| Isolation of genetic suppressor elements, inducing resistance to topoisomerase II-interactive cytotoxic drugs, from human topoisomerase II cDNA. | |
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MedLine Citation:
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PMID: 8386368 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Many cytotoxic anticancer drugs act at topoisomerase II (topo II) by stabilizing cleavable complexes with DNA formed by this enzyme. Several cell lines, selected for resistance to topo II-interactive drugs, show decreased expression or activity of topo II, suggesting that such a decrease may be responsible for drug resistance. In the present study, etoposide resistance was used as the selection strategy to isolate genetic suppressor elements (GSEs) from a retroviral library expressing random fragments of human topo II (alpha form) cDNA. Twelve GSEs were isolated, encoding either peptides corresponding to short segments of the topo II alpha molecule (2.4-6.5% of the protein) or 163- to 220-bp-long antisense RNA sequences. Expression of a GSE encoding antisense RNA led to decreased cellular expression of the topo II alpha protein. Both types of GSE induced resistance to several topo II poisons but not to drugs that do not act at topo II. These results provide direct evidence that inhibition of topo II results in resistance to topo II-interactive drugs, indicate structural domains of topo II capable of independent functional interactions, and demonstrate that expression selection of random fragments constitutes an efficient approach to the generation of GSEs in mammalian cells. |
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Authors:
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A V Gudkov; C R Zelnick; A R Kazarov; R Thimmapaya; D P Suttle; W T Beck; I B Roninson |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 90 ISSN: 0027-8424 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 1993 Apr |
Date Detail:
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Created Date: 1993-05-17 Completed Date: 1993-05-17 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 3231-5 Citation Subset: IM |
Affiliation:
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Department of Genetics, University of Illinois, Chicago 60612-7309. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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pharmacology* Base Sequence Cloning, Molecular DNA Topoisomerases, Type II / antagonists & inhibitors*, genetics* DNA, Neoplasm / genetics, isolation & purification Drug Resistance / genetics* Etoposide / pharmacology* Gene Library Genes, Suppressor* Hela Cells Humans Leukemia, Myelogenous, Chronic, BCR-ABL Positive Molecular Sequence Data Oligodeoxyribonucleotides Plasmids Polymerase Chain Reaction / methods RNA, Antisense / genetics Retroviridae / genetics Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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CA39365/CA/NCI NIH HHS; CA40333/CA/NCI NIH HHS; CA56736/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/DNA, Neoplasm; 0/Oligodeoxyribonucleotides; 0/RNA, Antisense; 33419-42-0/Etoposide; EC 5.99.1.3/DNA Topoisomerases, Type II |
| Comments/Corrections | |
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