Biosynthetic Products for Cancer Chemotherapy Volume} Biosynthetic Products for Cancer Chemotherapy Volume} George R. Pettit Arizona State University, Tempe PLENUM PRESS· NEW YORK AND LONDON Library of Congress Cataloging in Publication Data Pettit, George R Biosynthetic products for cancer chemotherapy. Bibliography: p. Includes index. 1. Cancer-Chemotherapy. 2. Antineoplastic agents. I. Title [DNLM: 1. Neo plasms-Drug therapy. 2. Antineoplastic agents. QZ267 PSllb] RC271.CSP47 616.9'94'061 76-S4146 ISBN-13: 978-1-4684-7232-S e-ISBN-13: 978-1-4684-7230-1 001: 10.1007/978-1-4684-7230-1 © 1977 Plenum Press, New York Softcover reprint of the hardcover 1st edition 1977 A Division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. 10011 All righ ts reserved No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microf"llming, recording, or otherwise, without written permission from the Publisher To the far-sighted. enlightened and dedicated present and past members of the National Cancer Institute whose great contributions and personal sacrifice have provided a firm basis for cancer chemotherapy and eventual control of human cancer. Preface Cancer exacts an incredibly destructive toll on the world's human populations. In recent years we have frequently heard the expression "war on cancer," but compared to the carnage inflicted by cancer, our scientific and medical efforts, to date, would seem more like a minor skirmish. Some comprehension of the cancer problem can be obtained from a look at the current and projected casualty list for the United States. In this country, about 700,000 new cases of cancer will be diagnosed in 1976 and over 1 million known cases will continue to be treated. Over 400,000 of these patients will die from cancer in our bicentennial year. With the incidence of cancer in the United States increasing to 5.2% in 1975, compared to the 1.1 % yearly rate experienced for decades, Dr. F. J. Rauscher, Jr.,338 Director of the National Cancer Institute, has estimated that more than 10 million people will be under treatment for cancer and nearly 4 million will expire from cancer in this decade. At that rate, cancer will appear in nearly two of three families and the necessary medical care will cost some $15-20 billion per year. Thus unless methods for the treatment and control of cancer are markedly improved, about 53 million Americans now alive will eventually be cancer patients. Unfor tunately the major types of human cancer are still beyond curative care by surgical and radiological techniques and because of the paucity of currently available cancer chemotherapeutic drugs with curative potential. The best hope for future control and curative treatment of cancer depends upon widespread application of preventive vii viii Preface measures and the further discovery and development of anti cancer drugs of both synthetic and biosynthetic origin. Both of the latter approaches to cancer therapy gained increasing support during the 1940's. Now we have reached the stage at which very useful drugs of synthetic and natural origin have been developed, especially in the U.S. National Cancer Institu tion's programs, capable of curative treatment for 11 types of human cancer. The search for cancer chemotherapeutic natural products has been rapidly accelerating in recent years and holds promise of leading to spectacular developments in cancer treatment over the next decade. Current clinical successes with actinomycin D, adriamycin, and vincristine (combined with the current poten tial of other biosynthetic products such as maytansine) have been quite promising. Now the search for still more effective cancer chemotherapeutic agents must receive the vigorous (and increased) support necessary to uncover the even more selective and effective cancer chemotherapy drugs of the future. The same must be said for the increased support urgently needed to explore further the synthetic modification of natural anticancer agents and the exploratory synthesis of cancer chemotherapeu tic drugs. The cancer research program now at Arizona State Univer sity was initiated in September 1957 at the University of Maine, and later that fall this writer agreed to undertake an evaluation of the Labiatae plant family for antineoplastic constituents as part of the newly organized National Cancer Institute program of systematic study of plants and microorganisms as sources of cancer chemotherapeutic agents. The first shipments of Labiatae extracts to the National Cancer Institute were made during the following year, but because of severe financial limitations, our plant program remained in barely active form for the next 10 years. Over this period, major emphasis was placed on synthesis of potential antineoplastic agents and synthetic modification of naturally occurring anticancer and cytotoxic substances. However, in 1966, it was possible to initiate substantial efforts in the then-unexplored fields of Pre/ace ix arthropod and marine animal antineoplastic constituents. By 1969, these endeavors concerned with plant and animal anti cancer agents accounted for nearly 90% of our total commit ment. In this same period, the 1969 review of plant anticancer agents by Hartwell and Abbott145 and the 1967 review of naturally occurring anticancer agents by Neuss and colleagues277 were made available. In the past 5 years, progress concerned with anticancer agents of biosynthetic origin has been rapidly increasing, and the need for a current treatment of the subject led to preparation of this survey. The principal objective of Volume 1 is to provide a current (to February 1976) overall view of the cancer problem and the development of cancer chemotherapeutic drugs of biosynthetic origin. In addition, it is hoped that the approach employed in Volume 1 will give the chemist and the biologist an appreciation of cancer treatment and the physician a view of how biosynthetic antineoplastic agents are discovered and developed. Volume 2 was prepared to provide a tabular summary (to April 1976) of all the naturally occurring antineoplastic and cytotoxic sub stances described in the chemical literature. In total, it is hoped that this effort to correlate and bring up to date the chemistry and cancer biology of biosynthetic anticancer agents will prove useful to a variety of disciplines and assist in advancing future progress toward better and more readily available cancer chemotherapeutic drugs with not only curative potential but far-reaching curative action. Many of the most significant and invaluable advances in the field of biosynthetic cancer chemotherapeutic agents witnessed, particularly over the past 10 years, are due in large measure to a number of scientists and clinicians at the National Cancer Institute whose brilliant leadership and devotion to duty has inspired and promoted this progress. Here I would like to single out for special recognition in cancer chemotherapeutic drug development Drs. John D. Douros, Robert R. Engle, Jonathan L. Hartwell, Ronald B. Ross, Harry B. Wood, and C. Gordon Zubrod. Other most admirable contributions have been made to the biological and clinical aspects of the NCI drug develop- x Preface ment program by, for example, Miss B. J. Abbott and Drs. P. P. Carbone, S. K. Carter, V. T. DeVita, A. Goldin, V. T. Oliverio, J. M. Venditti, and M. D. Walker. In respect to this work, I am very pleased to acknowledge the expert and splendid contribu tions of Mrs. Christine H. Duplissa and Mrs. Marie D. Baugh man in final preparation of the manuscript. George R. Pettit Paradise Valley, Arizona Contents Chapter 1 Introduction and Perspective . . . . . . . . . . . . . . . . . . . . 3 Chapter 2 Naturally Occurring Antineoplastic and Cytotoxic Agents.............................. 47 Chapter 3 Higher Plant Terpenoids 61 Chapter 4 Higher Plant Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . 89 Chapter 5 Higher Plant Lignans 97 Chapter 6 Quinones, Flavans, and Other Nonnitrogenous HigherPlantltoduc~ ................. 105 Chapter 7 Higher Plant Alkaloids, Amides, and Ansa Macrolides .......................... 109 Chapter 8 Fungi and Other Lower Plant Biosynthetic ltoducts ............................ 131 xi xii Contents Chapter 9 Marine Invertebrate and Other Lower Animal Biosynthetic Products ................. 165 Chapter 10 Marine Vertebrate and Other Higher Animal Biosynthetic Products ................. 177 References .................................. 187 Index. . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203