5. At the same time point was the binding of [(177)Lu]-DOTA(0)-Tyr(3)-octreotate to the cells measured after irradiation to an absorbed dose of 0.12?2.0 Gy and compared to the binding to nonirradiated cells. Results: mRNA expression of sstr1, sstr2, and sstr5 was increased by a factor of 1.5?2 in cells irradiated with absorbed doses?4 Gy and the binding of [(177)Lu]-DOTA(0)-Tyr(3)-octreotate was, accordingly, 2?3 times higher to irradiated cells for all absorbed doses, except 0.25 Gy. Conclusion: The binding of [(177)Lu]-DOTA(0)-Tyr(3)-octreotate was increased after radiation exposure. This increase was observed at low absorbed doses in parallel with up-regulation of sstr1, sstr2, and sstr5 mRNA.
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| 50. |
- Orlova, Anna, et al.
(författare)
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Comparative biodistribution of the radiohalogenated (Br, I and At) antibody A33 : Implications for in vivo dosimetry
- 2002
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Ingår i: Cancer Biotherapy and Radiopharmaceuticals. - : Mary Ann Liebert Inc. - 1084-9785 .- 1557-8852. ; 17:4, s. 385-96
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Tidskriftsartikel (refereegranskat)abstract
- The alpha-emitter astatine-211 (T(1/2) = 7.2 h) has great potential for use in targeted radionuclide therapy. Its potent alpha-radiation makes (211)At unsuitable for dose planning. Its x-rays can be used for gamma-camera monitoring of the radioactivity distribution during therapy but not for accurate estimation of absorbed dose in critical organs. This study was intended to establish whether the absorbed dose delivered by astatinated antibody could be accurately determined by analogue labeling with radiohalogens, better suited for quantitative measurements in vivo. PET facilitates quantitative pharmacokinetics; possible halogen labels are, e.g., (76)Br (T(1/2) = 16.2 h) and (124)I (T(1/2) = 4.18 d). Antibody A33 was labeled with (76)Br, (125)I and (211)At using N-succinimidyl-p-halobenzoates. The conjugates were co-injected into Sprague-Dawley rats. Radioactivity concentrations in different organs and tissues were measured at three time points. Pharmacokinetic data were used to calculate absorbed doses. (125)I and (76)Br reflected the biokinetics of astatine reasonably well. The absorbed doses in bladder, kidney, pancreas, liver, bone and brain were determined with 10% accuracy. The absorbed doses in stomach, spleen and thyroid were underestimated by a factor 2-3. Positron-emitting analogues can be used to predict the astatine-derived dose in critical organs. Correction factors should be used for stomach, spleen and thyroid.
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