Table Of ContentMPheydsicicasl /PBhioymsicesdical Engineering
Lehnert
SerieS editorS: John G. WebSter, e. ruSSell ritenour, Slavik tabakov, kWan-hoonG nG
RADIOSENSITIZERS AND R RADIOSENSITIZERS AND
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RADIOCHEMOTHERAPY IN THE D
RADIOCHEMOTHERAPY
I
O
TREATMENT OF CANCER S
E IN THE TREATMENT
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Radiosensitizers and Radiochemotherapy in the Treatment of T OF CANCER
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Cancer catalogs and describes the mechanism of action for entities HT
characterized as radiosensitizers. Developments in the biological and EIZ
physical sciences have introduced new radiosensitizers and defined novel TE
targets for radiosensitization. As a result, a book about radiosensitization RR
must now address a huge range of topics, covering everything from ES
molecular oxygen and high Z elements to monoclonal antibodies and A
A
complex phytochemicals. T
MN
At the molecular level, the understanding of the molecular consequences D
E
of DNA damage and the DNA damage response have informed the
NR
development of targeted radiosensitizers and shed light on the mode of
TA
action of radiochemotherapy protocols of known clinical efficacy.
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In this book the mechanisms of action at the molecular and cellular FI
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level are described for documented radiosensitizers including, where
CC
applicable, a brief history of their clinical use and most recent clinical
AH
results. In addition, the clinical context is addressed including the
NE
importance of factors such as dose and dose rate, normal tissue toxicity,
CM
and drug delivery. Intuitively organized by topic and application, the book
E
includes extensive illustrations, end-of-chapter summaries, and a wealth O
R
of references. T
H
E
R
A
P
Shirley Lehnert
Y
K11427
ISBN: 978-1-4398-92090002-08
9 781439829028
K11427_COVER_final.indd 1 10/24/14 10:29 AM
Radiosensitizers and
Radiochemotherapy
in the Treatment
of Cancer
Series in Medical Physics and Biomedical Engineering
Series Editors: John G Webster, E Russell Ritenour, Slavik Tabakov,
and Kwan-Hoong Ng
Other recent books in the series:
The Physiological Measurement Handbook
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Medical Equipment Management
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Targeted Muscle Reinnervation: A Neural Interface for Artificial Limbs
Todd A Kuiken; Aimee E Schultz Feuser; Ann K Barlow (Eds)
Quantifying Morphology and Physiology of the Human Body Using MRI
L Tugan Muftuler (Ed)
Monte Carlo Calculations in Nuclear Medicine, Second Edition: Applications in
Diagnostic Imaging
Michael Ljungberg, Sven-Erik Strand, and Michael A King (Eds)
Vibrational Spectroscopy for Tissue Analysis
Ihtesham ur Rehman, Zanyar Movasaghi, and Shazza Rehman
Webb’s Physics of Medical Imaging, Second Edition
M A Flower (Ed)
Correction Techniques in Emission Tomography
Mohammad Dawood, Xiaoyi Jiang, and Klaus Schäfers (Eds)
Physiology, Biophysics, and Biomedical Engineering
Andrew Wood (Ed)
Proton Therapy Physics
Harald Paganetti (Ed)
Practical Biomedical Signal Analysis Using MATLAB®
K J Blinowska and J Żygierewicz (Ed)
Physics for Diagnostic Radiology, Third Edition
P P Dendy and B Heaton (Eds)
Series in Medical Physics and Biomedical Engineering
Radiosensitizers and
Radiochemotherapy
in the Treatment
of Cancer
Shirley Lehnert
Department of Oncology
McGill University,
Montreal, Canada
CRC Press
Taylor & Francis Group
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Boca Raton, FL 33487-2742
© 2015 by Taylor & Francis Group, LLC
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
Version Date: 20141016
International Standard Book Number-13: 978-1-4398-2903-5 (eBook - PDF)
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For my mother, grandmother, and aunt.
They would have been pleased.
Contents
Series Preface, xxiii
Preface, xxvii
Acknowledgments, xxix
Author, xxxi
Chapter 1 ◾ R adiosensitization and Chemoradiation 1
1.1 A BRIEF HISTORY OF CHEMORADIATION 1
1.2 DEFINITIONS OF RADIOSENSITIZATION 1
1.2.1 Combining Two Agents Together: What Is Meant
by Additivity or Synergy? 3
1.2.1.1 The Isobologram 4
1.2.1.2 Median Effect Principle 5
1.2.2 Drugs and Radiation 6
1.2.3 Mechanisms of Benefit from Radiation–Drug Therapy 7
1.2.3.1 Cytotoxic Enhancement 7
1.2.3.2 Targeted Radiosensitizers 10
1.2.3.3 Biological Cooperation 12
1.2.3.4 Temporal Modulation 13
1.2.3.5 Spatial Cooperation 14
1.2.3.6 Normal Tissue Protection 14
1.2.4 Quantification of the Chemotherapy and Radiation
Interaction: The Therapeutic Ratio 15
1.2.5 Is Radiochemotherapy Preferable to Dose Escalation? 16
vii
viii ◾ Contents
1.2.6 The Relationship between Preclinical Studies and
Clinical Trials 18
1.3 WHAT THIS BOOK IS ABOUT 20
1.4 SUMMARY 20
REFERENCES 21
Chapter 2 ◾ R adiosensitization by Oxygen and Nitric Oxide 23
2.1 RADIOSENSITIZATION BY OXYGEN: THE OXYGEN
FIXATION HYPOTHESIS 23
2.1.1 Significance of the Oxygen Effect in the Treatment
of Cancer: Hypoxic Cells in Solid Tumors 25
2.1.2 Methods for Modification of Hypoxic Radioresistance 26
2.1.2.1 Increasing the Availability of Oxygen 26
2.1.2.2 Hypoxic Radiosensitizers 29
2.1.2.3 Hypoxic Cytotoxins 37
2.1.2.4 Clinical Trials with Hypoxic Cytotoxins 43
2.2 NITRIC OXIDE: A VERSATILE SMALL MOLECULE 46
2.2.1 Metabolism of Nitric Oxide 46
2.2.2 Mechanisms of Radiosensitization by Nitric Oxide 47
2.2.2.1 Direct Radiosensitization by NO 48
2.2.2.2 Indirect Radiosensitization: Increased
NO-Mediated Tumor Oxygenation 51
2.2.3 NO-Based Radiosensitization Strategies 53
2.2.3.1 Hypoxia-Activated NO Donors 54
2.2.3.2 Indirect Activation of Endogenous NOS 54
2.3 SUMMARY 55
REFERENCES 57
Chapter 3 ◾ R adioenhancement by Targeting Cellular
Redox Pathways and/or by Incorporation of
High-Z Materials into the Target 63
3.1 INTRODUCTION 63
3.2 DOSE ENHANCEMENT BY COMPOUNDS WITH
HIGH ATOMIC NUMBER 63
