A hexameric phosphorothioate oligonucleotide telomerase inhibitor arrests growth of Burkitt's lymphoma cells in vitro and in vivo.
Identifieur interne : 002A80 ( Ncbi/Checkpoint ); précédent : 002A79; suivant : 002A81A hexameric phosphorothioate oligonucleotide telomerase inhibitor arrests growth of Burkitt's lymphoma cells in vitro and in vivo.
Auteurs : J E Mata [États-Unis] ; S S Joshi ; B. Palen ; S J Pirruccello ; J D Jackson ; N. Elias ; T J Page ; K L Medlin ; P 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.
- Animals, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Tumor Cells, Cultured.
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. The in vivo efficacy 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 micrograms/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 mimic in vitro and in vivo and the potential utility of short oligonucleotides as telomerase inhibitors.
DOI: 10.1006/taap.1997.8103
PubMed: 9169084
Affiliations:
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Palen</name></author><author><name sortKey="Pirruccello, S J" sort="Pirruccello, S J" uniqKey="Pirruccello S" first="S J" last="Pirruccello">S J Pirruccello</name></author><author><name sortKey="Jackson, J D" sort="Jackson, J D" uniqKey="Jackson J" first="J D" last="Jackson">J D Jackson</name></author><author><name sortKey="Elias, N" sort="Elias, N" uniqKey="Elias N" first="N" last="Elias">N. 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Palen</name></author><author><name sortKey="Pirruccello, S J" sort="Pirruccello, S J" uniqKey="Pirruccello S" first="S J" last="Pirruccello">S J Pirruccello</name></author><author><name sortKey="Jackson, J D" sort="Jackson, J D" uniqKey="Jackson J" first="J D" last="Jackson">J D Jackson</name></author><author><name sortKey="Elias, N" sort="Elias, N" uniqKey="Elias N" first="N" last="Elias">N. Elias</name></author><author><name sortKey="Page, T J" sort="Page, T J" uniqKey="Page T" first="T J" last="Page">T J Page</name></author><author><name sortKey="Medlin, K L" sort="Medlin, K L" uniqKey="Medlin K" first="K L" last="Medlin">K L Medlin</name></author><author><name sortKey="Iversen, P L" sort="Iversen, P L" uniqKey="Iversen P" first="P L" last="Iversen">P L Iversen</name></author></analytic><series><title level="j">Toxicology and applied pharmacology</title><idno type="ISSN">0041-008X</idno><imprint><date when="1997" type="published">1997</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Burkitt Lymphoma (pathology)</term><term>Cell Division (drug effects)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Humans</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, 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="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Mice</term><term>Mice, Inbred BALB C</term><term>Mice, Nude</term><term>Neoplasm Transplantation</term><term>Tumor Cells, Cultured</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></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. The in vivo efficacy 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 micrograms/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 mimic in vitro and in vivo and the potential utility of short oligonucleotides as telomerase inhibitors.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Elias, N" sort="Elias, N" uniqKey="Elias N" first="N" last="Elias">N. Elias</name><name sortKey="Iversen, P L" sort="Iversen, P L" uniqKey="Iversen P" first="P L" last="Iversen">P L Iversen</name><name sortKey="Jackson, J D" sort="Jackson, J D" uniqKey="Jackson J" first="J D" last="Jackson">J D Jackson</name><name sortKey="Joshi, S S" sort="Joshi, S S" uniqKey="Joshi S" first="S S" last="Joshi">S S Joshi</name><name sortKey="Medlin, K L" sort="Medlin, K L" uniqKey="Medlin K" first="K L" last="Medlin">K L Medlin</name><name sortKey="Page, T J" sort="Page, T J" uniqKey="Page T" first="T J" last="Page">T J Page</name><name sortKey="Palen, B" sort="Palen, B" uniqKey="Palen B" first="B" last="Palen">B. Palen</name><name sortKey="Pirruccello, S J" sort="Pirruccello, S J" uniqKey="Pirruccello S" first="S J" last="Pirruccello">S J Pirruccello</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Mata, J E" sort="Mata, J E" uniqKey="Mata J" first="J E" last="Mata">J E Mata</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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