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Article on DNA Research

New DNA research study findings have been reported from Genzyme Corporation

2008 APR 7 -- Researchers detail in 'Next generation topoisomerase I inhibitors: Rationale and biomarker strategies,' new data in dna research. "Topoisomerase I (TopoI), an essential enzyme, produces a DNA single strand break allowing DNA relaxation for replication. The enzymatic mechanism involves sequential transesterifcations," scientists in the United States report.    "The breakage and closure reactions generate phosphodiester bonds and similar free energies, so the reaction is freely reversible. The TopoI reaction intermediate consists of enzyme covalently linked to DNA dubbed a 'cleavable complex'. Covalently bound TopoI-DNA complexes can be recovered. Camptothecin analogs, topotecan and irinotecan, are approved TopoI-targeted drugs. Both have limitations due to the equilibrium between the camptothecin lactone and ring-opened forms. Several strategies are being explored to develop improved TopoI inhibitors. Homocamptothecins, in which the metabolically labile camptothecin lactone is replaced with a more stable seven-membered beta-hydroxylactone, are potent anticancer agents. Gimatecan is a seven-position modified lipophilic camptothecin developed to provide rapid uptake and accumulation in cells and a stable TopoI-DNA-drug ternary complex. Diflomotecan, a homocamptothecin, and gimatecan are in Phase II clinical trial. Among non-camptothecins, edotecarin, an indolocarbazole that results in DNA C/T-G cleavage compared with T-G/A for camptothecins, is in Phase II clinical trial. Indenoisoquinolines were identified as TopoI inhibitors by the NCI 60-cell line COMPARE analysis. Co-crystal structures of two indenoisoquinolines with TopoI-DNA elucidated the structure of the ternary complex. Indenoisoquinolines are in preclinical development. Dibenzonaphthyridinone TopoI inhibitors have undergone extensive structure-activity examination. ARC-111 was selected for in-depth preclinical study. Biomarkers are under investigation to predict clinical efficacy from preclinical models, to allow determination of drug targeting in vivo and to aid selection of patients most likely to benefit from TopoI inhibitor therapy. gamma-H2AX formation may be a useful pharmacodynamic marker. A gene signature developed for topotecan sensitivity/resistance may have value in patient identification," wrote B.A Teicher and colleagues, Genzyme Corporation.    The researchers concluded: "Convergence of these efforts should result in clinically effective second generation TopoI inhibitors."    Teicher and colleagues published their study in Biochemical Pharmacology (Next generation topoisomerase I inhibitors: Rationale and biomarker strategies. Biochemical Pharmacology, 2008;75(6):1262-71).    For more information, contact B.A. Teicher, Genzyme Corporation, 1 Mountain Road, Framingham, MA 01701-9322 USA..    Publisher contact information for the journal Biochemical Pharmacology is: Pergamon-Elsevier Science Ltd., the Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, England.    Keywords: United States, Mountain Road, DNA Research, Anticancer Therapy, Antineoplastic, Biochemical Pharmacology, Biotechnology Business, Biotechnology Company, Camptothecin, Clinical Trial Research, DNA, Drugs, Enzyme Inhibitor, Enzyme Research, Enzymes, Enzymology, Genzyme Corporation, Irinotecan, Parasympathomimetic, Pharmaceutical Business, Pharmaceutical Company, Pharmaceuticals, Pharmacology, Prodrug, Proteins, Proteomics, Radiation-Sensitizing Agent, Therapies, Therapy, Topoisomerase, Topoisomerase I, Topotecan, Treatment.    This article was prepared by NewsRx editors from staff and other reports. Copyright 2008, NewsRx.com.

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