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Sökning: onr:"swepub:oai:DiVA.org:uu-473560" > Method To Visualize...

  • Strittmatter, NicoleAstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England (författare)

Method To Visualize the Intratumor Distribution and Impact of Gemcitabine in Pancreatic Ductal Adenocarcinoma by Multimodal Imaging

  • Artikel/kapitelEngelska2022

Förlag, utgivningsår, omfång ...

  • 2022-01-10
  • American Chemical Society (ACS),2022
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-473560
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-473560URI
  • https://doi.org/10.1021/acs.analchem.1c04579DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; therefore, visualizing the distribution of parent drug as well as its metabolites is important. A multimodal imaging approach was developed using spatially coregistered mass spectrometry imaging (MSI), imaging mass cytometry (IMC), multiplex immunofluorescence microscopy (mIF), and hematoxylin and eosin (H&E) staining to assess the local distribution and metabolism of gemcitabine in tumors from a genetically engineered mouse model of pancreatic cancer (KPC) allowing for comparisons between effects in the tumor tissue and its microenvironment. Mass spectrometry imaging (MSI) enabled the visualization of the distribution of gemcitabine (100 mg/kg), its phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP, and the inactive metabolite dFdU. Distribution was compared to small-molecule ATR inhibitor AZD6738 (25 mg/kg), which was codosed. Gemcitabine metabolites showed heterogeneous distribution within the tumor, which was different from the parent compound. The highest abundance of dFdCMP, dFdCDP, and dFdCTP correlated with distribution of endogenous AMP, ADP, and ATP in viable tumor cell regions, showing that gemcitabine active metabolites are reaching the tumor cell compartment, while AZD6738 was located to nonviable tumor regions. The method revealed that the generation of active, phosphorylated dFdC metabolites as well as treatment-induced DNA damage primarily correlated with sites of high proliferation in KPC PDAC tumor tissue, rather than sites of high parent drug abundance.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Richards, Frances M.Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England.;Astra Zeneca, Oncol R&D, Translat Med, Cambridge CB4 0WG, England (författare)
  • Race, Alan M.Philipps Univ Marburg, Inst Med Bioinformat & Biostat, D-35032 Marburg, Germany (författare)
  • Ling, StephanieAstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England (författare)
  • Sutton, DanielAstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England (författare)
  • Nilsson, AnnaUppsala universitet,Institutionen för farmaceutisk biovetenskap,Science for Life Laboratory, SciLifeLab(Swepub:uu)annil134 (författare)
  • Wallez, YannUniv Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England.;AstraZeneca, Oncol R&D, Biosci, Cambridge CB2 0RE, England (författare)
  • Barnes, JenniferAstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England (författare)
  • Maglennon, GarethAstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England (författare)
  • Gopinathan, AarthiUniv Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England (författare)
  • Brais, RebeccaCambridge Univ Hosp NHS Trust, Cambridge CB2 0QQ, England (författare)
  • Wong, EdmondAstraZeneca, R&D, Biol Engn, Cambridge CB12 6GH, England (författare)
  • Serra, Maria PaolaAstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England (författare)
  • Atkinson, JamesAstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England (författare)
  • Smith, AaronAstraZeneca, Oncol R&D, DMPK, Cambridge CB2 0RE, England (författare)
  • Wilson, JoanneAstraZeneca, Oncol R&D, DMPK, Cambridge CB2 0RE, England (författare)
  • Hamm, GregoryAstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England (författare)
  • Johnson, Timothy, IUniv Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England (författare)
  • Dunlop, Charles R.Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England (författare)
  • Kaistha, Brajesh P.Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England.;AstraZeneca, Early Oncol, Clin IO Grp, Cambridge CBI2 6GH, England (författare)
  • Bunch, JosephineNatl Phys Lab, Natl Ctr Excellence Mass Spectrometry Imaging, Teddington TW11 0LW, Middx, England.;Rosalind Franklin Inst, Didcot OX11 0QS, Oxon, England (författare)
  • Sansom, Owen J.Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland.;Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland (författare)
  • Takats, ZoltanRosalind Franklin Inst, Didcot OX11 0QS, Oxon, England.;Imperial Coll London, Dept Metab Digest & Reprod, London SW7 2AZ, England (författare)
  • Andrén, Per E.,Professor,1957-Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Science for Life Laboratory, SciLifeLab(Swepub:uu)perandre (författare)
  • Lau, AlanAstraZeneca, Oncol R&D, Biosci, Cambridge CB2 0RE, England (författare)
  • Barry, Simon T.AstraZeneca, Oncol R&D, Biosci, Cambridge CB2 0RE, England (författare)
  • Goodwin, Richard J. A.AstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, England.;Univ Glasgow, Inst Infect Immun & Inflammat, Glasgow G12 8TA, Lanark, Scotland (författare)
  • Jodrell, Duncan, IUniv Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England.;Univ Cambridge, Dept Oncol, Cambridge CB2 0XZ, England (författare)
  • AstraZeneca, R&D, Clin Pharmacol & Safety Sci, Imaging & Data Analyt, Cambridge CB4 0WG, EnglandUniv Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England.;Astra Zeneca, Oncol R&D, Translat Med, Cambridge CB4 0WG, England (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Analytical Chemistry: American Chemical Society (ACS)94:3, s. 1795-18030003-27001520-6882

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