Comparing the intra-tumoral distribution of gemcitabine, 5-fluorouracil, and capecitabine in a murine model of pancreatic ductal adenocarcinoma Journal Article

   


Authors: Fanchon, L. M.; Russell, J.; Pillarsetty, N.; O'Donoghue, I.; Gangangari, K.; Yu, K. H.; Humm, J. L.
Article Title: Comparing the intra-tumoral distribution of gemcitabine, 5-fluorouracil, and capecitabine in a murine model of pancreatic ductal adenocarcinoma
Abstract: Purpose To develop a technique to compare the intra-tumoral distribution of the drug gemcitabine, its surrogate [18F]-fluoroarabinocytosine ([18F]-FAC) and related chemotherapeutics 5-FU and capecitabine in a pre-clinical model of pancreatic ductal adenocarcinoma (PDAC). Experimental design Using a KPC-organoid derived model of PDAC, we obtained autoradiographic images of the tumor distribution of, [14C]-gemcitabine, [14C]-5-FU, [3H]-capecitabine. These were compared indirectly by co-administering [18F]-FAC, a close analog of gemcitabine with a proven equivalent intra-tumor distribution. The short half-life of 18F allows for clean separation of 3H/14C labeled drugs in specimens by dual isotope digital autoradiography. Autoradiographic images of [14C]-gemcitabine, [3H]-capecitabine and [14C]-5-FU were each correlated to [18F]-FAC on a pixel-by-pixel basis. The tumor drug penetration was compared using cumulative histograms. Results Gemcitabine distribution correlated strongly with FAC as expected. 5-FU also gave a similar microdistribution to that of FAC, whereas no correlation was found between capecitabine or its metabolic products and FAC distribution. Accumulation of Gemcitabine and 5-FU was lower in hypoxic regions of the tumor, whereas no such correlation was observed for capecitabine and its metabolites. Conclusions Gemcitabine and 5-FU target the same regions of the tumor, leaving hypoxic cells untreated. Capecitabine metabolites penetrate further into the tumor but it is yet to be determined whether these metabolites are the active form of the drug. © 2020 Public Library of Science. All rights reserved.
Keywords: controlled study; unclassified drug; fluorouracil; drug penetration; nonhuman; drug targeting; capecitabine; gemcitabine; mouse; animal tissue; image analysis; oxygen; animal experiment; animal model; correlation analysis; drug accumulation; drug distribution; pancreas adenocarcinoma; cell hypoxia; fluorine 18; tumor hypoxia; autoradiography; histogram; tritium; mouse model; carbon 14; cytosine derivative; article; organoid; 5 fluoroarabinocytosine
Journal Title: PLoS ONE
Volume: 15
Issue: 4
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2020-04-16
Start Page: e0231745
Language: English
DOI: 10.1371/journal.pone.0231745
PUBMED: 32298392
PROVIDER: scopus
PMCID: PMC7162455
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85083367789&doi=10.1371%2fjournal.pone.0231745&partnerID=40&md5=3e16b8def9741d498db8e58818f67fe8
Notes: Article -- Export Date: 1 May 2020 -- Source: Scopus
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MSK Authors
  1. Nagavarakishore Pillarsetty
    132 Pillarsetty
  2. Kenneth Ho-Ming Yu
    163 Yu
  3. John Laurence Humm
    433 Humm
  4. James Russell
    41 Russell
  5. Louise Marianne Fanchon
    14 Fanchon
  6. Kishore Kumar Gangangari
    11 Gangangari
  7. Isabella O'Donoghue
    4 O'Donoghue
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