Dataset Information

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.

SUBMITTER: Fanchon LM

PROVIDER: S-EPMC7162455 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma.

Fanchon Louise M LM Russell James J Pillarsetty Nagavarakishore N O'Donoghue Isabella I Gangangari Kishore K Yu Kenneth H KH Humm John L JL

PloS one 20200416 4

<h4>Purpose</h4>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).<h4>Experimental design</h4>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 ...[more]

PMID: 32298392

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most frequent and aggressive pancreatic tumor characterized by high metastatic risk and special tumor microenvironment. To comprehensively delineate the complex intra-tumoral heterogeneity and the underlying mechanism during metastatic lesions malignant progression, single-cell RNA sequencing (scRNA-seq) was employed. PCA and TSNE were used for dimensionality reduction analysis and cell clustering. Find All Markers function was used to calculate differential genes in each cluster, and Do Heatmap function was used to plot the distribution of differential genes in each cluster. GSVA was employed to assign pathway activity estimates to individual cells. Lineage trajectory progression was inferred by monocle. CNV status was inferred to compare the heterogeneity among patients and subtypes by infercnv. Ligand-receptor interactions were identified by CellPhoneDB, and regulons network of cells was analyzed by SCENIC. Through RNA-sequencing of 6236 individual cells from 5 liver metastatic PDAC lesions, 10 major cell clusters are identified by using unbiased clustering analysis of expression profiling and well-known cell markers. Cells with high CNV level were considered as malignant cells and pathway analyses were carried out to highlight intratumor heterogeneity in PDAC. Pseudotime trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. The complex cellular communication suggested potential immunotherapeutic targets in PDAC. Regulon network identified multiple candidates for promising cell-specific transcriptional factors. Finally, metastatic-related genes expression levels and signaling pathways were validated in bulk RNA Sequencing data. This study contributed a comprehensive single-cell transcriptome atlas and contributed into novel insight of intratumor heterogeneity and molecular mechanism in metastatic PDAC.

Project description:There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

Dataset Information

Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma.

Publications

Comparing the intra-tumoral distribution of Gemcitabine, 5-Fluorouracil, and Capecitabine in a murine model of pancreatic ductal adenocarcinoma.

Similar Datasets

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