Therapeutic Applications of Oligonucleotides

St, Crooke

doi:10.1146/annurev.pa.32.040192.001553

Cited by 398 publications

(144 citation statements)

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“…These modifications have been shown previously to enhance the potency of antisense oligonucleotides targeting mRNAs encoding other proteins (22,23). Because phosphorothioate oligonucleotides have been shown to commonly act through RNase H-dependent mRNA cleavage mechanism in cells (26), the ability of each oligodeoxynucleotide to specifically inhibit the expression of PP2A was initially determined by Northern blot analysis probing for levels of PP2A mRNA. PP2A mRNA was detected using PP2Aa-or PP2Ah-specific cDNA probes, which forms a hybrid with a single transcript of the target mRNA.…”

Section: Cantharidin Treatment Induces Abnormal Mitotic Spindle Formamentioning

confidence: 99%

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Bonness

Aragon

Rutland³

et al. 2006

Molecular Cancer Therapeutics

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Cantharidin, a natural vesicant, inhibits the activity of several PPP family phosphatases, displays antitumor activity, and induces apoptosis in many types of tumor cells. However, the molecular mechanisms underlying the antitumor activity of cantharidin are not clear. Here, doseresponse studies confirm a strong correlation between the suppression of phosphatase activity and cell death. Flow cytometry analysis indicates that before apoptosis, cantharidin delays cell cycle progression following DNA replication with no apparent effect on G 1 -S or S-G 2 phase progression. In contrast, studies with double thymidinesynchronized populations of cells indicate that cantharidin can rapidly arrest growth when added during G 2 or early M phase. Immunostaining indicates that cell cycle arrest occurs before the completion of mitosis and is associated with the appearance of aberrant mitotic spindles. Live cell imaging with time-lapse microscopy shows that cantharidin disrupts the metaphase alignment of chromosomes and produces a prolonged mitotic arrest, with the onset of apoptosis occurring before the onset of anaphase. To explore the contribution of individual phosphatases, antisense oligonucleotides and small interfering RNA were developed to suppress the expression of cantharidinsensitive phosphatases. The suppression of PP2AA, but not PP2AB, is sufficient to induce metaphase arrest, during which time lagging chromosomes are observed moving between the spindle poles and the metaphase plate. Immunostaining revealed slightly abnormal, yet predominately bipolar, mitotic spindles. Nonetheless, after a 10-to 15-hour delay, the cells enter anaphase, suggesting that an additional cantharidin-sensitive phosphatase is involved in the progression from metaphase into anaphase or to prevent the onset of apoptosis in cells arrested during mitosis.

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Section: Cantharidin Treatment Induces Abnormal Mitotic Spindle Formamentioning

confidence: 99%

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Bonness

Aragon

Rutland³

et al. 2006

Molecular Cancer Therapeutics

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“…1). Native (phosphodiester) antisense oligonucleotides have generally been reported to have little (2) or no inhibitory effect against HIV-1 in culture (3)(4)(5) because they are rapidly degraded in culture medium (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Antisense oligonucleotides in solution or encapsulated in immunoliposomes inhibit replication of HIV-1 by several different mechanisms

Zelphati¹,

Imbach²,

Signoret³

et al. 1994

Nucl Acids Res

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Phosphodiester and phosphorothioate oligonucleotides in a and , configurations directed against the initiation codon region of the HIV-1 rev gene were evaluated for their ability to inhibit HIV-1 replication in acutely and chronically infected human CEM cells. Encapsulation in antibody-targeted liposomes (immunoliposomes) permitted intracellular delivery and distinction between oligonucleotide-mediated inhibition of viral entry and intracellular effects on viral RNA. Our results are consistent with four mechanisms of antiviral activity for these antisense oligonucleotides: (i) interference with virus-mediated cell fusion by free but not liposome-encapsulated phosphorothioate oligonucleotides of any sequence; (ii) interference with reverse transcription in a sequence non-specific manner by phosphorothioate oligonucleotides in a and a configurations; (iii) interference with viral reverse transcription in a sequence-specific and RNase-H-independent manner by a and (3 phosphodiester oligonucleotides; (iv) interference with viral mRNA in a sequence-specific and RNase-H-dependent manner by 0-phosphorothioate oligonucleotides.

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“…The strong binding affinity of ONs to their mRNA targets makes these compounds potent and specific inhibitors of gene expression (6). To take advantage of this specificity, however, the ONs must also be delivered selectively to the intended target cells, where they can find and bind to their target mRNA sequences.…”

mentioning

confidence: 99%

Antisense Inhibition of Silica-induced Tumor Necrosis Factor in Alveolar Macrophages

Rojanasakul¹,

Weissman

Shi

et al. 1997

Journal of Biological Chemistry

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Tumor necrosis factor-␣ (TNF␣) has been shown to play an important role in the pathogenesis of silicotic fibrosis. In this study, antisense oligonucleotides targeted to TNF␣ mRNA were used to inhibit silica-induced TNF␣ gene expression in alveolar macrophages. To achieve macrophage-specific oligonucleotide delivery, a molecular conjugate consisting of mannosylated polylysine that exploits endocytosis via the macrophage mannose receptor was used. Complexes were formed between the mannosylated polylysine and oligonucleotides and added to the cells in the presence of silica. Enzyme-linked immunoadsorbent assay showed that the complex consisting of the conjugate and antisense oligomer effectively inhibited TNF␣ production, whereas the oligomer alone had much less effect. Reverse transcriptase-polymerase chain reaction analysis revealed that the reduction in TNF␣ secretion was associated with specific ablation of targeted TNF␣ mRNA. The conjugate alone or conjugate complexed with inverted or sense sequence oligonucleotide had no effect. The promoting effect of the conjugate on antisense activity was shown to be due to enhanced cellular uptake of the oligomer via mannose receptor-mediated endocytosis. Cells lacking mannose receptors showed no susceptibility to the conjugate treatment. These results indicate that effective and selective inhibition of macrophage TNF␣ expression can be achieved using the antisense mannosylated polylysine system.

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Therapeutic Applications of Oligonucleotides

Cited by 398 publications

References 0 publications

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Antisense oligonucleotides in solution or encapsulated in immunoliposomes inhibit replication of HIV-1 by several different mechanisms

Antisense Inhibition of Silica-induced Tumor Necrosis Factor in Alveolar Macrophages

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