Tumor Models in Cancer Research

Cancer Drug Discovery and Development Beverly A. Teicher, Series Editor

Tumor Models in Cancer Research, edited by Beverly A. Teicher, 2002 Tumor Suppressor Genes in Human Cancer, edited by David E. Fisher, 2001 Matrix Metalloproteinase Inhibitors in Cancer Therapy, edited by Neil J. Clendeninn

and Krzysztof Appelt, 2001 Farnesyltransferase Inhibitors in Cancer and Cardiovascular Therapy, edited by

Said M. Sebti and Andrew D. Hamilton, 2001 Platinum-Based Drugs in Cancer Therapy, edited by Lloyd R. Kelland and Nicholas P. Farrell,

2000 Apoptosis and Cancer Chemotherapy, edited by John A. Hickman and Caroline Dive, 1999 Signal Transduction and Cell Cycle Inhibitors in Cancer Therapy, edited by J. Silvio Gutkind,

1999 Antifolate Drugs in Cancer Therapy, edited by Ann L. Jackman, 1999 Antiangiogenic Agents in Cancer Therapy, edited by Beverly A. Teicher, 1999 Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval,

edited by Beverly A. Teicher, 1997 Cancer Therapeutics: Experimental and Clinical Agents, edited by Beverly A. Teicher, 1997

Tumor Models in Cancer Research

Edited by

Beverly A. Teicher Lilly Research Laboratories

Indianapolis, IN

Springer Science+Business Media, LLC

Dedication

For Joseph, the Black Warrior

© 2002 Springer Science+ Business Media New York Originally published by Hurnana Press Inc. in 2002 Softcover reprint of the hardcover 1st edition 2002

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Cover illustration: Background: A Comparison between the expression of 8-0hdG in Vitamin E and DMBA and DMBA­Induced oral carcinomas. (See Fig. 6, p. 153). Inset: External and internal images of liver lesions of AC3488-GFP. (See Fig. 9, p. I 08)

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Library of Congress Cataloging-in-Publication Data

Tumor Models in Cancer Research I edited by Beverly A. Teicher. p. ; ern. -- (Cancer drug discovery and development)

Includes bibliographical references and index. ISBN 978-1-4757-6883-1 ISBN 978-1-59259-100-8 (eBook) DOI 10.1007/978-1-59259-100-8 1. Tumors--Animal models. 2. Cancer cells. 3. Oncology, Experimental. I. Teicher,

Beverly A., 1952- II. Series. [DNLM: 1. Neoplasms, Experimental. 2. Disease Models, Animal. QZ 206 T925 2001]

RC267 .T855 2001 616.99'4027--dc21

2001024082

In Memoriam

In memory of Dr. Greg MacEwen, who passed away suddenly May 12, 2001. Greg was an internationally recognized leader in the field of comparative oncology for more than 25 years. Greg trained many young oncologists, some of whom have gone on to become leaders in the field. He also conducted numerous innovative clinical trials, particularly in the fields of immunotherapy, gene therapy, and experimental therapeutics. His leadership was central to the formation of the Veterinary Cancer Society, which provides a central forum for exchange of ideas and information regarding new frontiers in companion animal cancer therapy. Greg always had great concern for his patients, while at the same time not losing sight of the value his patients gave to the greater good of treating human patients with cancer. His leadership and friendship will be missed.

v

Preface

"My Nemesis rises to his full height, fixes me with a stern but pitying stare, and asks if I really believe all this work done in animals has anything whatsoever to do with the clini­cal problem? I would suggest that if past experience is any criterion, I would expect some, but certainly not all, of what has been observed in leukemic animals to carry over (in principle) to man. We are abundantly aware that many of the experiments we have carried out were under conditions far removed from the usual clinical situation; i.e., in most instances we have studied the effects of early treatment of animals bearing rela­tively small numbers of leukemic cells. In this particular research program we have been seeking fundamental scientific knowledge; I shall be surprised if some of it is not appli­

cable." -Howard E. Skipper, 1965

Progress in a given field is often dependent upon the development of appropriate, accurate models. In modern times, cancer research has been engaged in a focused search for such models for more than 50 years. The fore­most problem in developing such models is that cancer is many, many diseases arising from nearly every tissue and metastasizing to many. A major breakthrough for models in cancer research was the development of transplantable rodent tumors. Many ofthe early tumor lines were carcinogen-induced, but others arose naturally in elderly animals from inbred strains of mice. These syngeneic tumors grown in the inbred host of origin allowed reproducible tumor growth and repro­ducible response to anticancer agents to be achieved. These tumor lines also frequently allowed analysis of tumor metastasis in the host.

The mutual needs for as large an array as possible of tumor types and the expansion of true inbred strains of mice to carry these tumors led to the identifica­tion of mutant mice with characteristics of deficient immunity suitable for the growth of human tumors as xenografts. The most frequently used of these mutant mouse strains are nude mice and SCID mice. Human tumor xenograft models were established from the many human tumor cell lines developed in the 1970s and 1980s and from fresh tumor explants. Since techniques for genetic manipu­lation have become more routine, animals expressing "oncogenes" or missing "tumor suppressor" genes have been developed, allowing a new level of under­standing of the process of malignancy and new models for testing anticancer agent efficacy. Through the use of these techniques for some diseases and tar­gets, it has been possible to establish specific animal models.

vii

viii Preface

Therapeutic index continues to be a critical variable for anticancer agents directed toward any cellular target related to proliferation. Animal models devel­oped to determine potential normal tissue toxicities of new agents as well as the potential of normal tissue protectors have focused on proliferating normal tissues such as mucosa, gut, skin, and bone marrow although cardiac, renal, and lung toxicity can also be modeled. Still, it is the determination of meaningful experi­mental endpoints that defines the usefulness of models to a field. Increase-in­lifespan (survival) was an endpoint used by Dr. Howard E. Skipper and colleagues in their groundbreaking murine leukemia studies. Many current models, espe­cially solid tumor models, are not amenable to a survival endpoint; therefore, other measures of tumor response, usually involving tumor volume measurements, are applied. Endpoints such as tumor growth delay and tumor growth inhibition closely mimic clinical endpoints such as response time and time to recurrence. Other endpoints, such as ratio of treated group to control group, log kill, percent apoptosis, and tumor cell survival, depend upon the availability of an untreated or vehicle-treated control group in the experiment.

An ideal tumor model would imitate in scale and mirror in response the human disease. Though no such ideal models exist for the diseases that are can­cer, the models described herein represent the efforts of many investigators for many years and approach with closer and closer precision examples that can serve as guides for the selection of agents and combinations for the treatment of human malignancy.

Beverly A. Teicher

Contents

In Memoriam .................................................................................................................. v

Preface ......................................................................................................................... vii

Contributors ................................................................................................................ xiii

PART I: INTRODUCTION

1 Perspective on the History of Tumor Models .................................. 3 Steadman Harrison

PART II: TRANSPLANTABLE SYNGENEIC RODENT TUMORS

2 Murine Ll210 and P388 Leukemias .............................................. 23 Donald J. Dykes and William R. Waud

3 Transplantable Syngeneic Rodent Tumors: Solid Tumors in Mice .................................................................. 41

Thomas H. Corbett, Lisa Polin, Bill J. Roberts, Alfred J. Lawson, Wilbur R. Leopold III, Kathryn White, Juiwanna Kushner, Jennifer Paluch, Stuart Hazeldine, Richard Moore, James Rake, and Jerome P. Horwitz

4 B16 Murine Melanoma: Historical Perspective on the Development of a Solid Tumor Model ............................ 73

Enrique Alvarez

PART III: HUMAN TUMOR XENOGRAFTS

5 Xenotransplantation of Human Cell Cultures in Nude Mice ......... 93 Beppino Giovanella

6 GFP-Expressing Metastatic-Cancer Mouse Models ...................... 99 Robert M. Hoffman

7 Human Tumor Xenografts and Ex plants ...................................... 113 Heinz-Herbert Fiebig and Angelika M. Burger

PART IV: CARCINOGEN-INDUCED TUMORS: MODELS OF CARCINOGENESIS AND USE FOR THERAPY

8 Hamster Oral Cancer Model ......................................................... 141 Joel Schwartz and Xinbin Gu

9 Mammary Cancer in Rats ............................................................. 173 Henry J. Thompson and Michael B. Sporn

ix

X Contents

10 Carcinogen-Induced Colon-Cancer Models for Chemoprevention and Nutritional Studies ......................... 183

Bandaru S. Reddy

PART V: MUTANT, TRANSGENIC, AND KNOCKOUT MOUSE MODELS

11 Cancer Models: Manipulating the Transforming Growth Factor-~ Pathway in Mice .......................................... 195

John J, Letterio

12 Cyclin Dl Transgenic Mouse Models .......................................... 223 Oliver G. Opitz, Hiroshi Nakagawa, and Anil K. Rustgi

13 Mice Expressing the Human Carcinoembryonic Antigen: An Experimental Model of Immunotherapy Directed at a Self, Tumor Antigen ........................................... 231

John W. Greiner

14 The p53-Deficient Mouse as a Cancer Model.. ............................ 247 Sundaresan Venkatachalam, Stuart Tyner,

and Lawrence A. Donehower

15 The Utility of Transgenic Mouse Models for Cancer Prevention Research ............................................... 263

Stephen D. Bursting and Ronald A. Lubet

PART VI: METASTASIS MODELS

16 Metastasis Models: Lungs, Spleen/Liver, Bone, and Brain .................................................................................. 277

Krishna Menon and Beverly A. Teicher

17 Models for Evaluation of Targeted Therapies of Metastatic Disease ................................................................ 293

Suzanne A. Eccles

PART VII: NORMAL TISSUE RESPONSE MODELS

18 Animal Models of Oral Mucositis Induced by Antineoplastic Drugs and Radiation ................................... 323

Stephen T. Sonis

19 The Intestine as a Model for Studying Stem-Cell Behavior .................................................................................... 337

Catherine Booth and Christopher S. Potten

20 SEN CAR Mouse-Skin Tumorigenesis Model ............................. 359 Rana P. Singh and Rajesh Agarwal

21 Murine Models of Bone-Marrow Transplant Conditioning ............................................................................. 381

Ronald van Os and Julian D. Down

22 Anesthetic Considerations for the Study of Murine Tumor Models ......................................................... 407

Robert E. Meyer, Rod D. Braun, and Mark W. Dewhirst

Contents xi

PART VIII: DISEASE AND TARGET-SPECIFIC MODELS

23 Tissue-Isolated Tumors in Mice: Ex Vivo Perfusion of Human Tumor Xenografts ..................... 435

Paul E. G. Kristjansen

24 Human Breast-Cancer Xenografts as Models of the Human Disease ............................................................... 453

Robert Clarke

25 Animal Models of Melanoma ....................................................... 4 71 William E. Carson III and Michael]. Walker

26 Experimental Animal Models for Renal Cell Carcinoma ............ 493 Gilda G. Hillman

27 Animal Models of Mesothelioma ................................................. 507 Harvey I. Pass, Orlin Hadjiev, and Michele Carbone

28 SCID Mouse Models of Human Leukemia and Lymphoma as Tools for New Agent Development ....................................... 521

Fatih M. Uckun and Martha G. Sensei

29 Models for Studying the Action of Topoisomerase-I Targeted Drugs ........................................ 541

Joyce Thompson, Clinton F. Stewart, and Peter]. Houghton

30 Spontaneous Pet Animal Cancers ................................................. 565 Mark W. Dewhirst, Donald Thrall,

and E. Gregory MacEwen

PART IX: EXPERIMENTAL METHODS AND END POINTS

31 In Vivo Tumor Response End Points ........................................... 593 Beverly A. Teicher

32 Tumor-Cell Survival ..................................................................... 617 Sara Rockwell

33 Apoptosis In Vivo ......................................................................... 633 L. Clifton Stephens and Raymond E. Meyn

34 Transparent Window Models and Intravital Microscopy: Imaging Gene Expression, Physiological Function, and Drug Delivery in Tumors .................................................. 647

Rakesh K. Jain, Lance L. Munn, and Dai Fukumura

Index ........................................................................................................................... 673

Contributors

RAJESH AGARWAL • Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO

ENRIQUE ALVAREZ • Division of Cancer Research, Lilly Research Laboratories, Indianapolis, IN

CATHERINE BooTH • EpiStem Ltd., Manchester, UK RoD D. BRAUN • Department of Anatomy/Cell Biology, Karmanos Cancer Institute,

Wayne State University School of Medicine, Detroit, MI ANGELIKA M. BuRGER • Institute for Experimental Oncology, University of Freiburg,

Freiburg, Germany MrcHELE CARBONE • Cardinal Bernardin Cancer Center, Loyola University, Maywood, IL WILLIAM E. CARSO"J III • Division of Surgical Oncology, Arthur G. James Comprehensive

Cancer Center, The Ohio State University, Columbus, OH RoBERT CLARKE • Department of Oncology, Georgetown University School of Medicine,

Washington, DC THOMAS H. CoRBETT • Prentice Cancer Research Center, Barbara Ann Karmanos Cancer

Institute, Detroit, MI MARK W. DEWHIRST • Department of Radiation Oncology, Duke University Medical

Center, Durham, NC LAWRENCE A. DoNEHOWER • Department of Molecular Virology and Microbiology, Baylor

College of Medicine, Houston, TX JuuAN D. DowN • BioTransplant Inc., Charlestown, MA DoNALD J. DYKES • Southern Research Institute, Birmingham, AL SuzANNE A. EccLES • McElwain Labs, Institute of Cancer Research, CRC Center

for Cancer Therapeutics, Surrey, UK HEINZ-HERBERT FIEBIG • Institute for Experimental Oncology, Tumor Biology Center,

University of Freiburg, Freiburg, Germany DAr FuKUMURA • Edwin L. Steele Laboratory, Department of Radiation Oncology,

Massachusetts General Hospital and Harvard Medical School, Boston, MA BEPPINO GrovANELLA • Stehlin Foundation for Cancer Research, Houston, TX JoHN W. GREINER • Laboratory of Tumor Immunology and Biology, National Cancer

Institute, National Institutes of Health, Bethesda, MD XrNBIN Gu • Department of Oral Maxillofacial Pathology, Howard University College

of Dentistry, Washington, DC 0RLIN HADJIEV • Wayne State University, School of Medicine, Detroit, MI STEADMAN HARRISON • EMD Pharmaceuticals Inc., Research Triangle Park, NC STUART HAZELDINE • Karmanos Cancer Institute, Wayne State University School

of Medicine, Detroit, MI

xiii

xiv Contributors

GILDA G. HILLMAN • Department of Radiation Oncology, Barbara Ann Karmanos Cancer Institute, Detroit, MI

RoBERT M. HoFFMAN • AntiCancer Inc., and Department of Surgery, University of California, San Diego, CA

JEROME P. HoRWITZ • Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI

PETERJ. HouGHTON • Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN

STEPHEN D. HuRSTING • Division of Cancer Prevention and Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD

RAKESH K. ]AIN • Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA

PAUL E.G. KRrsTJANSEN • Institute for Molecular Pathology, University of Copenhagen, Copenhagen, Denmark

JurwANNA KusHNER • Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI

ALFRED J. LAwsoN • Varian Medical Equipment, Bartlett, TN WILBUR R. LEOPOLD III • Warner-Lambert/Parke-Davis Pharmaceutical Research,

Ann Arbor, MI JoHN J. LETTERIO • Laboratory of Cell Regulation and Carcinogenesis, National Cancer

Institute, National Institutes of Health, Bethesda, MD RoNALD A. LuBET • Division of Cancer Prevention, National Cancer Institute, National

Institutes of Health, Bethesda, MD E. GREGORY MAcEwEN • Department of Medicine, School of Veterinary Medicine,

University of Wisconsin, Madison, WI KRisHNA MENON • Lilly Research Laboratories, Indianapolis, IN ROBERT E. MEYER • Department of Anatomy, Physiological Sciences, and Radiology,

College of Veterinary Medicine, North Carolina State University, Raleigh, NC RAYMOND E. MEYN • Department of Experimental Radiation Oncology, The University

of Texas MD Anderson Cancer Center, Houston, TX RicHARD MooRE • Department of Chemistry, University of Hawaii, Honolulu, HI LANcE L. MuNN • Edwin L. Steele Laboratory, Department of Radiation Oncology,

Massachusetts General Hospital and Harvard Medical School, Boston, MA HIROSHI NAKAGAWA • Division of Gastroenterology, University of Pennsylvania School

of Medicine, Philadelphia, PA OLIVER G. OPITZ • Division of Gastroenterology, University of Pennsylvania School

of Medicine, Philadelphia, PA JENNIFER PALUCH • Karmanos Cancer Institute, Wayne State University School

of Medicine, Detroit, MI HARVEY I. PASS • Barbara Ann Karmanos Cancer Institute, Harper Hospital, Detroit, MI LISA PoLIN • Karmanos Cancer Institute, Wayne State University School of Medicine,

Detroit, MI CHRISTOPHER S. PoTTEN • EpiStem Ltd., Manchester, UK }AMES RAKE • Sanofi-Synthelabo Research, Malvern, PA BANDARU S. REDDY • Division of Nutritional Carcinogenesis, American Health

Foundation, Valhalla, NY

Contributors XV

BILL J. RoBERTS • Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, MI SARA RocKWELL • Department of Therapeutic Radiology, Yale University School

of Medicine, New Haven, CT ANIL K. RusTGI • Division of Gastroenterology, Department of Genetics, Cancer Center,

University of Pennsylvania, Philadelphia, PA JoEL ScHWARTZ • Department of Oral Maxillofacial Pathology, Howard University

College of Dentistry, Washington, DC MARTHA G. SENSEL • Children's Cancer Group ALL Biology Reference Laboratory, Parker

Hughes Institute, St. Paul, MN RANA P. SINGH • Department of Pharmaceutical Sciences, School of Pharmacy, University

of Colorado Health Sciences Center, Denver, CO STEPHEN T. SoNIS • Division of Oral Medicine, Oral and Maxillofacial Surgery,

and Dentistry, Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, MA

MicHAEL B. SPORN • Department of Pharmacology, Dartmouth Medical School, Hanover, NH L. CLIFTON STEPHENS • Department of Veterinary Medicine, The University of Texas MD

Anderson Cancer Center, Houston, TX CLINTON F. STEWART • Department of Pharmaceutical Science, St. Jude Children's

Research Hospital, Memphis, TN BEvERLY A. TEICHER • Lilly Research Laboratories, Indianapolis, IN HENRY J. THOMPSON • AMC Cancer Research Center, Denver, CO JoYCE THOMPSON • Department of Hematology-Oncology, St. Jude Children's Research

Hospital, Memphis, TN DoNALD THRALL • Department of Anatomy, Physiology, and Radiology, College

of Veterinary Medicine, North Carolina State University, Raleigh, NC STuART TYNER • Department of Molecular Virology and Microbiology, Baylor College

of Medicine, Houston, TX FATIH M. UcKUN • Parker Hughes Cancer Center, Parker Hughes Institute, St. Paul, MN RoNALD VAN Os • Department of Hematology, Leiden University Medical Center, Leiden,

The Netherlands SUNDARESAN VENKATACHALAM • Department of Molecular Virology and Microbiology,

Baylor College of Medicine, Houston, TX MICHAEL J. WALKER • Division of Surgical Oncology, Arthur G. James Comprehensive

Cancer Center, The Ohio State University, Columbus, OH WILLIAM R. W AUD • Southern Research Institute, Birmingham, AL .KATHRYN WHITE • Karmanos Cancer Institute, Wayne State University School

of Medicine, Detroit, MI