Distribution of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) uracil in mice bearing colorectal cancer xenografts: Rationale for therapeutic use and as a positron emission tomography probe for thymidylate synthase
In colorectal, breast, and head and neck cancers, response to 5-fluorouracil is associated with low expression of thymidylate synthase. In contrast, tumors with high expression of thymidylate synthase may be more sensitive to prodrugs such as 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil (FAU)...
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| creator | EISEMAN, Julie L BROWN-PROCTOR, Clive KLECKER, Raymond W KINAHAN, Paul E COLLINS, Jerry M ANDERSON, Lawrence W JOSEPH, Erin HAMBURGER, Deborah R PAN, Su-Shu MATHIS, Chester A EGORIN, Merrill J |
| description | In colorectal, breast, and head and neck cancers, response to 5-fluorouracil is associated with low expression of thymidylate synthase. In contrast, tumors with high expression of thymidylate synthase may be more sensitive to prodrugs such as 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil (FAU) that are activated by thymidylate synthase. These studies were designed to evaluate FAU as a potential therapeutic and diagnostic probe.
[18F]-FAU and [3H]-FAU were synthesized with >97% radiochemical purity. [3H]-FAU or [18F]-FAU was administered intravenously to severe combined immunodeficient mice bearing either HT29 (low thymidylate synthase) or LS174T (high thymidylate synthase) human colon cancer xenografts. Four hours after [3H]-FAU dosing, tissue distribution of total radioactivity and incorporation of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) 5-methyluracil (FMAU), derived from thymidylate synthase activation of FAU, into tumor DNA was measured. Positron emission tomography (PET) images were obtained for 90 minutes after injection of [18F]-FAU. Thymidylate synthase activity was determined in vitro in tumors from untreated mice by [3H] release from [3H]dUMP. Each cell line was incubated in vitro with [3H]-FAU or [3H]-FMAU in the absence or presence of 5-fluoro-2'-deoxyuridine (FdUrd) and then was analyzed for incorporation of radiolabel into DNA.
Thymidylate synthase enzymatic activity in LS174T xenografts was approximately 3.5-fold higher than in HT29 xenografts, and incorporation of radioactivity derived from [3H]-FAU into LS174T DNA was approximately 2-fold higher than into HT29 DNA. At 240 minutes, radioactivity derived from [3H]-FAU was approximately 2-fold higher in tumors than in skeletal muscle. At times up to 90 minutes, PET imaging detected only small differences in uptake of [18F]-FAU between the tumor types. Fluorine-18 in skeletal muscle was higher than in tumor for the first 90 minutes and plateaued earlier, whereas [18F] in tumor continued to increase during the 90-minute imaging period. For both cell lines in vitro, FdUrd decreased the rate of incorporation of [3H]-FAU into DNA, whereas the incorporation of [3H]-FMAU was increased.
These results for FAU incorporation into DNA in vitro and in vivo further support clinical evaluation of FAU as a therapeutic agent in tumors with high concentrations of thymidylate synthase that are less likely to respond to 5-fluorouracil treatment. The high circulating concentrations of thymidine reporte |
| doi_str_mv | 10.1158/1078-0432.CCR-03-0686 |
| format | Article |
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[18F]-FAU and [3H]-FAU were synthesized with >97% radiochemical purity. [3H]-FAU or [18F]-FAU was administered intravenously to severe combined immunodeficient mice bearing either HT29 (low thymidylate synthase) or LS174T (high thymidylate synthase) human colon cancer xenografts. Four hours after [3H]-FAU dosing, tissue distribution of total radioactivity and incorporation of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) 5-methyluracil (FMAU), derived from thymidylate synthase activation of FAU, into tumor DNA was measured. Positron emission tomography (PET) images were obtained for 90 minutes after injection of [18F]-FAU. Thymidylate synthase activity was determined in vitro in tumors from untreated mice by [3H] release from [3H]dUMP. Each cell line was incubated in vitro with [3H]-FAU or [3H]-FMAU in the absence or presence of 5-fluoro-2'-deoxyuridine (FdUrd) and then was analyzed for incorporation of radiolabel into DNA.
Thymidylate synthase enzymatic activity in LS174T xenografts was approximately 3.5-fold higher than in HT29 xenografts, and incorporation of radioactivity derived from [3H]-FAU into LS174T DNA was approximately 2-fold higher than into HT29 DNA. At 240 minutes, radioactivity derived from [3H]-FAU was approximately 2-fold higher in tumors than in skeletal muscle. At times up to 90 minutes, PET imaging detected only small differences in uptake of [18F]-FAU between the tumor types. Fluorine-18 in skeletal muscle was higher than in tumor for the first 90 minutes and plateaued earlier, whereas [18F] in tumor continued to increase during the 90-minute imaging period. For both cell lines in vitro, FdUrd decreased the rate of incorporation of [3H]-FAU into DNA, whereas the incorporation of [3H]-FMAU was increased.
These results for FAU incorporation into DNA in vitro and in vivo further support clinical evaluation of FAU as a therapeutic agent in tumors with high concentrations of thymidylate synthase that are less likely to respond to 5-fluorouracil treatment. The high circulating concentrations of thymidine reported in mice may limit their utility in evaluating FAU as a PET probe.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-03-0686</identifier><identifier>PMID: 15475457</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Arabinofuranosyluracil - analogs & derivatives ; Arabinofuranosyluracil - pharmacokinetics ; Arabinofuranosyluracil - therapeutic use ; Biological and medical sciences ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - metabolism ; Colorectal Neoplasms - pathology ; DNA, Neoplasm - metabolism ; Female ; Fluorouracil - analogs & derivatives ; Fluorouracil - pharmacokinetics ; Fluorouracil - therapeutic use ; HT29 Cells ; Humans ; Medical sciences ; Mice ; Mice, SCID ; Pharmacology. Drug treatments ; Positron-Emission Tomography ; Thymidylate Synthase - metabolism ; Time Factors ; Tissue Distribution ; Tritium ; Tumors ; Xenograft Model Antitumor Assays - methods</subject><ispartof>Clinical cancer research, 2004-10, Vol.10 (19), p.6669-6676</ispartof><rights>2004 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c289t-268751c182c0c78bf4a4b2d5341f4b9296cebd3f150f00cac23c0be46429e4a03</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16182285$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15475457$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>EISEMAN, Julie L</creatorcontrib><creatorcontrib>BROWN-PROCTOR, Clive</creatorcontrib><creatorcontrib>KLECKER, Raymond W</creatorcontrib><creatorcontrib>KINAHAN, Paul E</creatorcontrib><creatorcontrib>COLLINS, Jerry M</creatorcontrib><creatorcontrib>ANDERSON, Lawrence W</creatorcontrib><creatorcontrib>JOSEPH, Erin</creatorcontrib><creatorcontrib>HAMBURGER, Deborah R</creatorcontrib><creatorcontrib>PAN, Su-Shu</creatorcontrib><creatorcontrib>MATHIS, Chester A</creatorcontrib><creatorcontrib>EGORIN, Merrill J</creatorcontrib><title>Distribution of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) uracil in mice bearing colorectal cancer xenografts: Rationale for therapeutic use and as a positron emission tomography probe for thymidylate synthase</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>In colorectal, breast, and head and neck cancers, response to 5-fluorouracil is associated with low expression of thymidylate synthase. In contrast, tumors with high expression of thymidylate synthase may be more sensitive to prodrugs such as 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil (FAU) that are activated by thymidylate synthase. These studies were designed to evaluate FAU as a potential therapeutic and diagnostic probe.
[18F]-FAU and [3H]-FAU were synthesized with >97% radiochemical purity. [3H]-FAU or [18F]-FAU was administered intravenously to severe combined immunodeficient mice bearing either HT29 (low thymidylate synthase) or LS174T (high thymidylate synthase) human colon cancer xenografts. Four hours after [3H]-FAU dosing, tissue distribution of total radioactivity and incorporation of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) 5-methyluracil (FMAU), derived from thymidylate synthase activation of FAU, into tumor DNA was measured. Positron emission tomography (PET) images were obtained for 90 minutes after injection of [18F]-FAU. Thymidylate synthase activity was determined in vitro in tumors from untreated mice by [3H] release from [3H]dUMP. Each cell line was incubated in vitro with [3H]-FAU or [3H]-FMAU in the absence or presence of 5-fluoro-2'-deoxyuridine (FdUrd) and then was analyzed for incorporation of radiolabel into DNA.
Thymidylate synthase enzymatic activity in LS174T xenografts was approximately 3.5-fold higher than in HT29 xenografts, and incorporation of radioactivity derived from [3H]-FAU into LS174T DNA was approximately 2-fold higher than into HT29 DNA. At 240 minutes, radioactivity derived from [3H]-FAU was approximately 2-fold higher in tumors than in skeletal muscle. At times up to 90 minutes, PET imaging detected only small differences in uptake of [18F]-FAU between the tumor types. Fluorine-18 in skeletal muscle was higher than in tumor for the first 90 minutes and plateaued earlier, whereas [18F] in tumor continued to increase during the 90-minute imaging period. For both cell lines in vitro, FdUrd decreased the rate of incorporation of [3H]-FAU into DNA, whereas the incorporation of [3H]-FMAU was increased.
These results for FAU incorporation into DNA in vitro and in vivo further support clinical evaluation of FAU as a therapeutic agent in tumors with high concentrations of thymidylate synthase that are less likely to respond to 5-fluorouracil treatment. The high circulating concentrations of thymidine reported in mice may limit their utility in evaluating FAU as a PET probe.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Arabinofuranosyluracil - analogs & derivatives</subject><subject>Arabinofuranosyluracil - pharmacokinetics</subject><subject>Arabinofuranosyluracil - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - metabolism</subject><subject>Colorectal Neoplasms - pathology</subject><subject>DNA, Neoplasm - metabolism</subject><subject>Female</subject><subject>Fluorouracil - analogs & derivatives</subject><subject>Fluorouracil - pharmacokinetics</subject><subject>Fluorouracil - therapeutic use</subject><subject>HT29 Cells</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Pharmacology. Drug treatments</subject><subject>Positron-Emission Tomography</subject><subject>Thymidylate Synthase - metabolism</subject><subject>Time Factors</subject><subject>Tissue Distribution</subject><subject>Tritium</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays - methods</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkM1u1TAQhSMEoqXwCKDZIMHCxXbsJJcduuVPqoRUwboaO-NeI8eObEdqXosHYcETkSt6xWrO4ptzjk7TvBT8Ugg9vBO8HxhXrbzc728Ybxnvhu5Rcy607lkrO_140yfmrHlWyk_OhRJcPW3OhFa9Vro_b_5c-VKzN0v1KUJyINgbyUZK9yuTzIUl5cR-_2JXDDMaH5NbMsZU1vAWNmV9AB9h8pbAEGYf78CmkDLZigEsRksZ7immu4yulvdwg8ckDAQuZagHyjjTlm5hKQQYR8ACCHMqvuatEk2-lGO3mqajyXxYYc7JnP7XyY9rwEpQ1lgPWOh588RhKPTi4V40Pz59_L7_wq6_ff66_3DNrBx2lclu6LWwYpCW234wTqEyctStEk6Zndx1lszYOqG549yila3lhlSn5I4U8vaiefXPd17MROPtnP2Eeb09jbsBrx8ALBaD24azvvznui1bDrr9CzlWkAM</recordid><startdate>20041001</startdate><enddate>20041001</enddate><creator>EISEMAN, Julie L</creator><creator>BROWN-PROCTOR, Clive</creator><creator>KLECKER, Raymond W</creator><creator>KINAHAN, Paul E</creator><creator>COLLINS, Jerry M</creator><creator>ANDERSON, Lawrence W</creator><creator>JOSEPH, Erin</creator><creator>HAMBURGER, Deborah R</creator><creator>PAN, Su-Shu</creator><creator>MATHIS, Chester A</creator><creator>EGORIN, Merrill J</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20041001</creationdate><title>Distribution of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) uracil in mice bearing colorectal cancer xenografts: Rationale for therapeutic use and as a positron emission tomography probe for thymidylate synthase</title><author>EISEMAN, Julie L ; BROWN-PROCTOR, Clive ; KLECKER, Raymond W ; KINAHAN, Paul E ; COLLINS, Jerry M ; ANDERSON, Lawrence W ; JOSEPH, Erin ; HAMBURGER, Deborah R ; PAN, Su-Shu ; MATHIS, Chester A ; EGORIN, Merrill J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c289t-268751c182c0c78bf4a4b2d5341f4b9296cebd3f150f00cac23c0be46429e4a03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Arabinofuranosyluracil - analogs & derivatives</topic><topic>Arabinofuranosyluracil - pharmacokinetics</topic><topic>Arabinofuranosyluracil - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - metabolism</topic><topic>Colorectal Neoplasms - pathology</topic><topic>DNA, Neoplasm - metabolism</topic><topic>Female</topic><topic>Fluorouracil - analogs & derivatives</topic><topic>Fluorouracil - pharmacokinetics</topic><topic>Fluorouracil - therapeutic use</topic><topic>HT29 Cells</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Pharmacology. Drug treatments</topic><topic>Positron-Emission Tomography</topic><topic>Thymidylate Synthase - metabolism</topic><topic>Time Factors</topic><topic>Tissue Distribution</topic><topic>Tritium</topic><topic>Tumors</topic><topic>Xenograft Model Antitumor Assays - methods</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>EISEMAN, Julie L</creatorcontrib><creatorcontrib>BROWN-PROCTOR, Clive</creatorcontrib><creatorcontrib>KLECKER, Raymond W</creatorcontrib><creatorcontrib>KINAHAN, Paul E</creatorcontrib><creatorcontrib>COLLINS, Jerry M</creatorcontrib><creatorcontrib>ANDERSON, Lawrence W</creatorcontrib><creatorcontrib>JOSEPH, Erin</creatorcontrib><creatorcontrib>HAMBURGER, Deborah R</creatorcontrib><creatorcontrib>PAN, Su-Shu</creatorcontrib><creatorcontrib>MATHIS, Chester A</creatorcontrib><creatorcontrib>EGORIN, Merrill J</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>EISEMAN, Julie L</au><au>BROWN-PROCTOR, Clive</au><au>KLECKER, Raymond W</au><au>KINAHAN, Paul E</au><au>COLLINS, Jerry M</au><au>ANDERSON, Lawrence W</au><au>JOSEPH, Erin</au><au>HAMBURGER, Deborah R</au><au>PAN, Su-Shu</au><au>MATHIS, Chester A</au><au>EGORIN, Merrill J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Distribution of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) uracil in mice bearing colorectal cancer xenografts: Rationale for therapeutic use and as a positron emission tomography probe for thymidylate synthase</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2004-10-01</date><risdate>2004</risdate><volume>10</volume><issue>19</issue><spage>6669</spage><epage>6676</epage><pages>6669-6676</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>In colorectal, breast, and head and neck cancers, response to 5-fluorouracil is associated with low expression of thymidylate synthase. In contrast, tumors with high expression of thymidylate synthase may be more sensitive to prodrugs such as 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil (FAU) that are activated by thymidylate synthase. These studies were designed to evaluate FAU as a potential therapeutic and diagnostic probe.
[18F]-FAU and [3H]-FAU were synthesized with >97% radiochemical purity. [3H]-FAU or [18F]-FAU was administered intravenously to severe combined immunodeficient mice bearing either HT29 (low thymidylate synthase) or LS174T (high thymidylate synthase) human colon cancer xenografts. Four hours after [3H]-FAU dosing, tissue distribution of total radioactivity and incorporation of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) 5-methyluracil (FMAU), derived from thymidylate synthase activation of FAU, into tumor DNA was measured. Positron emission tomography (PET) images were obtained for 90 minutes after injection of [18F]-FAU. Thymidylate synthase activity was determined in vitro in tumors from untreated mice by [3H] release from [3H]dUMP. Each cell line was incubated in vitro with [3H]-FAU or [3H]-FMAU in the absence or presence of 5-fluoro-2'-deoxyuridine (FdUrd) and then was analyzed for incorporation of radiolabel into DNA.
Thymidylate synthase enzymatic activity in LS174T xenografts was approximately 3.5-fold higher than in HT29 xenografts, and incorporation of radioactivity derived from [3H]-FAU into LS174T DNA was approximately 2-fold higher than into HT29 DNA. At 240 minutes, radioactivity derived from [3H]-FAU was approximately 2-fold higher in tumors than in skeletal muscle. At times up to 90 minutes, PET imaging detected only small differences in uptake of [18F]-FAU between the tumor types. Fluorine-18 in skeletal muscle was higher than in tumor for the first 90 minutes and plateaued earlier, whereas [18F] in tumor continued to increase during the 90-minute imaging period. For both cell lines in vitro, FdUrd decreased the rate of incorporation of [3H]-FAU into DNA, whereas the incorporation of [3H]-FMAU was increased.
These results for FAU incorporation into DNA in vitro and in vivo further support clinical evaluation of FAU as a therapeutic agent in tumors with high concentrations of thymidylate synthase that are less likely to respond to 5-fluorouracil treatment. The high circulating concentrations of thymidine reported in mice may limit their utility in evaluating FAU as a PET probe.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>15475457</pmid><doi>10.1158/1078-0432.CCR-03-0686</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Clinical cancer research, 2004-10, Vol.10 (19), p.6669-6676 |
| issn | 1078-0432 1557-3265 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Animals Antineoplastic agents Arabinofuranosyluracil - analogs & derivatives Arabinofuranosyluracil - pharmacokinetics Arabinofuranosyluracil - therapeutic use Biological and medical sciences Colorectal Neoplasms - drug therapy Colorectal Neoplasms - metabolism Colorectal Neoplasms - pathology DNA, Neoplasm - metabolism Female Fluorouracil - analogs & derivatives Fluorouracil - pharmacokinetics Fluorouracil - therapeutic use HT29 Cells Humans Medical sciences Mice Mice, SCID Pharmacology. Drug treatments Positron-Emission Tomography Thymidylate Synthase - metabolism Time Factors Tissue Distribution Tritium Tumors Xenograft Model Antitumor Assays - methods |
| title | Distribution of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl) uracil in mice bearing colorectal cancer xenografts: Rationale for therapeutic use and as a positron emission tomography probe for thymidylate synthase |
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