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Inhibition of the erbB-2 tyrosine kinase receptor in breast cancer cells by phosphoromonothioate and phosphorodithioate antisense oligonucleotides. 1996

J P Vaughn, and J Stekler, and S Demirdji, and J K Mills, and M H Caruthers, and J D Iglehart, and J R Marks
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.

Antisense activity against erbB-2 of a variety of sulfur-modified oligonucleotides was examined in a breast cancer cell line which overexpresses this oncogene. Using a 15 base anti-erbB-2 sequence previously shown to be effective, various backbone configurations containing phosphoromonothioate or phosphorodithioate linkages were evaluated for antisense activity by a two-color flow cytometric assay. This sequence was effective in inhibiting the production of erbB-2 protein when it was configured as a monothioate at each linkage and as an alternating dithioate/phosphodiester. Both of these compounds were also able to specifically inhibit erbB-2 mRNA expression, indicative of RNase H-mediated activity. The same sequence protected by either three dithioate or three monothioate linkages at each end was ineffective as an antisense reagent, suggesting that endonuclease activity is a significant determinant of the stability of oligonucleotides. Finally, the erbB-2 sequence target was shifted in an effort to improve antisense activity. A new lead sequence was identified that was significantly more effective in inhibiting erbB-2 protein levels and retained activity at lower concentrations.

UI MeSH Term Description Entries
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D001943 Breast Neoplasms Tumors or cancer of the human BREAST. Breast Cancer,Breast Tumors,Cancer of Breast,Breast Carcinoma,Cancer of the Breast,Human Mammary Carcinoma,Malignant Neoplasm of Breast,Malignant Tumor of Breast,Mammary Cancer,Mammary Carcinoma, Human,Mammary Neoplasm, Human,Mammary Neoplasms, Human,Neoplasms, Breast,Tumors, Breast,Breast Carcinomas,Breast Malignant Neoplasm,Breast Malignant Neoplasms,Breast Malignant Tumor,Breast Malignant Tumors,Breast Neoplasm,Breast Tumor,Cancer, Breast,Cancer, Mammary,Cancers, Mammary,Carcinoma, Breast,Carcinoma, Human Mammary,Carcinomas, Breast,Carcinomas, Human Mammary,Human Mammary Carcinomas,Human Mammary Neoplasm,Human Mammary Neoplasms,Mammary Cancers,Mammary Carcinomas, Human,Neoplasm, Breast,Neoplasm, Human Mammary,Neoplasms, Human Mammary,Tumor, Breast
D005260 Female Females
D005434 Flow Cytometry Technique using an instrument system for making, processing, and displaying one or more measurements on individual cells obtained from a cell suspension. Cells are usually stained with one or more fluorescent dyes specific to cell components of interest, e.g., DNA, and fluorescence of each cell is measured as it rapidly transverses the excitation beam (laser or mercury arc lamp). Fluorescence provides a quantitative measure of various biochemical and biophysical properties of the cell, as well as a basis for cell sorting. Other measurable optical parameters include light absorption and light scattering, the latter being applicable to the measurement of cell size, shape, density, granularity, and stain uptake. Cytofluorometry, Flow,Cytometry, Flow,Flow Microfluorimetry,Fluorescence-Activated Cell Sorting,Microfluorometry, Flow,Cell Sorting, Fluorescence-Activated,Cell Sortings, Fluorescence-Activated,Cytofluorometries, Flow,Cytometries, Flow,Flow Cytofluorometries,Flow Cytofluorometry,Flow Cytometries,Flow Microfluorometries,Flow Microfluorometry,Fluorescence Activated Cell Sorting,Fluorescence-Activated Cell Sortings,Microfluorimetry, Flow,Microfluorometries, Flow,Sorting, Fluorescence-Activated Cell,Sortings, Fluorescence-Activated Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001483 Base Sequence The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence. DNA Sequence,Nucleotide Sequence,RNA Sequence,DNA Sequences,Base Sequences,Nucleotide Sequences,RNA Sequences,Sequence, Base,Sequence, DNA,Sequence, Nucleotide,Sequence, RNA,Sequences, Base,Sequences, DNA,Sequences, Nucleotide,Sequences, RNA
D014407 Tumor Cells, Cultured Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely. Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D016376 Oligonucleotides, Antisense Short fragments of DNA or RNA that are used to alter the function of target RNAs or DNAs to which they hybridize. Anti-Sense Oligonucleotide,Antisense Oligonucleotide,Antisense Oligonucleotides,Anti-Sense Oligonucleotides,Anti Sense Oligonucleotide,Anti Sense Oligonucleotides,Oligonucleotide, Anti-Sense,Oligonucleotide, Antisense,Oligonucleotides, Anti-Sense
D018719 Receptor, ErbB-2 A cell surface protein-tyrosine kinase receptor that is overexpressed in a variety of ADENOCARCINOMAS. It has extensive homology to and heterodimerizes with the EGF RECEPTOR, the ERBB-3 RECEPTOR, and the ERBB-4 RECEPTOR. Activation of the erbB-2 receptor occurs through heterodimer formation with a ligand-bound erbB receptor family member. HER-2 Proto-Oncogene Protein,Proto-Oncogene Protein HER-2,Proto-Oncogene Protein p185(neu),c-erbB-2 Protein,erbB-2 Proto-Oncogene Protein,erbB-2 Receptor Protein-Tyrosine Kinase,neu Proto-Oncogene Protein,Antigens, CD340,CD340 Antigen,Erb-b2 Receptor Tyrosine Kinases,Metastatic Lymph Node Gene 19 Protein,Neu Receptor,Oncogene Protein HER-2,Proto-Oncogene Proteins c-erbB-2,Proto-oncogene Protein Neu,Receptor, Neu,Receptors, erbB-2,Tyrosine Kinase-type Cell Surface Receptor HER2,p185(c-neu),p185erbB2 Protein,CD340 Antigens,Erb b2 Receptor Tyrosine Kinases,ErbB-2 Receptor,HER 2 Proto Oncogene Protein,Oncogene Protein HER 2,Proto Oncogene Protein HER 2,Proto Oncogene Proteins c erbB 2,Proto-Oncogene Protein, HER-2,Proto-Oncogene Protein, erbB-2,Proto-Oncogene Protein, neu,Tyrosine Kinase type Cell Surface Receptor HER2,c erbB 2 Protein,erbB 2 Proto Oncogene Protein,erbB 2 Receptor Protein Tyrosine Kinase,erbB-2 Receptors,neu Proto Oncogene Protein
D020794 Receptor Protein-Tyrosine Kinases A class of cellular receptors that have an intrinsic PROTEIN-TYROSINE KINASE activity. PTK Receptor,Receptors, Protein-Tyrosine Kinase,Tyrosine Kinase Linked Receptor,Tyrosine Kinase Linked Receptors,Tyrosine Kinase Receptor,Tyrosine Kinase Receptors,PTK Receptors,Protein-Tyrosine Kinase Receptor,Receptor Protein-Tyrosine Kinase,Kinase Receptor, Tyrosine,Kinase, Receptor Protein-Tyrosine,Kinases, Receptor Protein-Tyrosine,Protein-Tyrosine Kinase Receptors,Protein-Tyrosine Kinase, Receptor,Protein-Tyrosine Kinases, Receptor,Receptor Protein Tyrosine Kinase,Receptor Protein Tyrosine Kinases,Receptor, PTK,Receptor, Protein-Tyrosine Kinase,Receptor, Tyrosine Kinase,Receptors, PTK,Receptors, Protein Tyrosine Kinase

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