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Chemistry and Biological Actions of 4-Nitroquinoline 1-Oxide PDF

111 Pages·1971·4.563 MB·English
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Recent Results in Cancer Research Fortschritte der Krebsforschung Progres dans les recherches sur Ie cancer 34 Edited by V. G. Allfrey, New York . M. Allgower, Basel . K. H. Bauer, Heidelberg I. Berenblum, Rehovoth . F. Bergel, jersey . j. Bernard, Paris . W. Bern hard, Villejuif • N. N. Blokhin, Moskva' H. E. Bock, Tubingen . P. Bucalossi, Milano' A. V. Chaklin, Moskva' M. Chorazy, Gliwice . G. j. Cunningham, Richmond . W. Dameshek t, Boston • M. Dargent, Lyon . G. Della Porta, Milano' P. Denoix, Villejuif . R. Dulbecco, La jolla· H. Eagle, New York R. Eker, Oslo' P. Grabar, Paris.' H. Hamperl, Bonn' R. j. C. Harris, London E. Hecker, Heidelberg . R. Herbeuval, Nancy • j. Higginson, Lyon W. C. Hueper, Fort Myers' H. Isliker, Lausanne' D. A. Karnofsky t, New York . J. Kieler, Kobenhavn . G. Klein, Stockholm • H. Koprowski, Phil adelphia' L. G. Koss, New York· G. Martz, Zurich· G. Mathe, Villejuif O. Muhlbock, Amsterdam' W. Nakahara, Tokyo' V. R. Potter, Madison A. B. Sabin, Rehovoth . L. Sachs, Rehovoth . E. A. Saxen, Helsinki C. G. Schmidt, Essen • S. Spiegelman, New York . W. Szybalski, Madison H. Tagnon, Bruxelles . R. M. Taylor, Toronto . A. Tissieres, Geneve E. Uehlinger, Zurich· R. W. Wissler, Chicago' T. Yoshida, Tokyo Editor in chief P. Rentchnick, Geneve Springer-Verlag New York· Heidelberg' Berlin 1971 Chemistry and Biological Actions of 4-Nitroquinoline 1-0xide Edited by H. Endo . T.Ono . T. Sugimura With 12 Figures Springer-Verlag New York· Heidelberg· Berlin 1971 Sponsored by the Swiss League against Cancer ISBN 978-3-642-49283-9 ISBN 978-3-642-49281-5 (eBook) DOl 10.1007/978-3-642-49281-5 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying madtine or similar means, and storage in data banks. Under § 54 of the German Copyright Law where copies are made for other than private use, a fee is payable to the publisher, the amount of the fee to be determined by agreement with the publisher. © by Springer-Verlag Berlin' Heidelberg 1971. Library of Congress Catalog Card Number 76-129622. Softcover reprint of the hardcover I st edition 1971 The use of general descriptive names, trade names, trade marks, etc. in this publication, even if the former are not especially identified, is not be taken as a sign that sudt names, as understood by the Trade Marks and Merdtandise Marks Act, may accordingly be used freely by anyone. Typesetting, To Dr. Waro Nakahara Pioneer worker on the carcinogenicity of4 -nitroquinoline l-oxide, this monograph is dedicated with profound respect and affection by authors who worked under his SUper7JlSZOn Preface During the last decade a considerable body of knowledge has come into existence concerning a class of carcinogenic molecules chiefly represented by 4-nitroquinoline i-oxide. Original papers on this subject are numerous and widely scattered over many branches of science; it was felt that these papers should be reviewed and the knowledge brought together in one volume before it became too unwieldy. This we have attempted to do in this monograph. Our aim has been to include all relevant papers published to date, so that it may serve as an epitome of the present status of knowledge on this important subject. We have been fortunate in securing the cooperation of several colleagues who have contributed chapters, each dealing with one aspect of the subject. We have been doubly fortunate in that these contributors, like ourselves, were at one time or another members of the group belonging to the scientific staff of Dr. WARO NAKA HARA, Director of the National Cancer Center Research Institute, Tokyo, Japan. The development of research on carcinogenesis by 4-nitroquinoline i-oxide has in many ways been dominated by Dr. NAKAHARA'S outstanding contribution, and it has been under his leadership that much of the progress in understanding the mechanism of the action of this carcinogen has been achieved. We felt it proper to honor him at this stage, and we offer this volume as a tribute, both from those who contributed to it and those who could not, to his pioneering achievement, and as an expression of our deep and sincere admiration for this distinguished personality. January, 1968 HIDEYAENDO TETsuoONo T AKASHI SUGIMURA Contents Chapter 1 Introduction. TAKASHI SUGIMURA 1 Chapter 2 Chemical Properties. YUTAKA KAWAZOE . 3 Chapter 3 Biophysics. CHlKAYOSHI NAGATA 17 Chapter 4 Carcinogenicity. HIDEYA ENDO . 32 Chapter 5 Metabolism. TAIJIRO MA TSUSHIMA and TAKASHI SUGIMURA . 53 Chapter 6 Molecular Aspects of the Action. HIDEYA ENDo, TETSUO ONO, and HIROTO NAORA . 60 Chapter 7 Anti-tumor Effect. FUMIKO FUKUOKA . 67 Chapter 8 Microbiology. TAKASHI MITA 74 References. 85 Subject Index 99 Contributors HmEYA ENDo, Department of Chemistry, Cancer Researdt Institute Kyushu Uni versity, Fukuoka FUMIKO FUKUOKA, Chemotherapy Division, National Cancer Center Researdt Insti tute, Tokyo YUTAKA KAWAZOE, Chemotherapy Division, National Cancer Center Researdt Institute, Tokyo TAIJIRO MATSUSHIMA, Biodtemistry Division, National Cancer Center Researdt Institute, Tokyo TAKASHI MITA, Biology Division, National Cancer Center Research Institute, Tokyo CHlKAYOSHI NAGATA, Biophysics Division, National Cancer Center Researdt Insti tute, Tokyo HIROTO NAORO, Research School of Biological Sciences, The Australian National University, Canberra, Australia TESTUO ONO, Department of Chemistry, Cancer Institute, Japanese Foundation for Cancer Researdt, Tokyo . TAKASHI SUGIMURA, Biodtemistry Division, National Cancer Center Research Insti tute, Tokyo Chapter 1 Introduction T AKASHI SUGIMURA 4-Nitroquinoline 1-oxide was first synthesized by OCHIAI and his collaborators in 1942 and the carcinogenicity of this compound was established in 1957 by NAKAHARA and his colleagues at the Cancer Institute, Japanese Foundation for Cancer Research. The motive which led them to the discovery of the carcinogenic action of 4-nitro quinoline 1-oxide arose out of earlier work on its mutagenic action on microbes and tumoricidal action on Ehrlich ascites tumor. It has been well known since HADDOW'S postulate (1935) that a certain type of carcinogen exhibits anticancer action and vice versa. Moreover, there has been abundant evidence to indicate that compounds showing carcinogenic action often possess mutagenic activity for microbial systems. Thus, the mutagenic and tumoricidal activity of 4-nitroquinoline 1-oxide led NAKAHARA and his colleagues to presume that this compound might be carcinogenic. The first paper in 1957 was based on skin painting experiments in mice, demon strating the ready production of squamous cell carcinoma and sometimes fibro sarcoma of the skin. A year later, after testing several related derivatives, it was established that the nitro group at position 4 and the oxygen atom attached to the nitrogen (position 1) of the quinoline ring were essential to the carcinogenic activity of the molecule. The production of sarcoma, also in mice, by subcutaneous injections was reported in 1959. These three papers by NAKAHARA and his associates built the firm foundation for further studies, which have since developed extensively, as described in this monograph. The papers of NAKAHARA and his colleagues on carcinogenesis by 4-nitro quinoline 1-oxide attracted the attention of many cancer researchers in Japan and later in other countries, since the structure and the chemical reactivity of this compound are relatively simple. From the technical viewpoint, this compound has the advantage of being more water-soluble than other typical carcinogens, such as hydrocarbons. There followed many reports indicating carcinogenesis in lung, ovary, uterus, tongue, stomach, gingiva and other organs. Animals tested with positive results now include, beside mice, rats, hamsters, guinea pigs and rabbits. The group of organic chemists, headed by OCHIAI, specializing in the chemistry of quinoline compounds made the various derivatives of 4-nitroquinoline 1-oxide available to workers in cancer research, and the studies on the relationship between carcinogenic activity and chemical structure developed very rapidly. The particularly interesting chemical structure of 4-nitroquinoline 1-oxide attracted much attention. 4-Nitroquinoline 1-oxide, having two strong polar groups 1 RRCR, Vol. 34 Endo et al. 2 T. SUGIMURA: Introduction in the molecule, the N-oxide and nitro groups, is susceptible to nucleophilic attack in chemical reaction and also behaves as an electron acceptor in the charge transfer complex formation. The relationship between the n-electron density of charge transfer and carcinogenicity in 4-nitroquinoline 1-oxide and its derivatives, was investigated in detail. A new breakthrough was the discovery of the carcinogenicity of 4-hydroxy aminoquinoline 1-oxide, the reduced product of 4-nitroquinoline 1-oxide. Another reduced compound, 4-aminoquinoline 1-oxide, has no carcinogenic activity. The metabolic pathway by which 4-hydroxyaminoquinoline 1-oxide and 4-amino quinoline 1-oxide are formed from 4-nitroquinoline 1-oxide was found to exist in mammalian cells. Other biological actions besides carcinogenicity were observed with 4-nitro quinoline 1-oxide. These were the induction of mutation in microbes, the induction of phage formation in lysogenic bacteria, the formation of intranuclear inclusion bodies in tissue culture cells, the cytocidal effect on protozoa with photodynamic actions and the carcinostatic action. All these biological actions of 4-nitroquinoline 1-oxide were also exerted by 4-hydroxyaminoquinoline 1-oxide. Especially note worthy is the fact, however, that 4-hydroxyaminoquinoline 1-oxide inactivates the isolated transforming DNA and the bacteriophage in vitro, whereas 4-nitroquinoline 1-oxide does not. Since such systems are devoid of the capability to form the 4-hydroxyamino compound from 4-nitroquinoline 1-oxide, these results led some investigators tq suggest that 4-hydroxyaminoquinoline 1-oxide is a proximate carcinogen. The interactions of quinoline derivatives with biological substances, especially with DNA in vitro and in vivo, were widely investigated; it was established that 4-nitroquinoline 1-oxide or 4-hydroxyaminoquinoline 1-oxide injected into rats could produce the fluorescence compound covalently bound with DNA. This kind of DNA showed depressed template activity for DNA-dependent RNA polymerase. More recently, pleomorphic clones of Tetrahymena with abnormal behavior at nuclear division were established by treatment with 4-nitroquinoline 1-oXide at a certain phase of synchronous cell division. This may serve as a model system for the studies on carcinogenesis. Recently two Japanese working groups have succeeded independently in demonstrating the malignant transformation in vitro of cultured mammalian cells by 4-nitroquinoline 1-oxide and 4-hydroxyaminoquinoline 1-oxide. Of great interest is the fact that the transformation was effected by treating the cells with 4-hydroxy aminoquinoline 1-oxide for only 15 minutes. Further studies on the nature of the interaction of 4-nitroquinoline 1-oxide and 4-hydroxyaininoquinoline 1-oxide with biological materials may result in our final understanding of the carcinogenic processes initiated by 4-nitroquinoline 1-oxide and, by extrapolation, of those of chemical carcinogenesis in general.

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