Table Of ContentNITROSOUREAS
CURRENT STATUS AND NEW DEVELOPMENTS
Edited by
Archie W. Prestayko Laurence H. Baker
Bristol Laboratories Department of Oncology
Syracuse, New York Wayne State University
Detroit, Michigan
Stanley T. Crooke
Stephen K. Carter
SmithKline and French
Northern California Cancer Program
Philadelphia, Pennsylvania
Palo Alto, California
Philip S. Schein
Departments of Medicine and Pharmacology
Georgetown University Medical Center
Washington, D.C.
Assisted by
Nancy A. Alder
Philadelphia, Pennsylvania
ACADEMIC PRESS
A Subsidiary of Harcourt Brace Jovanovich, Publishers
New York London Toronto Sydney San Francisco 1981
COPYRIGHT © 1981, BY ACADEMIC PRESS, INC.
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United Kingdom Edition published by
ACADEMIC PRESS, INC. (LONDON) LTD.
24/28 Oval Road, London NW1 7DX
Library of Congress Cataloging in Publication Data
Main entry under title:
Nitrosoureas: current status and new developments.
Includes bibliographical references.
1. Nitrosoureas—Therapeutic use—Congresses.
2. Cancer—Chemotherapy—Congresses. 3. Nitrosoureas
—Testing—Congresses. 4. Nitrosoureas—Metabolism—
Congresses. I. Prestayko, Archie W. [DNLM: 1. Drug
therapy, Combination—Congresses. 2. Neoplasma—Drug
therapy—Congresses. 3. Nitrosoureas compounds—
Therapeutic use—Congresses. 4. Nitrosoureas compounds—
Administration and dosage—Congresses. QZ 267 N731 1980]
RC271.N56N57 616.99f4061 81-413
ISBN 0-12-565060-4
PRINTED IN THE UNITED STATES OF AMERICA
81 82 83 84 9 8 7 6 5 4 3 2 1
CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors' contributions begin.
MUHYIAL-SARRAF (301), Department of Oncology, Wayne State University,
Grace Hospital, Detroit, Michigan 48201
MICHAEL ALEXANDER (221), Department of Medicine, Stanford University
Medical Center, Stanford, California 94305
M. BERGER (27), Institute of Toxicology and Chemotherapy, German Cancer
Research Center, Heidelberg, Federal Republic of Germany.
CLARA D. BLOOMFIELD (181), School of Medicine, University of Min-
nesota, Minneapolis, Minnesota 55455
ROBERT A. BRUNDRETT, JR. (43), Pharmacology Laboratory, Johns Hop-
kins Oncology Center, Baltimore, Maryland 21205
PAUL A. BUNN, JR. (233), National Cancer Institute, Veterans Administration
Medical Oncology Branch, Division of Cancer Treatment, Washington,
D.C. 20422
TAUSEEF BUTT (123), Department of Biochemistry and The Vincent T. Lom-
bardi Cancer Center, Georgetown University Medical Center, Washington,
D.C. 20007
PATRICK J. BYRNE (367), Department of Medicine, Division of Medical
Oncology, Georgetown University Hospital, Washington, D.C. 20007
GEORGE CANELLOS (155), Division of Medicine, Sidney Färber Cancer Insti-
tute, Boston, Massachusetts 02130
STEPHEN K. CARTER (221, 411), Northern California Cancer Program, Palo
Alto, California 94304
LINDA CHAK (221), Department of Radiology, Stanford University Medical
Center, Stanford, California 94305
MARTIN H. COHEN (245), National Cancer Institute, Veterans Administration
Medical Oncology Branch, Veterans Administration Hospital, Washington,
D.C. 20422
MICHAEL J. COL VIN (43), Pharmacology Laboratory, Johns Hopkins Oncol-
ogy Center, Baltimore, Maryland 21205
ROBERT L. COMIS (209), Division of Hematology/Oncology, State University
of New York, Upstate Medical Center, Syracuse, New York 13210
M. ROBERT COOPER (181), Bowman Gray School of Medicine, Winston-
Salem, North Carolina 27103
xiii
XIV Contributors
THOMAS H. CORBETT (9), Chemotherapy Research Department, Southern
Research Institute, Birmingham, Alabama 35255
GIBBONS G. COR WELL (313), Norris Cotton Cancer Center and Dartmouth-
Hitchcock Medical Center, Hanover, New Hampshire 03755
E. CSÂNYI (27), Institut Drug Res., Semmelweis University, Budapest, Hun-
gary
M. ELAINE CURRY (361), Tissue Cloning, Bristol Laboratories, Syracuse,
New York 13201
JOAN C. D'AOUST (293), Department of Clinical Cancer Research, Bristol
Laboratories, Syracuse, New York 13201
JOHN R. DANIELS (221), University of Southern California, Division of Medi-
cal Oncology, LAC-USC Medical Center, Stanford University Medical
Center, Stanford, California 94305
JONATHAN DUCORE (69), Laboratory of Molecular Pharmacology, Devel-
opmental Therapeutics Program, Division of Cancer Treatment, National
Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205
LUZ DUQUE-HAMMERSHAIMB (145, 387), Cancer Therapy Evaluation Pro-
gram, Division of Cancer Treatment, National Cancer Institute, Bethesda,
Maryland 20205
JOHN R. DURANT (199), Comprehensive Cancer Center, University of
Alabama, University Station, Birmingham, Alabama 35294
G. EISENBRAND (27), Institute of Toxicology and Chemotherapy, German
Cancer Research Center, Heidelberg, Federal Republic of Germany
LEONARD C. ERICKSON (69), Laboratory of Molecular Pharmacology, De-
velopmental Therapeutics Program, Division of Cancer Treatment, Na-
tional Cancer Institute, National Institutes of Health, Bethesda, Maryland
20205
REGINA A. EWIG (69), Laboratory of Molecular Pharmacology, Developmen-
tal Therapeutics Program, Division of Cancer Treatment, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland 20205
P. FALAUTANO (27), Mario Negri Institute for Pharmacological Research,
Milan, Italy
JOSEPH W. FAY (337), Department of Internal Medicine, Washington Univer-
sity School of Medicine, St. Louis, Missouri 63110
H. H. FIEBIG (27), Medizinische Universitatklinik, Freiburg, Federal Republic
of Germany
S. FILIPPESCHI (27), Mario Negri Institute for Pharmacological Research,
Milan, Italy
EMIL FREI (155), Division of Medicine, Sidney Färber Cancer Institute, Bos-
ton, Massachusetts 02130
MICHAEL A. FRIEDMAN (379), Cancer Research Institute, Department of
Medicine, University of California, San Francisco, California 94143
RICHARD A. GAMS (199), Comprehensive Cancer Center, University of
Alabama, University Station, Birmingham, Alabama 35294
Contributors xv
SANDRA J. GINSBERG (209), Department of Hematology/Oncology, State
University of New York, Upstate Medical Center, Syracuse, New York
13210
AR VIN S. GLICKSMAN (181), Rhode Island Hospital, Providence, Rhode
Island 02908
LINDA P. GLOWIENKA (313), Cancer and Leukemia Group B, Scarsdale,
New York 10583
ARLAN J. GOTTLIEB (181), Department of Hematology, State University of
New York, Upstate Medical Center, Syracuse, New York 13210
DANIEL P. GRISWOLD, JR. (9), Chemotherapy Research Department, South-
ern Research Institute, Birmingham, Alabama 35255
M. HABS (27), Institute of Toxicology and Chemotherapy, German Cancer
Research Center, Heidelberg, Federal Republic of Germany
JOHN HARLEY (313), Memorial Hospital, Johnstown, Pennsylvania 15907
GEOFFREY P. HERZIG (337), Department of Internal Medicine, Washington
University School of Medicine, St. Louis, Missouri 63110
ROGER H. HERZIG (337), Department of Internal Medicine, Washington Uni-
versity School of Medicine, St. Louis, Missouri 63110
FRED HOCHBERG (155), Division of Medicine, Sidney Färber Cancer Insti-
tute, Boston, Massachusetts 02130
JAMES F. HOLLAND (181), Department of Neoplastic Disease, The Mount
Sinai Hospital School of Medicine, New York, New York 10029
DANIEL F. HOTH (387), Investigational Drug Branch, Division of Cancer
Treatment, National Cancer Institute, National Institutes of Health, Beth-
esda, Maryland 20205
BRIAN F. ISSELL (293, 361), Department of Clinical Cancer Research, Bristol
Laboratories, Syracuse, New York 13201
DON JUMP (123), Department of Biochemistry and The Vincent T. Lombardi
Cancer Center, Georgetown University Medical Center, Washington, D.C.
20007
HERBERT E. KANN, JR. (95), Department of Medicine, Emory University
School of Medicine, Atlanta, Georgia 30322
SHAUL KOCHWA (313), The Mount Sinai Hospital, New York, New York
10029
MARSHA KÖHLER (221), Stanford University Medical Center, Northern
California Cancer Program, Stanford, California 94305
KURT W. KOHN (69), Laboratory of Molecular Pharmacology, Developmental
Therapeutic Program, Division of Cancer Treatment, National Cancer In-
stitute, National Institutes of Health, Bethesda, Maryland 20205
ROBERT KYLE (313), Department of Hematology, Mayo Clinic, Rochester,
Minnesota 55905
W. RUSSELL LASTER, JR. (9), Chemotherapy Research Department, South-
ern Research Institute, Birmingham, Alabama 35255
GUY LAURENT (69), Laboratory of Molecular Pharmacology, Developmental
XVI Contributors
Therapeutics Program, Division of Cancer Treatment, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland 20205
HILLARD M. LAZARUS (337), Washington University School of Medicine,
St. Louis, Missouri 63110
LOUIS LEONE (313), Rhode Island Hospital, Providence, Rhode Island 02908
VICTOR A. LEVIN (171, 259), Brain Tumor Chemotherapy Service, Brain
Tumor Research Center, Department of Neurological Surgery, School of
Medicine, and Department of Pharmaceutical Chemistry, School of Phar-
macy, University of California, San Francisco, California 94143
DAVID B. LUDLUM (85), Division of Oncology, Department of Medicine,
Albany Medical College, Albany, New York 12208
JOHN S. MACDONALD (145), Cancer Therapy Evaluation Program, Division
of Cancer Treatment, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland 20205
L. HERBERT MAURER (209), Section of Hematology/Oncology, Dartmouth-
Hitchcock Medical Center, Hanover, New Hampshire 03755
O. ROSS McINTYRE (313), Norris Cotton Cancer Center and Dartmouth-
Hitchcock Medical Center, Hanover, New Hampshire 03755
GERALD METTER (343), Department of Biostatistics, City of Hope Medical
Center, Duarte, California 91010
JOHN A. MONTGOMERY (3), Southern Research Institute, Birmingham,
Alabama 35205
NIS I. NISSEN (181), Finsen Institute, Copenhagen, Denmark
NANCY NOLAN (123), Department of Biochemistry and The Vincent T. Lom-
bardi Cancer Center, Georgetown University Medical Center, Washington,
D.C. 20007
MAKOTO OGAWA (399), Division of Clinical Chemotherapy, Cancer
Chemotherapy Center, Japanese Foundation for Cancer Research, Kami-
Ikebukuro, Toshima-ku, Tokyo 170 Japan
THOMAS F. PAJAK (181, 209, 313), Cancer and Leukemia Group B, Scars-
dale, New York 10583
LEROY PARKER (155), Division of Medicine, Sidney Färber Cancer Institute,
Boston, Massachusetts 02130
GORDON L. PHILLIPS (337), Washington University School of Medicine,
St. Louis, Missouri 63110
DONALD POSTER (145), Cancer Therapy Evaluation Program, Division of
Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205
CARY A. PRES ANT (343), Department of Medical Oncology, City of Hope
Medical Center, Duarte, California 91010
ARCHIE W. PRESTAYKO (293), Research and Development, Bristol
Laboratories, Syracuse, New York 13201 and Department of Pharmacol-
ogy, Baylor College of Medicine, Houston, Texas 77030
RICHARD PROFFITT (343), Department of Medical Oncology, City of Hope
Medical Center, Duarte, California 91010
Contributors xvii
DONALD J. REED (51), Biochemistry and Biophysics, Oregon State Univer-
sity, Corvallis, Oregon 97331
SAUL E. RIVKIN (325), Tumor Institute of the Swedish Hospital Medical
Center, Seattle, Washington 98104
JEFFREY G. ROSENSTOCK (269), Division of Oncology, University of
Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, Pennsyl-
vania 19104
FRANK M. SCHABEL, JR. (9), Chemotherapy Research Department, Southern
Research Institute, Birmingham, Alabama 35225
PHILIP S. SCHEIN (367), Departments of Medicine and Pharmacology, Divi-
sion of Medical Oncology, Georgetown University Medical Center,
Washington, D.C. 20007
D. SCHMÄHL (27), Institute of Toxicology and Chemotherapy, German Cancer
Research Center, Heidelberg, Federal Republic of Germany
NANCY SHARKEY (69), Laboratory of Molecular Pharmacology, Develop-
mental Therapeutics Program, Division of Cancer Treatment, National
Cancer Institute, National Institutes of Health, Bethesda, Maryland 20205
BRANIMIR I. SIKIC (221), Department of Medicine (Oncology and Clinical
Pharmacology), Stanford University Medical Center, Stanford, California
94305
T. SMINK (27), Radiobiological Institute TNO, Rijswijk, The Netherlands
MARK SMULSON (123), Department of Biochemistry and The Vincent T.
Lombardi Cancer Center, Georgetown University Medical Center,
Washington, D.C. 20007
S. SOMFAI-RELLE (27), Research Institute of Oncopathology, Budapest, Hun-
gary
FEDERICO SPREAFICO (27), Mario Negri Institute for Pharmacological Re-
search, Milan, Italy
SWAROOP SUDHAKAR (123), Department of Biochemistry and The Vincent
T. Lombardi Cancer Center, Georgetown University Medical Center,
Washington, D.C. 20007
TAK TAKVORIAN (155), Division of Medicine, Sidney Färber Cancer Insti-
tute, Boston, Massachusetts 02130
KENNETH D. TEW (107), Division of Medical Oncology, Department of
Biochemistry, Georgetown University, Washington, D.C. 20007
CLAUDE TIHON (361), Tissue Cloning, Bristol Laboratories, Syracuse, New
York 13201
WILLIAM P. TONG (85), Division of Oncology, Department of Medicine,
Albany Medical College, Albany, New York 12208
MARY W. TRADER (9), Chemotherapy Research Department, Southern Re-
search Institute, Birmingham, Alabama 35255
FREDERICK VALERIOTE (343), MaillincKrogt Institute of Radiology,
Washington University School of Medicine, St. Louis, Missouri 63110
Will Contributors
L. M. VAN PUTTEN (27), Radiobiological Institute TNO, Rijswijk, The
Netherlands
MICHAEL E. WALKER (277), Stroke and Trauma Program, National Institute
of Neurological and Communicative Disorders and Stroke, National Insti-
tutes of Health, Bethesda, Maryland 20205
R. L. WEINER (337), Washington University School of Medicine, St. Louis,
Missouri 63110
RAYMOND B. WEISS (145), Cancer Therapy Evaluation Program, Division of
Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20205
BABETTE B. WEKSLER (313), New York Hospital, Cornell Medical Center,
New York, New York 10021
STEVE N. WOLFF (337), Washington University School of Medicine, St.
Louis, Missouri 63110
PAUL V. WOOLLEY III (285), Departments of Medicine and Pharmacology,
Schools of Medicine and Denistry, The Vincent T. Lombardi Cancer Re-
search Center, Georgetown University School of Medicine, Washington,
D.C. 20007
V. ZELLER (27), Institute of Toxicology and Chemotherapy, German Cancer
Research Center, Heidelberg, Federal Republic of Germany
NICHOLAS ZERVAS (155), Division of Medicine, Sidney Färber Cancer Insti-
tute, Boston, Massachusetts 02130
PREFACE
The nitrosoureas constitute one of the most extensively studied classes of
anticancer agents. Beginning with BCNU in the early 1960s, a total of six
nitrosourea compounds have been actively studied in the United States. Two of
these drugs, BCNU and CCNU, have reached commercial application.
Additional nitrosourea compounds have been placed into clinical study through-
out the world in places such as Japan, France, and the Soviet Union. As a class,
the nitrosoureas are actively used in a range of solid tumors and the malignant
lymphomas. Their continuity in central nervous system neoplasms is particularly
noteworthy.
Both the preclinical and clinical status of these agents are reviewed. The
literature and data on these compounds are so vast that this volume can touch
only on some areas in broad overview. It is hoped that both practicing on-
cologists and scientists working in drug development will find the book valuable.
xix
Nitrosoureas
Chapter 1
THE DEVELOPMENT OF THE NITROSOUREAS:
A STUDY IN CONGENER SYNTHESIS
John A. Montgomery
I. N-Nitroso Function 3
II. Chloroethyl Moiety 4
III. Antitumor Activity in Animal Tumors 5
IV. Conclusion 8
References 8
I. N-NITROSO FUNCTION
In 1955 the United States government launched a national cooperative cancer
drug research program under the auspices of the National Cancer Institute (NCI).
It began with the screening in animal tumor systems of chemical compounds that
might show activity against human cancer (Endicott, 1965). Four years later
N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a compound marketed by the
Aldrich Chemical Company for the preparation of diazomethane used by organic
chemists for synthetic work, was tested in the laboratories of the Wisconsin
Alumni Research Foundation, one of the NCI screening contractors, and found to
have significant activity against leukemia LI210, although it was inactive against
sarcoma 180 and adenocarcinoma 755, the other two tumors used in the primary
screen at that time. In later, confirmatory tests at Hazleton Laboratories and
Southern Research Institute, MNNG barely qualified as an LI210 active (Leiter
and Schneiderman, 1959).
Nevertheless, these findings stimulated the author to submit N-
methyl-N-nitrosourea, another, less stable precursor of diazomethane, to the
primary screen, with negative results in all the preliminary tests. Since the dose
selected for the initial LI210 test—based on the prior results in the S 180 and Ca
755 system—proved to be toxic, no further tests were scheduled. Lower doses,
tested at the author's request, produced increases in life span of leukemic mice
Copyright © 1981 by Academic Press, Inc.
All rights of reproduction in any form reserved.
3 ISBN 0-12-565060-4
