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Antisense Oligodeoxynucleotide

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Yoon S Chochung – 1st expert on this subject based on the ideXlab platform

  • an Antisense Oligodeoxynucleotide that depletes riα subunit of cyclic amp dependent protein kinase induces growth inhibition in human cancer cells
    Cancer Research, 1993
    Co-Authors: Hiroshi Yokozaki, Giampaolo Tortora, Alfredo Budillon, Scott Meissner, Serge Beaucage, Keizaburo Miki, Yoon S Chochung


    Abstract Enhanced expression of the RI α subunit of cyclic AMP-dependent protein kinase type I has been correlated with cancer cell growth. We provide evidence that RI α is a growth-inducing protein that may be essential for neoplastic cell growth. Human colon, breast, and gastric carcinoma and neuroblastoma cell lines exposed to a 21-mer human RI α Antisense phosphorothioate Oligodeoxynucleotide (S-Oligodeoxynucleotide) exhibited growth inhibition with no sign of cytotoxicity. Mismatched sequence (random) S-Oligodeoxynucleotides of the same length exhibited no effect. The growth inhibitory effect of RI α Antisense oligomer correlated with a decrease in the RI α mRNA and protein levels and with an increase in RII β (the regulatory subunit of protein kinase type II) expression. The growth inhibition was abolished, however, when cells were exposed simultaneously to both RI α and RII β Antisense S-Oligodeoxynucleotides. The RII β Antisense S-Oligodeoxynucleotide alone, exhibiting suppression of RII β along with enhancement of RI α expression, led to slight stimulation of cell growth. These results demonstrate that two isoforms of cyclic AMP receptor proteins, RI α and RII β , are reciprocally related in the growth control of cancer cells and that the RI α Antisense Oligodeoxynucleotide, which efficiently depletes the growth stimulatory RI α , is a powerful biological tool toward suppression of malignancy.

  • differentiation of hl 60 leukemia by type i regulatory subunit Antisense Oligodeoxynucleotide of camp dependent protein kinase
    Proceedings of the National Academy of Sciences of the United States of America, 1991
    Co-Authors: Giampaolo Tortora, Hiroshi Yokozaki, Stefano Pepe, Timothy Clair, Yoon S Chochung


    A marked decrease in the type I cAMP-dependent protein kinase regulatory subunit (RI alpha) and an increase in the type II protein kinase regulatory subunit (RII beta) correlate with growth inhibition and differentiation induced in a variety of types of human cancer cells, in vitro and in vivo, by site-selective cAMP analogs. To directly determine whether RI alpha is a growth-inducing protein essential for neoplastic cell growth, human HL-60 promyelocytic leukemia cells were exposed to 21-mer RI alpha Antisense Oligodeoxynucleotide, and the effects on cell replication and differentiation were examined. The RI alpha Antisense oligomer brought about growth inhibition and monocytic differentiation, bypassing the effects of an exogenous cAMP analog. These effects of RI alpha Antisense Oligodeoxynucleotide correlated with a decrease in RI alpha receptor and an increase in RII beta receptor level. The growth inhibition and differentiation were abolished, however, when these cells were exposed simultaneously to both RI alpha and RII beta Antisense Oligodeoxynucleotides. The RII beta Antisense Oligodeoxynucleotide alone has been previously shown to specifically block the differentiation inducible by cAMP analogs. These results provide direct evidence that RI alpha cAMP receptor plays a critical role in neoplastic cell growth and that cAMP receptor isoforms display specific roles in cAMP regulation of cell growth and differentiation.

  • an Antisense Oligodeoxynucleotide targeted against the type ii beta regulatory subunit mrna of protein kinase inhibits camp induced differentiation in hl 60 leukemia cells without affecting phorbol ester effects
    Proceedings of the National Academy of Sciences of the United States of America, 1990
    Co-Authors: Giampaolo Tortora, Timothy Clair, Yoon S Chochung


    The type II beta regulatory subunit of cAMP-dependent protein kinase (RII beta) has been hypothesized to play an important role in the growth inhibition and differentiation induced by site-selective cAMP analogs in human cancer cells, but direct proof of this function has been lacking. To address this issue, HL-60 human promyelocytic leukemia cells were exposed to RII beta Antisense synthetic Oligodeoxynucleotide, and the effects on cAMP-induced growth regulation were examined. Exposure of these cells to RII beta Antisense Oligodeoxynucleotide resulted in a decrease in cAMP analog-induced growth inhibition and differentiation without apparent effect on differentiation induced by phorbol esters. This loss in cAMP growth regulatory function correlated with a decrease in basal and induced levels of RII beta protein. Exposure to RII beta sense, RI alpha and RII alpha Antisense, or irrelevant Oligodeoxynucleotides had no such effect. These results show that the RII beta regulatory subunit of protein kinase plays a critical role in the cAMP-induced growth regulation of HL-60 leukemia cells.

Sudhir Agrawal – 2nd expert on this subject based on the ideXlab platform

  • Antisense depletion of RIα subunit of protein kinase A induces apoptosis and growth arrest in human breast cancer cells
    Breast Cancer Research and Treatment, 1998
    Co-Authors: Rakesh K. Srivastava, Sudhir Agrawal, Aparna R. Srivastava, Yun Gyu Park, Yoon S. Cho-chung


    In recent years, several laboratories have explored the possibility of using Antisense Oligodeoxynucleotides for specific manipulation of gene expression leading to cancer treatment. The enhanced expression of the RIα subunit of cyclic AMP-dependent protein kinase type I (PKA-I) has been correlated with cancer cell growth. In the present study, the effects of an Antisense Oligodeoxynucleotide targeted against RIα subunit of PKA-I on growth inhibition and apoptosis in MDA-MB-231 human breast cancer cells were investigated. The growth inhibitory effects of RIα Antisense Oligodeoxynucleotide correlated with a decrease in the RIα mRNA and protein levels. The growth inhibition was accompanied by changes in the cell cycle phase distribution, cell morpbology, cleavage of poly (ADP-ribose) polymerase (PARP), and appearance of apoptotic nuclei. By comparison, mismatched control Oligodeoxynucleotide had no effect. On the basis of these results, it can be suggested that the RIα Antisense Oligodeoxynucleotide, which efficiently depletes the growth stimulatory RIα and induces apoptosis/differentiation, could be used as a therapeutic agent for breast cancer treatment.

  • pharmacokinetics of an anti human immunodeficiency virus Antisense Oligodeoxynucleotide phosphorothioate gem 91 in hiv infected subjects
    Clinical Pharmacology & Therapeutics, 1995
    Co-Authors: Ruiwen Zhang, Harout Shahinian, Girish Amin, Zhihong Lu, Michael S Saag, Zhiwei Jiang, Jamal Temsamani, Russell R Martin, Paul J Schechter, Sudhir Agrawal


    Human pharmacokinetics of an Antisense Oligodeoxynucleotide phosphorothioate (GEM 91) developed as an anti—human immunodeficiency virus (HIV) agent was carried out in this study. 35S-Labeled GEM 91 was administered to six HIV-infected individuals by means of 2-hour intravenous infusions at a dose of 0.1 mg/kg. Plasma disappearance curves for GEM 91—derived radioactivity could be described by the sum of two exponentials, with half-life values of 0.18 ± 0.04 and 26.71 ± 1.67 hours. The radioactivity in plasma was further evaluated by polyacrylamide gel electrophoresis, showing the presence of both intact GEM 91 and lower molecular weight metabolites. Urinary excretion represented the major pathway of elimination, with 49.15% ± 6.80% of the administered dose excreted within 24 hours and 70.37% ± 6.72% over 96 hours after dosing. The radioactivity in urine was associated with lower molecular weight metabolites. No drug-related toxicity was observed.

    Clinical Pharmacology & Therapeutics (1995) 58, 44–53; doi: 10.1016/0009-9236(95)90071-3

  • Antisense Oligodeoxynucleotide phosphorothioate complementary to gag mrna blocks replication of human immunodeficiency virus type 1 in human peripheral blood cells
    Proceedings of the National Academy of Sciences of the United States of America, 1994
    Co-Authors: Julianna Lisziewicz, Frank F Weichold, Alain R Thierry, Paolo Lusso, Jinyan Tang, Robert C Gallo, Sudhir Agrawal


    Gene-expression modulator 91 (GEM91) is a 25-nt Antisense Oligodeoxynucleotide phosphorothioate complementary to the Gag mRNA of human immunodeficiency virus type 1 (HIV-1). Cellular uptake and intracellular distribution of GEM91 within cells suggest that this oligomer is readily available for Antisense activity. GEM91 inhibited HIV-1 replication in a dose-dependent and sequence-specific manner. In a comparative study, 2 microM GEM91 was as effective as 5 microM 3′-azido-3′-deoxythymidine in blocking virus replication during the 28-day treatment of an HIV-1-infected T-cell line. GEM91 also completely inhibited (> 99%) the growth of three different HIV-1 isolates in primary lymphocytes and prevented the cytopathic effect of the virus in primary CD4+ T cells. Similarly, treatment with GEM91 for 3 weeks of HIV-1/BaL-infected primary macrophages blocked virus replication. Based on GEM91 anti-HIV-activity, safety, and pharmacokinetic profile in animals, a clinical trial was started using this compound as an Antisense oligonucleotide drug for the treatment of the acquired immunodeficiency syndrome.

Gavril W. Pasternak – 3rd expert on this subject based on the ideXlab platform

  • Antisense mapping of MOR-1 in rats: distinguishing between morphine and morphine-6beta-glucuronide antinociception.
    The Journal of pharmacology and experimental therapeutics, 1997
    Co-Authors: G.c. Rossi, Liza Leventhal, Y. X. Pan, J Cole, Weilian Su, Richard J. Bodnar, Gavril W. Pasternak


    In an effort to correlate the recently cloned MOR-1 receptor with the pharmacological actions of morphine and morphine-6beta-glucuronide (M6G), we have used an Antisense paradigm. Rats were injected intracerebroventricularly (i.c.v.) with Antisense Oligodeoxynucleotides on days 1, 3 and 5 and tested for analgesia on day 6 after administration of morphine or M6G i.c.v. or after microinjection of morphine directly into either the periaqueductal gray or the locus coeruleus. When given i.c.v., the Antisense Oligodeoxynucleotide targeting the 5′-untranslated region of exon 1 significantly decreased the analgesic actions of morphine administered i.c.v. or microinjected directly into the periaqueductal gray or locus coeruleus, with the most profound inhibition occurring in the periaqueductal gray. Thus, Antisense Oligodeoxynucleotides administered into the lateral ventricle can diffuse into the brainstem and interfere with morphine actions. A mismatch Antisense Oligodeoxynucleotide with the same base composition in which the sequence of four bases was changed was inactive. This same exon 1 Antisense Oligodeoxynucleotide, which was active against morphine analgesia, failed to block M6G analgesia. In contrast, Antisense sequences from exons 2 and 3 decreased M6G, and not morphine, analgesia. The Antisense Oligodeoxynucleotide against exon 4 slightly decreased both morphine and M6G antinociception. These results confirm the Antisense mapping studies on exons 1, 2 and 3 of MOR-1 in mice, which implied the presence of a novel mu receptor subtype responsible for M6G analgesia that may represent a splice variant of MOR-1. Unlike in mice, the probe against exon 4 had a small effect on M6G analgesia.

  • Differential blockade of morphine and morphine-6β-glucuronide analgesia by Antisense Oligodeoxynucleotides directed against MOR-1 and G-protein α subunits in rats
    Neuroscience Letters, 1995
    Co-Authors: G.c. Rossi, Kelly M. Standifer, Gavril W. Pasternak


    Abstract An Antisense Oligodeoxynucleotide directed against the 5′-untranslated region of MOR-1 blocks the analgesic actions of the μ 1 analgesics morphine and [ d -Ala 2 , d -Leu 5 jenkephalin (DADL) when they are microinjected into the periaqueductal gray. In contrast, morphine-6β-glucuronide (M6G) analgesia is unaffected by this treatment. Antisense Oligodeoxynucleotides directed against distinct G i α subunits also distinguish between morphine and M6G analgesia. A probe targeting G i α2 blocks morphine analgesia, as previously reported, but is inactive against M6G analgesia. Conversely, an Antisense Oligodeoxynucleotide against G i αI inhibits M6G analgesia without affecting morphine analgesia. The Antisense Oligodeoxynucleotide directed against G 0 α is ineffective against both compounds. These results confirm the prior association of G i α2 with morphine analgesia and strongly suggests that M6G acts through a different opioid receptor, as revealed by its insensitivity towards the MOR-1 Antisense probe and differential sensitivity towards G-protein α subunit Antisense Oligodeoxynucleotides.

  • Selective loss of δ opioid analgesia and binding by Antisense Oligodeoxynucleotides to a δ opioid receptor
    Neuron, 1994
    Co-Authors: Kelly M. Standifer, Chih Cheng Chien, Claes Wahlestedt, George P. Brown, Gavril W. Pasternak


    Abstract Antisense Oligodeoxynucleotides (18–20 bases) to a cloned δ opioid receptor (DOR-1) lower δ binding in NG108-15 cells by 40%–50%. Changing 4 bases to generate a mismatch Antisense Oligodeoxynucleotide or mixing the corresponding sense and Antisense Oligodeoxynucleotides prior to treatment of the cells eliminates the inhibition of binding, confirming the specificity of the response. In vivo, an Antisense Oligodeoxynucleotide to DOR-1 given intrathecally lowers δ, but not μ or κ 1 spinal analgesia. The mismatch Antisense Oligodeoxynucleotide is inactive. δ analgesic sensitivity gradually returns by 5 days after the last Antisense treatment, indicating the lack of irreversible damage or toxicity. These studies demonstrate that DOR-1 mediates δ analgesia at the level of the spinal cord and confirm at the molecular level traditional pharmacological studies implying distinct receptor mechanisms for δ, μ, and ϰ 1 analgesia. The use of Antisense approaches may prove valuable in understanding the receptors mediating opioid pharmacology.