Desensitization and sensitization of cells to fluoropyrimidines with different antisenses directed against thymidylate synthase messenger RNA.
Identifieur interne : 003A09 ( Main/Exploration ); précédent : 003A08; suivant : 003A10Desensitization and sensitization of cells to fluoropyrimidines with different antisenses directed against thymidylate synthase messenger RNA.
Auteurs : J. Ju [États-Unis] ; S E Kane ; H J Lenz ; K D Danenberg ; E. Chu ; P V DanenbergSource :
- Clinical cancer research : an official journal of the American Association for Cancer Research [ 1078-0432 ] ; 1998.
Descripteurs français
- KwdFr :
- ARN messager (génétique), ARN messager (métabolisme), Animaux, Antinéoplasiques antimétabolites (pharmacologie), Cellules HT29 (), Cellules HT29 (enzymologie), Cellules KB, Floxuridine (pharmacologie), Humains, Interactions médicamenteuses, Lapins, Oligoribonucléotides antisens (génétique), Oligoribonucléotides antisens (pharmacologie), Plasmides (génétique), Tests de criblage d'agents antitumoraux, Thymidylate synthase (biosynthèse), Thymidylate synthase (génétique), Transfection.
- MESH :
- biosynthèse : Thymidylate synthase.
- enzymologie : Cellules HT29.
- génétique : ARN messager, Oligoribonucléotides antisens, Plasmides, Thymidylate synthase.
- métabolisme : ARN messager.
- pharmacologie : Antinéoplasiques antimétabolites, Floxuridine, Oligoribonucléotides antisens.
- Animaux, Cellules HT29, Cellules KB, Humains, Interactions médicamenteuses, Lapins, Tests de criblage d'agents antitumoraux, Transfection.
English descriptors
- KwdEn :
- Animals, Antimetabolites, Antineoplastic (pharmacology), Drug Interactions, Drug Screening Assays, Antitumor, Floxuridine (pharmacology), HT29 Cells (drug effects), HT29 Cells (enzymology), Humans, KB Cells, Oligoribonucleotides, Antisense (genetics), Oligoribonucleotides, Antisense (pharmacology), Plasmids (genetics), RNA, Messenger (genetics), RNA, Messenger (metabolism), Rabbits, Thymidylate Synthase (biosynthesis), Thymidylate Synthase (genetics), Transfection.
- MESH :
- chemical , biosynthesis : Thymidylate Synthase.
- chemical , genetics : Oligoribonucleotides, Antisense, RNA, Messenger, Thymidylate Synthase.
- chemical , metabolism : RNA, Messenger.
- chemical , pharmacology : Antimetabolites, Antineoplastic, Floxuridine, Oligoribonucleotides, Antisense.
- drug effects : HT29 Cells.
- enzymology : HT29 Cells.
- genetics : Plasmids.
- Animals, Drug Interactions, Drug Screening Assays, Antitumor, Humans, KB Cells, Rabbits, Transfection.
Abstract
Previous studies have shown that the cytotoxicity of fluoropyrimidines is mediated, in large part, by inhibition of the enzyme thymidylate synthase (TS). The aim of this study was to determine whether the chemosensitivity of human cancer cells to fluoropyrimidines could be increased by decreasing TS expression with antisense oligodeoxyribonucleotides (ODNs). ODNs (18-mers) targeted at the AUG translational initiation site of TS mRNA inhibited translation in a sequence- and dose-dependent manner in a rabbit reticulocyte lysate in vitro translation system. Treatment of human colon cancer HT-29 cells with antisense ODNs decreased TS catalytic activity in the cells in a dose-dependent manner over a short period, but the longer-term effect of the TS antisense ODN treatment was actually to increase the amount of TS in the cells and to decrease their sensitivity to 5-fluoro-2'-deoxyuridine (FdUrd). However, when human nasopharyngeal cancer KB31 cells were transfected with a plasmid (pHaMAGRP) construct containing the TS antisense fragment (+ 1 to + 422) under the control of a glucose-regulated promoter, the expression of both TS protein and TS catalytic activity was decreased by nearly 30% (P = 0.014), and sensitivity of these cells to FdUrd was enhanced by approximately 8-fold (P = 0.021). No changes in the levels of expression of TS protein or FdUrd-associated cytotoxicity were observed in control, vector-transfected cells. No change was observed in the sensitivity of transfected cells toward either cisplatin or Adriamycin. These results show that the level of expression of TS in human malignant cells can be down-regulated with antisense TS RNA, and their sensitivity to fluoropyrimidines can, thereby, be increased.
PubMed: 9748143
Affiliations:
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Le document en format XML
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Ju</name><affiliation wicri:level="4"><nlm:affiliation>USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles 90033, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles 90033</wicri:regionArea><placeName><settlement type="city">Los Angeles</settlement><region type="state">Californie</region></placeName><orgName type="university">Université de Californie du Sud</orgName><placeName><settlement type="city">Los Angeles</settlement><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Kane, S E" sort="Kane, S E" uniqKey="Kane S" first="S E" last="Kane">S E Kane</name></author><author><name sortKey="Lenz, H J" sort="Lenz, H J" uniqKey="Lenz H" first="H J" last="Lenz">H J Lenz</name></author><author><name sortKey="Danenberg, K D" sort="Danenberg, K D" uniqKey="Danenberg K" first="K D" last="Danenberg">K D Danenberg</name></author><author><name sortKey="Chu, E" sort="Chu, E" uniqKey="Chu E" first="E" last="Chu">E. 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Ju</name><affiliation wicri:level="4"><nlm:affiliation>USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles 90033, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>USC/Norris Comprehensive Cancer Center, University of Southern California, Los Angeles 90033</wicri:regionArea><placeName><settlement type="city">Los Angeles</settlement><region type="state">Californie</region></placeName><orgName type="university">Université de Californie du Sud</orgName><placeName><settlement type="city">Los Angeles</settlement><region type="state">Californie</region></placeName></affiliation></author><author><name sortKey="Kane, S E" sort="Kane, S E" uniqKey="Kane S" first="S E" last="Kane">S E Kane</name></author><author><name sortKey="Lenz, H J" sort="Lenz, H J" uniqKey="Lenz H" first="H J" last="Lenz">H J Lenz</name></author><author><name sortKey="Danenberg, K D" sort="Danenberg, K D" uniqKey="Danenberg K" first="K D" last="Danenberg">K D Danenberg</name></author><author><name sortKey="Chu, E" sort="Chu, E" uniqKey="Chu E" first="E" last="Chu">E. Chu</name></author><author><name sortKey="Danenberg, P V" sort="Danenberg, P V" uniqKey="Danenberg P" first="P V" last="Danenberg">P V Danenberg</name></author></analytic><series><title level="j">Clinical cancer research : an official journal of the American Association for Cancer Research</title><idno type="ISSN">1078-0432</idno><imprint><date when="1998" type="published">1998</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antimetabolites, Antineoplastic (pharmacology)</term><term>Drug Interactions</term><term>Drug Screening Assays, Antitumor</term><term>Floxuridine (pharmacology)</term><term>HT29 Cells (drug effects)</term><term>HT29 Cells (enzymology)</term><term>Humans</term><term>KB Cells</term><term>Oligoribonucleotides, Antisense (genetics)</term><term>Oligoribonucleotides, Antisense (pharmacology)</term><term>Plasmids (genetics)</term><term>RNA, Messenger (genetics)</term><term>RNA, Messenger (metabolism)</term><term>Rabbits</term><term>Thymidylate Synthase (biosynthesis)</term><term>Thymidylate Synthase (genetics)</term><term>Transfection</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN messager (génétique)</term><term>ARN messager (métabolisme)</term><term>Animaux</term><term>Antinéoplasiques antimétabolites (pharmacologie)</term><term>Cellules HT29 ()</term><term>Cellules HT29 (enzymologie)</term><term>Cellules KB</term><term>Floxuridine (pharmacologie)</term><term>Humains</term><term>Interactions médicamenteuses</term><term>Lapins</term><term>Oligoribonucléotides antisens (génétique)</term><term>Oligoribonucléotides antisens (pharmacologie)</term><term>Plasmides (génétique)</term><term>Tests de criblage d'agents antitumoraux</term><term>Thymidylate synthase (biosynthèse)</term><term>Thymidylate synthase (génétique)</term><term>Transfection</term></keywords><keywords scheme="MESH" type="chemical" qualifier="biosynthesis" xml:lang="en"><term>Thymidylate Synthase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Oligoribonucleotides, Antisense</term><term>RNA, Messenger</term><term>Thymidylate Synthase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>RNA, Messenger</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antimetabolites, Antineoplastic</term><term>Floxuridine</term><term>Oligoribonucleotides, Antisense</term></keywords><keywords scheme="MESH" qualifier="biosynthèse" xml:lang="fr"><term>Thymidylate synthase</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HT29 Cells</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Cellules HT29</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>HT29 Cells</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Plasmids</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN messager</term><term>Oligoribonucléotides antisens</term><term>Plasmides</term><term>Thymidylate synthase</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ARN messager</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques antimétabolites</term><term>Floxuridine</term><term>Oligoribonucléotides antisens</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Drug Interactions</term><term>Drug Screening Assays, Antitumor</term><term>Humans</term><term>KB Cells</term><term>Rabbits</term><term>Transfection</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules HT29</term><term>Cellules KB</term><term>Humains</term><term>Interactions médicamenteuses</term><term>Lapins</term><term>Tests de criblage d'agents antitumoraux</term><term>Transfection</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Previous studies have shown that the cytotoxicity of fluoropyrimidines is mediated, in large part, by inhibition of the enzyme thymidylate synthase (TS). The aim of this study was to determine whether the chemosensitivity of human cancer cells to fluoropyrimidines could be increased by decreasing TS expression with antisense oligodeoxyribonucleotides (ODNs). ODNs (18-mers) targeted at the AUG translational initiation site of TS mRNA inhibited translation in a sequence- and dose-dependent manner in a rabbit reticulocyte lysate in vitro translation system. Treatment of human colon cancer HT-29 cells with antisense ODNs decreased TS catalytic activity in the cells in a dose-dependent manner over a short period, but the longer-term effect of the TS antisense ODN treatment was actually to increase the amount of TS in the cells and to decrease their sensitivity to 5-fluoro-2'-deoxyuridine (FdUrd). However, when human nasopharyngeal cancer KB31 cells were transfected with a plasmid (pHaMAGRP) construct containing the TS antisense fragment (+ 1 to + 422) under the control of a glucose-regulated promoter, the expression of both TS protein and TS catalytic activity was decreased by nearly 30% (P = 0.014), and sensitivity of these cells to FdUrd was enhanced by approximately 8-fold (P = 0.021). No changes in the levels of expression of TS protein or FdUrd-associated cytotoxicity were observed in control, vector-transfected cells. No change was observed in the sensitivity of transfected cells toward either cisplatin or Adriamycin. These results show that the level of expression of TS in human malignant cells can be down-regulated with antisense TS RNA, and their sensitivity to fluoropyrimidines can, thereby, be increased.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li></region><settlement><li>Los Angeles</li></settlement><orgName><li>Université de Californie du Sud</li></orgName></list><tree><noCountry><name sortKey="Chu, E" sort="Chu, E" uniqKey="Chu E" first="E" last="Chu">E. Chu</name><name sortKey="Danenberg, K D" sort="Danenberg, K D" uniqKey="Danenberg K" first="K D" last="Danenberg">K D Danenberg</name><name sortKey="Danenberg, P V" sort="Danenberg, P V" uniqKey="Danenberg P" first="P V" last="Danenberg">P V Danenberg</name><name sortKey="Kane, S E" sort="Kane, S E" uniqKey="Kane S" first="S E" last="Kane">S E Kane</name><name sortKey="Lenz, H J" sort="Lenz, H J" uniqKey="Lenz H" first="H J" last="Lenz">H J Lenz</name></noCountry><country name="États-Unis"><region name="Californie"><name sortKey="Ju, J" sort="Ju, J" uniqKey="Ju J" first="J" last="Ju">J. Ju</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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