The Experts below are selected from a list of 7803 Experts worldwide ranked by ideXlab platform

David R.p. Guay - One of the best experts on this subject based on the ideXlab platform.

  • Tolcapone, a selective catechol-O-Methyltransferase Inhibitor for treatment of Parkinson's disease.
    Pharmacotherapy, 1999
    Co-Authors: David R.p. Guay
    Abstract:

    Tolcapone is a selective peripheral and central catechol-O-Methyltransferase (COMT) Inhibitor recently approved as adjunctive therapy in patients with idiopathic Parkinson's disease who are already being treated with a levodopa-peripheral dopa decarboxylase Inhibitor (DDI) combination. Tolcapone potentiates and prolongs the effect of levodopa in the central nervous system (CNS) by enhancing levodopa's delivery to the CNS and slowing dopamine's central metabolism. A short terminal disposition half-life of 2 hours mandates dosing 3 times/day. Dosage adjustment is generally unnecessary in the presence of mild to moderate renal and hepatic impairment. Coadministration of tolcapone with levodopa-DDI results in significant amelioration of the wearing-off and on-off phenomena and frequently allows significant levodopa dosage reduction. In patients with stable disease, tolcapone improves "on" time. As might be expected from its potentiation of levodopa effects, dopaminergic side effects are prominent with this agent. Although the main objective of drug treatment in Parkinson's disease remains clinical improvement with an optimum dose and frequency of levodopa administration, tolcapone may prove a useful adjunct to such therapy, especially in the presence of the wearing-off and on-off phenomena. The relative merits of this agent vis-a-vis dopamine receptor agonists are somewhat unclear at present. However, recent guidelines from the American Academy of Neurology suggest that a COMT Inhibitor be added to levodopa-dopamine agonist therapy in patients with advanced disease.

Minmin Liu - One of the best experts on this subject based on the ideXlab platform.

  • integrative epigenetic analysis reveals therapeutic targets to the dna Methyltransferase Inhibitor guadecitabine sgi 110 in hepatocellular carcinoma
    Hepatology, 2018
    Co-Authors: Minmin Liu, Lian Zhang, Toshinori Hinoue, Wanding Zhou, Hitoshi Ohtani, Anthony B Elkhoueiry, John R Daniels
    Abstract:

    There is an urgent need to develop more effective therapies for hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA Methyltransferase Inhibitor (DNMTi), which is currently in clinical trials for HCC and shows greater stability and performance over first-generation DNMTis. In order to identify potential therapeutic targets of SGI-110 for clinical trials, HCC cell lines (SNU398, HepG2, and SNU475) were used to evaluate the effects of transient SGI-110 treatment by an integrative analysis of DNA methylation, nucleosome accessibility, gene expression profiles, and its clinical relevance by comparison to The Cancer Genome Atlas (TCGA) HCC clinical data. Each HCC cell line represents a different DNA methylation subtype of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged antiproliferation effects. Expression of up-regulated genes, including tumor suppressors, was positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation. Alternatively, expression of down-regulated genes, such as oncogenes, was negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. SGI-110 can also act as a dual Inhibitor to down-regulate polycomb repressive complex 2 (PRC2) genes by demethylating their gene bodies, resulting in reactivation of PRC2 repressed genes without involvement of DNA methylation. Furthermore, it can up-regulate endogenous retroviruses to reactivate immune pathways. Finally, about 48% of frequently altered genes in primary HCC tumors can be reversed by SGI-110 treatment. CONCLUSION Our integrative analysis has successfully linked the antitumor effects of SGI-110 to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets, and provided a rationale for combination treatments of SGI-110 with immune checkpoint therapies.

Stephen B Baylin - One of the best experts on this subject based on the ideXlab platform.

  • epigenetic therapy for epithelioid sarcoma
    Cell, 2020
    Co-Authors: Scott B Rothbart, Stephen B Baylin
    Abstract:

    Tazemetostat is the first epigenetic therapy to gain FDA approval in a solid tumor. This lysine Methyltransferase Inhibitor targets EZH2, the enzymatic subunit of the PRC2 transcriptional silencing complex. Tumors with mutations in subunits of the SWI/SNF chromatin remodeling complex, inclusive of most epithelioid sarcomas, are sensitive to EZH2 inhibition.

Stephen J. Benkovic - One of the best experts on this subject based on the ideXlab platform.

  • Genetic selection of cyclic peptide dam Methyltransferase Inhibitors
    ChemBioChem, 2008
    Co-Authors: Todd A. Naumann, Ali Tavassoli, Stephen J. Benkovic
    Abstract:

    We report the development of a transposition based genetic selection methodology used to uncover three cyclic peptide Inhibitors of the E. coli Methyltransferase. The activity of the selected cyclic peptides was confirmed in vivo and in vitro. The IC50 of the most active cyclic peptide (SGWYVRNM, shown in the figure) was comparable to that of the known Methyltransferase Inhibitor, sinefungin.

John R Daniels - One of the best experts on this subject based on the ideXlab platform.

  • integrative epigenetic analysis reveals therapeutic targets to the dna Methyltransferase Inhibitor guadecitabine sgi 110 in hepatocellular carcinoma
    Hepatology, 2018
    Co-Authors: Minmin Liu, Lian Zhang, Toshinori Hinoue, Wanding Zhou, Hitoshi Ohtani, Anthony B Elkhoueiry, John R Daniels
    Abstract:

    There is an urgent need to develop more effective therapies for hepatocellular carcinoma (HCC) because of its aggressiveness. Guadecitabine (SGI-110) is a second-generation DNA Methyltransferase Inhibitor (DNMTi), which is currently in clinical trials for HCC and shows greater stability and performance over first-generation DNMTis. In order to identify potential therapeutic targets of SGI-110 for clinical trials, HCC cell lines (SNU398, HepG2, and SNU475) were used to evaluate the effects of transient SGI-110 treatment by an integrative analysis of DNA methylation, nucleosome accessibility, gene expression profiles, and its clinical relevance by comparison to The Cancer Genome Atlas (TCGA) HCC clinical data. Each HCC cell line represents a different DNA methylation subtype of primary HCC tumors based on TCGA data. After SGI-110 treatment, all cell lines were sensitive to SGI-110 with prolonged antiproliferation effects. Expression of up-regulated genes, including tumor suppressors, was positively correlated with nucleosome accessibility and negatively correlated with gene promoter DNA methylation. Alternatively, expression of down-regulated genes, such as oncogenes, was negatively correlated with nucleosome accessibility and positively correlated with gene body DNA methylation. SGI-110 can also act as a dual Inhibitor to down-regulate polycomb repressive complex 2 (PRC2) genes by demethylating their gene bodies, resulting in reactivation of PRC2 repressed genes without involvement of DNA methylation. Furthermore, it can up-regulate endogenous retroviruses to reactivate immune pathways. Finally, about 48% of frequently altered genes in primary HCC tumors can be reversed by SGI-110 treatment. CONCLUSION Our integrative analysis has successfully linked the antitumor effects of SGI-110 to detailed epigenetic alterations in HCC cells, identified potential therapeutic targets, and provided a rationale for combination treatments of SGI-110 with immune checkpoint therapies.