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Trastuzumab cotreat...
Trastuzumab cotreatment improves survival of mice with PC-3 prostate cancer xenografts treated with the GRPR antagonist 177Lu-DOTAGA-PEG2-RM26
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- Mitran, Bogdan (författare)
- Uppsala universitet,Theranostics
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- Rinne, Sara S. (författare)
- Uppsala universitet,Theranostics
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- Konijnenberg, Mark W. (författare)
- Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands
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- Maina, Theodosia (författare)
- NCSR Demokritos, INRASTES, Mol Radiopharm, Athens, Greece
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- Nock, Berthold A. (författare)
- NCSR Demokritos, INRASTES, Mol Radiopharm, Athens, Greece
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- Altai, Mohamed (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Vorobyeva, Anzhelika (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Larhed, Mats (författare)
- Uppsala universitet,Preparativ läkemedelskemi,Theranostics,Science for Life Laboratory, SciLifeLab
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- Tolmachev, Vladimir (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- de Jong, Marion (författare)
- Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands
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- Rosenström, Ulrika (författare)
- Uppsala universitet,Preparativ läkemedelskemi
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- Orlova, Anna, 1960- (författare)
- Uppsala universitet,Theranostics,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2019-05-23
- 2019
- Engelska.
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:12, s. 3347-3358
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Gastrin-releasing peptide receptors (GRPRs) are overexpressed in prostate cancer and are suitable for targeted radionuclidetherapy (TRT). We optimized the bombesin-derived GRPR-antagonist PEG2-RM26 for labeling with 177Lu and further determinedthe effect of treatment with 177Lu-labeled peptide alone or in combination with the anti-HER2 antibody trastuzumab in amurine model. The PEG2-RM26 analog was coupled to NOTA, NODAGA, DOTA and DOTAGA chelators. The peptide-chelatorconjugates were labeled with 177Lu and characterized in vitro and in vivo. A preclinical therapeutic study was performed in PC-3xenografted mice. Mice were treated with intravenous injections (6 cycles) of (A) PBS, (B) DOTAGA-PEG2-RM26, (C) 177LuDOTAGA-PEG2-RM26, (D) trastuzumab or (E) 177Lu-DOTAGA-PEG2-RM26 in combination with trastuzumab. 177Lu-DOTAGA-PEG2-RM26 demonstrated quantitative labeling yield at high molar activity (450 GBq/μmol), high in vivo stability (5 min pi >98% ofradioligand remained when coinjected with phosphoramidon), high affinity to GRPR (KD = 0.4 0.2 nM), and favorablebiodistribution (1 hr pi tumor uptake was higher than in healthy tissues, including the kidneys). Therapy with 177Lu-DOTAGAPEG2-RM26 induced a significant inhibition of tumor growth. The median survival for control groups was significantly shorterthan for treated groups (Group C 66 days, Group E 74 days). Trastuzumab together with radionuclide therapy significantlyimproved survival. No treatment-related toxicity was observed. In conclusion, based on in vitro and in vivo characterization ofthe four 177Lu-labeled PEG2-RM26 analogs, we concluded that 177Lu-DOTAGA-PEG2-RM26 was the most promising analog forTRT. Radiotherapy using 177Lu-DOTAGA-PEG2-RM26 effectively inhibited tumor growth in vivo in a murine prostate cancermodel. Anti-HER2 therapy additionally improved survival.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- radionuclide therapy
- GRPR
- HER2
- prostate cancer
- lutetium-177
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Mitran, Bogdan
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Rinne, Sara S.
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Konijnenberg, Ma ...
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Maina, Theodosia
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Nock, Berthold A ...
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Altai, Mohamed
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visa fler...
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Vorobyeva, Anzhe ...
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Larhed, Mats
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Tolmachev, Vladi ...
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de Jong, Marion
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Rosenström, Ulri ...
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Orlova, Anna, 19 ...
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Uppsala universitet