Postgrad Med J: first published as 10.1136/pgmj.37.428.360 on 1 June 1961. Downloaded from POSTGRAD. MED. J. (ig6I), 37, 360

CANCER RESEARCH IN THE FAR EAST E. BOYLAND, D.Sc. Professor of Biochemistry, Institute af Cancer Research, Royal Cancer Hospital, Fulham Road, London, S.W.3

WITH the recognition of the widespread incidence liver occur more frequently in Japan than in of cancer, research into its occurrence, cause and western countries; the elucidation of the causes of treatment is being pursued in an increasing these forms of cancer presents important, interest- number of centres. This research is supported ing, but difficult problems which are being by governments, by industry and by private studied. The incidence of these forms of cancer subscription. The biggest effort is undoubtedly appears to be influenced by diet, but the relation- being made in the United States of America ship between diet and cancer in man remains where very large sums of money are being spent, obscure. One of the dietary factors suspected as particularly in the field of chemotherapy of possibly responsible for cancer in man is yellowed cancer; this is financed mainly by the government or mouldy rice. One of the moulds which is United States Health Service and the American commonly present in rice stored in damp condi- Cancer Society which relies on private donations. tions is Penicillium islandicum. Feeding of rice One had the impression that the support of artificially infected with the penicillium induced a cancer research in Japan was to some extent few tumours in rats. Consumption of mouldy dependent on industry. Cancer research in China rice might conceivably play a part in the induction is necessarily entirely under government support of cancer in man (Miyake, Saito, Enomoto,by copyright. and control, but some of the buildings used for Shikata, Ishiko, Uraguchi, Sakai, Tatsuno, Tusk- the research in Chinese cities were originally ioka and Noguchi, i960). provided by western benefactions. Investigations in the field of cancer chemo- therapy in Japan have been mainly along two Japan lines; the alkylating agents and antibiotics. Among Cancer research in Japan has a relatively long the alkylating agents the Japanese drug Nitromin, history. The original work of Yamagiwa and which is an N-oxide of nitrogen mustard (HN2), Ichikawa (i9i6) carried out almost 50 years ago was introduced by Ishidate, Kobayashi, Sakurai, showed that coal tar would induce cancer when Sato and Yoshida (x95i) and has been usedhttp://pmj.bmj.com/ painted on the ears of rabbits. Later Tsutsui extensively in the East. Nitromin is probably (i9i8) showed that painting of tar on the backs of inactive as such, but is reduced in the body to the mice induced skin tumours. These findings have active nitrogen mustard. Nitromin is much less been the basis of subsequent work in the study of toxic than nitrogen mustard and can be adminis- carcinogenesis, particularly in the field of poly- tered by mouth; it appears to be a useful drug in cyclic hydrocarbons. Dr. C. Huggins suggested to the treatment of lymphoid tumours. Another me that the Japanese workers succeeded in the interesting development in the study of nitrogen induction of cancer in animals when western mustard derivatives is that of Sakurai (i96i) who on September 25, 2021 by guest. Protected investigators had failed to do this for two reasons: has synthesised a series of chloroalkyl chloro- the Japanese were accustomed to painting because ethylamines with different alkyl groups with differ- they wrote with a brush; and they are extremely ent numbers of carbon atoms varying from two to persistent. The induction of cancer in animals six. These compounds have, up till now, only takes many months or even years. Later Yoshida been tested in animals. Antitumour activity (1934) and Kinosita (1940) showed that certain azo occurred with compounds with a side chain with dyes such as ortho-aminoazotoluene and butter 3, 4, 5 or 6 carbon atoms. Benzyl-(2-chloroethyl)- yellow (4-dimethylaminoazobenzene) can induce (6-chlorohexyl) amine and benzyl-(2-chloroethyl)- cancer of the liver. This work has led to investiga- (3-propyl) amine inhibited the growth of tumours tions in many countries on the genesis of liver in rats. These compounds are examples of a new cancer. type of drug and it will be interesting to see if Most of the present-day cancer research in they have any clinical value. Japan is concerned with epidemiology and chemo- Japanese chemists and biochemists have isolated therapy. Cancer of the stomach and cancer of the many antibiotics or fermentation products with June i96i BOYLAND:, Cancer Research in the Far East 36i Postgrad Med J: first published as 10.1136/pgmj.37.428.360 on 1 June 1961. Downloaded from interesting properties. One of these substances, appeared to be the polarographic test for cancer Mitomycin C, although extremely toxic, inhibits diagnosis which had been introduced in Prague. tumours in sub-toxic doses. The chemical struc- There are about 30 graduates in the department ture of Mitomycin C has not been determined but of experimental biology of the Academia Sinica it has been used clinically in some hundreds of at Shanghai working on cancer research. Most cancer patients and has produced beneficial of the problems on which they are engaged are also effects in some of these. Mitomycin C is adminis- being studied by many workers in other countries. tered by injection and the total dose used in a Thus they are studying the polyoma virus in course of treatment should not exceed 40 mg. animal and human tumours by injecting tumour Japanese workers are actively investigating dif- extracts into young rats, mice and hamsters, and ferent fermentation products from the point of applying extracts to normal cells growing in tissue view of chemistry and pharmacology. In Japan culture. The human tumours investigated were there is often close co-operation between workers mostly hepatomas-none of the extracts had in University laboratories and the pharmaceutical produced tumours in animals, but extracts of industry. one human liver cancer had induced abnormalities Takizawa and Murayama (i960) have described in tissue cultures. They are also examining the the induction of sarcomata in rats by injection of pre-cancerous changes in experimental liver hypertonic solutions of different reducing sugars cancer in rats, particularly in relation to the type such as mannose or galactose, but not with sucrose. of liver damage which precedes and is associated In these experiments the incidence of tumours was with hepatoma development following treatment always low-generally below the usually accepted with acetylaminofluorene and other agents under level of statistical significance. The occurrence of different dietary conditions. Another team in this these tumours has frequently been used as indicat- department were studying the immunological ing that injection experiments are of little value in reactions of cell fractions from normal and malig- testing of food additives for carcinogenic activity. nant tissues. The reactions were being measured The action of these solutions may be due to the by complement fixation, by anaphylactic responses physical effect of the osmotic pressure; the and by precipitin reactions. In the tissue culture observations present interesting problems which laboratory (under the direction of Dr. Chen who by copyright. deserve further investigation. at one time had worked with Dr. H. Fell at the Strangeways Institute, Cambridge), 22 different China strains of cells were maintained. Cancer research in China started on a large The department of Materia Medica of the scale some three years ago when the authorities Academia Sinica in Shanghai has a total staff of considered that the problems of infectious 500, of which about ioo are graduates in either diseases were being sufficiently investigated. The science or medicine. There are extensive facilities Academia Sinica has laboratories in several for animal experimentation and many new com- Chinese cities which carry out investigations in pounds and preparations are tested for possible http://pmj.bmj.com/ many fields of pure and applied science. The application in the treatment of infectious diseases, laboratories in Shanghai, which occupy buildings cardiovascular diseases and cancer. In the which used to be the Lester Institute, are devoted cancer chemotherapy screening programme a to biology and biochemistry. In these laboratories, range of io different animal tumours were em- which are well equipped with apparatus from all ployed. One of the lines of approach was the over the world (including the U.S.A.), there are a synthesis of nitrogen mustard derivatives of local

number of scientists who have worked in Britain anesthetics; this work is under the direction of on September 25, 2021 by guest. Protected or America in the past. Thus the physiology Dr. Y. S. Kao who had worked with Sir Robert department is under the direction of Dr. Feng, Robinson in Oxford some years ago. Another who had worked with Prof. A. V. Hill in London group of workers were preparing extracts from and Dr. Bronk in Philadelphia. The biochemistry native Chinese plants. Extracts of the Chinese department was run by Dr. Y. C. Wang, who had plant Narcissus Tazita var. Chinesis Rhoeme have worked with Prof. Keilin and Dr. T. C. Tsao, been found to inhibit the growth of transplanted who had collaborated with Dr. K. Bailey in tumours in animals. The active principle from Cambridge. Most of the research in the bio- the narcissus has not been isolated but it appeared chemistry department is of a fundamental nature, to have some of the biological properties of on the problems of protein synthesis, the isolation colchicine. and nature of proteins from blood and tissues Cancer research in Peking is mainly under the (particularly muscle and brain), and enzyme direction of the Academy of Medical Science, action including proteolysis and oxidation pro- which is in part housed in the old Peking Union cesses. The only cancer problem being studied Medical College and a cancer hospital, which was 362 POSTGRADUATE MEDICAL JOURNAL June 196I Postgrad Med J: first published as 10.1136/pgmj.37.428.360 on 1 June 1961. Downloaded from built only three years ago in the eastern suburbs of Hong Kong the city. This hospital has zoo beds and is Although most of the cancer research in the equipped with a cobalt bomb unit from Canada Far East is carried out in China and Japan, and X-ray apparatus from many countries. About interesting work is proceeding in other centres. In ioo doctors are attached to the hospital, but Hong Kong Prof. Hou and Dr. Ma Lin are many of these are under training, as the centre is investigating the genesis of liver cancer. Post- used to give instruction in treatment of cancer for mortem and other examination of subjects with doctors from all over China. The cytology liver cancer indicate that there is an association laboratory had a staff of four workers who were between infection with clonorbis and liver cancer. using the Papanicolaou technique for the detection Infection with clonorbis arises from eating raw of cancer of the cervix. fresh water fish. The fish were fed on human Cancer of the cervix is one of the common fxces so that there was a cycle which led to forms of cancer in China. Investigations on the continuous fresh infection. By preventing the epidemiology of cancer in China are difficult in eating of the particular raw fish, it is thought that view of the large area and population of the the incidence of liver cancer from this source country, but this has begun in certain limited should be reduced. The organisms themselves areas of the country. Other forms of cancer which isolated from livers of infected patients and of appear to be peculiarly common are cancer of the infected cats have been investigated by chemical Esophagus in North China and cancer of the analysis. The organisms appear to have a very nasopharynx in South China and other countries high copper content. of South-East Asia. Nasopharyngeal cancer is a Cancer of the liver occurs much more frequently particularly interesting problem. The occurrence in Africa and Asia than in Europe and America. of the disease is compatible with there being some Prof. Macfadzean in Hong Kong has found that environmental or similar causes. Suggested the presence of liver cancer often has profound causes of this disease are the incense from burning effects on carbohydrate metabolism of the subject. joss-sticks, the smoke from wood or other fuels Patients with liver cancer frequently have muscular used in cooking, the consumption of particularly weakness, which can be reversed by administra- hot (either in temperature or flavour) food, or the tion of insulin. It is remarkable that liver cancerby copyright. morphology of the nose in Chinese and other should effect carbohydrate metabolism of the races in South-East Asia. Some investigators whole body. consider that the disease only occurs in persons The problems of the origin, nature and treat- living near the sea. Most of the cases occur ment of cancer are of universal interest and in cities such as Shanghai, Canton, Hong Kong development of many of these would be facilitated and Singapore. by good international co-operation. Such co- In view of the current interest in polyoma virus operation, particularly between the East and it might be of value to examine tissue from naso- West, is helped by interchange of workers between pharyngeal cancer for the presence of a tumour- different countries. It is to be hoped that there will http://pmj.bmj.com/ inducing virus. The disease is not limited to be more opportunity for young research workers Chinese, as the incidence of the disease in Singa- from Eastern countries to work in American, pore and Kuala Lampur is similar in the Malayan British or European laboratories in the next few and Chinese populations. years.

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