A Hexameric Phosphorothioate Oligonucleotide Telomerase Inhibitor Arrests Growth of Burkitt's Lymphoma Cells in Vitro and in Vivo
Identifieur interne : 003E02 ( Main/Exploration ); précédent : 003E01; suivant : 003E03A Hexameric Phosphorothioate Oligonucleotide Telomerase Inhibitor Arrests Growth of Burkitt's Lymphoma Cells in Vitro and in Vivo
Auteurs : John E. Mata ; Shantaram S. Joshi ; Brian Palen ; Samuel J. Pirruccello ; John D. Jackson ; Nadia Elias ; Todd J. Page ; Kristin L. Medlin ; Patrick L. IversenSource :
- Toxicology and Applied Pharmacology [ 0041-008X ] ; 1997.
Descripteurs français
- KwdFr :
- Animaux, Antienzymes (pharmacologie), Cellules cancéreuses en culture, Composés organiques du phosphore (pharmacologie), Division cellulaire (), Humains, Lymphome de Burkitt (anatomopathologie), Souris, Souris de lignée BALB C, Souris nude, Telomerase (antagonistes et inhibiteurs), Thionucléotides (pharmacologie), Transplantation tumorale.
- MESH :
- anatomopathologie : Lymphome de Burkitt.
- antagonistes et inhibiteurs : Telomerase.
- pharmacologie : Antienzymes, Composés organiques du phosphore, Thionucléotides.
- Animaux, Cellules cancéreuses en culture, Division cellulaire, Humains, Souris, Souris de lignée BALB C, Souris nude, Transplantation tumorale.
English descriptors
- KwdEn :
- Animals, Burkitt Lymphoma (pathology), Cell Division (drug effects), Enzyme Inhibitors (pharmacology), Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Organophosphorus Compounds (pharmacology), Telomerase (antagonists & inhibitors), Thionucleotides (pharmacology), Tumor Cells, Cultured.
- MESH :
- chemical , antagonists & inhibitors : Telomerase.
- chemical , pharmacology : Enzyme Inhibitors, Organophosphorus Compounds, Thionucleotides.
- drug effects : Cell Division.
- pathology : Burkitt Lymphoma.
- Teeft :
- Animals, Antisense, Antisense odns, Antisense oligodeoxynucleotides, Antitumor activity, Assay, Bone marrow cells, Cancer cells, Cell culture, Cell growth, Cell line, Cell lysates, Cell morphology, Dose dependency, Enzyme mechanisms, Gene product, Genescan software, Hexameric phosphorothioate oligonucleotide telomerase inhibitor arrests growth, Higher doses, Human papillomavirus type, Humans, Initial studies, Intraperitoneal injection, Inverted microscope, Lymphoma cells, Malignant cells, Metastatic nodules, Mice, Mice, Inbred BALB C, Mice, Nude, Mouse, Mung bean nuclease, Neoplasm Transplantation, Nodule, Nuclease digestion, Nucleic acids, Nucleoside phosphorothioates, Nude mice, Odns, Oligonucleotide, Oligonucleotides, Petri dishes, Phosphorothioate, Phosphorothioate oligonucleotides, Relative number, Selective inhibition, Solid tumor foci, Spleen, Standard error, Sterile water, Subsequent studies, Telomerase, Telomerase activity, Telomerase enzyme, Telomerase inhibitors, Telomere, Telomere sequence, Toxas, Trap assay, Treatment groups, Tumor Cells, Cultured, Tumor cells, Tumor nodules, Tumor size, Units penicillin, Urine, Vivo, Vivo studies.
Abstract
Abstract: A phosphorothioate oligonucleotide (PS-ODN) with sequence identical to the repeat sequence of the mammalian telomere, 5′-d(TTAGGG)-3′, was incubated with a Burkitt's lymphoma-derived (OMA-BL1) cell line. This hexanucleotide inhibits telomerase activity in cell lysates, lengthens cell doubling time, and induces apoptosis. Concatenated repeats (12-, 18-, and 24-mers) of the 5′-d(TTAGGG)-3′ motif induce similar cellular responses. Scrambled sequences do not efficiently inhibit telomerase activity or significantly alter cell growth and viability. Thein vivoefficacy of this PS-ODN was evaluated in a xenograft human–nude mouse model. Once tumors were established these animals were administered the telomere mimic, 5′-d(TTAGGG)-3′, a control scrambled sequence 5′-d(TGTGAG)-3′, or saline for 14 days via a subcutaneous osmotic pumps in a blinded study monitoring tumor size with dose and time. A significant decrease in tumor size was observed in animals given 50 μg/mouse/day 5′-d(TTAGGG)-3′, but not following 5′-d(TGTGAG)-3′, relative to the saline-treated animals. The antitumor activity of the 6-mer telomere mimic demonstrated a dose dependency including a reduction in metastatic nodules in the spleen. No activity was observed with the scrambled controls. In addition to antitumor activity we observed an increase in the mouse hematopoietic progenitor cell populations, BFU-e and CFU-GM. These results demonstrated the effects of a short hexameric oligonucleotide telomere mimicin vitroandin vivoand the potential utility of short oligonucleotides as telomerase inhibitors.
Url:
DOI: 10.1006/taap.1997.8103
Affiliations:
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Nude</term><term>Neoplasm Transplantation</term><term>Organophosphorus Compounds (pharmacology)</term><term>Telomerase (antagonists & inhibitors)</term><term>Thionucleotides (pharmacology)</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Antienzymes (pharmacologie)</term><term>Cellules cancéreuses en culture</term><term>Composés organiques du phosphore (pharmacologie)</term><term>Division cellulaire ()</term><term>Humains</term><term>Lymphome de Burkitt (anatomopathologie)</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris nude</term><term>Telomerase (antagonistes et inhibiteurs)</term><term>Thionucléotides (pharmacologie)</term><term>Transplantation tumorale</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Telomerase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Enzyme Inhibitors</term><term>Organophosphorus Compounds</term><term>Thionucleotides</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Lymphome de Burkitt</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Telomerase</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Division</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Burkitt Lymphoma</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antienzymes</term><term>Composés organiques du phosphore</term><term>Thionucléotides</term></keywords><keywords scheme="Teeft" xml:lang="en"><term>Animals</term><term>Antisense</term><term>Antisense odns</term><term>Antisense oligodeoxynucleotides</term><term>Antitumor activity</term><term>Assay</term><term>Bone marrow cells</term><term>Cancer cells</term><term>Cell culture</term><term>Cell growth</term><term>Cell line</term><term>Cell lysates</term><term>Cell morphology</term><term>Dose dependency</term><term>Enzyme mechanisms</term><term>Gene product</term><term>Genescan software</term><term>Hexameric phosphorothioate oligonucleotide telomerase inhibitor arrests growth</term><term>Higher doses</term><term>Human papillomavirus type</term><term>Humans</term><term>Initial studies</term><term>Intraperitoneal injection</term><term>Inverted microscope</term><term>Lymphoma cells</term><term>Malignant cells</term><term>Metastatic nodules</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Nude</term><term>Mouse</term><term>Mung bean nuclease</term><term>Neoplasm Transplantation</term><term>Nodule</term><term>Nuclease digestion</term><term>Nucleic acids</term><term>Nucleoside phosphorothioates</term><term>Nude mice</term><term>Odns</term><term>Oligonucleotide</term><term>Oligonucleotides</term><term>Petri dishes</term><term>Phosphorothioate</term><term>Phosphorothioate oligonucleotides</term><term>Relative number</term><term>Selective inhibition</term><term>Solid tumor foci</term><term>Spleen</term><term>Standard error</term><term>Sterile water</term><term>Subsequent studies</term><term>Telomerase</term><term>Telomerase activity</term><term>Telomerase enzyme</term><term>Telomerase inhibitors</term><term>Telomere</term><term>Telomere sequence</term><term>Toxas</term><term>Trap assay</term><term>Treatment groups</term><term>Tumor Cells, Cultured</term><term>Tumor cells</term><term>Tumor nodules</term><term>Tumor size</term><term>Units penicillin</term><term>Urine</term><term>Vivo</term><term>Vivo studies</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules cancéreuses en culture</term><term>Division cellulaire</term><term>Humains</term><term>Souris</term><term>Souris de lignée BALB C</term><term>Souris nude</term><term>Transplantation tumorale</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Abstract: A phosphorothioate oligonucleotide (PS-ODN) with sequence identical to the repeat sequence of the mammalian telomere, 5′-d(TTAGGG)-3′, was incubated with a Burkitt's lymphoma-derived (OMA-BL1) cell line. This hexanucleotide inhibits telomerase activity in cell lysates, lengthens cell doubling time, and induces apoptosis. Concatenated repeats (12-, 18-, and 24-mers) of the 5′-d(TTAGGG)-3′ motif induce similar cellular responses. Scrambled sequences do not efficiently inhibit telomerase activity or significantly alter cell growth and viability. Thein vivoefficacy of this PS-ODN was evaluated in a xenograft human–nude mouse model. Once tumors were established these animals were administered the telomere mimic, 5′-d(TTAGGG)-3′, a control scrambled sequence 5′-d(TGTGAG)-3′, or saline for 14 days via a subcutaneous osmotic pumps in a blinded study monitoring tumor size with dose and time. A significant decrease in tumor size was observed in animals given 50 μg/mouse/day 5′-d(TTAGGG)-3′, but not following 5′-d(TGTGAG)-3′, relative to the saline-treated animals. The antitumor activity of the 6-mer telomere mimic demonstrated a dose dependency including a reduction in metastatic nodules in the spleen. No activity was observed with the scrambled controls. In addition to antitumor activity we observed an increase in the mouse hematopoietic progenitor cell populations, BFU-e and CFU-GM. These results demonstrated the effects of a short hexameric oligonucleotide telomere mimicin vitroandin vivoand the potential utility of short oligonucleotides as telomerase inhibitors.</div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Elias, Nadia" sort="Elias, Nadia" uniqKey="Elias N" first="Nadia" last="Elias">Nadia Elias</name><name sortKey="Iversen, Patrick L" sort="Iversen, Patrick L" uniqKey="Iversen P" first="Patrick L." last="Iversen">Patrick L. Iversen</name><name sortKey="Jackson, John D" sort="Jackson, John D" uniqKey="Jackson J" first="John D." last="Jackson">John D. Jackson</name><name sortKey="Joshi, Shantaram S" sort="Joshi, Shantaram S" uniqKey="Joshi S" first="Shantaram S." last="Joshi">Shantaram S. Joshi</name><name sortKey="Mata, John E" sort="Mata, John E" uniqKey="Mata J" first="John E." last="Mata">John E. Mata</name><name sortKey="Medlin, Kristin L" sort="Medlin, Kristin L" uniqKey="Medlin K" first="Kristin L." last="Medlin">Kristin L. Medlin</name><name sortKey="Page, Todd J" sort="Page, Todd J" uniqKey="Page T" first="Todd J." last="Page">Todd J. Page</name><name sortKey="Palen, Brian" sort="Palen, Brian" uniqKey="Palen B" first="Brian" last="Palen">Brian Palen</name><name sortKey="Pirruccello, Samuel J" sort="Pirruccello, Samuel J" uniqKey="Pirruccello S" first="Samuel J." last="Pirruccello">Samuel J. Pirruccello</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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