Enhanced activity of an antisense oligonucleotide targeting murine protein kinase C-alpha by the incorporation of 2'-O-propyl modifications

McKay, Robert A.; Cummins, Lendell L.; Graham, Mark; Lesnik, Elena A.; Owens, Stephen R.; Winniman, Michael; Dean, Nicholas M.

doi:10.1093/nar/24.3.411

Cited by 59 publications

(28 citation statements)

References 24 publications

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“…In Vitro Nuclease Stability-Oligonucleotide resistance to snake venom 3Ј-phosphodiesterase was determined as described previously (11). Briefly, the oligonucleotides were gel purified and 5Ј-end-labeled with high performance liquid chromatography-purified [␥-…”

Section: Methodsmentioning

confidence: 99%

“…The long half-lives of some PKC proteins (and other proteins which have been targeted with antisense oligonucleotides) have proven problematic, as we have found that the most widely used oligonucleotide modification available, the phosphorothioate (PϭS) oligodeoxynucleotide, is metabolized in cells over time. This leads to a loss of activity over a 48 -72-h period, which can make inhibition of some PKC isozymes difficult (7,8,11).…”

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confidence: 99%

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Characterization of a Potent and Specific Class of Antisense Oligonucleotide Inhibitor of Human Protein Kinase C-α Expression

McKay

Miraglia

Cummins³

et al. 1999

Journal of Biological Chemistry

204

140

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The use of antisense oligonucleotides to inhibit the expression of targeted mRNA sequences is becoming increasingly commonplace. Although effective, the most widely used oligonucleotide modification (phosphorothioate) has some limitations. In previous studies we have described a 20-mer phosphorothioate oligodeoxynucleotide inhibitor of human protein kinase C-␣ expression. In an effort to identify improved antisense inhibitors of protein kinase C expression, a series of 2 modifications have been incorporated into the protein kinase C-␣ targeting oligonucleotide, and the effects on oligonucleotide biophysical characteristics and pharmacology evaluated. The incorporation of 2-O-(2-methoxy)ethyl chemistry resulted in a number of significant improvements in oligonucleotide characteristics. These include an increase in hybridization affinity toward a complementary RNA (1.5°C per modification) and an increase in resistance toward both 3-exonuclease and intracellular nucleases. These improvements result in a substantial increase in oligonucleotide potency (>20-fold after 72 h). The most active compound identified was used to examine the role played by protein kinase C-␣ in mediating the phorbol ester-induced changes in c-fos, c-jun, and junB expression in A549 lung epithelial cells. Depletion of protein kinase C-␣ protein expression by this oligonucleotide lead to a reduction in c-jun expression but not c-fos or junB. These results demonstrate that 2-O-(2-methoxy)ethyl-modified antisense oligonucleotides are 1) effective inhibitors of protein kinase C-␣ expression, and 2) represent a class of antisense oligonucleotide which are much more effective inhibitors of gene expression than the widely used phosphorothioate antisense oligodeoxynucleotides.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Characterization of a Potent and Specific Class of Antisense Oligonucleotide Inhibitor of Human Protein Kinase C-α Expression

McKay

Miraglia

Cummins³

et al. 1999

Journal of Biological Chemistry

204

140

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“…Indeed, the antisense oligonucleotide ISIS 3521, an oligonucleotide of 20-mer that impedes the expression of PKCα, markedly reduced tumor proliferation and invasion in laboratory animals [134,135]. ISIS 3521 is now undergoing clinical testing [136,137].…”

Section: Pkc-inhibiting Agents: Preclinical and Clinical Studiesmentioning

confidence: 99%

Targeting Protein Kinase C: New Therapeutic Opportunities Against High-Grade Malignant Gliomas?

et al. 2002

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A large body of evidence suggests that the abnormal phenotype of neoplastic astrocytes, including their excessive proliferation rate and high propensity to invade surrounding tissues, results from mutations in critical genes involved in key cellular events. These genetic alterations can affect cell-surface-associated receptors, elements of signaling pathways, or components of the cell cycle clock, conferring a gain or a loss of relevant metabolic functions of the cells. The understanding of such phenomena may allow the development of more efficacious forms of cancer treatment. Examples are therapies specifically directed against overexpressed epidermal growth factor receptor, hyperactive Ras, excessively stimulated Raf-1, overproduced ornithine decarboxylase, or aberrantly activated cyclindependent kinases. The applicability of some of these approaches is now being assessed in patients suffering from primary malignant central nervous system tumors that are not amenable to current therapeutic modalities. Another potentially useful therapeutic strategy against such tumors involves the inhibition of hyperactive or overexpressed protein kinase C (PKC). This strategy is justified by the decrease in cell proliferation and invasion following inhibition of the activity of this enzyme observed in preclinical glioma models. Thus, interference with PKC activity may represent a novel form of experimental cancer treatment that may simultaneously restrain the hyperproliferative state and the invasive capacity of high-grade malignant gliomas without inducing the expected toxicity of classical cytotoxic agents. Of note, the experimental use of PKC-inhibiting agents in patients with refractory high-grade malignant gliomas has indeed led to some clinical responses. The present paper reviews the current status of the biochemistry and molecular biology of PKC, as well as the possibilities for developing novel anti-PKC-based therapies for central nervous system malignancies. The

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“…An alternative approach is the use of ASOs (Dolnik 1991, Crooke 1995. Because the specificity of ASOs is derived from selective hybridization to a target mRNA sequence, it is possible to design oligonucteotide inhibitors of members of a closely related gene family such as PKC (Dean & McKay 1994, McKay et al 1996. ISIS 3521 is a 20-mer phosphorothioate oligodeoxynucleotide (ODN) that hybridizes to the 3 0 -untranslated region of human PKC mRNA, resulting in its degradation by RNase H. Preclinical evidence of antitumor activity and PKC inhibition by an antisense mechanism was demonstrated in a variety of in vitro and in vivo experiments (Dean et al 1994).…”

Section: Protein Kinase C (Pkc) and Isis 3521mentioning

confidence: 99%

Therapeutic integration of signal transduction targeting agents and conventional anti-cancer treatments.

Melisi

Troiani²,

Damiano³

et al. 2004

Endocr Relat Cancer

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The currently available treatment of cancer patients is based on the use of cytotoxic drugs and/or of ionizing radiations, which have potent antitumor activity, but also cause clinically relevant side effects, since they affect cellular targets that are common to both cancer cells and normal proliferating cells. In the past 20 years, the discoveries on the molecular mechanisms of cancer development and progression have prompted the search for agents which are more selective for cancer cell molecular targets. The possibility of combining conventional cytotoxic drugs with novel agents that specifically interfere with key pathways controlling cancer cell survival, proliferation, invasion and/or metastatic spreading has generated a wide interest. This could be a promising therapeutic approach for several reasons. First, since the cellular targets for these agents and their mechanism(s) of action are different from those of cytotoxic drugs, it is possible for their combination with chemotherapy without crossresistance. Second, alterations in the expression and/or the activity of genes that regulate mitogenic signals not only can directly cause perturbation of cell growth, but also may affect the sensitivity of cancer cells to conventional chemotherapy and radiotherapy. In this review, we will discuss the biologic bases of the combination of molecular targeted drugs with conventional medical cancer treatments and the available results of the first series of clinical trials in cancer patients.

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Enhanced activity of an antisense oligonucleotide targeting murine protein kinase C-alpha by the incorporation of 2'-O-propyl modifications

Cited by 59 publications

References 24 publications

Characterization of a Potent and Specific Class of Antisense Oligonucleotide Inhibitor of Human Protein Kinase C-α Expression

Characterization of a Potent and Specific Class of Antisense Oligonucleotide Inhibitor of Human Protein Kinase C-α Expression

Targeting Protein Kinase C: New Therapeutic Opportunities Against High-Grade Malignant Gliomas?

Therapeutic integration of signal transduction targeting agents and conventional anti-cancer treatments.

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