Radionuclide Peptide Cancer Therapy, 1st Edition
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Library of Congress Cataloging-in-Publication Data
Radionuclide peptide cancer therapy / edited by Marco Chinol, Giovanni Paganelli.
p. cm.
Includes bibliographical references and index.
ISBN-13: 978-0-8247-2887-8 (alk. paper)
ISBN-10: 0-8247-2887-4 (alk. paper)
1. Cancer--Radioimmunoimaging. 2. Peptides--Therapeutic use. 3. Radioisotopes--Therapeutic
use. I. Chinol, Marco. II. Paganelli, Giovanni.
RC271.R26R33 2006
616.99’407575--dc22 2005046649
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Foreword
Selectively killing tumor cells while sparing normal tissues has been the goal of
research in nuclear medicine ever since Paul Ehrlich’s theory of the "magic
bullet."
For the last two decades monoclonal antibodies have been regarded as the
ideal vector for delivering high loads of radioactivity to tumor cells disseminated
throughout the body.
Despite the fact that two radiolabeled monoclonal antibodies have finally
been launched on the market for the treatment of hematologic tumors,
fundamental issues, such as the very low concentration of radiolabeled antibodies
in the neoplastic tissues, their potential unspecific accumulation in normal
organs, and production of immunologic reactions preventing multiple cycles of
therapy still remain to be resolved before we see an antibody-based radio-
pharmaceutical against solid tumors.
In contrast to larger molecules, peptides have the advantage of being
flexible messenger molecules with easy penetration into all tissues. Therefore,
peptide research has been and still is heavily focused on developing
metabolically stable peptides which eventually could be radiolabeled for clinical
use. The discovery that tumors originating from the neural crest overexpress
somatostatin receptors has spurred the development of somatostatin analogs
designed to target tumor cells so that the enhanced radiation delivery will occur
mostly at the receptor expressing tumor cells.
In this book the Editors have brought together outstanding studies by
experts in the field, providing basic background, latest clinical applications,
dosimetric aspects, and regulatory requirements.
This comprehensive book on these new radiolabled molecules, which are in
the forefront of the fight against cancer, comes at a time when we are celebrating
iii
iv Foreword
the first ten years of the European Institute of Oncology, whose primary goal is
research into innovative treatments to combat cancer.
The combination of antitumor efficacy and high "quality of life" treatment
regimens represents a fundamental and achievable goal which, with the advent of
radiolabeled peptides, seems well within our reach.
I believe that this book will not only be warmly welcomed by scientists
working in this field but will also benefit those investigators working in centers
that focus more and more on this new approach to the treatment of cancer.
Umberto Veronesi
Preface
Over its extensive period of development, the field of radioimmunotherapy has
enjoyed much progress, including the selection of suitable radionuclides,
chelation chemistry, and novel targets on tumor cells. The knowledge accrued
has accelerated the advancement of radiolabeled peptides, which have already
demonstrated their pivotal role in the fight against cancer. Despite just a few years
of development, a large amount of data is available in the literature to support
their clinical applications.
This book provides a comprehensive set of chapters that describe the state
of art in the field of radiolabeled peptides for cancer therapy. Included are
chapters reviewing the technology of peptide production, aspects of radiolabel-
ing, and the results of their clinical applications obtained in outstanding
institutions. This book also includes two perspective sections presenting novel
strategies to enhance the spectrum of application of peptides.
The progress described in these chapters offers strong and compelling
evidence of the success of radiolabeled peptides and foresees the potential
development which the field will undergo in the coming years.
We wish to express our heartfelt gratitute to all the authors who contributed
to the writing of this book and we thank the European Institute of Oncology for its
continuous and unstinting support towards our research efforts.
Marco Chinol
Giovanni Paganelli
v
Contents
Foreword . . . . iii
Preface . . . . v
Contributors . . . . xiii
1. Peptide Structure and Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Carlo Pedone, Giancarlo Morelli, Diego Tesauro, and
Michele Saviano
Introduction . . . . 1
Peptide Conformation and Structures . . . . 3
Methodologies for Peptide Design . . . . 5
Methodologies for Peptide Synthesis . . . . 11
Methodologies for Peptide Modifications Toward
the Obtainment of a Peptide-Based
Radiopharmaceutical . . . . 16
Spectroscopic Studies . . . . 19
Biomolecular Three-Dimensional Structures from X-Ray and
Nuclear Magnetic Resonance Techniques . . . . 22
References . . . . 26
2. Radiopeptide Targeting for Tumor Therapy: Peptide
Receptor Distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Jean Claude Reubi
Introduction . . . . 31
Which Tumors Express Which Peptide Receptor? . . . . 31
vii
viii Contents
Multireceptor Targeting . . . . 37
References . . . . 38
3. Developments of Radiolabeled Peptides. . . . . . . . . . . . . . . . . . 41
Ronald E. Weiner and Mathew L. Thakur
Introduction . . . . 41
Background . . . . 46
Somatostatin Analogs . . . . 48
Cholecystokinin-B/Gastrin . . . . 56
Bombesin . . . . 60
Alpha Melanocyte Stimulating Hormone . . . . 65
avb3 Antagonists . . . . 70
Conclusion . . . . 75
References . . . . 76
4. The Labeling of Peptides with Positron-Emitting
Radionuclides: The Importance of PET in Cancer
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Stefano Papi, Nicoletta Urbano, Esteban R. Obenaus,
and Marco Chinol
Introduction . . . . 87
The Different Positron-Emitting Radioisotopes . . . . 88
Labeling Reactions with bC Emitters . . . . 93
Overview of Positron-Labeled Peptide Families Useful in Cancer
Diagnosis and Therapy: Current Status and Future
Perspectives . . . . 104
Conclusion . . . . 112
References . . . . 113
5. Radiolabeling DOTA-Peptides with 90Y and 177Lu to a High
Specific Activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Wouter A. P. Breeman, Erik de Blois, Willem H. Bakker,
and Eric P. Krenning
Radiolabeling DOTA-Peptides with 90Y and 177Lu to a High
Specific Activity . . . . 119
Conclusions . . . . 123
References . . . . 124
Contents ix
6. Peptide Receptor Radionuclide Therapy: Preclinical
Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Astrid Capello, Wouter A. P. Breeman, Bert Bernard,
Marion de Jong, and Eric P. Krenning
Introduction . . . . 127
Octreotide . . . . 128
Octreotide Analogs . . . . 130
Lanreotide . . . . 134
RC-160 . . . . 135
RGD-Octreotate . . . . 136
Conclusion . . . . 138
References . . . . 138
7. Pathological Evaluation and Biochemical Characterization
of Peptide Receptors Other Than Somatostatin Receptors
as Potential Tumor Targets for Radionuclide Diagnosis
and Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Giuseppe Pelosi, Michele Masullo, and Giuseppe Viale
Introduction . . . . 145
Methodological Aspects . . . . 147
Biochemical and Functional Characterization of Peptide Receptors
and Their Normal Distribution . . . . 152
Assessing Peptide Receptor Expression in
Human Tumors . . . . 156
Co-expression of Peptide Receptors in Tumors: A New
Challenge for the Pathologist . . . . 159
Conclusive Remarks and Future Perspectives . . . . 161
References . . . . 162
8. Peptide Receptor Therapy with 90Y-Dotatoc: The Emerging
Experience in Chile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Horacio Amaral
Introduction . . . . 173
Patient Population and Methods . . . . 174
Results . . . . 174
Selected Cases . . . . 174
Conclusion . . . . 178
References . . . . 179
x Contents
9. Therapeutic Potential of Radiolabeled Peptides: The Basel
Experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Christian Waldherr and Jan Müller-Brand
PRRT with 90Y-DOTATOC in Patients with Neuroendocrine
Tumors and with Thyroid Cancer . . . . 182
Locoregional PRRT with 90Y-DOTATOC in Patients with
Glioma . . . . 201
Discussion . . . . 206
References . . . . 206
10. Somatostatin Receptor-Mediated Radionuclide Therapy
for Cancer: Therapy with 90Y-DOTA-Lanreotide . . . . . . 209
Irene Virgolini, Tatjana Traub-Weidinger, Michael Gabriel,
Drik Heute, and Margarida Rodrigues
Summary . . . . 209
Introduction . . . . 210
Selection of Patients . . . . 211
Preparation of 111In-/90Y-DOTA-Lanreotide . . . . 212
Diagnostic and Dosimetric Evaluation . . . . 212
Dose and Administration of 90Y-DOTA-Lanreotide . . . . 213
Evaluation of Therapeutic Response . . . . 214
Results . . . . 214
Tumor Uptake of 111In-DOTA-Lanreotide Compared with
Octreotide Derivates . . . . 216
Drawbacks . . . . 217
Conclusions . . . . 218
Future Outlook . . . . 218
References . . . . 218
11. Receptor Radionuclide Therapy with 90Y-[DOTA0]-Tyr3-
Octreotide (90Y-DOTATOC): The IEO Experience. . . . . 221
Lisa Bodei and Giovanni Paganelli
Introduction . . . . 221
Safety Aspects . . . . 223
Efficacy . . . . 225
Conclusions . . . . 230
References . . . . 230
12. New Clinical Studies with 177Lu-Labelled Somatostatin
Analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Dik J. Kwekkeboom and Eric P. Krenning
Perspective . . . . 236
References . . . . 237
Contents xi
13. Radiation Dosimetry Methods for Therapy . . . . . . . . . . . . . 239
Michael G. Stabin
Introduction . . . . 239
Internal Dosimetry Methods . . . . 241
Resources for Performing Calculations . . . . 247
Progress in 3D Dosimetry and Treatment Planning . . . . 251
Relating Observed Doses to Biological Effects . . . . 253
References . . . . 256
14. Dosimetry Applied to Peptide Radionuclide
Receptor Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263
Marta Cremonesi
Introduction . . . . 263
Radionuclides and Radiocompounds . . . . 264
Methods for Pretherapy Dosimetry . . . . 266
Dosimetric Results in PRRT Trials . . . . 278
Physical and Radiobiological Factors Related to
Kidney Damage . . . . 285
Practical Considerations and Conclusions . . . . 292
References . . . . 293
Further Reading . . . . 299
15. Methods to Reduce Radiation Exposure to Personnel During
Radiolabelling and Infusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
Mahila Ferrari
Introduction . . . . 301
Shielding Requirements . . . . 303
Local Skin Dose . . . . 303
Radiopharmaceutical Preparation: Radiation Protection
in the Hot Lab . . . . 304
Dose Calibrator . . . . 308
Dose to Skin Due to Contamination . . . . 308
Radiation Protection During the Infusion . . . . 309
Systemic Infusion . . . . 309
Locoregional Infusion . . . . 309
Patient Hospitalization . . . . 310
Conclusions and Recommendations . . . . 312
References . . . . 313
16. Regulatory Requirements for Therapy Trials. . . . . . . . . . . 315
Giampiero Tosi
Introduction . . . . 315
xii Contents
Justification and Optimization in the Use of Ionizing
Radiation for Medical Purposes . . . . 317
Medical Trials with the Use of Ionizing Radiation . . . . 318
Risk Categorization (Based on ICRP 62) . . . . 320
References . . . . 322
17. Pretargeted Peptide Delivery with Irreversible
Antibody. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
David A. Goodwin and Claude F. Meares
Introduction . . . . 323
Evolution of Pretargeting Systems . . . . 324
Irreversible Antibodies . . . . 328
Pegylation . . . . 330
Conclusions . . . . 331
References . . . . 333
18. Targeted Chemotherapy: New Approaches to Treatment
of Various Cancers Based on Cytotoxic Analogs of
Luteinizing Hormone-Releasing Hormone (LH-RH),
Somatostatin and Bombesin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Andrew V. Schally, Attila Nagy, and Ana Maria Comaru-Schally
Background . . . . 337
Preclinical Studies with Cytotoxic Somatostatin Analog
AN-238 . . . . 339
Preclinical Studies with Cytotoxic Bombesin Analog
AN-215 . . . . 341
Clinical Remarks . . . . 341
Conclusions . . . . 342
References . . . . 342
Index . . . . 345
Contributors
Horacio Amaral Nuclear Medicine Center, Clinica Alemana and A. Lopez
Perez Foundation, and Faculty of Medicine, Universidad del Desarrollo,
Santiago, Chile
Willem H. Bakker Department of Nuclear Medicine, Erasmus MC
Rotterdam, Rotterdam, The Netherlands
Bert Bernard Department of Nuclear Medicine, Erasmus MC Rotterdam,
Rotterdam, The Netherlands
Lisa Bodei Division of Nuclear Medicine, European Institute of Oncology,
Milan, Italy
Wouter A. P. Breeman Department of Nuclear Medicine, Erasmus MC
Rotterdam, Rotterdam, The Netherlands
Astrid Capello Department of Nuclear Medicine, Erasmus MC Rotterdam,
Rotterdam, The Netherlands
Marco Chinol Division of Nuclear Medicine, European Institute of
Oncology, Milan, Italy
Ana Maria Comaru-Schally Department of Medicine, Endocrine,
Polypeptide, and Cancer Institute, Veterans Affairs Medical Center and
Section of Experimental Medicine, Tulane University School of Medicine,
New Orleans, Louisiana, U.S.A.
xiii
xiv Contributors
Marta Cremonesi Medical Physics Department, European Institute of
Oncology, Milan, Italy
Erik de Blois Department of Nuclear Medicine, Erasmus MC Rotterdam,
Rotterdam, The Netherlands
Marion de Jong Department of Nuclear Medicine, Erasmus MC
Rotterdam, Rotterdam, The Netherlands
Mahila Ferrari Medical Physics Department, European Institute of
Oncology, Milan, Italy
Michael Gabriel Department of Nuclear Medicine, Innsbruck Medical
University, Innsbruck, Austria
David A. Goodwin Stanford University, Stanford and VA Palo Alto Health
Care System, Palo Alto, California, U.S.A.
Dirk Heute Department of Nuclear Medicine, Innsbruck Medical
University, Innsbruck, Austria
Eric P. Krenning Department of Nuclear Medicine, and Department of
Internal Medicine, Erasmus MC Rotterdam, Rotterdam, The Netherlands
Dik J. Kwekkeboom Department of Nuclear Medicine, Erasmus MC
Rotterdam, Rotterdam, The Netherlands
Michelle Masullo Division of Pathology and Laboratory Medicine,
European Institute of Oncology and University of Milan School of Medicine,
Milan, Italy
Claude F. Meares Chemistry Department, University of California Davis,
Davis, California, U.S.A.
Giancarlo Morelli InterUniversity Center on Bioactive Peptides (CIRPeB)
at University of Naples “Federico II” and Institute of Biostructures and
Bioimaging, C.N.R.—Via Mezzocannone, Napoli, Italy
Jan Müller-Brand Institute of Nuclear Medicine, University Hospital
Basel, Basel, Switzerland
Attila Nagy Department of Medicine, Endocrine, Polypeptide, and Cancer
Institute, Veterans Affairs Medical Center and Section of Experimental
Medicine, Tulane University School of Medicine, New Orleans,
Louisiana, U.S.A.
Esteban R. Obenaus Division of Nuclear Medicine, European Institute of
Oncology, Milan, Italy
Contributors xv
Giovanni Paganelli Division of Nuclear Medicine, European Institute of
Oncology, Milan, Italy
Stefano Papi Division of Nuclear Medicine, European Institute of
Oncology, Milan, Italy
Carlo Pedone InterUniversity Center on Bioactive Peptides (CIRPeB)
at University of Naples “Federico II” and Institute of Biostructures and
Bioimaging, C.N.R.—Via Mezzocannone, Napoli, Italy
Giuseppe Pelosi Division of Pathology and Laboratory Medicine,
European Institute of Oncology and University of Milan School of Medicine,
Milan, Italy
Jean Claude Reubi Division of Cell Biology and Experimental Cancer
Research, Institute of Pathology, University of Berne, Berne, Switzerland
Margarida Rodrigues Department of Nuclear Medicine, Innsbruck
Medical University, Innsbruck, Austria
Michele Saviano InterUniversity Center on Bioactive Peptides (CIRPeB)
at University of Naples “Federico II” and Institute of Biostructures and
Bioimaging, C.N.R.—Via Mezzocannone, Napoli, Italy
Andrew V. Schally Department of Medicine, Endocrine, Polypeptide, and
Cancer Institute, Veterans Affairs Medical Center and Section of
Experimental Medicine, Tulane University School of Medicine, New
Orleans, Louisiana, U.S.A.
Michael G. Stabin Department of Radiology and Radiological Sciences,
Vanderbilt University, Nashville, Tennessee, U.S.A.
Diego Tesauro InterUniversity Center on Bioactive Peptides (CIRPeB)
at University of Naples “Federico II” and Institute of Biostructures and
Bioimaging, C.N.R.—Via Mezzocannone, Napoli, Italy
Mathew L. Thakur Department of Radiology, Thomas Jefferson
University Hospital, Philadelphia, Pennsylvania, U.S.A.
Giampiero Tosi Medical Physics Department, European Institute of
Oncology, Milan, Italy
Tatjana Traub-Weidinger Department of Nuclear Medicine, Innsbruck
Medical University, Innsbruck, Austria
Nicoletta Urbano Division of Nuclear Medicine, European Institute of
Oncology, Milan, Italy
xvi Contributors
Giuseppe Viale Division of Pathology and Laboratory Medicine,
European Institute of Oncology and University of Milan School of Medicine,
Milan, Italy
Irene Virgolini Department of Nuclear Medicine, Innsbruck Medical
University, Innsbruck, Austria
Christian Waldherr Institute of Nuclear Medicine, University Hospital
Basel, Basel, and Department of Diagnostic Radiology, University Hospital
Bern, Bern, Switzerland, and Department of Molecular and Medical
Pharmacology, Ahmanson Biological Imaging Center, David Geffen School
of Medicine, University of California, Los Angeles, California, U.S.A.
Ronald E. Weiner Department of Diagnostic Imaging and Therapeutics,
University of Connecticut Health Center, Farmington, Connecticut, U.S.A.
1
Peptide Structure and Analysis
Carlo Pedone, Giancarlo Morelli, Diego Tesauro, and
Michele Saviano
InterUniversity Center on Bioactive Peptides (CIRPeB) at University of
Naples “Federico II” and Institute of Biostructures and Bioimaging,
C.N.R.—Via Mezzocannone, Napoli, Italy
INTRODUCTION
Peptides of natural or synthetic origin are compounds involved in a variety of
biological functions. They are hormones, opioides, sweeteners, antibiotics,
protein substrates, inhibitors, releasing factors, regulators of biological functions,
citoprotectors, and so on (1).
From the chemical point of view peptides are formed when two or more
amino acid residues are condensed together, leading to a secondary amide bond,
and, consequently, to a peptide unit. Peptides are, then, chains of a certain number
of covalently linked amino acid residues, each of which is intrinsically asym-
metric because of the optically active a-carbon atoms. The amino acid sequence
along the chain, the spatial configuration of the asymmetric Ca atoms of each
residue, and the local conformation of part of the molecule or the overall
conformation of the entire peptide, together with the intra-molecular and inter-
molecular interactions of various types, are all important factors in determining
the biological activity and the mechanism of its action.
Establishing the molecular and structural formula, the stereo-configuration
of the atoms, and the molecular conformation and inter- or intra-molecular
interactions is often the key to discovering the relationships between structure
and properties of the compounds under investigation, especially for natural
substances such as protein and biologically active compounds.
