| 1. |
- Elgqvist, Jörgen, et al.
(author)
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Radiosensitivity of Prostate Cancer Cell Lines for Irradiation from Beta Particle-emitting Radionuclide ¹⁷⁷Lu Compared to Alpha Particles and Gamma Rays
- 2016
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In: Anticancer research. - 1791-7530. ; 36:1, s. 103-109
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Journal article (peer-reviewed)abstract
- AIM: The purpose of the present study was to investigate the radiosensitivity of the prostate cancer cell lines LNCaP, DU145, and PC3 when irradiated with beta particles emitted from (177)Lu, and to compare the effect with irradiation using alpha particles or gamma rays.MATERIALS AND METHODS: Cells were irradiated with beta particles emitted from (177)Lu, alpha particles from (241)Am, or gamma rays from (137)Cs. A non-specific polyclonal antibody was labeled with (177)Lu and used to irradiate cells in suspension with beta particles. A previously described in-house developed alpha-particle irradiator based on a (241)Am source was used to irradiate cells with alpha particles. External gamma-ray irradiation was achieved using a standard (137)Cs irradiator. Cells were irradiated to absorbed doses equal to 0, 0.5, 1, 2, 4, 6, 8, or 10 Gy. The absorbed doses were calculated as mean absorbed doses. For evaluation of cell survival, the tetrazolium-based WST-1 assay was used. After irradiation, WST-1 was added to the cell solutions, incubated, and then measured for level of absorbance at 450 nm, indicating the live and viable cells.RESULTS: LNCaP, DU145, and PC3 cell lines all had similar patterns of survival for the different radiation types. No significant difference in surviving fractions were observed between cells treated with beta-particle and gamma-ray irradiation, represented for example by the surviving fraction values (mean±SD) at 2, 6, and 10 Gy (SF2, SF6, and SF10) for DU145 after beta-particle irradiation: 0.700±0.090, 0.186±0.050 and 0.056±0.010, respectively. A strong radiosensitivity to alpha particles was observed, with SF2 values of 0.048±0.008, 0.018±0.006 and 0.015±0.005 for LNCaP, DU145, and PC3, respectively.CONCLUSION: The surviving fractions after irradiation using beta particles or gamma rays did not differ significantly at the absorbed dose levels and dose rates used. Irradiation using alpha particles led to a high level of cell killing. The results show that the beta-particle emitter (177)Lu as well as alpha-particles are both good candidates for radionuclide-therapy applications in the treatment of prostate cancer.
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| 2. |
- Larsson, Erik, et al.
(author)
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Use of Monte Carlo simulations with a realistic rat phantom for examining the correlation between hematopoietic system response and red marrow absorbed dose in Brown Norway rats undergoing radionuclide therapy with (177)Lu- and (90)Y-BR96 mAbs.
- 2012
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In: Medical Physics. - : Wiley. - 0094-2405. ; 39:7, s. 4434-4443
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Journal article (peer-reviewed)abstract
- Purpose: Biokinetic and dosimetry studies in laboratory animals often precede clinical radionuclide therapies in humans. A reliable evaluation of therapeutic efficacy is essential and should be based on accurate dosimetry data from a realistic dosimetry model. The aim of this study was to develop an anatomically realistic dosimetry model for Brown Norway rats to calculate S factors for use in evaluating correlations between absorbed dose and biological effects in a preclinical therapy study. Methods: A realistic rat phantom (Roby) was used, which has some flexibility that allows for a redefinition of organ sizes. The phantom was modified to represent the anatomic geometry of a Brown Norway rat, which was used for Monte Carlo calculations of S factors. Kinetic data for radiolabeled BR96 monoclonal antibodies were used to calculate the absorbed dose. Biological data were gathered from an activity escalation study with (90)Y- and (177)Lu-labeled BR96 monoclonal antibodies, in which blood cell counts and bodyweight were examined up to 2 months follow-up after injection. Reductions in white blood cell and platelet counts and declines in bodyweight were quantified by four methods and compared to the calculated absorbed dose to the bone marrow or the total body. Results: A red marrow absorbed dose-dependent effect on hematological parameters was observed, which could be evaluated by a decrease in blood cell counts. The absorbed dose to the bone marrow, corresponding to the maximal tolerable activity that could safely be administered, was determined to 8.3 Gy for (177)Lu and 12.5 Gy for (90)Y. Conclusions: There was a clear correlation between the hematological effects, quantified with some of the studied parameters, and the calculated red marrow absorbed doses. The decline in body weight was stronger correlated to the total body absorbed dose, rather than the red marrow absorbed dose. Finally, when considering a constant activity concentration, the phantom weight, ranging from 225 g to 300 g, appeared to have no substantial effect for the estimated absorbed dose.
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| 3. |
- Meerkhan, Suaad, et al.
(author)
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Testis dosimetry in individual patients by combining a small-scale dosimetry model and pharmacokinetic modeling-application of (111)In-Ibritumomab Tiuxetan (Zevalin(®)).
- 2014
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In: Physics in Medicine and Biology. - : IOP Publishing. - 1361-6560 .- 0031-9155. ; 59:24, s. 7889-7904
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Journal article (peer-reviewed)abstract
- A heterogeneous distribution of radionuclides emitting low-energy electrons in the testicles may result in a significant difference between an absorbed dose to the radiosensitive spermatogonia and the mean absorbed dose to the whole testis. This study focused on absorbed dose distribution in patients at a finer scale than normally available in clinical dosimetry, which was accomplished by combining a small-scale dosimetry model with patient pharmacokinetic data. The activity in the testes was measured and blood sampling was performed for patients that underwent pre-therapy imaging with (111)In-Zevalin(®). Using compartment modeling, testicular activity was separated into two components: vascular and extravascular. The uncertainty of absorbed dose due to geometry variations between testicles was explored by an assumed activity micro-distribution and by varying the radius of the interstitial tubule. Results showed that the absorbed dose to germ cells might be strongly dependent on the location of the radioactive source, and may exceed the absorbed dose to the whole testis by as much as a factor of two. Small-scale dosimetry combined with compartmental analysis of clinical data proved useful for gauging tissue dosimetry and interpreting how intrinsic geometric variation influences the absorbed dose.
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| 4. |
- Stenvall, Anna, et al.
(author)
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A small-scale anatomical dosimetry model of the liver.
- 2014
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In: Physics in Medicine and Biology. - : IOP Publishing. - 1361-6560 .- 0031-9155. ; 59:13, s. 3353-3371
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Journal article (peer-reviewed)abstract
- Radionuclide therapy is a growing and promising approach for treating and prolonging the lives of patients with cancer. For therapies where high activities are administered, the liver can become a dose-limiting organ; often with a complex, non-uniform activity distribution and resulting non-uniform absorbed-dose distribution. This paper therefore presents a small-scale dosimetry model for various source-target combinations within the human liver microarchitecture. Using Monte Carlo simulations, Medical Internal Radiation Dose formalism-compatible specific absorbed fractions were calculated for monoenergetic electrons; photons; alpha particles; and (125)I, (90)Y, (211)At, (99m)Tc, (111)In, (177)Lu, (131)I and (18)F. S values and the ratio of local absorbed dose to the whole-organ average absorbed dose was calculated, enabling a transformation of dosimetry calculations from macro- to microstructure level. For heterogeneous activity distributions, for example uptake in Kupffer cells of radionuclides emitting low-energy electrons ((125)I) or high-LET alpha particles ((211)At) the target absorbed dose for the part of the space of Disse, closest to the source, was more than eight- and five-fold the average absorbed dose to the liver, respectively. With the increasing interest in radionuclide therapy of the liver, the presented model is an applicable tool for small-scale liver dosimetry in order to study detailed dose-effect relationships in the liver.
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| 5. |
- Stenvall, Anna, et al.
(author)
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Quantitative γ-H2AX immunofluorescence method for DNA double-strand break analysis in testis and liver after intravenous administration of 111InCl3
- 2020
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In: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 10:1
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Journal article (peer-reviewed)abstract
- Background: It is well known that a severe cell injury after exposure to ionizing radiation is the induction of DNA double-strand breaks (DSBs). After exposure, an early response to DSBs is the phosphorylation of the histone H2AX molecule regions adjacent to the DSBs, referred to as γ-H2AX foci. The γ-H2AX assay after external exposure is a good tool for investigating the link between the absorbed dose and biological effect. However, less is known about DNA DSBs and γ-H2AX foci within the tissue microarchitecture after internal irradiation from radiopharmaceuticals. Therefore, in this study, we aimed to develop and validate a quantitative ex vivo model using γ-H2AX immunofluorescence staining and confocal laser scanning microscopy (CLSM) to investigate its applicability in nuclear medicine dosimetry research. Liver and testis were selected as the organs to study after intravenous administration of 111InCl3. Results: In this study, we developed and validated a method that combines ex vivo γ-H2AX foci labeling of tissue sections with in vivo systemically irradiated mouse testis and liver tissues. The method includes CLSM imaging for intracellular cell-specific γ-H2AX foci detection and quantification and absorbed dose calculations. After exposure to ionizing radiation from 111InCl3, both hepatocytes and non-hepatocytes within the liver showed an absorbed dose-dependent elevation of γ-H2AX foci, whereas no such correlation was seen for the testis tissue. Conclusion: It is possible to detect and quantify the radiation-induced γ-H2AX foci within the tissues of organs at risk after internal irradiation. We conclude that our method developed is an appropriate tool to study dose–response relationships in animal organs and human tissue biopsies after internal exposure to radiation.
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| 6. |
- Timmermand, Oskar Vilhelmsson, et al.
(author)
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Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics
- 2019
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In: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 9:8, s. 2129-2142
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Journal article (peer-reviewed)abstract
- Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 (225Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 (177Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177Lu is quantitatively accurate and can be used to perform treatment planning. [177Lu]hu11B6 therefore has significant potential as a theranostic agent. Materials and Methods: Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [177Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR). Results: Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [177Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [177Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177Lu and decreasing tumor volumes. For [177Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017). Conclusions: This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide 177Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using 225Ac labeled hu11B6, however emerging at a later timepoint.
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| 7. |
- Vilhelmsson Timmermand, Oskar, et al.
(author)
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High resolution digital autoradiographic and dosimetric analysis of heterogeneous radioactivity distribution in xenografted prostate tumors
- 2016
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In: Medical Physics. - : Wiley. - 0094-2405. ; 43:12, s. 6632-6643
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Journal article (peer-reviewed)abstract
- The first main aim of this study was to illustrate the absorbed dose rate distribution from 177Lu in sections of xenografted prostate cancer (PCa) tumors using high resolution digital autoradiography (DAR) and compare it with hypothetical identical radioactivity distributions of 90Y or 7 MeV alpha-particles. Three dosimetry models based on either dose point kernels or Monte Carlo simulations were used and evaluated. The second and overlapping aim, was to perform DAR imaging and dosimetric analysis of the distribution of radioactivity, and hence the absorbed dose rate, in tumor sections at an early time point after injection during radioimmunotherapy using 177Lu-h11B6, directed against the human kallikrein 2 antigen.
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| 8. |
- Alattar, Abdul Ghani, et al.
(author)
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Recombinant alpha(1)-Microglobulin (rA1M) Protects against Hematopoietic and Renal Toxicity, Alone and in Combination with Amino Acids, in a Lu-177-DOTATATE Mouse Radiation Model
- 2023
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In: Biomolecules. - 2218-273X. ; 13:6
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Journal article (peer-reviewed)abstract
- Lu-177-DOTATATE peptide receptor radionuclide therapy (PRRT) is used clinically to treat metastasized or unresectable neuroendocrine tumors (NETs). Although Lu-177-DOTATATE is mostly well tolerated in patients, bone marrow suppression and long-term renal toxicity are still side effects that should be considered. Amino acids are often used to minimize renal radiotoxicity, however, they are associated with nausea and vomiting in patients. alpha (1)-microglobulin (A1M) is an antioxidant with heme- and radical-scavenging abilities. A recombinant form (rA1M) has previously been shown to be renoprotective in preclinical models, including in PRRT-induced kidney damage. Here, we further investigated rA1M's renal protective effect in a mouse Lu-177-DOTATATE model in terms of administration route and dosing regimen and as a combined therapy with amino acids (Vamin). Moreover, we investigated the protective effect of rA1M on peripheral blood and bone marrow cells, as well as circulatory biomarkers. Intravenous (i.v.) administration of rA1M reduced albuminuria levels and circulatory levels of the oxidative stress-related protein fibroblast growth factor-21 (FGF-21). Dual injections of rA1M (i.e., at 0 and 24 h post-Lu-177-DOTATATE administration) preserved bone marrow cellularity and peripheral blood reticulocytes. Administration of Vamin, alone or in combination with rA1M, did not show any protection of bone marrow cellularity or peripheral reticulocytes. In conclusion, this study suggests that rA1M, administered i.v. for two consecutive days in conjunction with Lu-177-DOTATATE, may reduce hematopoietic and kidney toxicity during PRRT with Lu-177-DOTATATE.
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| 9. |
- Bardies, Manuel, et al.
(author)
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Quantitative imaging for clinical dosimetry
- 2006
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In: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier BV. - 0167-5087 .- 0168-9002. ; 569:2, s. 467-471
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Journal article (peer-reviewed)abstract
- Patient-specific dosimetry in nuclear medicine is now a legal requirement in many countries throughout the EU for targeted radionuclide therapy (TRT) applications. In order to achieve that goal, an increased level of accuracy in dosimetry procedures is needed. Current research in nuclear medicine dosimetry should not only aim at developing new methods to assess the delivered radiation absorbed dose at the patient level, but also to ensure that the proposed methods can be put into practice in a sufficient number of institutions. A unified dosimetry methodology is required for making clinical outcome comparisons possible.
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| 10. |
- Bicak, Mesude, et al.
(author)
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Genetic signature of prostate cancer mouse models resistant to optimized hK2 targeted α-particle therapy
- 2020
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 117:26, s. 15172-15181
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Journal article (peer-reviewed)abstract
- Hu11B6 is a monoclonal antibody that internalizes in cells expressing androgen receptor (AR)-regulated prostate-specific enzyme human kallikrein-related peptidase 2 (hK2; KLK2). In multiple rodent models, Actinium-225-labeled hu11B6-IgG1 ([225Ac]hu11B6-IgG1) has shown promising treatment efficacy. In the present study, we investigated options to enhance and optimize [225Ac]hu11B6 treatment. First, we evaluated the possibility of exploiting IgG3, the IgG subclass with superior activation of complement and ability to mediate FC-γ-receptor binding, for immunotherapeutically enhanced hK2 targeted α-radioimmunotherapy. Second, we compared the therapeutic efficacy of a single high activity vs. fractionated activity. Finally, we used RNA sequencing to analyze the genomic signatures of prostate cancer that progressed after targeted α-therapy. [225Ac]hu11B6-IgG3 was a functionally enhanced alternative to [225Ac]hu11B6-IgG1 but offered no improvement of therapeutic efficacy. Progression-free survival was slightly increased with a single high activity compared to fractionated activity. Tumor-free animals succumbing after treatment revealed no evidence of treatment-associated toxicity. In addition to up-regulation of canonical aggressive prostate cancer genes, such as MMP7, ETV1, NTS, and SCHLAP1, we also noted a significant decrease in both KLK3 (prostate-specific antigen ) and FOLH1 (prostate-specific membrane antigen) but not in AR and KLK2, demonstrating efficacy of sequential [225Ac]hu11B6 in a mouse model.
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