Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53
Malignant gliomas of astrocytic origin have commonly expressed several features such as alterations in the tumor-suppressor gene p53 or p16 or the acquisition of telomerase activity, which are distinctive from astrocytes. Therefore, restoration of the tumor-suppressor gene or telomerase inhibition i...
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| Veröffentlicht in: | Gene therapy 2000-12, Vol.7 (24), p.2071-2079 |
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| creator | KOMATA, T KONDO, Y KOGA, S KO, S. C CHUNG, L. W. K KONDO, S |
| description | Malignant gliomas of astrocytic origin have commonly expressed several features such as alterations in the tumor-suppressor gene p53 or p16 or the acquisition of telomerase activity, which are distinctive from astrocytes. Therefore, restoration of the tumor-suppressor gene or telomerase inhibition is expected to provide a cure for malignant gliomas. We have recently demonstrated that the treatment with a 19-mer antisense oligonucleotide against human telomerase RNA linked to a 2',5'-oligoadenylate (2-5A-anti-hTR) inhibited the growth of malignant glioma cells. From a therapeutic point of view, it is very important to investigate the antitumor efficacy of 2-5A-anti-hTR combined with the restoration of p53 or p16 gene. In this study, we evaluated the antitumor effect of 2-5A-anti-hTR in combination with recombinant adenoviruses bearing p53, its associated p21WAF1/CIP1, or p16CDKN2 gene (Ad5CMV-p53, Ad5CMV-p21, or Ad5CMV-p16) against malignant glioma cells in vitro and in vivo. Five malignant glioma cell lines expressing the mutant p53 gene (A172, GB-1, T98G, U251-MG and U373-MG) were more sensitive to the combination of 2-5A-anti-hTR and Ad5CMV-p53 than to other combinations. The additive effect of the combination therapy was due to induction of caspase-dependent apoptosis and cell growth arrest. Furthermore, the 2-5A-anti-hTR treatment when combined with Ad5CMV-p53 showed greater efficacy against subcutaneous U251-MG tumors in nude mice. In contrast, U87-MG cells expressing the wild-type p53 gene were insensitive to Ad5CMV-p53, although the treatment with 2-5A-anti-hTR was significantly effective. These results indicate that combining 2-5A-anti-hTR with Ad5CMV-p53 has the most therapeutic potential for malignant gliomas with mutant p53. For tumors exhibiting wild-type p53, it may be useful to treat with 2-5A-anti-hTR. Gene Therapy (2000) 7, 2071-2079. |
| doi_str_mv | 10.1038/sj.gt.3301327 |
| format | Article |
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C ; CHUNG, L. W. K ; KONDO, S</creator><creatorcontrib>KOMATA, T ; KONDO, Y ; KOGA, S ; KO, S. C ; CHUNG, L. W. K ; KONDO, S</creatorcontrib><description>Malignant gliomas of astrocytic origin have commonly expressed several features such as alterations in the tumor-suppressor gene p53 or p16 or the acquisition of telomerase activity, which are distinctive from astrocytes. Therefore, restoration of the tumor-suppressor gene or telomerase inhibition is expected to provide a cure for malignant gliomas. We have recently demonstrated that the treatment with a 19-mer antisense oligonucleotide against human telomerase RNA linked to a 2',5'-oligoadenylate (2-5A-anti-hTR) inhibited the growth of malignant glioma cells. From a therapeutic point of view, it is very important to investigate the antitumor efficacy of 2-5A-anti-hTR combined with the restoration of p53 or p16 gene. In this study, we evaluated the antitumor effect of 2-5A-anti-hTR in combination with recombinant adenoviruses bearing p53, its associated p21WAF1/CIP1, or p16CDKN2 gene (Ad5CMV-p53, Ad5CMV-p21, or Ad5CMV-p16) against malignant glioma cells in vitro and in vivo. Five malignant glioma cell lines expressing the mutant p53 gene (A172, GB-1, T98G, U251-MG and U373-MG) were more sensitive to the combination of 2-5A-anti-hTR and Ad5CMV-p53 than to other combinations. The additive effect of the combination therapy was due to induction of caspase-dependent apoptosis and cell growth arrest. Furthermore, the 2-5A-anti-hTR treatment when combined with Ad5CMV-p53 showed greater efficacy against subcutaneous U251-MG tumors in nude mice. In contrast, U87-MG cells expressing the wild-type p53 gene were insensitive to Ad5CMV-p53, although the treatment with 2-5A-anti-hTR was significantly effective. These results indicate that combining 2-5A-anti-hTR with Ad5CMV-p53 has the most therapeutic potential for malignant gliomas with mutant p53. For tumors exhibiting wild-type p53, it may be useful to treat with 2-5A-anti-hTR. Gene Therapy (2000) 7, 2071-2079.</description><identifier>ISSN: 0969-7128</identifier><identifier>EISSN: 1476-5462</identifier><identifier>DOI: 10.1038/sj.gt.3301327</identifier><identifier>PMID: 11223987</identifier><language>eng</language><publisher>Basingstoke: Nature Publishing Group</publisher><subject>2',5'-oligoadenylate ; Adenoviridae - genetics ; Adenovirus ; Adenoviruses ; Animals ; Antisense oligonucleotides ; Antisense RNA ; Antitumor activity ; Apoptosis ; Astrocytes ; Biological and medical sciences ; Biotechnology ; Brain tumors ; Caspase ; CDKN2 gene ; Central Nervous System Neoplasms - pathology ; Central Nervous System Neoplasms - therapy ; CIP gene ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclins - genetics ; Flow Cytometry ; Fundamental and applied biological sciences. Psychology ; Gene therapy ; Genes, p16 ; Genes, p53 ; Genetic Therapy - methods ; Genetic Vectors - administration & dosage ; Glioma ; Glioma - pathology ; Glioma - therapy ; Glioma cells ; Health. 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Economical aspects ; Male ; Mice ; Mice, Nude ; Mutants ; Neoplasms, Experimental - therapy ; p16 gene ; p16 Protein ; p16CDKN2 gene ; p21 gene ; p21WAF1/CIP gene ; p53 gene ; p53 Protein ; RNA, Antisense - administration & dosage ; Telomerase ; Telomerase - genetics ; Tumor Cells, Cultured ; Tumors ; WAF1 gene</subject><ispartof>Gene therapy, 2000-12, Vol.7 (24), p.2071-2079</ispartof><rights>2001 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Dec 2000</rights><rights>Macmillan Publishers Limited 2000.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-12a6c2d1c0feb783f28c47384386ad59d0c37b02f06214f0502db59189fb1a93</citedby><cites>FETCH-LOGICAL-c442t-12a6c2d1c0feb783f28c47384386ad59d0c37b02f06214f0502db59189fb1a93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=898536$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11223987$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KOMATA, T</creatorcontrib><creatorcontrib>KONDO, Y</creatorcontrib><creatorcontrib>KOGA, S</creatorcontrib><creatorcontrib>KO, S. C</creatorcontrib><creatorcontrib>CHUNG, L. W. K</creatorcontrib><creatorcontrib>KONDO, S</creatorcontrib><title>Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53</title><title>Gene therapy</title><addtitle>Gene Ther</addtitle><description>Malignant gliomas of astrocytic origin have commonly expressed several features such as alterations in the tumor-suppressor gene p53 or p16 or the acquisition of telomerase activity, which are distinctive from astrocytes. Therefore, restoration of the tumor-suppressor gene or telomerase inhibition is expected to provide a cure for malignant gliomas. We have recently demonstrated that the treatment with a 19-mer antisense oligonucleotide against human telomerase RNA linked to a 2',5'-oligoadenylate (2-5A-anti-hTR) inhibited the growth of malignant glioma cells. From a therapeutic point of view, it is very important to investigate the antitumor efficacy of 2-5A-anti-hTR combined with the restoration of p53 or p16 gene. In this study, we evaluated the antitumor effect of 2-5A-anti-hTR in combination with recombinant adenoviruses bearing p53, its associated p21WAF1/CIP1, or p16CDKN2 gene (Ad5CMV-p53, Ad5CMV-p21, or Ad5CMV-p16) against malignant glioma cells in vitro and in vivo. Five malignant glioma cell lines expressing the mutant p53 gene (A172, GB-1, T98G, U251-MG and U373-MG) were more sensitive to the combination of 2-5A-anti-hTR and Ad5CMV-p53 than to other combinations. The additive effect of the combination therapy was due to induction of caspase-dependent apoptosis and cell growth arrest. Furthermore, the 2-5A-anti-hTR treatment when combined with Ad5CMV-p53 showed greater efficacy against subcutaneous U251-MG tumors in nude mice. In contrast, U87-MG cells expressing the wild-type p53 gene were insensitive to Ad5CMV-p53, although the treatment with 2-5A-anti-hTR was significantly effective. These results indicate that combining 2-5A-anti-hTR with Ad5CMV-p53 has the most therapeutic potential for malignant gliomas with mutant p53. For tumors exhibiting wild-type p53, it may be useful to treat with 2-5A-anti-hTR. Gene Therapy (2000) 7, 2071-2079.</description><subject>2',5'-oligoadenylate</subject><subject>Adenoviridae - genetics</subject><subject>Adenovirus</subject><subject>Adenoviruses</subject><subject>Animals</subject><subject>Antisense oligonucleotides</subject><subject>Antisense RNA</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Astrocytes</subject><subject>Biological and medical sciences</subject><subject>Biotechnology</subject><subject>Brain tumors</subject><subject>Caspase</subject><subject>CDKN2 gene</subject><subject>Central Nervous System Neoplasms - pathology</subject><subject>Central Nervous System Neoplasms - therapy</subject><subject>CIP gene</subject><subject>Cyclin-Dependent Kinase Inhibitor p21</subject><subject>Cyclins - genetics</subject><subject>Flow Cytometry</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene therapy</subject><subject>Genes, p16</subject><subject>Genes, p53</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - administration & dosage</subject><subject>Glioma</subject><subject>Glioma - pathology</subject><subject>Glioma - therapy</subject><subject>Glioma cells</subject><subject>Health. Pharmaceutical industry</subject><subject>Humans</subject><subject>Industrial applications and implications. Economical aspects</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Mutants</subject><subject>Neoplasms, Experimental - therapy</subject><subject>p16 gene</subject><subject>p16 Protein</subject><subject>p16CDKN2 gene</subject><subject>p21 gene</subject><subject>p21WAF1/CIP gene</subject><subject>p53 gene</subject><subject>p53 Protein</subject><subject>RNA, Antisense - administration & dosage</subject><subject>Telomerase</subject><subject>Telomerase - genetics</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><subject>WAF1 gene</subject><issn>0969-7128</issn><issn>1476-5462</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkc2LFDEQxYO4uOPq0asEF7z1mO-kj8PgqrC4IHsP6XQym6E7GZP0yv73ZphBRRBPVVC_evWKB8AbjNYYUfWh7Ne7uqYUYUrkM7DCTIqOM0GegxXqRd9JTNQleFnKHiHEpCIvwCXGhNBeyRVI2zQPIZoaUoT1wWVzeILJw9lMYRdNrHA3hTQbaN00Ffgj1AdIOr7p2igUF4uD1U1pbout_fZ1A00cYXb2JNv2zehiegx5KfDA6Stw4c1U3OtzvQL3Nx_vt5-727tPX7ab284yRmqHiRGWjNgi7wapqCfKMkkVo0qYkfcjslQOiHgkCGYecUTGgfdY9X7ApqdX4P1J9pDT98WVqudQji-Y6NJStCRcSorYf0EspURc8QZe_wXu05Jj-0ETwZjAXPW4Ue_-SWEliRL4eLM7QTanUrLz-pDDbPKTxkgfQ9Vlr3dVn0Nt_Nuz6DLMbvxNn1P8w5sp1kw-m2hD-cWpvvkX9CdTzqg_</recordid><startdate>20001201</startdate><enddate>20001201</enddate><creator>KOMATA, T</creator><creator>KONDO, Y</creator><creator>KOGA, S</creator><creator>KO, S. 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K ; KONDO, S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-12a6c2d1c0feb783f28c47384386ad59d0c37b02f06214f0502db59189fb1a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>2',5'-oligoadenylate</topic><topic>Adenoviridae - genetics</topic><topic>Adenovirus</topic><topic>Adenoviruses</topic><topic>Animals</topic><topic>Antisense oligonucleotides</topic><topic>Antisense RNA</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Astrocytes</topic><topic>Biological and medical sciences</topic><topic>Biotechnology</topic><topic>Brain tumors</topic><topic>Caspase</topic><topic>CDKN2 gene</topic><topic>Central Nervous System Neoplasms - pathology</topic><topic>Central Nervous System Neoplasms - therapy</topic><topic>CIP gene</topic><topic>Cyclin-Dependent Kinase Inhibitor p21</topic><topic>Cyclins - genetics</topic><topic>Flow Cytometry</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene therapy</topic><topic>Genes, p16</topic><topic>Genes, p53</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors - administration & dosage</topic><topic>Glioma</topic><topic>Glioma - pathology</topic><topic>Glioma - therapy</topic><topic>Glioma cells</topic><topic>Health. Pharmaceutical industry</topic><topic>Humans</topic><topic>Industrial applications and implications. Economical aspects</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Mutants</topic><topic>Neoplasms, Experimental - therapy</topic><topic>p16 gene</topic><topic>p16 Protein</topic><topic>p16CDKN2 gene</topic><topic>p21 gene</topic><topic>p21WAF1/CIP gene</topic><topic>p53 gene</topic><topic>p53 Protein</topic><topic>RNA, Antisense - administration & dosage</topic><topic>Telomerase</topic><topic>Telomerase - genetics</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><topic>WAF1 gene</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KOMATA, T</creatorcontrib><creatorcontrib>KONDO, Y</creatorcontrib><creatorcontrib>KOGA, S</creatorcontrib><creatorcontrib>KO, S. C</creatorcontrib><creatorcontrib>CHUNG, L. W. 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We have recently demonstrated that the treatment with a 19-mer antisense oligonucleotide against human telomerase RNA linked to a 2',5'-oligoadenylate (2-5A-anti-hTR) inhibited the growth of malignant glioma cells. From a therapeutic point of view, it is very important to investigate the antitumor efficacy of 2-5A-anti-hTR combined with the restoration of p53 or p16 gene. In this study, we evaluated the antitumor effect of 2-5A-anti-hTR in combination with recombinant adenoviruses bearing p53, its associated p21WAF1/CIP1, or p16CDKN2 gene (Ad5CMV-p53, Ad5CMV-p21, or Ad5CMV-p16) against malignant glioma cells in vitro and in vivo. Five malignant glioma cell lines expressing the mutant p53 gene (A172, GB-1, T98G, U251-MG and U373-MG) were more sensitive to the combination of 2-5A-anti-hTR and Ad5CMV-p53 than to other combinations. The additive effect of the combination therapy was due to induction of caspase-dependent apoptosis and cell growth arrest. Furthermore, the 2-5A-anti-hTR treatment when combined with Ad5CMV-p53 showed greater efficacy against subcutaneous U251-MG tumors in nude mice. In contrast, U87-MG cells expressing the wild-type p53 gene were insensitive to Ad5CMV-p53, although the treatment with 2-5A-anti-hTR was significantly effective. These results indicate that combining 2-5A-anti-hTR with Ad5CMV-p53 has the most therapeutic potential for malignant gliomas with mutant p53. For tumors exhibiting wild-type p53, it may be useful to treat with 2-5A-anti-hTR. Gene Therapy (2000) 7, 2071-2079.</abstract><cop>Basingstoke</cop><pub>Nature Publishing Group</pub><pmid>11223987</pmid><doi>10.1038/sj.gt.3301327</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Gene therapy, 2000-12, Vol.7 (24), p.2071-2079 |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Springer Nature - Complete Springer Journals |
| subjects | 2',5'-oligoadenylate Adenoviridae - genetics Adenovirus Adenoviruses Animals Antisense oligonucleotides Antisense RNA Antitumor activity Apoptosis Astrocytes Biological and medical sciences Biotechnology Brain tumors Caspase CDKN2 gene Central Nervous System Neoplasms - pathology Central Nervous System Neoplasms - therapy CIP gene Cyclin-Dependent Kinase Inhibitor p21 Cyclins - genetics Flow Cytometry Fundamental and applied biological sciences. Psychology Gene therapy Genes, p16 Genes, p53 Genetic Therapy - methods Genetic Vectors - administration & dosage Glioma Glioma - pathology Glioma - therapy Glioma cells Health. Pharmaceutical industry Humans Industrial applications and implications. Economical aspects Male Mice Mice, Nude Mutants Neoplasms, Experimental - therapy p16 gene p16 Protein p16CDKN2 gene p21 gene p21WAF1/CIP gene p53 gene p53 Protein RNA, Antisense - administration & dosage Telomerase Telomerase - genetics Tumor Cells, Cultured Tumors WAF1 gene |
| title | Combination therapy of malignant glioma cells with 2-5A-antisense telomerase RNA and recombinant adenovirus p53 |
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