Table Of ContentRecent Results in Cancer Research
Fortschritte der Krebsforschung
Progres dans les recherches sur Ie cancer
34
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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
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© by Springer-Verlag Berlin' Heidelberg 1971. Library of Congress Catalog Card Number 76-129622.
Softcover reprint of the hardcover I st edition 1971
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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.
