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Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine

BACKGROUND: Hundreds of systemic chemotherapy trials in diffuse intrinsic pontine glioma (DIPG) have not improved survival, potentially due to lack of intratumoral penetration, which has not previously been assessed in humans. METHODS: We used gemcitabine as a model agent to assess DIPG intratumoral...

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Autores principales: Green, Adam L, Flannery, Patrick, Hankinson, Todd C, O’Neill, Brent, Amani, Vladimir, DeSisto, John, Knox, Aaron, Chatwin, Hannah, Lemma, Rakeb, Hoffman, Lindsey M, Mulcahy Levy, Jean, Raybin, Jennifer, Hemenway, Molly, Gilani, Ahmed, Koschmann, Carl, Dahl, Nathan, Handler, Michael, Pierce, Angela, Venkataraman, Sujatha, Foreman, Nicholas, Vibhakar, Rajeev, Wempe, Michael F, Dorris, Kathleen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212907/
https://www.ncbi.nlm.nih.gov/pubmed/32642682
http://dx.doi.org/10.1093/noajnl/vdaa021
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author Green, Adam L
Flannery, Patrick
Hankinson, Todd C
O’Neill, Brent
Amani, Vladimir
DeSisto, John
Knox, Aaron
Chatwin, Hannah
Lemma, Rakeb
Hoffman, Lindsey M
Mulcahy Levy, Jean
Raybin, Jennifer
Hemenway, Molly
Gilani, Ahmed
Koschmann, Carl
Dahl, Nathan
Handler, Michael
Pierce, Angela
Venkataraman, Sujatha
Foreman, Nicholas
Vibhakar, Rajeev
Wempe, Michael F
Dorris, Kathleen
author_facet Green, Adam L
Flannery, Patrick
Hankinson, Todd C
O’Neill, Brent
Amani, Vladimir
DeSisto, John
Knox, Aaron
Chatwin, Hannah
Lemma, Rakeb
Hoffman, Lindsey M
Mulcahy Levy, Jean
Raybin, Jennifer
Hemenway, Molly
Gilani, Ahmed
Koschmann, Carl
Dahl, Nathan
Handler, Michael
Pierce, Angela
Venkataraman, Sujatha
Foreman, Nicholas
Vibhakar, Rajeev
Wempe, Michael F
Dorris, Kathleen
author_sort Green, Adam L
collection PubMed
description BACKGROUND: Hundreds of systemic chemotherapy trials in diffuse intrinsic pontine glioma (DIPG) have not improved survival, potentially due to lack of intratumoral penetration, which has not previously been assessed in humans. METHODS: We used gemcitabine as a model agent to assess DIPG intratumoral pharmacokinetics (PK) using mass spectrometry. RESULTS: In a phase 0 clinical trial of i.v. gemcitabine prior to biopsy in children newly diagnosed with DIPG by MRI, mean concentration in 4 biopsy cores in patient 1 (H3K27M diffuse midline glioma) was 7.65 µM. These compare favorably to levels for patient 2 (mean 3.85 µM, found to have an H3K27-wildtype low-grade glioma on histology), and from a similar study in adult glioblastoma (adjusted mean 3.48 µM). In orthotopic patient-derived xenograft (PDX) models of DIPG and H3K27M-wildtype pediatric glioblastoma, gemcitabine levels and clearance were similar in tumor, pons, and cortex and did not depend on H3K27 mutation status or tumor location. Normalized gemcitabine levels were similar in patient 1 and the DIPG PDX. CONCLUSIONS: These findings, while limited to one agent, provide preliminary evidence for the hypotheses that lack of intratumoral penetration is not why systemic chemotherapy has failed in DIPG, and orthotopic PDX models can adequately model intratumoral PK in human DIPG.
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spelling pubmed-72129072020-07-07 Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine Green, Adam L Flannery, Patrick Hankinson, Todd C O’Neill, Brent Amani, Vladimir DeSisto, John Knox, Aaron Chatwin, Hannah Lemma, Rakeb Hoffman, Lindsey M Mulcahy Levy, Jean Raybin, Jennifer Hemenway, Molly Gilani, Ahmed Koschmann, Carl Dahl, Nathan Handler, Michael Pierce, Angela Venkataraman, Sujatha Foreman, Nicholas Vibhakar, Rajeev Wempe, Michael F Dorris, Kathleen Neurooncol Adv Basic and Translational Investigations BACKGROUND: Hundreds of systemic chemotherapy trials in diffuse intrinsic pontine glioma (DIPG) have not improved survival, potentially due to lack of intratumoral penetration, which has not previously been assessed in humans. METHODS: We used gemcitabine as a model agent to assess DIPG intratumoral pharmacokinetics (PK) using mass spectrometry. RESULTS: In a phase 0 clinical trial of i.v. gemcitabine prior to biopsy in children newly diagnosed with DIPG by MRI, mean concentration in 4 biopsy cores in patient 1 (H3K27M diffuse midline glioma) was 7.65 µM. These compare favorably to levels for patient 2 (mean 3.85 µM, found to have an H3K27-wildtype low-grade glioma on histology), and from a similar study in adult glioblastoma (adjusted mean 3.48 µM). In orthotopic patient-derived xenograft (PDX) models of DIPG and H3K27M-wildtype pediatric glioblastoma, gemcitabine levels and clearance were similar in tumor, pons, and cortex and did not depend on H3K27 mutation status or tumor location. Normalized gemcitabine levels were similar in patient 1 and the DIPG PDX. CONCLUSIONS: These findings, while limited to one agent, provide preliminary evidence for the hypotheses that lack of intratumoral penetration is not why systemic chemotherapy has failed in DIPG, and orthotopic PDX models can adequately model intratumoral PK in human DIPG. Oxford University Press 2020-02-24 /pmc/articles/PMC7212907/ /pubmed/32642682 http://dx.doi.org/10.1093/noajnl/vdaa021 Text en © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Basic and Translational Investigations
Green, Adam L
Flannery, Patrick
Hankinson, Todd C
O’Neill, Brent
Amani, Vladimir
DeSisto, John
Knox, Aaron
Chatwin, Hannah
Lemma, Rakeb
Hoffman, Lindsey M
Mulcahy Levy, Jean
Raybin, Jennifer
Hemenway, Molly
Gilani, Ahmed
Koschmann, Carl
Dahl, Nathan
Handler, Michael
Pierce, Angela
Venkataraman, Sujatha
Foreman, Nicholas
Vibhakar, Rajeev
Wempe, Michael F
Dorris, Kathleen
Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine
title Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine
title_full Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine
title_fullStr Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine
title_full_unstemmed Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine
title_short Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine
title_sort preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in dipg using gemcitabine
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212907/
https://www.ncbi.nlm.nih.gov/pubmed/32642682
http://dx.doi.org/10.1093/noajnl/vdaa021
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