Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo
Background: The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS G12D ; p53 R172H ; pdx-Cre (KPC) tha...
Gespeichert in:
| Veröffentlicht in: | British journal of cancer 2014-07, Vol.111 (2), p.318-325 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 325 |
|---|---|
| container_issue | 2 |
| container_start_page | 318 |
| container_title | British journal of cancer |
| container_volume | 111 |
| creator | Bapiro, T E Frese, K K Courtin, A Bramhall, J L Madhu, B Cook, N Neesse, A Griffiths, J R Tuveson, D A Jodrell, D I Richards, F M |
| description | Background:
The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS
G12D
; p53
R172H
; pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism.
Methods:
LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay.
Results:
In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates
in vitro
, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells
in vitro
, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition.
Conclusions:
GdPC is an important element of the intra-tumoural dFdC metabolic pathway
in vivo
. |
| doi_str_mv | 10.1038/bjc.2014.288 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4102943</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3373650551</sourcerecordid><originalsourceid>FETCH-LOGICAL-c616t-90a48a01c20d29389a1aece0200083b32ad84e88358edcb26fa5e78dbc2242a53</originalsourceid><addsrcrecordid>eNptkU2P0zAQhi0EYsvCjTOyhLiRYjtO41yQ0AoWxEpc4GxNnOnGJYmD7XbVf89ELcsicfJ43sfz4Zexl1KspSjNu3bn1kpIvVbGPGIrWZWqkEbVj9lKCFEXolHigj1LaUfXRpj6KbtQ2tRaG71id9c4Op-h9RPyzs99SHMPGbnrw7DkfOLAR9iFyEckjrKkkvQTO54Dzz3yrzhN2B35DLm_gyP3E4WTiwjZO-4oRHodOhzSoh38ITxnT7YwJHxxPi_Zj08fv199Lm6-XX-5-nBTuI3c5KIRoA0I6ZToVFOaBiSgQ6FoF1O2pYLOaDSmrAx2rlWbLVRYm651SmkFVXnJ3p_qzvt2JASnHGGwc_QjxKMN4O2_yuR7exsOVkuhGl1SgdfnAjH82mPKdhf2caKZrax0pUSzaRbq7YlyMaQUcXvfQQq72GTJJrvYZMkmwl89nOoe_uMLAW_OACQHwzbSH_r0lzO1kEIufYsTl0iabjE-mO5_jX8D25Cr4w</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1545209693</pqid></control><display><type>article</type><title>Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo</title><source>MEDLINE</source><source>Nature</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Bapiro, T E ; Frese, K K ; Courtin, A ; Bramhall, J L ; Madhu, B ; Cook, N ; Neesse, A ; Griffiths, J R ; Tuveson, D A ; Jodrell, D I ; Richards, F M</creator><creatorcontrib>Bapiro, T E ; Frese, K K ; Courtin, A ; Bramhall, J L ; Madhu, B ; Cook, N ; Neesse, A ; Griffiths, J R ; Tuveson, D A ; Jodrell, D I ; Richards, F M</creatorcontrib><description>Background:
The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS
G12D
; p53
R172H
; pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism.
Methods:
LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay.
Results:
In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates
in vitro
, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells
in vitro
, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition.
Conclusions:
GdPC is an important element of the intra-tumoural dFdC metabolic pathway
in vivo
.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/bjc.2014.288</identifier><identifier>PMID: 24874484</identifier><identifier>CODEN: BJCAAI</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/154/436 ; 631/67/1504/1713 ; 631/67/2327 ; Animals ; Antimetabolites, Antineoplastic - pharmacokinetics ; Antimetabolites, Antineoplastic - pharmacology ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - metabolism ; Choline - metabolism ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - metabolism ; Deoxycytidine - pharmacokinetics ; Deoxycytidine - pharmacology ; Diphosphates - metabolism ; Drug Resistance ; Epidemiology ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Gemcitabine ; Humans ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Medicine ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Oncology ; Pancreatic cancer ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - metabolism ; Translational Therapeutics ; Tumor Cells, Cultured ; Tumors</subject><ispartof>British journal of cancer, 2014-07, Vol.111 (2), p.318-325</ispartof><rights>The Author(s) 2014</rights><rights>2015 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Jul 15, 2014</rights><rights>Copyright © 2014 Cancer Research UK 2014 Cancer Research UK</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c616t-90a48a01c20d29389a1aece0200083b32ad84e88358edcb26fa5e78dbc2242a53</citedby><cites>FETCH-LOGICAL-c616t-90a48a01c20d29389a1aece0200083b32ad84e88358edcb26fa5e78dbc2242a53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102943/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102943/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28701013$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24874484$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bapiro, T E</creatorcontrib><creatorcontrib>Frese, K K</creatorcontrib><creatorcontrib>Courtin, A</creatorcontrib><creatorcontrib>Bramhall, J L</creatorcontrib><creatorcontrib>Madhu, B</creatorcontrib><creatorcontrib>Cook, N</creatorcontrib><creatorcontrib>Neesse, A</creatorcontrib><creatorcontrib>Griffiths, J R</creatorcontrib><creatorcontrib>Tuveson, D A</creatorcontrib><creatorcontrib>Jodrell, D I</creatorcontrib><creatorcontrib>Richards, F M</creatorcontrib><title>Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Background:
The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS
G12D
; p53
R172H
; pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism.
Methods:
LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay.
Results:
In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates
in vitro
, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells
in vitro
, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition.
Conclusions:
GdPC is an important element of the intra-tumoural dFdC metabolic pathway
in vivo
.</description><subject>631/154/436</subject><subject>631/67/1504/1713</subject><subject>631/67/2327</subject><subject>Animals</subject><subject>Antimetabolites, Antineoplastic - pharmacokinetics</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Carcinoma, Pancreatic Ductal - drug therapy</subject><subject>Carcinoma, Pancreatic Ductal - metabolism</subject><subject>Choline - metabolism</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - metabolism</subject><subject>Deoxycytidine - pharmacokinetics</subject><subject>Deoxycytidine - pharmacology</subject><subject>Diphosphates - metabolism</subject><subject>Drug Resistance</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gemcitabine</subject><subject>Humans</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Molecular Medicine</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Oncology</subject><subject>Pancreatic cancer</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - metabolism</subject><subject>Translational Therapeutics</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0007-0920</issn><issn>1532-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptkU2P0zAQhi0EYsvCjTOyhLiRYjtO41yQ0AoWxEpc4GxNnOnGJYmD7XbVf89ELcsicfJ43sfz4Zexl1KspSjNu3bn1kpIvVbGPGIrWZWqkEbVj9lKCFEXolHigj1LaUfXRpj6KbtQ2tRaG71id9c4Op-h9RPyzs99SHMPGbnrw7DkfOLAR9iFyEckjrKkkvQTO54Dzz3yrzhN2B35DLm_gyP3E4WTiwjZO-4oRHodOhzSoh38ITxnT7YwJHxxPi_Zj08fv199Lm6-XX-5-nBTuI3c5KIRoA0I6ZToVFOaBiSgQ6FoF1O2pYLOaDSmrAx2rlWbLVRYm651SmkFVXnJ3p_qzvt2JASnHGGwc_QjxKMN4O2_yuR7exsOVkuhGl1SgdfnAjH82mPKdhf2caKZrax0pUSzaRbq7YlyMaQUcXvfQQq72GTJJrvYZMkmwl89nOoe_uMLAW_OACQHwzbSH_r0lzO1kEIufYsTl0iabjE-mO5_jX8D25Cr4w</recordid><startdate>20140715</startdate><enddate>20140715</enddate><creator>Bapiro, T E</creator><creator>Frese, K K</creator><creator>Courtin, A</creator><creator>Bramhall, J L</creator><creator>Madhu, B</creator><creator>Cook, N</creator><creator>Neesse, A</creator><creator>Griffiths, J R</creator><creator>Tuveson, D A</creator><creator>Jodrell, D I</creator><creator>Richards, F M</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>IQODW</scope><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>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20140715</creationdate><title>Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo</title><author>Bapiro, T E ; Frese, K K ; Courtin, A ; Bramhall, J L ; Madhu, B ; Cook, N ; Neesse, A ; Griffiths, J R ; Tuveson, D A ; Jodrell, D I ; Richards, F M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c616t-90a48a01c20d29389a1aece0200083b32ad84e88358edcb26fa5e78dbc2242a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>631/154/436</topic><topic>631/67/1504/1713</topic><topic>631/67/2327</topic><topic>Animals</topic><topic>Antimetabolites, Antineoplastic - pharmacokinetics</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Carcinoma, Pancreatic Ductal - drug therapy</topic><topic>Carcinoma, Pancreatic Ductal - metabolism</topic><topic>Choline - metabolism</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Deoxycytidine - metabolism</topic><topic>Deoxycytidine - pharmacokinetics</topic><topic>Deoxycytidine - pharmacology</topic><topic>Diphosphates - metabolism</topic><topic>Drug Resistance</topic><topic>Epidemiology</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gemcitabine</topic><topic>Humans</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Molecular Medicine</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Oncology</topic><topic>Pancreatic cancer</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - metabolism</topic><topic>Translational Therapeutics</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bapiro, T E</creatorcontrib><creatorcontrib>Frese, K K</creatorcontrib><creatorcontrib>Courtin, A</creatorcontrib><creatorcontrib>Bramhall, J L</creatorcontrib><creatorcontrib>Madhu, B</creatorcontrib><creatorcontrib>Cook, N</creatorcontrib><creatorcontrib>Neesse, A</creatorcontrib><creatorcontrib>Griffiths, J R</creatorcontrib><creatorcontrib>Tuveson, D A</creatorcontrib><creatorcontrib>Jodrell, D I</creatorcontrib><creatorcontrib>Richards, F M</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bapiro, T E</au><au>Frese, K K</au><au>Courtin, A</au><au>Bramhall, J L</au><au>Madhu, B</au><au>Cook, N</au><au>Neesse, A</au><au>Griffiths, J R</au><au>Tuveson, D A</au><au>Jodrell, D I</au><au>Richards, F M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2014-07-15</date><risdate>2014</risdate><volume>111</volume><issue>2</issue><spage>318</spage><epage>325</epage><pages>318-325</pages><issn>0007-0920</issn><eissn>1532-1827</eissn><coden>BJCAAI</coden><abstract>Background:
The modest benefits of gemcitabine (dFdC) therapy in patients with pancreatic ductal adenocarcinoma (PDAC) are well documented, with drug delivery and metabolic lability cited as important contributing factors. We have used a mouse model of PDAC: KRAS
G12D
; p53
R172H
; pdx-Cre (KPC) that recapitulates the human disease to study dFdC intra-tumoural metabolism.
Methods:
LC-MS/MS and NMR were used to measure drug and physiological analytes. Cytotoxicity was assessed by the Sulphorhodamine B assay.
Results:
In KPC tumour tissue, we identified a new, Kennedy pathway-linked dFdC metabolite (gemcitabine diphosphate choline (GdPC)) present at equimolar amounts to its precursor, the accepted active metabolite gemcitabine triphosphate (dFdCTP). Utilising additional subcutaneous PDAC tumour models, we demonstrated an inverse correlation between GdPC/dFdCTP ratios and cytidine triphosphate (CTP). In tumour homogenates
in vitro
, CTP inhibited GdPC formation from dFdCTP, indicating competition between CTP and dFdCTP for CTP:phosphocholine cytidylyltransferase (CCT). As the structure of GdPC precludes entry into cells, potential cytotoxicity was assessed by stimulating CCT activity using linoleate in KPC cells
in vitro
, leading to increased GdPC concentration and synergistic growth inhibition after dFdC addition.
Conclusions:
GdPC is an important element of the intra-tumoural dFdC metabolic pathway
in vivo
.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24874484</pmid><doi>10.1038/bjc.2014.288</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0007-0920 |
| ispartof | British journal of cancer, 2014-07, Vol.111 (2), p.318-325 |
| issn | 0007-0920 1532-1827 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4102943 |
| source | MEDLINE; Nature; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | 631/154/436 631/67/1504/1713 631/67/2327 Animals Antimetabolites, Antineoplastic - pharmacokinetics Antimetabolites, Antineoplastic - pharmacology Biological and medical sciences Biomedical and Life Sciences Biomedicine Cancer Research Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - metabolism Choline - metabolism Deoxycytidine - analogs & derivatives Deoxycytidine - metabolism Deoxycytidine - pharmacokinetics Deoxycytidine - pharmacology Diphosphates - metabolism Drug Resistance Epidemiology Female Gastroenterology. Liver. Pancreas. Abdomen Gemcitabine Humans Liver. Biliary tract. Portal circulation. Exocrine pancreas Medical sciences Mice Mice, Inbred BALB C Mice, Nude Molecular Medicine Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Oncology Pancreatic cancer Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Translational Therapeutics Tumor Cells, Cultured Tumors |
| title | Gemcitabine diphosphate choline is a major metabolite linked to the Kennedy pathway in pancreatic cancer models in vivo |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T14%3A37%3A26IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Gemcitabine%20diphosphate%20choline%20is%20a%20major%20metabolite%20linked%20to%20the%20Kennedy%20pathway%20in%20pancreatic%20cancer%20models%20in%20vivo&rft.jtitle=British%20journal%20of%20cancer&rft.au=Bapiro,%20T%20E&rft.date=2014-07-15&rft.volume=111&rft.issue=2&rft.spage=318&rft.epage=325&rft.pages=318-325&rft.issn=0007-0920&rft.eissn=1532-1827&rft.coden=BJCAAI&rft_id=info:doi/10.1038/bjc.2014.288&rft_dat=%3Cproquest_pubme%3E3373650551%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1545209693&rft_id=info:pmid/24874484&rfr_iscdi=true |