E-Book Content
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
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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
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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
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Contents
VI. The Medicinal Chemistry of Oligonucleotides A. Introduction 31 B. Heterocycle Modifications 3 1 VII. Conclusions 38 References 38
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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