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The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo

Background: To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [(111)In]In-DOTA...

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Autores principales: Klomp, Maria J., Hofland, Leo J., van den Brink, Lilian, van Koetsveld, Peter M., Dogan, Fadime, de Ridder, Corrina M. A., Stuurman, Debra C., Clahsen-van Groningen, Marian C., de Jong, Marion, Dalm, Simone U.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779846/
https://www.ncbi.nlm.nih.gov/pubmed/35057069
http://dx.doi.org/10.3390/pharmaceutics14010173
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author Klomp, Maria J.
Hofland, Leo J.
van den Brink, Lilian
van Koetsveld, Peter M.
Dogan, Fadime
de Ridder, Corrina M. A.
Stuurman, Debra C.
Clahsen-van Groningen, Marian C.
de Jong, Marion
Dalm, Simone U.
author_facet Klomp, Maria J.
Hofland, Leo J.
van den Brink, Lilian
van Koetsveld, Peter M.
Dogan, Fadime
de Ridder, Corrina M. A.
Stuurman, Debra C.
Clahsen-van Groningen, Marian C.
de Jong, Marion
Dalm, Simone U.
author_sort Klomp, Maria J.
collection PubMed
description Background: To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [(111)In]In-DOTATATE uptake studies, RT-qPCR and immunohistochemistry analysis. Furthermore, NCI-H69 xenografted mice were treated with VPA or vehicle, followed by [(177)Lu]Lu-DOTATATE injection. Biodistribution studies were performed, and tissues were collected for further analysis. Results: VPA significantly increased SSTR2 expression in vitro. In animals, a statistically significant increased [(177)Lu]Lu-DOTATATE tumoral uptake was observed when VPA was administered eight hours before [(177)Lu]Lu-DOTATATE administration, but increased tumor SSTR2 expression levels were lacking. The animals also presented significantly higher [(177)Lu]Lu-DOTATATE blood levels, as well as an elevated renal tubular damage score. This suggests that the enhanced tumor uptake was presumably a consequence of the increased radiotracer circulation and the induced kidney damage. Conclusions: VPA increases SSTR2 expression in vitro. In vivo, the observed increase in tumoral [(177)Lu]Lu-DOTATATE uptake is not caused by SSTR2 upregulation, but rather by other mechanisms, e.g., an increased [(177)Lu]Lu-DOTATATE circulation time and renal toxicity. However, since both drugs are safely used in humans, the potential of VPA to improve PRRT remains open for investigation.
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spelling pubmed-87798462022-01-22 The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo Klomp, Maria J. Hofland, Leo J. van den Brink, Lilian van Koetsveld, Peter M. Dogan, Fadime de Ridder, Corrina M. A. Stuurman, Debra C. Clahsen-van Groningen, Marian C. de Jong, Marion Dalm, Simone U. Pharmaceutics Article Background: To improve peptide receptor radionuclide therapy (PRRT), we aimed to enhance the expression of somatostatin type-2 receptors (SSTR2) in vitro and in vivo, using valproic acid (VPA). Methods: Human NCI-H69 small-cell lung carcinoma cells were treated with VPA, followed by [(111)In]In-DOTATATE uptake studies, RT-qPCR and immunohistochemistry analysis. Furthermore, NCI-H69 xenografted mice were treated with VPA or vehicle, followed by [(177)Lu]Lu-DOTATATE injection. Biodistribution studies were performed, and tissues were collected for further analysis. Results: VPA significantly increased SSTR2 expression in vitro. In animals, a statistically significant increased [(177)Lu]Lu-DOTATATE tumoral uptake was observed when VPA was administered eight hours before [(177)Lu]Lu-DOTATATE administration, but increased tumor SSTR2 expression levels were lacking. The animals also presented significantly higher [(177)Lu]Lu-DOTATATE blood levels, as well as an elevated renal tubular damage score. This suggests that the enhanced tumor uptake was presumably a consequence of the increased radiotracer circulation and the induced kidney damage. Conclusions: VPA increases SSTR2 expression in vitro. In vivo, the observed increase in tumoral [(177)Lu]Lu-DOTATATE uptake is not caused by SSTR2 upregulation, but rather by other mechanisms, e.g., an increased [(177)Lu]Lu-DOTATATE circulation time and renal toxicity. However, since both drugs are safely used in humans, the potential of VPA to improve PRRT remains open for investigation. MDPI 2022-01-12 /pmc/articles/PMC8779846/ /pubmed/35057069 http://dx.doi.org/10.3390/pharmaceutics14010173 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Klomp, Maria J.
Hofland, Leo J.
van den Brink, Lilian
van Koetsveld, Peter M.
Dogan, Fadime
de Ridder, Corrina M. A.
Stuurman, Debra C.
Clahsen-van Groningen, Marian C.
de Jong, Marion
Dalm, Simone U.
The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo
title The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo
title_full The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo
title_fullStr The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo
title_full_unstemmed The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo
title_short The Effect of VPA Treatment on Radiolabeled DOTATATE Uptake: Differences Observed In Vitro and In Vivo
title_sort effect of vpa treatment on radiolabeled dotatate uptake: differences observed in vitro and in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779846/
https://www.ncbi.nlm.nih.gov/pubmed/35057069
http://dx.doi.org/10.3390/pharmaceutics14010173
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