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- Romiani, Arman, 1991, et al.
(författare)
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Better therapeutic results after fractionated administration of Lu-177-octreotate in mice bearing human neuroblastoma
- 2018
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Ingår i: The European Association of Nuclear Medicine (EANM).
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Neuroblastoma (NB) is a neuroendocrine tumor and one of the most common cancer types in infants. NB is a heterogeneous cancer form, meaning that it has various characteristics and features, with diverse outcomes. High-risk NB has a 5-year survival rate of only 40-50%, demonstrating the need for new and improved treatment options for this patient group. Since NB overexpresses somatostatin receptors Lu-177-octreotate has the potential to be a treatment option. Our previous in vitro studies indicated high and specific uptake of Lu-177-octreotate in the human NB cell lines CLB-Bar and IMR-32. Furthermore, biodistribution studies of Lu-177-octreotate in NB-xenografted mice showed high uptake in tumor tissue in comparison with risk organs. These promising results encouraged studies on the anti-tumor effects of Lu-177-octreotate therapy. The aim of this work was to study the anti-tumor effects after fractionated administration of Lu-177-octreotate in nude mice bearing CLB-Bar. Methods: Nude BALB/c mice aged 5-6 weeks were injected with 2x10^6 CLB-Bar cells on the flank of the mice. Mice with tumors between 250 and 1100 mm^3 were included in the study. Three groups of mice were i.v injected with totally 15 MBq Lu-177-octreotate: given as 15 MBq x1, 7.5 MBq x2 with a 2-h interval or 5 MBq x3 with 1-h interval. The tumor volume was measured with a caliper twice a week after injection and the mice were killed when the tumor mass exceeded 10 % of the body weight. Results: The relative tumor volume 7 days post injection was 2.0, 1.7 and 1.3 for the 15 MBq x1, 7.5 MBq x2 and 5 MBq x3 group, respectively, corresponding mean survival time after study start was of 9.6, 14 and 16 days, respectively. Conclusion: The fractionated administration of Lu-177-octreotate resulted in a better anti-tumor effect, with the most prominent results from 3x5 MBq. These results might be due to saturation of the somatostatin receptors for the higher amounts of Lu-177-octreotate or upregulation of receptors from previous fractions. Further studies are needed to optimize the fractionation scheme and to evaluate the mechanisms behind the results.
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- Romiani, Arman, 1991, et al.
(författare)
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Neuroblastoma xenograft models demonstrate the therapeutic potential of Lu-177-octreotate
- 2021
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Neuroblastoma (NB) is one of the most frequently diagnosed tumors in infants. NB is a neuroendocrine tumor type with various characteristics and features, and with diverse outcome. The most malignant NBs have a 5-year survival rate of only 40-50%, indicating the need for novel and improved treatment options. Lu-177-octreotate is routinely administered for treatment of neuroendocrine tumors overexpressing somatostatin receptors (SSTR). The aim of this study was to examine the biodistribution of Lu-177-octreotate in mice bearing aggressive human NB cell lines, in order to evaluate the potential usefulness of Lu-177-octreotate for treatment of NB. Methods BALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5-7/group) were i.v. injected with 0.15 MBq, 1.5 MBq or 15 MBq Lu-177-octreotate and sacrificed 1 h, 24 h, 48 h and 168 h after administration. The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated. Immunohistochemical (IHC) staining for SSTR1-5, and Ki67 were carried out for tumor xenografts from the three cell lines. Results High Lu-177 concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72%IA/g 24 h p.i.; 1.5 MBq Lu-177-octreotate). The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq Lu-177-octreotate. Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered. IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32. Conclusion T/N values for all three human NB tumor xenograft types investigated were high relative to previously investigated neuroendocrine tumor types. The results indicate a clear potential of Lu-177-octreotate as a therapeutic alternative for metastatic NB.
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- Romiani, Arman, 1991, et al.
(författare)
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The potential of Lu-177-octreotate as a therapeutic alternative for metastatic neuroblastoma
- 2016
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Ingår i: 62nd Annual International Meeting Radiation Research Society, Waikoloa, HI, USA, October 16-19, 2016.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Radionuclide therapy using 177Lu-octreotate is a promising treatment option for neuroendocrine tumors with overexpression of somatostatin receptors (SSTR). In order to screen and evaluate the usefulness of 177Lu-octreotate for therapy of a specific neuroendocrine tumor type, knowledge of the binding and internalization of the 177Lu-octreotate to tumor cells is needed. The aim of this study was to determine the binding and internalization of 177Lu-octreotate in three neuroblastoma (NB) cell lines and to perform biodistribution studies in animals bearing NB. Binding and internalization of 177Lu-octreotate to the human NB cell lines IMR-32 and CLB-BAR were investigated in vitro. Cell cultures were incubated with various amounts of 177Lu-octreotate with or without excess of octreotide and harvested at 24 h and 48 h after administration. The amount of 177Lu associated to the membrane and internalized into the cells were determined. IMR-32, CLB-BAR and GEMO bearing BALB/c nude mice (n=5-6/group) were i.v. injected with 15 MBq 177Lu-octreotate and killed 1 h, 24 h and 7 days after administration. Tissue samples were collected and radioactivity concentrations were determined. Tumor-to-normal-tissue ratios (T/N) were calculated and compared with previous data. The highest binding and internalization of 177Lu in vitro occurred after 48 h: 78% and 47% of the 177Lu-octreotate in IMR-32 and CLB-BAR cells, respectively. Binding and internalization was successfully blocked with octreotide, indicating a specific uptake. In the mice bearing GEMO, T/Blood and T/Kidney values 1 h after injection were 18 and 0.71, respectively, and 7 days after injection 2300 and 27, respectively. Corresponding values for IMR-32 were 7.5 and 0.40; 1300 and 7.8, 1 h and 7 d after injection, respectively. Corresponding values for CLB-BAR were 18 and 0.24; 113 and 0.94, 1 h and 7 d after injection, respectively. This study clearly shows the potential of 177Lu-octreotate as a therapeutic alternative in the treatment of metastatic NB. The T/N values for all three tumor types investigated showed high values compared with previously investigated neuroendocrine tumor types. The results are very promising, and future studies will characterize anti-tumor effects following 177Lu-octreotate therapy.
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- Saadati, Sofia, 1992, et al.
(författare)
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Binding and internalization of 177Lu-octreotate in human tumor cell lines of different origin
- 2017
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Ingår i: 63rd Annual Meeting of the Radiation Research Society, Cancun, Mexico.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-octreotate is used for systemic treatment of patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumors (NETs), mainly for small-intestine NETs and endocrine pancreatic tumors. Further research is needed to evaluate the possibility of using this type of treatment in patients with other SSTR-expressing tumors. Tumor binding and uptake of the radiopharmaceutical is highly dependent on SSTR expression. In order to determine the potential of using 177Lu-octreotate for treatment of other tumor cell lines, in vitro studies of binding and internalization are needed. The aim of this study was to asses binding and internalization of 177Lu-octreotate in various cancer cell lines and compare with our previous results. In vitro studies were performed on neuroblastoma (CLB-BAR, IMR-32), lung adenocarcinoma (h1975, h2228) and invasive breast carcinoma (BT474, MCF-7, MDA-MB-231, MDA-MB-361, T47D, ZR-75-1) cell lines. Cell cultures were incubated with low or high amounts of 177Lu-octreotate. To block SSTR and thereby determine the specific uptake, control groups were incubated with 177Lu-octreotate and excess octreotide. The amount of unbound, membrane-bound, and internalized 177Lu in each sample was determined after 24 h. Several of the studied tumor cell lines showed specific binding of 177Lu-octreotate. The highest binding and internalization after 24 h was seen for the neuroblastoma cell lines IMR-32 (58% internalized, 9.4% membrane-bound) and CLB-BAR (26% internalized, 3.4% membrane-bound). Specific binding was also found in some breast cancer cell lines (e.g. 3.1% internalized, 0.5% membrane-bound in MDA-MB-361). No specific binding was found in lung adenocarcinoma. In comparison with our previous findings in NET and NET-like cell lines, these results indicate that SSTR-based PRRT may be a potential treatment option for patients with neuroblastoma and certain types of breast cancer. Promising results showing specific tumor uptake of 177Lu-octreotate were obtained for SSTR-expressing tumor cell lines in vitro, indicating the possibility of using SSTR-based diagnostic and therapeutic regimes on more tumor types than those in current clinical practice.
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