Document Detail

Reversal of multiple drug resistance in vitro by phosphorothioate oligonucleotides and ribozymes.
MedLine Citation:
PMID:  7756675     Owner:  NLM     Status:  MEDLINE    
In the present study we investigated the effectiveness of 14, 15 and 18 nucleotide antisense phosphorothioate oligonucleotides (S-ODNs) directed to four different regions of the published mdr-1 gene sequence to reduce the level of mdr-1 gene product (p170, P-glycoprotein) and its function in the over-expressing cell lines Lo-VoDxR, S180DxR and KBChR8-5. The highest efficiency in reduction of multiple drug resistance was obtained at a concentration of 2 microM. In proliferation assays a growth reduction of 50% was observed after exposure of doxorubicin-resistant cells to S-ODN3. p170 protein expression of the resistant cell line LoVoDxR was reduced to the level of the sensitive cell line LoVo as shown by Western blot analysis. S-ODN3 reduced the ID50 of the two human cell lines up to 60% (LoVoDxR) and 21% (KBChR8-5), respectively, but showed no effect in the murine cell line S180DxR. In contrast, S-ODN1 was most effective in the murine system (67% reduction of the ID50), less effective in LoVoDxR (34%) and exhibited no effect in cell line KBChR8-5. Based on the results with the antisense oligonucleotides, a ribozyme directed against the mRNA target region of S-ODN3 was designed. This ribozyme was able to reduce the mdr-1 mRNA in total RNA preparations from cell line LoVoDxR up to 80% after an incubation time of 6 h in the presence of 10 mM MgCl2 at pH 7.5. A modified ribozyme was investigated in cell culture and reduced chemo-resistance of the resistant cell line LoVoDxR and ex vivo cultured blasts of acute myeloid leukemia patients up to 50%.
J Bertram; K Palfner; M Killian; W Brysch; K H Schlingensiepen; W Hiddemann; M Kneba
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  6     ISSN:  0959-4973     ISO Abbreviation:  Anticancer Drugs     Publication Date:  1995 Feb 
Date Detail:
Created Date:  1995-06-26     Completed Date:  1995-06-26     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  124-34     Citation Subset:  IM    
Department of Hematology/Oncology, University Clinics, Göttingen, Germany.
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MeSH Terms
Base Sequence
Cell Division / drug effects
Doxorubicin / pharmacology
Drug Resistance, Multiple* / genetics
Genes, Neoplasm / drug effects*
Molecular Sequence Data
Neoplasm Proteins / genetics*
Oligonucleotides, Antisense / pharmacology*
P-Glycoprotein / genetics*
RNA, Catalytic / pharmacology*
RNA, Messenger / antagonists & inhibitors
RNA, Neoplasm / antagonists & inhibitors
Tamoxifen / pharmacology
Thionucleotides / pharmacology*
Tumor Cells, Cultured / drug effects
Verapamil / pharmacology
Reg. No./Substance:
0/Neoplasm Proteins; 0/Oligonucleotides, Antisense; 0/P-Glycoprotein; 0/RNA, Catalytic; 0/RNA, Messenger; 0/RNA, Neoplasm; 0/Thionucleotides; 10540-29-1/Tamoxifen; 23214-92-8/Doxorubicin; 52-53-9/Verapamil

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