Advances In Pharmacology


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GENE THERAPY ADVANCES IN PHARMACOLOGY VOLUME 40 ADVANCES IN PHARMACOLOGY SERIAL EDITORS J. Thomas August Ferid Murad Baltimore, Maryland Lake Forest, Illinois M. W. Anders Joseph T. Coyle Rochester, New York Belmont, Massachusetts ADVISORY BOARD R. Wayne Alexander Floyd E. Bloom Boston, Massachusetts La Jolla, California Thomas F. Burke Leroy Liu Houston, Texas Piscataway, New Jersey Anthony R. Means G. Alan Robison Durham, North Carolina Houston, Texas John A. Thomas Thomas C. Westfall San Antonio, Texas St. Louis, Missouri GENE THERAPY Edited by J. Thomas August Department of Pharmacology Johns Hopkins University Baltimore, Maryland ADVANCES IN PHARMACOLOGY VOLUME 40 ACADEMIC PRESS San Diego London Boston New York Sydney Tokyo Toronto This book is printed on acid-free paper. @ Copyright 0 1997 by ACADEMIC PRESS All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the Publisher. The appearance of the code at the bottom of the first page of a chapter in this book indicates the Publisher’s consent that copies of the chapter may be made for personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc. (222 Rosewood Drive, Danvers, Massachusetts 01923), for copying beyond that permitted by Sections 107 or 108 of the U S . Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale. Copy fees for pre-1997 chapters are as shown on the title pages, if no fee code appears on the title page, the copy fee is the same as for current chapters. 1054-3589/97 $25 .OO Academic Press a division of Harcourt Brace & Company 525 B Street, Suite 1900, San Diego, California 92101-4495, USA http://www .apnet.com Academic Press Limited 24-28 Oval Road, London NWI 7DX, UK http:l/www.hbuk.co.uk/ap/ International Standard Book Number: 0- 12-032941-7 D STATES OF AMERICA PRINTED IN THE W 97 98 9 9 0 0 01 0 2 B B 9 8 7 6 5 4 3 2 1 Contents Contributors xiii Advances in Understanding the Pharmacological Properties of Antisense Oligonucleotides Stanley T. Crooke I. Introduction 1 11. History 2 111. Proof of Mechanism 3 A. Factors That May Influence Experimental Interpretations 3 B. Recommendations: Positive Demonstration of Antisense Mechanism and Specificity 6 IV.Molecular Mechanisms of Antisense Drugs 7 A. Occupancy Only-Mediated Mechanisms 7 B. Occupancy-Activated Destabilization 9 C. Other Mechanisms 10 D. Activation of RNase H 11 V. Characteristics of Phosphorothioate Oligodeoxynucleotides 13 A. Introduction 13 B. Hybridization 13 C. Interactions with Proteins 14 D. Pharmacokinetic Properties 16 E. Pharmacological Properties 20 F. Toxicological Properties 26 G. Therapeutic Index 29 H. Conclusions 30 V vi Contents VI. The Medicinal Chemistry of Oligonucleotides A. Introduction 31 B. Heterocycle Modifications 3 1 VII. Conclusions 38 References 38 31 Targeted Tumor Cytotoxicity Mediated by lntracellular Single-Chain Anti-oncogene Antibodies David T. Curie1 Text 51 References 80 In Vivo Gene Therapy with Adeno-Assoc
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