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dc.contributor.authorStrittmatter, Nicole
dc.contributor.authorRichards, Frances M
dc.contributor.authorRace, Alan M
dc.contributor.authorLing, Stephanie
dc.contributor.authorSutton, Daniel
dc.contributor.authorNilsson, Anna
dc.contributor.authorWallez, Yann
dc.contributor.authorBarnes, Jennifer
dc.contributor.authorMaglennon, Gareth
dc.contributor.authorGopinathan, Aarthi
dc.contributor.authorBrais, Rebecca
dc.contributor.authorWong, Edmond
dc.contributor.authorSerra, Maria Paola
dc.contributor.authorAtkinson, James
dc.contributor.authorSmith, Aaron
dc.contributor.authorWilson, Joanne
dc.contributor.authorHamm, Gregory
dc.contributor.authorJohnson, Timothy I
dc.contributor.authorDunlop, Charles R
dc.contributor.authorKaistha, Brajesh P
dc.contributor.authorBunch, Josephine
dc.contributor.authorSansom, Owen J
dc.contributor.authorTakats, Zoltan
dc.contributor.authorAndrén, Per E
dc.contributor.authorLau, Alan
dc.contributor.authorBarry, Simon T
dc.contributor.authorGoodwin, Richard JA
dc.contributor.authorJodrell, Duncan
dc.date.accessioned2021-12-24T00:31:10Z
dc.date.available2021-12-24T00:31:10Z
dc.date.issued2022-01-25
dc.identifier.issn0003-2700
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331767
dc.description.abstractGemcitabine (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.
dc.publisherAmerican Chemical Society (ACS)
dc.rightsAll Rights Reserved
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserved
dc.titleMethod To Visualize the Intratumor Distribution and Impact of Gemcitabine in Pancreatic Ductal Adenocarcinoma by Multimodal Imaging.
dc.typeArticle
dc.publisher.departmentDepartment of Oncology
dc.date.updated2021-12-22T12:01:46Z
prism.publicationNameAnal Chem
dc.identifier.doi10.17863/CAM.79216
dcterms.dateAccepted2021-12-16
rioxxterms.versionofrecord10.1021/acs.analchem.1c04579
rioxxterms.versionAM
dc.contributor.orcidStrittmatter, Nicole [0000-0003-1277-9608]
dc.contributor.orcidRace, Alan M [0000-0001-8996-2641]
dc.contributor.orcidLing, Stephanie [0000-0002-1237-091X]
dc.contributor.orcidTakats, Zoltan [0000-0002-0795-3467]
dc.contributor.orcidAndrén, Per E [0000-0002-4062-7743]
dc.contributor.orcidJodrell, Duncan [0000-0001-9360-1670]
dc.identifier.eissn1520-6882
rioxxterms.typeJournal Article/Review
pubs.funder-project-idCancer Research UK (CB4270)
pubs.funder-project-idPancreatic Cancer UK (FutureLeaders)
pubs.funder-project-idCancer Research UK (15678)
pubs.funder-project-idPancreatic Cancer UK (FLF2015_03_Cambridge)
cam.issuedOnline2022-01-10
cam.orpheus.successTue Feb 01 19:02:34 GMT 2022 - Embargo updated*
cam.depositDate2021-12-22
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement
rioxxterms.freetoread.startdate2023-01-10


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