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Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor

Previously published digital autoradiography of (3)H‐labeled capecitabine reveals a near‐uniform distribution of activity throughout a murine pancreatic model. This is in contrast both to (14)C‐labeled gemcitabine, and established expectations, as the dense stroma of pancreatic cancer is understood...

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Autores principales: Russell, James, Fanchon, Louise, Alwaseem, Hanan, Molina, Henrik, O’Donoghue, Isabella, Bahr, Amber, de Stanchina, Elisa, Pillarsetty, Nagavarakishore, Humm, John L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902142/
https://www.ncbi.nlm.nih.gov/pubmed/35257504
http://dx.doi.org/10.1002/prp2.898
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author Russell, James
Fanchon, Louise
Alwaseem, Hanan
Molina, Henrik
O’Donoghue, Isabella
Bahr, Amber
de Stanchina, Elisa
Pillarsetty, Nagavarakishore
Humm, John L.
author_facet Russell, James
Fanchon, Louise
Alwaseem, Hanan
Molina, Henrik
O’Donoghue, Isabella
Bahr, Amber
de Stanchina, Elisa
Pillarsetty, Nagavarakishore
Humm, John L.
author_sort Russell, James
collection PubMed
description Previously published digital autoradiography of (3)H‐labeled capecitabine reveals a near‐uniform distribution of activity throughout a murine pancreatic model. This is in contrast both to (14)C‐labeled gemcitabine, and established expectations, as the dense stroma of pancreatic cancer is understood to inhibit drug penetration. Capecitabine is a pro‐drug for 5 FU. The positioning of the radiolabel on capecitabine leaves open the possibility that much of the autoradiographic signal is generated by nontoxic compounds. Studies were performed on tumors derived via organoid culture from a murine KPC tumor. As before, we performed autoradiography comparing (3)H capecitabine to the gemcitabine analog (18)F‐FAC. The metabolism of capecitabine in this model was studied through LC–MS of tumor tissue. The autoradiographs confirmed that the (3)H label from capecitabine was much more uniformly distributed through the tumor than the (18)F from the gemcitabine analog. LC–MS revealed that approximately 75% of the molar mass of capecitabine had been converted into 5 FU or pre‐5 FU compounds. The remainder had been converted into nontoxic species. Therapeutically relevant capecitabine metabolites achieve a relatively even distribution in this pancreatic cancer model, in contrast to the gemcitabine analog (18)F‐FAC. In a human xenograft model, (BxPC3), the (3)H label from capecitabine was also uniformly spread across the tumor autoradiographs. However, at 2 h post‐administration the metabolism of capecitabine had proceeded further and the bulk of the agent was in the form of nontoxic species.
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spelling pubmed-89021422022-03-11 Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor Russell, James Fanchon, Louise Alwaseem, Hanan Molina, Henrik O’Donoghue, Isabella Bahr, Amber de Stanchina, Elisa Pillarsetty, Nagavarakishore Humm, John L. Pharmacol Res Perspect Original Articles Previously published digital autoradiography of (3)H‐labeled capecitabine reveals a near‐uniform distribution of activity throughout a murine pancreatic model. This is in contrast both to (14)C‐labeled gemcitabine, and established expectations, as the dense stroma of pancreatic cancer is understood to inhibit drug penetration. Capecitabine is a pro‐drug for 5 FU. The positioning of the radiolabel on capecitabine leaves open the possibility that much of the autoradiographic signal is generated by nontoxic compounds. Studies were performed on tumors derived via organoid culture from a murine KPC tumor. As before, we performed autoradiography comparing (3)H capecitabine to the gemcitabine analog (18)F‐FAC. The metabolism of capecitabine in this model was studied through LC–MS of tumor tissue. The autoradiographs confirmed that the (3)H label from capecitabine was much more uniformly distributed through the tumor than the (18)F from the gemcitabine analog. LC–MS revealed that approximately 75% of the molar mass of capecitabine had been converted into 5 FU or pre‐5 FU compounds. The remainder had been converted into nontoxic species. Therapeutically relevant capecitabine metabolites achieve a relatively even distribution in this pancreatic cancer model, in contrast to the gemcitabine analog (18)F‐FAC. In a human xenograft model, (BxPC3), the (3)H label from capecitabine was also uniformly spread across the tumor autoradiographs. However, at 2 h post‐administration the metabolism of capecitabine had proceeded further and the bulk of the agent was in the form of nontoxic species. John Wiley and Sons Inc. 2022-03-07 /pmc/articles/PMC8902142/ /pubmed/35257504 http://dx.doi.org/10.1002/prp2.898 Text en © 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Russell, James
Fanchon, Louise
Alwaseem, Hanan
Molina, Henrik
O’Donoghue, Isabella
Bahr, Amber
de Stanchina, Elisa
Pillarsetty, Nagavarakishore
Humm, John L.
Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor
title Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor
title_full Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor
title_fullStr Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor
title_full_unstemmed Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor
title_short Analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor
title_sort analysis of capecitabine metabolites in conjunction with digital autoradiography in a murine model of pancreatic cancer suggests extensive drug penetration through the tumor
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8902142/
https://www.ncbi.nlm.nih.gov/pubmed/35257504
http://dx.doi.org/10.1002/prp2.898
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