| 1. |
- Bäck, Tom, 1964, et al.
(författare)
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Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated alpha-Radioimmunotherapy with At-211-MX35-F(ab')(2): Influence of Absorbed Tumor Dose and Effect on Long-Term Survival
- 2017
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 2159-662X. ; 58:4, s. 598-604
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Tidskriftsartikel (refereegranskat)abstract
- The goal of this study was to investigate whether targeted a-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of alpha-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Methods: Mice bearing subcutaneous tumors (50 mm(3), NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with At-211-MX35-F (ab')(2) at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from bio-distribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Results: Effects on tumor growth after fractionated alpha-radioimmunotherapy with 211At-MX35-F(ab')(2) was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after a-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Conclusion: Having observed complete eradication of solid tumor xenografts, we conclude that targeted alpha-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival.
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| 2. |
- Claesson, Kristina, 1965, et al.
(författare)
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RBE of α-particles from 211At for complex DNA damage and cell survival in relation to cell cycle positio.
- 2011
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Ingår i: International journal of radiation biology. - : Informa UK Limited. - 1362-3095 .- 0955-3002.
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Tidskriftsartikel (refereegranskat)abstract
- Purpose:To investigate cell cycle effects and relative biological effectiveness (RBE) of α-particles from the clinically relevant radionuclide Astatine-211 ((211)At), using X-rays as reference radiation. Double-strand breaks (DSB), non-DSB clusters containing oxidised purines and clonogenic survival were investigated. Materials and methods:Asynchronous V79-379A fibroblasts or cells synchronised with mimosine in G1, early, mid and late S phase or in mitosis were irradiated with X-rays (100 kV(p)) or (211)At (mean linear energy transfer (LET) 110 keV/μm). Induction of DSB and clusters was determined using pulsed-field gel electrophoresis with fragment analysis. Cell survival was obtained with the clonogenic assay. Results:In asynchronous cells RBE for DSB- and cluster-induction was 3.5 and 0.59, respectively. RBE for 37% cell survival was 8.6. In different cell cycle phases RBE varied from 1.8-3.9 for DSB and 3.1-7.9 for 37% survival (survival at 2 Gy was 6.9-38 times lower after α-irradiation). (211)At induced 6 times more DSB and X-rays induced 11 times more DSB in mitotic cells with highly compacted chromatin relative G1. Conclusions:The radio-response is cell cycle dependent and differs between proliferating and non-cycling cells for both low- and high-LET radiation, resulting in a variation in RBE of α-particles between 1.8 and 8.6.
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| 3. |
- 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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| 4. |
- Elgqvist, Jörgen, 1963, et al.
(författare)
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Intraperitoneal Alpha-Radioimmunotherapy of Advanced Ovarian Cancer in Nude Mice using Different High Specific Activities
- 2010
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Ingår i: World Journal of Oncology. - : Elmer Press, Inc.. - 1920-4531. ; 1:3, s. 101-110
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate the therapeutic efficacy of advanced ovarian cancer in mice, using α-radioimmunotherapy with different high specific activities. The study was performed using the monoclonal antibody (mAb) MX35 F(ab´)2 labeled with the α-particle emitter 211At.Methods: Animals were intraperitoneally inoculated with ≥1 × 107 cells of the ovarian cancer cell line NIH:OVCAR-3. Four weeks later 9 groups of animals were given 25, 50, or 400 kBq 211At-MX35 F(ab´)2 with specific activities equal to 1/80, 1/500, or 1/1200 (211At atom/number of mAbs) for every activity level respectively (n = 10 in each group). As controls, animals were given PBS or unlabeled MX35 F(ab´)2 in PBS (n = 10 in each group). Eight weeks after treatment the animals were sacrificed and the presence of macroscopic tumors was determined by meticulous ocular examination of the abdominal cavity. Cumulated activity and absorbed dose calculations on tumor cells and tumors were performed using in house developed program. Specimens for scanning electron-microscopy analysis were collected from the peritoneum at the time of dissection.Results: Summing over the different activity levels (25, 50, and 400 kBq 211At-MX35 F(ab´)2) the number of animals with macroscopic tumors was 13, 17, and 22 (n = 30 for each group) for the specific activities equal to 1/80, 1/500, or 1/1200, respectively. Logistic-regression analysis showed a significant trend that higher specific activity means less probability for macroscopic tumors (P = 0.02).Conclusions: Increasing the specific activity indicates a way to enhance the therapeutic outcome of advanced ovarian cancer, regarding macroscopic tumors. Further studies of the role of the specific activity are therefore justified.
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| 5. |
- Elgqvist, Jörgen, 1963, et al.
(författare)
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Repeated Intraperitoneal alpha-Radioimmunotherapy of Ovarian Cancer in Mice.
- 2010
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Ingår i: Journal of oncology. - : Hindawi Limited. - 1687-8450 .- 1687-8469. ; 2010
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the therapeutic efficacy of alpha-radioimmunotherapy of ovarian cancer in mice using different fractionated treatment regimens. The study was performed using the monoclonal antibody MX35 F(ab')(2) labeled with the alpha-particle emitter (211)At. Methods. Nude mice were intraperitoneally inoculated with ~1 x 10(7) cells of the cell line NIH:OVCAR-3. Four weeks later 6 groups of animals were given 400 kBq (211)At-MX35 F(ab')(2) as a single or as a repeated treatment of up to 6 times (n = 18 in each group). The fractionated treatments were given every seventh day. Control animals were treated with unlabeled MX35 F(ab')(2) (n = 12). Eight weeks posttreatment 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 0.17, 0.11, 0.39, 0.44, 0.44, and 0.67 when treated with 400 kBq (211)At-MX35 F(ab')(2) once or 2, 3, 4, 5, or 6 times, respectively. Repeated treatment 3 times or more resulted in a significantly higher (P < .05) TFF than compared to treatment once or twice. The presence of ascites decreased from 15 out of 18 animals in the group given only one treatment to zero for the 2 groups given 5 or 6 fractions. Treatment with unlabeled MX35 F(ab')(2) resulted in a TFF of zero. Conclusion. Weekly repeated intraperitoneal injections of tolerable amounts of activity of (211)At-MX35 F(ab')(2) of up to 6 times produced increased therapeutic efficacy without observed toxicity, indicating a potential increase of the therapeutic index.
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| 6. |
- Karlsson, M R, et al.
(författare)
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Hypersensitivity and oral tolerance in the absence of a secretory immune system.
- 2010
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 65:5, s. 561-70
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal immunity protects the epithelial barrier by immune exclusion of foreign antigens and by anti-inflammatory tolerance mechanisms, but there is a continuing debate about the role of secretory immunoglobulins (SIgs), particularly SIgA, in the protection against allergy and other inflammatory diseases. Lack of secretory antibodies may cause immune dysfunction and affect mucosally induced (oral) tolerance against food antigens.
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| 7. |
- Karlsson, Malin, et al.
(författare)
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"Tolerosomes” are produced by intestinal epithelial cells
- 2001
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Ingår i: European Journal of Immunology. ; 31, s. 2892-2900
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Tidskriftsartikel (refereegranskat)abstract
- The development of immunological tolerance to orally fed antigens depends on the sampling, processing and transportation events followed in the intestinal epithelium. We present here a description of a ’’tolerosome’’: a supra-molecular, exosome-like structure assembled in and released from the small intestinal epithelial cell. The tolerosome is a e 40 nm large vesicular structure that carries MHC class II (MHC II) with bound antigenic peptides sampled from the gut lumen. Tolerosomes isolated from serum shortly after antigen feeding or from an in vitro pulsed intestinal epithelial cell line are fully capable of inducing antigen specific tolerance in naive recipient animals. Purified tolerosomes represent a structure by which fed antigens can be efficiently presented to the immune system. Removal of the tolerosomes from serum by ultracentrifugation or absorption of MHC II results in abrogated tolerance development.
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| 8. |
- Lyckesvärd, Madeleine Nordén, et al.
(författare)
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Alpha particle induced DNA damage and repair in normal cultured thyrocytes of different proliferation status.
- 2014
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Ingår i: Mutation research. Fundamental and molecular mechanisms of mutagenesis. - : Elsevier BV. - 1879-2871 .- 0027-5107. ; 765, s. 48-56
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Tidskriftsartikel (refereegranskat)abstract
- Childhood exposure to ionizing radiation increases the risk of developing thyroid cancer later in life and this is suggested to be due to higher proliferation of the young thyroid. The interest of using high-LET alpha particles from Astatine-211 ((211)At), concentrated in the thyroid by the same mechanism as (131)I [1], in cancer treatment has increased during recent years because of its high efficiency in inducing biological damage and beneficial dose distribution when compared to low-LET radiation. Most knowledge of the DNA damage response in thyroid is from studies using low-LET irradiation and much less is known of high-LET irradiation. In this paper we investigated the DNA damage response and biological consequences to photons from Cobolt-60 ((60)Co) and alpha particles from (211)At in normal primary thyrocytes of different cell cycle status. For both radiation qualities the intensity levels of γH2AX decreased during the first 24h in both cycling and stationary cultures and complete repair was seen in all cultures but cycling cells exposed to (211)At. Compared to stationary cells alpha particles were more harmful for cycling cultures, an effect also seen at the pChk2 levels. Increasing ratios of micronuclei per cell nuclei were seen up to 1Gy (211)At. We found that primary thyrocytes were much more sensitive to alpha particle exposure compared with low-LET photons. Calculations of the relative biological effectiveness yielded higher RBE for cycling cells compared with stationary cultures at a modest level of damage, clearly demonstrating that cell cycle status influences the relative effectiveness of alpha particles.
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| 9. |
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| 10. |
- Sandberg, Elisabeth, 1956, et al.
(författare)
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Inflammatogenic and adjuvant properties of HEMA in mice.
- 2005
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Ingår i: European journal of oral sciences. - : Wiley. - 0909-8836 .- 1600-0722. ; 113:5, s. 410-6
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Tidskriftsartikel (refereegranskat)abstract
- 2-Hydroxyethylmethacrylate (HEMA), a common constituent in dental materials, is known to cause hypersensitivity reactions. While the means by which this small molecule causes adverse responses has not been ascertained, we have previously demonstrated that it binds to protein and in mice induces the production of autoantibodies to HEMA-conjugated self-protein. The present study explores the inflammatory and adjuvant properties of HEMA in response to the subcutaneous injection of HEMA and a protein. Ovalbumin (OVA) was used as a 'reporter antigen', and mouse serum albumin (MSA), conjugated in vitro with HEMA (MSA(H)) to a low degree (0.5 molecules of HEMA per molecule of MSA on average), was used to mimic a possible in vivo situation. Inflammatory responses at injection sites were scored by using an ordinal scale, and immunoglobulin (Ig)G1, IgG2a, and IgE activities to OVA or MSA were assessed by enzyme-linked immunosorbent assay (ELISA). Injections of 20 micromol HEMA induced overt inflammatory skin responses, the severity of which was influenced by the co-administered substances. A significantly higher IgG1 and IgE response to OVA was induced by the presence of HEMA. Interestingly, injections with low conjugated MSA(H) only induced the production of autoantibodies if free HEMA was included at the time of immunization. These findings suggest that HEMA is an inflammatogenic substance with adjuvant properties.
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