Document Detail

Inhibition of human collagenase activity by antisense oligonucleoside methylphosphonates.
MedLine Citation:
PMID:  9012863     Owner:  NLM     Status:  MEDLINE    
Oligodeoxyribonucleoside methylphosphonates (d-OMP) were synthesized whose sequences are complementary to sequences found in the mRNA coding for the 72-kDa (MMP-2) or 92-kDA (MMP-9) forms of human collagenase i.v., matrix metalloproteinases (MMP) whose excessive secretion correlates with the metastatic potential of tumor cells. The effects of these oligomers on MMP-2 and MMP-9 activities secreted by HT1080 cells, a human fibrosarcoma cell line, were studied using a gelatin zymography assay. A d-OMP, M2.3, complementary to nucleotides 14 to 28 of the initiation codon region of MMP-2 mRNA selectively inhibited MMP-2 activity, whereas a d-OMP, M9.1, which was targeted to nucleotides -19 to -5 of the 5'-untranslated region of MMP-9 mRNA selectively inhibited MMP-9 activity over the concentration range 5-50 microM. At 100 microM concentration, both M2.3 and M9.1 inhibited the activities of both MMP-2 and MMP-9. These oligomers were completely stable under cell culture conditions and did not appear to adversely affect cell growth after 48 hours at concentrations up to 100 microM, although 100 microM M9.1 did reduce cell growth 30% after prolonged, 120-hours exposure. Other d-OMP tested either had no effect on collagenase activity or inhibited both MMP-2 and MMP-9 activities. The latter oligomer was complementary to MMP-2 mRNA and partially complementary to MMP-9 mRNA. Oligomer M2.3 was also tested for its effects on the morphology of malignant human lung cells, BZR-T33, growing on the surface of reconstituted base membrane, Matrigel, in culture. In absence of oligomer, the BZR-T33 cells formed extensive networks indicative of the ability of the cells to invade the Matrigel substrate. In the presence of 100 microM M2.3, BZR-T33 formed colonies of rounded cells, a morphology typical of noninvasive cells. Other non-complementary d-OMP had no effect on the morphology of BZR-T33 under these conditions. These results suggest that antisense d-OMP may be useful for inhibiting expression of collagenase in human tumor cells and for studying the role of collagenase expression in tumor cell metastasis.
R K Delong; P S Miller
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Antisense & nucleic acid drug development     Volume:  6     ISSN:  1087-2906     ISO Abbreviation:  Antisense Nucleic Acid Drug Dev.     Publication Date:  1996  
Date Detail:
Created Date:  1997-04-15     Completed Date:  1997-04-15     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9606142     Medline TA:  Antisense Nucleic Acid Drug Dev     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  273-80     Citation Subset:  IM    
Department of Biochemistry, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
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MeSH Terms
Collagenases / antagonists & inhibitors*,  genetics
Electrophoresis, Polyacrylamide Gel
Enzyme Inhibitors / pharmacology*
Gelatinases / antagonists & inhibitors*,  genetics
Lung Neoplasms / pathology
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Metalloendopeptidases / antagonists & inhibitors*,  genetics
Neoplasm Metastasis
Oligonucleotides, Antisense / pharmacology*
Organophosphorus Compounds / pharmacology*
RNA, Messenger / genetics*
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Oligonucleotides, Antisense; 0/Organophosphorus Compounds; 0/RNA, Messenger; EC 3.4.24.-/Collagenases; EC 3.4.24.-/Gelatinases; EC 3.4.24.-/Metalloendopeptidases; EC Metalloproteinase 2; EC Metalloproteinase 9

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