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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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- Sandblom, Viktor, 1987, et al.
(författare)
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Combination therapy of medullary thyroid cancer using radiation and vandetanib
- 2017
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. Annual Congress of the European Association of Nuclear Medicine October 21 – 25, 2017 Vienna, Austria. Vol. 44, Suppl. 2. EP-0792. - : Springer. - 1619-7070 .- 1619-7089.
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Konferensbidrag (refereegranskat)abstract
- INTRODUCTION Most patients diagnosed with medullary thyroid cancer (MTC) present with metastatic disease. MTC are rare neuroendocrine tumours that occur either sporadically or in a hereditary form. Surgical resection of the thyroid gland followed by external beam radiotherapy (EBRT) or the use of tyrosine kinase inhibitors are current clinical methods for management of MTC. Unfortunately, the 10-year survival for patients with metastatic disease is only about 40%. However, many MTC tumours overexpress somatostatin receptors as molecular targets. Therefore, one option for patients with MTC is systemic treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) that bind with high affinity and specificity to somatostatin receptors on the tumour cells. In addition, the tyrosine kinase inhibitor vandetanib has recently been approved for single-agent treatment of MTC by the U.S. Food and Drug Administration (FDA). The aim of this study was to investigate the potential synergistic effect of combining irradiation and vandetanib for treatment of MTC. SUBJECTS & METHODS BALB/c nude mice were transplanted with patient-derived MTC cells (GOT2). When developed tumours reached a volume of about 500 mm3, the mice were treated with EBRT, vandetanib or a combination of both. The radiation dose and the amount of vandetanib were chosen to give moderate effect as single treatment to enable detection of any increased effect from the combination. Tumour volume was followed and compared with that in untreated mice. RESULTS We found that the largest treatment effect over time was seen for the animals receiving a combination of both EBRT and vandetanib. Given as single-agent treatment, EBRT and vandetanib resulted in a reduction in tumour size or in tumour growth arrest. For example, at two weeks after start of treatment, the tumour volume was reduced by 64%, 52%, and 73% compared with the untreated control group, for the animals treated with single EBRT, single vandetanib, and the combination, respectively. CONCLUSION The results indicate that an additive or even synergistic effect could be achieved when combining irradiation with vandetanib for treatment of patients with MTC. Further studies are needed to investigate the possibility of using 177Lu-octreotate for treatment of MTC, both as single-agent treatment or in combination with vandetanib.
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- Sandblom, Viktor, 1987, et al.
(författare)
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Gemcitabine potentiates the anti-tumour effect of radiation on medullary thyroid cancer.
- 2019
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Ingår i: PloS One. - : Public Library of Science (PLoS). - 1932-6203. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- Patients with medullary thyroid cancer (MTC) are often diagnosed with spread tumour disease and the development of better systemic treatment options for these patients is important. Treatment with the radiolabelled somatostatin analogue 177Lu-octreotate is already a promising option but can be optimised. For example, combination treatment with another substance could increase the effect on tumour tissue. Gemcitabine is a nucleoside analogue that has been shown to sensitise tumour cells to radiation. The aim of this study was to investigate potentially additive or synergistic effects of combining radiation with gemcitabine for treatment of MTC. Nude mice transplanted with patient-derived MTC tumours (GOT2) were divided into groups and treated with radiation and/or gemcitabine. Radiation treatment was given as 177Lu-octreotate or external beam radiotherapy (EBRT). The volume of treated and untreated tumours was followed. The absorbed dose and amount of gemcitabine were chosen to give moderate tumour volume reduction when given as monotherapy to enable detection of increased effects from combination treatment. After follow-up, the mice were killed and tumours were immunohistochemically (IHC) analysed. Overall, the animals that received a combination of EBRT and gemcitabine showed the largest reduction in tumour volume. Monotherapy with EBRT or gemcitabine also resulted in a clear detrimental effect on tumour volume, while the animals that received 177Lu-octreotate monotherapy showed similar response as the untreated animals. The GOT2 tumour was confirmed in the IHC analyses by markers for MTC. The IHC analyses also revealed that the proliferative activity of tumour cells was similar in all tumours, but indicated that fibrotic tissue was more common after EBRT and/or gemcitabine treatment. The results indicate that an additive, or even synergistic, effect may be achieved by combining radiation with gemcitabine for treatment of MTC. Future studies should be performed to evaluate the full potential of combining 177Lu-octreotate with gemcitabine in patients.
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- Sandblom, Viktor, 1987, et al.
(författare)
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Gemcitabine potentiates the anti-tumour effect of radiation therapy on medullary thyroid cancer
- 2016
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Ingår i: 4th Swedish Cancer Research Meeting, 7-8 november 2016, Gothenburg, Sweden..
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND Most patients diagnosed with medullary thyroid cancer (MTC) present with metastatic disease and the 10-year survival for these patients is only about 40%. Since many MTCs overexpress somatostatin receptors, one option for these patients is systemic treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate). In addition, the nucleoside gemcitabine has shown anti-tumour activity in MTC. The aim of this study was to investigate potential synergistic effects of combining gemcitabine with irradiation for treatment of MTC. MATERIALS & METHODS Nude mice carrying a patient-derived MTC (GOT2) was divided into treatment groups. They received radiation therapy (as external beam radiotherapy (EBRT) or 177Lu-octreotate) and gemcitabine both as single-agent treatment and in combination. The radiation dose and the amount of gemcitabine were kept low to enable detection of any synergistic effects. Tumour volume was followed and compared with that in untreated mice. RESULTS The largest treatment effect was seen for the animals receiving a combination of both EBRT and gemcitabine. Given as single-agent treatment, both EBRT and gemcitabine resulted in a reduction in tumour growth arrest or even a reduction in tumour volume. The animals treated with only 177Lu-octreotate showed similar response as the control group. CONCLUSIONS It is possible that an additive or even synergistic effect on tumour tissue would be achieved when combining gemcitabine with irradiation for treatment of patients with MTC. Further studies should be performed to evaluate the possibility of using 177Lu-octreotate for treatment of MTC, both as single-agent treatment or in combination with gemcitabine.
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- Sandblom, Viktor, 1987, et al.
(författare)
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Increased therapeutic effect on medullary thyroid cancer using a combination of radiation and tyrosine kinase inhibitors : Increased effect on medullary thyroid cancer by combining radiation with tyrosine kinase inhibitors
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:5
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Tidskriftsartikel (refereegranskat)abstract
- Since patients with medullary thyroid cancer (MTC) often have metastatic disease at the time of diagnosis, the development of efficient systemic treatment options for MTC is important. Vandetanib and cabozantinib are two tyrosine kinase inhibitors (TKIs) that were recently approved by FDA and EMA for systemic treatment of metastatic MTC. Additionally, since MTC is of a neuroendocrine tumour type, treatment with radiolabelled somatostatin analogues (e.g. 177Lu-octreotate) is a valid option for patients with MTC. The aim of this study was to investigate the potentially increased therapeutic effect of combining radiation therapy with these TKIs for treatment of MTC in a mouse model. Nude mice carrying patient-derived MTC tumours (GOT2) were treated with external beam radiotherapy (EBRT) and/or one of the two TKIs vandetanib or cabozantinib. The tumour volume was determined and compared with that of mock-treated controls. The treatment doses were chosen to give a moderate effect as monotherapy to be able to detect any increased therapeutic effect from the combination therapy. At the end of follow-up, tumours were processed for immunohistochemical (IHC) analyses. The animals in the combination therapy groups showed the largest reduction in tumour volume and the longest time to tumour progression. Two weeks after start of treatment, the tumour volume for these mice was reduced by about 70-75% compared with controls. Furthermore, also EBRT and TKI monotherapy resulted in a clear anti-tumour effect with a reduced tumour growth compared with controls. The results show that an increased therapeutic effect could be achieved when irradiation is combined with TKIs for treatment of MTC. Future studies should evaluate the potential of using 177Lu-octreotate therapy in combination with TKIs in patients.
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