Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer
Leflunomide (Lef) is an agent used in autoimmune disorders that interferes with DNA synthesis. pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combinat...
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| Veröffentlicht in: | International journal of biological sciences 2021-01, Vol.17 (9), p.2240-2251 |
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| creator | Phan, Thuy Nguyen, Vu H Buettner, Ralf Morales, Corey Yang, Lifeng Wong, Paul Tsai, Weiman Salazar, Marcela d'Alincourt Gil, Ziv Diamond, Don J Rabinowitz, Joshua D Rosen, Steven Melstrom, Laleh G |
| description | Leflunomide (Lef) is an agent used in autoimmune disorders that interferes with DNA synthesis.
pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combination with Gem, in a syngeneic mouse model of pancreatic cancer.
MTS proliferation assays were conducted to assess growth inhibition by Gem (0-20 nM), Lef (0-40 uM) and Gem+Lef in KPC (KrasLSL.G12D/+;p53R172H/+; PdxCretg/+) cells
. An
heterotopic KPC model was used and cohorts were treated with: PBS (control), Gem (75 mg/kg/q3d), Lef (40 mg/kg/d), or Gem+Lef. At d28 post-treatment, tumor burden, proliferation index (Ki67), and vascularity (CD31) were measured. Changes in the frequency of peripheral and intratumoral immune cell subsets were evaluated via FACS. Liquid chromatography-mass spectrometry was used for metabolomics profiling.
Lef inhibits KPC cell growth and synergizes with Gem
(P |
| doi_str_mv | 10.7150/ijbs.60473 |
| format | Article |
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pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combination with Gem, in a syngeneic mouse model of pancreatic cancer.
MTS proliferation assays were conducted to assess growth inhibition by Gem (0-20 nM), Lef (0-40 uM) and Gem+Lef in KPC (KrasLSL.G12D/+;p53R172H/+; PdxCretg/+) cells
. An
heterotopic KPC model was used and cohorts were treated with: PBS (control), Gem (75 mg/kg/q3d), Lef (40 mg/kg/d), or Gem+Lef. At d28 post-treatment, tumor burden, proliferation index (Ki67), and vascularity (CD31) were measured. Changes in the frequency of peripheral and intratumoral immune cell subsets were evaluated via FACS. Liquid chromatography-mass spectrometry was used for metabolomics profiling.
Lef inhibits KPC cell growth and synergizes with Gem
(P<0.05; Combination Index 0.44 (<1 indicates synergy).
, Lef alone and in combination with Gem delays KPC tumor progression (P<0.001). CTLA-4+T cells are also significantly decreased in tumors treated with Lef, Gem or in combination (Gem+Lef) compared to controls (P<0.05). Combination therapy also decreased the Ki67 and vascularity (P<0.01). Leflunomide inhibits
pyrimidine synthesis both
(p<0.0001) and
(p<0.05).
In this study, we demonstrated that Gem+Lef inhibits pancreatic cancer growth, decrease T cell exhaustion, vascularity and as proof of principle inhibits
pyrimidine synthesis. Further characterization of changes in adaptive immunity are necessary to characterize the mechanism of tumor growth inhibition and facilitate translation to a clinical trial.]]></description><identifier>ISSN: 1449-2288</identifier><identifier>EISSN: 1449-2288</identifier><identifier>DOI: 10.7150/ijbs.60473</identifier><identifier>PMID: 34239352</identifier><language>eng</language><publisher>Australia: Ivyspring International Publisher Pty Ltd</publisher><subject>Adaptive immunity ; Animals ; Antimetabolites, Antineoplastic - pharmacology ; Apoptosis - drug effects ; Autoimmune diseases ; Cancer ; Cancer therapies ; Cell growth ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chemotherapy ; CTLA-4 protein ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - pharmacology ; Disease ; Disease Models, Animal ; DNA biosynthesis ; Drug dosages ; Drug synergism ; Enzymes ; Female ; Flow cytometry ; Gemcitabine ; Growth inhibition ; Immune system ; Immunocompetence ; In vivo methods and tests ; Ki-67 Antigen - metabolism ; LEF protein ; Leflunomide ; Liquid chromatography ; Lymphocytes ; Lymphocytes T ; Mass spectrometry ; Mass spectroscopy ; Metabolism ; Metabolomics ; Mice ; Mice, Inbred C57BL ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - metabolism ; Pancreatic Neoplasms - pathology ; Research Paper ; Synthesis ; Tumor microenvironment ; Tumor Microenvironment - drug effects ; Tumors</subject><ispartof>International journal of biological sciences, 2021-01, Vol.17 (9), p.2240-2251</ispartof><rights>The author(s).</rights><rights>2021. This work is published under https://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The author(s) 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c406t-88f3331522d05e4b050127c7d9b5d7beac2a4401b0035d1faf124579d27ce8473</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241727/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241727/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34239352$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Phan, Thuy</creatorcontrib><creatorcontrib>Nguyen, Vu H</creatorcontrib><creatorcontrib>Buettner, Ralf</creatorcontrib><creatorcontrib>Morales, Corey</creatorcontrib><creatorcontrib>Yang, Lifeng</creatorcontrib><creatorcontrib>Wong, Paul</creatorcontrib><creatorcontrib>Tsai, Weiman</creatorcontrib><creatorcontrib>Salazar, Marcela d'Alincourt</creatorcontrib><creatorcontrib>Gil, Ziv</creatorcontrib><creatorcontrib>Diamond, Don J</creatorcontrib><creatorcontrib>Rabinowitz, Joshua D</creatorcontrib><creatorcontrib>Rosen, Steven</creatorcontrib><creatorcontrib>Melstrom, Laleh G</creatorcontrib><title>Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer</title><title>International journal of biological sciences</title><addtitle>Int J Biol Sci</addtitle><description><![CDATA[Leflunomide (Lef) is an agent used in autoimmune disorders that interferes with DNA synthesis.
pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combination with Gem, in a syngeneic mouse model of pancreatic cancer.
MTS proliferation assays were conducted to assess growth inhibition by Gem (0-20 nM), Lef (0-40 uM) and Gem+Lef in KPC (KrasLSL.G12D/+;p53R172H/+; PdxCretg/+) cells
. An
heterotopic KPC model was used and cohorts were treated with: PBS (control), Gem (75 mg/kg/q3d), Lef (40 mg/kg/d), or Gem+Lef. At d28 post-treatment, tumor burden, proliferation index (Ki67), and vascularity (CD31) were measured. Changes in the frequency of peripheral and intratumoral immune cell subsets were evaluated via FACS. Liquid chromatography-mass spectrometry was used for metabolomics profiling.
Lef inhibits KPC cell growth and synergizes with Gem
(P<0.05; Combination Index 0.44 (<1 indicates synergy).
, Lef alone and in combination with Gem delays KPC tumor progression (P<0.001). CTLA-4+T cells are also significantly decreased in tumors treated with Lef, Gem or in combination (Gem+Lef) compared to controls (P<0.05). Combination therapy also decreased the Ki67 and vascularity (P<0.01). Leflunomide inhibits
pyrimidine synthesis both
(p<0.0001) and
(p<0.05).
In this study, we demonstrated that Gem+Lef inhibits pancreatic cancer growth, decrease T cell exhaustion, vascularity and as proof of principle inhibits
pyrimidine synthesis. Further characterization of changes in adaptive immunity are necessary to characterize the mechanism of tumor growth inhibition and facilitate translation to a clinical trial.]]></description><subject>Adaptive immunity</subject><subject>Animals</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Apoptosis - drug effects</subject><subject>Autoimmune diseases</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemotherapy</subject><subject>CTLA-4 protein</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - pharmacology</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>DNA biosynthesis</subject><subject>Drug dosages</subject><subject>Drug synergism</subject><subject>Enzymes</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Gemcitabine</subject><subject>Growth inhibition</subject><subject>Immune system</subject><subject>Immunocompetence</subject><subject>In vivo methods and tests</subject><subject>Ki-67 Antigen - metabolism</subject><subject>LEF protein</subject><subject>Leflunomide</subject><subject>Liquid chromatography</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Metabolism</subject><subject>Metabolomics</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Research Paper</subject><subject>Synthesis</subject><subject>Tumor microenvironment</subject><subject>Tumor Microenvironment - drug effects</subject><subject>Tumors</subject><issn>1449-2288</issn><issn>1449-2288</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNpdkd9qFDEUxoNYbK3e-AAS8KYIW_N3J3MjSNFaKPSmXodMcmY3yyQZk5mWfQWfupm2LtWb5ITzy5fv5EPoAyXnDZXki9915XxNRMNfoRMqRLtiTKnXL-pj9LaUHSF8LRV5g465YLzlkp2gP1dx6zs_-RRx6rEDHNNdwuM---Cdj4DLPk5bKL5gM28CxKngSwjWT6Zb2j662YLDm5zup209HuR8xKauIcwx2RRGmOplHJKDYXlqNNFmMJO32NYS8jt01JuhwPvn_RT9-vH99uLn6vrm8uri2_XKCrKeVkr1nHMqGXNEguiIJJQ1tnFtJ13TgbHMCEFoV8eVjvamp0zIpnUVAlU_6RR9fdId5y6As9VVNoMe68Qm73UyXv_biX6rN-lOKyZowxaBs2eBnH7PUCYdfLEwDCZCmotmUhK2Zo2kFf30H7pLc451vEq1iislpKjU5yfK5lRKhv5ghhK9RKyXiPVjxBX--NL-Af2bKX8Ax4ilfw</recordid><startdate>20210101</startdate><enddate>20210101</enddate><creator>Phan, Thuy</creator><creator>Nguyen, Vu H</creator><creator>Buettner, Ralf</creator><creator>Morales, Corey</creator><creator>Yang, Lifeng</creator><creator>Wong, Paul</creator><creator>Tsai, Weiman</creator><creator>Salazar, Marcela d'Alincourt</creator><creator>Gil, Ziv</creator><creator>Diamond, Don J</creator><creator>Rabinowitz, Joshua D</creator><creator>Rosen, Steven</creator><creator>Melstrom, Laleh G</creator><general>Ivyspring International Publisher Pty Ltd</general><general>Ivyspring International Publisher</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7U9</scope><scope>8FD</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20210101</creationdate><title>Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer</title><author>Phan, Thuy ; Nguyen, Vu H ; Buettner, Ralf ; Morales, Corey ; Yang, Lifeng ; Wong, Paul ; Tsai, Weiman ; Salazar, Marcela d'Alincourt ; Gil, Ziv ; Diamond, Don J ; Rabinowitz, Joshua D ; Rosen, Steven ; Melstrom, Laleh G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-88f3331522d05e4b050127c7d9b5d7beac2a4401b0035d1faf124579d27ce8473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adaptive immunity</topic><topic>Animals</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Apoptosis - drug effects</topic><topic>Autoimmune diseases</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Chemotherapy</topic><topic>CTLA-4 protein</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Deoxycytidine - pharmacology</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>DNA biosynthesis</topic><topic>Drug dosages</topic><topic>Drug synergism</topic><topic>Enzymes</topic><topic>Female</topic><topic>Flow cytometry</topic><topic>Gemcitabine</topic><topic>Growth inhibition</topic><topic>Immune system</topic><topic>Immunocompetence</topic><topic>In vivo methods and tests</topic><topic>Ki-67 Antigen - metabolism</topic><topic>LEF protein</topic><topic>Leflunomide</topic><topic>Liquid chromatography</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Mass spectrometry</topic><topic>Mass spectroscopy</topic><topic>Metabolism</topic><topic>Metabolomics</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Research Paper</topic><topic>Synthesis</topic><topic>Tumor microenvironment</topic><topic>Tumor Microenvironment - drug effects</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Phan, Thuy</creatorcontrib><creatorcontrib>Nguyen, Vu H</creatorcontrib><creatorcontrib>Buettner, Ralf</creatorcontrib><creatorcontrib>Morales, Corey</creatorcontrib><creatorcontrib>Yang, Lifeng</creatorcontrib><creatorcontrib>Wong, Paul</creatorcontrib><creatorcontrib>Tsai, Weiman</creatorcontrib><creatorcontrib>Salazar, Marcela d'Alincourt</creatorcontrib><creatorcontrib>Gil, Ziv</creatorcontrib><creatorcontrib>Diamond, Don J</creatorcontrib><creatorcontrib>Rabinowitz, Joshua D</creatorcontrib><creatorcontrib>Rosen, Steven</creatorcontrib><creatorcontrib>Melstrom, Laleh G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of biological sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Phan, Thuy</au><au>Nguyen, Vu H</au><au>Buettner, Ralf</au><au>Morales, Corey</au><au>Yang, Lifeng</au><au>Wong, Paul</au><au>Tsai, Weiman</au><au>Salazar, Marcela d'Alincourt</au><au>Gil, Ziv</au><au>Diamond, Don J</au><au>Rabinowitz, Joshua D</au><au>Rosen, Steven</au><au>Melstrom, Laleh G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer</atitle><jtitle>International journal of biological sciences</jtitle><addtitle>Int J Biol Sci</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>17</volume><issue>9</issue><spage>2240</spage><epage>2251</epage><pages>2240-2251</pages><issn>1449-2288</issn><eissn>1449-2288</eissn><abstract><![CDATA[Leflunomide (Lef) is an agent used in autoimmune disorders that interferes with DNA synthesis.
pyrimidine synthesis is a mechanism of Gemcitabine (Gem) resistance in pancreatic cancer. This study aims to assess the efficacy and changes in the tumor microenvironment of Lef monotherapy and in combination with Gem, in a syngeneic mouse model of pancreatic cancer.
MTS proliferation assays were conducted to assess growth inhibition by Gem (0-20 nM), Lef (0-40 uM) and Gem+Lef in KPC (KrasLSL.G12D/+;p53R172H/+; PdxCretg/+) cells
. An
heterotopic KPC model was used and cohorts were treated with: PBS (control), Gem (75 mg/kg/q3d), Lef (40 mg/kg/d), or Gem+Lef. At d28 post-treatment, tumor burden, proliferation index (Ki67), and vascularity (CD31) were measured. Changes in the frequency of peripheral and intratumoral immune cell subsets were evaluated via FACS. Liquid chromatography-mass spectrometry was used for metabolomics profiling.
Lef inhibits KPC cell growth and synergizes with Gem
(P<0.05; Combination Index 0.44 (<1 indicates synergy).
, Lef alone and in combination with Gem delays KPC tumor progression (P<0.001). CTLA-4+T cells are also significantly decreased in tumors treated with Lef, Gem or in combination (Gem+Lef) compared to controls (P<0.05). Combination therapy also decreased the Ki67 and vascularity (P<0.01). Leflunomide inhibits
pyrimidine synthesis both
(p<0.0001) and
(p<0.05).
In this study, we demonstrated that Gem+Lef inhibits pancreatic cancer growth, decrease T cell exhaustion, vascularity and as proof of principle inhibits
pyrimidine synthesis. Further characterization of changes in adaptive immunity are necessary to characterize the mechanism of tumor growth inhibition and facilitate translation to a clinical trial.]]></abstract><cop>Australia</cop><pub>Ivyspring International Publisher Pty Ltd</pub><pmid>34239352</pmid><doi>10.7150/ijbs.60473</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; PubMed Central Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Adaptive immunity Animals Antimetabolites, Antineoplastic - pharmacology Apoptosis - drug effects Autoimmune diseases Cancer Cancer therapies Cell growth Cell Line, Tumor Cell Proliferation - drug effects Chemotherapy CTLA-4 protein Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology Disease Disease Models, Animal DNA biosynthesis Drug dosages Drug synergism Enzymes Female Flow cytometry Gemcitabine Growth inhibition Immune system Immunocompetence In vivo methods and tests Ki-67 Antigen - metabolism LEF protein Leflunomide Liquid chromatography Lymphocytes Lymphocytes T Mass spectrometry Mass spectroscopy Metabolism Metabolomics Mice Mice, Inbred C57BL Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Research Paper Synthesis Tumor microenvironment Tumor Microenvironment - drug effects Tumors |
| title | Inhibition of de novo pyrimidine synthesis augments Gemcitabine induced growth inhibition in an immunocompetent model of pancreatic cancer |
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