Nitrosoureas. Current Status and New Developments PDF
Preview Nitrosoureas. Current Status and New Developments
NITROSOUREAS 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. 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. ACADEMIC PRESS, INC. 111 Fifth Avenue, New York, New York 10003 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
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