MINUTES OF THE THIRD ANNUAL JOINT MEETING

UNITED STATES-JAPAN COOPERATIVE CANCER RESEARCH PROGRAM

Miyako Hotel, Kyoto, Japan October 12-13, 1976

Opening Session-October 12, 1976
The Third Annual Joint Meeting of the Joint NCI-JSPS Scientific Groups was called to order by Dr. Haruo Sugano, Chairman of the JSPS Scientific Group, at 8:30 a.m. at the Miyako Hotel, Kyoto, Japan.
In his opening remarks, Dr. Sugano welcomed the members of the NCI Scientific Group and expressed his pleasure to meet again in the historic capital city of Japan. He expressed his deep appreciation to the Program Coordinators for their efforts and contributions towards the success of the United States-Japan Cooperative Cancer Research Program. He also reported that through their efforts and effective organization of their respective program areas, it has been possible to involve some 500 scientists from both countries during the first two and one-half years since the initiation of this Program. Each of these researchers and clinical scientists has contributed towards the success of the Program, either as participants and observers at scientific meetings, conferences and workshops or as exchange scientists under the auspices of the Program.
Dr. Sugano expressed his personal appreciation to the JSPS and NCI staff for compiling all the reports and information for the publication of the First Report 1974-1975, United States-Japan Cooperative Cancer Research Program. He thanked Ms. Yuko Kitamura, Dr. Yoji Ikawa and Dr. Robert Omata for their contribution towards the publication.
He also stated that he was extremely impressed by the team visit concept which has evolved from the scientist exchange segment of this Program. This has made it possible for the various Program Areas, such as the Cancer Therapy and High LET Radiation Therapy Programs, to approach the various problems for further discussion and exchange of ideas and viewpoints.
He has also been impressed by the fact that some of the Program Areas, such as Bladder Cancer and Analytical Epidemiology, have convened meetings and workshops with intergroup and multidisciplinary approach to discuss ideas and exchange information. In this way, there is greater exposure for wider dissemination of information.
Dr. Sugano also expressed his great interest in the future possibilities of joint publications of meetings and workshops supported by the United States-Japan Cooperative Cancer Research Program.
The purpose of this meeting was to provide the Program Coordinators an opportunity to present their Annual Reports on the activities during the past year and also to present plans for the coming year. In this way, the Joint Scientific Group will be able to review and evaluate the progress of the Program with open and informal discussion.
Dr. Sugano stated that the format of this year's meeting was modified, at the suggestion of Dr. Robert Miller, to include two scientific sessions, namely Chemical Carcinogenesis and Cancer Therapy, to inform the members of some of the latest information in these areas. These sessions will encourage open discussions of two very important areas of cancer research.
Finally, Dr. Sugano acknowledged the contributions made by Mr. Genkichi Hara and Dr. Robert Omata towards the progress of the whole Program and gave special recognition to Dr. Yohei Ito and Ms. Yuko Kitamura for their efforts in making the necessary arrangements for this Annual Meeting.
Dr. Guy R. Newell, Chairman of the NCI Scientific Group, expressed the appreciation and gratitude of the NCI Scientific Group to Dr. Sugano and the JSPS Scientific Group for their hospitality. Dr. Newell expressed his personal appreciation and joy at being in the ancient and historic capital and that the meeting was being held in the center of the ancient area of Kyoto. He stated that this was an appropriate setting for a historic country with its origin dating back many centuries, to invite representatives of a young nation, which is just celebrating its bicentenniel year.
He stated that the Program had recovered from its initial period of “growing pains” and produced a healthy, vigorous adolescent within two and one-half years. Many problems have been solved, but in the future other problems, a very different set of problems, will be facing the Program. He is confident that they will be solved with the efforts of everyone associated with the Program. He has been extremely impressed with the progress of the Program and that each of the participants has had an opportunity to fulfill their goals and commitments with pleasure. He then stated that on behalf of the American members he wished to thank the Japanese Scientific Group for their warm hospitality and looked forward to a very successful meeting.
Dr. Newell introduced the American delegation as follows: Dr. Arthur Upton, Dr. William Terry, Dr. Stephen Carter, Dr. Franco Muggia, Dr. Oleg Selawry, Dr. George Bryan, Dr. Glenn Sheline, Dr. Chester Herman, Dr. Philip Stansly, Dr. Robert Miller, Dr. David Clayson, and Dr. Robert Omata.
Dr. Sugano, in turn, introduced the following members of the Japanese Delegation: Dr. Takeshi Hirayama, Dr. Yoji Ikawa, Professor Yohei Ito, Dr. Kiyoji Kumura, Dr. Yoshio Sakurai, Professor Haruo Sato, Mr. Toru Sawada, Dr. Takashi Sugimura, Dr. Akira Tsuya, Dr. Hamao Umezawa, Dr. Osamu Yoshida, Professor Tadashi Yamamoto, Professor Yuichi Yamamura, Dr. Isao Amagi, Mr. Genkichi Hara, Mr. Naganide Onozawa, and Ms. Yuko Kitamura.
The Chairman asked for a motion from the floor to accept the agenda of the meeting in order to proceed. Dr. Upton made the motion to accept the agenda and Dr. Sugimura seconded. The motion was accepted by a unanimous vote.
Dr. Newell called on the following Program Coordinators to present their report to the Joint Scientific Group:

1. Cancer Virology Program Area: Dr. Robert McAllister, Dr. Yohei Ito
Dr. Ito first read a letter from Dr. McAllister expressing his regrets for being unable to attend the meeting. He then reported on the activities of the Cancer Virology Program Area, stating that the Program Area was initially considered very broad by necessity since it was quite vast and expanding. The discussions at the first meeting in 1975 involved many lines of research in viral oncology, particularly the RNA and DNA viruses. At the second meeting in Kyoto, held in March 1976, several specific topics on the molecular biology of animal and human viruses and the description of type C viruses recovered from human myelocytic leukemia cells were discussed.
Drs. Ito and McAllister, in their Joint Annual Report, expressed their belief that the joint program was progressing very well and several of their goals have been fulfilled. The commitments and objectives of both the American and Japanese scientists are the same and they expect to continue their efforts to develop the program into a worthwhile cooperation. The next meeting is being planned for May 1977 in Pasadena, California.
During the past year, there has been a considerable amount of exchange of scientific personnel with seven American scientists visiting several research institutions and presenting 13 or more seminars and lectures on cancer virology to many Japanese scientists. This alone has been a major and important contribution in exchanging and disseminating recent developments and knowledge. In addition, several young Japanese scientists have spent some time in American laboratories. The Program Coordinators plan to continue the exchange of scientists.
The exchange of precious and invaluable reagents, cell lines, and virus specimens has been most helpful in nurturing cooperative research. Opportunities for further collaborative research will be sought and encouraged in future years.
Dr. Newell acknowledged and commended Dr. Ito’s presentation and contributions toward the joint program and complimented the mutual friendship developed between the scientists from both sides.

2. Bladder Cancer Program Area: Dr. Osamu Yoshida, Dr. George Bryan
Dr. Bryan reviewed the three meetings and workshops sponsored under the Bladder Cancer Program Area since the last joint meeting in San Francisco as part of the four activities which the Program has developed; namely, joint scientific meetings, exchange of personnel, exchange of materials, and jointly conducted investigations, which have been developed from the previous person-to-person joint studies.
The joint meeting on “Experimental Models for Bladder Cancer” in December 1976, in Hawaii, was highly successful since it was deliberately planned for a multidisciplinary approach to the problem of studying bladder cancer. It provided opportunities to introduce molecular pathology and cytopathology to basic and clinical researchers. There was a great deal of person-to-person interaction and interchange of experimental data.
Since then, several Japanese scientists were invited to participate and act as consultants at the annual meeting of the U.S. National Bladder Cancer Project. This will provide opportunities for the continuing review of the progress of research on bladder cancer.
The third conference, just held in Kyoto, was designed as an interdisciplinary meeting to review the “Etiology of Bladder Cancer” in order to have biochemists, experimental pathologists, and clinical scientists discuss the broad subject from different viewpoints. There was much enthusiasm and it is hoped that new connections have been made in order to stimulate new collaborative studies. The potential spin-off should be considered in the future years.
The meetings and exchanges that have been sponsored these past two years have helped to set the stage for jointly sponsored clinical studies and clinical trials. In the future, joint clinical investigations will be planned using patient materials from both countries, and joint protocols will be developed for patient surveillence, epidemiology, pathology, and morphology follow-up studies. It is hoped that the cooperative clinical trials using radiotherapy and combined therapy will be developed in future years, resulting from the continuing exchange of information and sharing of experiences between the Japanese and American scientists and clinicians.
Dr. Yoshida commended Dr. Bryan's presentation and reported on the secondary benefits that have been derived from the joint activities that were presented.
As a result of the previous meetings, several American scientists have visited Japan to present several seminars and provide new information to different research groups. It is hoped that more visits by American scientists will develop in the future. He expressed his great pleasure in having Dr. Bryan visit his institution and several other research centers in Japan after the recent Kyoto meeting.
Dr. Ikawa asked the Program Coordinators if there has been any research done on modified carcinogenic or organotropic agents in relation to bladder cancer. The response was that little or no studies were being done at this time.

3. Chemical Carcinogenesis Program Area: Dr. Takashi Sugimura, Dr. Arthur Upton
Drs. Upton and Sugimura reported that the activities of the Chemical Carcinogenesis Program Area have consisted for the most part in conferences, workshops, exchange of scientists, and exchange of resources. Because of the breadth and complexity of the field of chemical carcinogenesis, the diversity of agents and mechanisms of carcinogenesis, and the emergence of new techniques and methods and other problems, the Program has been necessarily broad in scope. Nevertheless, it cannot be expected that optimal progress will be made in this field without adequate coverage of its various developing specific areas.
Notably, there were two highly valuable meetings sponsored in bringing together the relevant scientists from both countries for in-depth exchange of information and new approaches. In the area of cell regulation, “The Conference on Cellular and Molecular Controls in Neoplasia,” and the exchange of information will greatly enhance the effectiveness of related research in both countries. Similarly, the discussions on carcinogenicity testing and evaluation in animals will help coordinate the efforts of both countries in this difficult and costly activity.
The exchange of scientists has been very successful this past year with the sharing of ideas, methods, and technology, particularly the survey of the hair dyes for mutagenicity using the Ames method, which has already led to steps for public health safety. Other scientists have contributed considerably to the research programs in both countries, as well as continuing some of the collaborative efforts.
Particularly noteworthy are the contributions the Japanese group made in providing large supplies of new protease inhibiting compounds, which in turn were distributed to many American scientists for cancer research. Already there are promising experimental results from some of the early studies to be reported. Dr. Upton made special recognition and appreciation to the JSPS and Dr. Umezawa for their generosity.
As a result of this year’s activity, the “Proceedings for the Conference on Cellular and Molecular Controls in Neoplasia” will be published in the very near future.
In the near future, a meeting on “Polycyclic Aromatic Hydrocarbons” will be held in New Orleans, Louisiana, in January 1977. This is being organized by Drs. Nagata and Gelboin. A future meeting is being planned on the carcinogenic effects of ionizing radiation.
Thus far, there has been a very good balance between fundamental and practical research in the field of carcinogenesis and, most importantly, cooperative relationships between the scientists from both countries have been developed and they will continue to collaborate on problems of common interest and for mutual advantage and benefit.
Dr. Sugimura emphasized that due to the data developed from the bacterial mutagenicity and animal testing, the information can be helpful to the Japanese Government in the revision of the new guidelines on carcinogenic compounds.
At this juncture, the first of the two scientific sessions was held. Dr. Sugano introduced Drs. Sugimura and Upton as the moderators. Dr. David Clayson, Deputy Director, Eppley Institute, University of Nebraska, Omaha, Nebraska, and Professor Sohei Kondo, Faculty of Medicine, Osaka University, Osaka, Japan, were introduced as invited guests.
The Program Coordinators have been provided a summary of the Scientific Session on Chemical Carcinogenesis (see page 72).
The meeting was adjourned at 12:15 p.m. for lunch.
The meeting was reconvened at 2:00 p.m. by Dr. Newell as Chairman. He congratulated Drs. Upton and Sugimura for organizing the discussion and expressed his appreciation to Professor Kondo and Dr. Clayson for participating in the interesting subject which has great and broad implications in the entire field of cancer research.

4. Analytical Epidemiology Program Area: Dr. Takeshi Hirayama, Dr. Robert Miller
Dr. Miller reported that a meeting on “Precious Cases for Epidemiological Studies” was held in Florida in December 1975, in conjunction with the NCI-sponsored symposium on the “Genetics of Cancer in Man.” This provided several scientists an opportunity to participate at both meetings. As a result of this meeting, emphasis for the future year has been planned to explore four areas of mutual interest: genetics of human cancer, use of special binational data for comparative studies, the use of county data on cancer mortality in each country for “hot spots,” and the value of biostatistics in cancer and medical research.
A noteworthy result has been the October 1975 visit of Dr. William Blot to several Japanese institutions to lecture on biostatistics in cancer epidemiology and consulting on the value of statistics in biomedical research. His visit has stimulated interest among the Japanese statisticians to apply biostatistics for medical research purposes.
On October 8 and 9, 1976, a workshop on the “Comparative Studies of Cancer Mortality” was held in Tokyo. There was a broad representation from the U.S., including an epidemiologist, a clinical researcher, biostatisticians, and a basic scientist as well as a cross-section of Japanese cancer specialists, to discuss childhood cancer, immune deficiency problems, the epidemiology of Hodgkins disease, and leukemia.
In addition, there was an exchange of charts and graphs on cancer mortality data in U.S. whites, U.S. blacks, and Japanese over time, with respect to age, sex, and anatomic site. Dr. Hirayama stressed that the exchange of this important information will be most helpful in accumulating additional information for a future joint publication on the comparison of cancer mortality in Japan and in the U.S. In addition, the multidisciplinary approach to cancer epidemiology is most important and there will be a great need for the Analytical Epidemiology Program to cooperate with other program areas.
It was concluded that the activities of the past year have been very productive and have provided opportunities for a greater degree of cooperation and collaboration.

5. High LET Radiation Therapy Program Area: Dr. Akira Tsuya, Dr. Glenn Sheline
Dr. Sheline reported that as a result of a planning meeting in San Francisco, California, in October 1975, plans were made for the exchange of scientists and for the holding of a workshop for intercomparison studies. During the past year, three Japanese physicists and radiologists spent time at American institutions to engage in collaborative studies. In turn, three American scientists initiated some physical dosimetry studies and one radiologist was involved in collaborative research.
These informal exchanges have resulted in a team of nine Japanese visiting installations and facilities at Stanford University, Los Alamos and the University of California at Berkeley, in conjunction with a Workshop on High Energy Radiation. Beginning in December 1976, three teams of two American radiologists will visit Japanese laboratories for intercomparison studies on fast neutron therapy beams. The physical and radiobiological dosimetry measurements will set the groundwork for a future workshop to be held one year from now to review data and to develop clinical protocols for cooperative clinical studies.
Dr. Tsuya reported that the site visits of the U.S. facilities by the Japanese scientists were very useful and fruitful for the development of high energy radiation therapy in Japan. He also reported that new high energy radiation sources for cancer research and treatment were being installed at Tohoku University and a new booster synchrotron will be working in the near future at Mt. Tsukuba for clinical studies. With the collaboration that has been developed and the present and new. facilities available in the U.S. and Japan, plans are being made for collaborative clinical trials.
The cooperation in this Program Area has been developing very rapidly and further collaboration will be most fruitful.

6. Cytology Program Area: Dr. Kiyoji Kimura, Dr. Richard Malmgren, Dr. Chester Herman
Dr. Herman, who has replaced Dr. Malmgren as Program Coordinator, represented the U.S. side of the Cytology Program. He reported that the first phase of the Cytology Program Area has been primarily in the area of cytology automation and the initial stages have been involved with the exchange of technical information on design and performance of automated screening systems, currently under development in the U.S. and Japan. Prior commitments in each country have been made to develop specific systems, such as the flow system and the slide screening system. Through the U.S.-Japan Cooperative Cancer Research Program, the Japanese and American investigators have now come to understand the different design and instrumental performance of the automated screening systems.
During the second phase, a common area of attack to develop methods to target on the biology of normal and cancer cells by looking at the nucleic acids and proteins in the normal and abnormal cells has been highlighted. At the second joint meeting in Hawaii in July 1976, there was a discussion on the comparison of the operating characteristics of the two systems in order to improve the performance on chemical materials. Efforts are now being made to look for methods to compare the two systems, particularly the staining of cellular materials for comparative studies.
Drs. Kimura and Herman are now planning a meeting in April 1977, in Tokyo to analyze the error rates of the various systems now in use and to discuss the quantification and definition of premalignant and malignant changes occurring in cells. Special attention will be placed on DNA and protein markers as well as other cell particles, such as enzymes, histones, etc.
They reported that the exchange of scientists has resulted in the valuable exchange of ideas and information, with the exchange and development of new techniques and special and newly developed apparatus and equipment which has been useful for comparative studies.
Dr. Newell complimented Drs. Kimura and Herman on the progress made and the exciting new developments resulting from this cooperative program.

7. Metastasis Program Area: Dr. Haruo Sato, Dr. Philip Stansly
Dr. Stansly and Dr. Sato presented a brief summary of the “Workshop on Metastasis,” which was held in Kona, Hawaii, in May 1976. The aim was to conduct a broad survey of the field of metastasis from both the basic and clinical levels. There was good, lively interchange among the delegates from both sides. The proceedings of the workshop are being prepared for publication in GANN in April 1977.
The workshop was followed by a conference on metastasis, sponsored by Roswell Park Memorial Institute in Buffalo, New York, to which two Japanese were invited to participate. As an outgrowth of these meetings, Dr. Sato and two other Japanese investigators were invited to attend the “Workshop on Cancer Invasion and Metastasis: Biological Mechanisms and Therapy,” which is being sponsored by the NCI and the Memorial Sloan-Kettering Cancer Center on November 29-December 1, 1976.
At recent informal planning meetings, the Program Coordinators discussed the present seminars at leading research institutions, and the future exchange of scientists from both sides to engage in collaborative research.
It was reported that there is considerable interest in planning a meeting on the role of liposomes in the mechanism of action of cancer therapy drugs on tumor cells. This is an area of considerable interest to basic and clinical investigators.
There are long-range possibilities that research on the mechanism of drug action at the cellular level will be a subject which will require the merging of several program areas to hold a joint conference on cancer therapy and immunotherapy. There are other possibilities for workshops: (1) specific segments of the metastatic process, or (2) a process on specific types of cancer, such as breast cancer, focused on the basic and clinical aspects from the standpoint of metastasis.
The Program Coordinators believe that effective communication between Japanese and American investigators, on a person-to-person level, is the most effective stimulus to active communication. Interaction by means of meetings and continuing personal communication will be encouraged for the exchange of information and to seek out ways for active collaboration in the future.

Executive Session

After the intermission, Dr. Sugano convened the Joint Scientific Group for an executive session to discuss several items of business.
The floor was opened for discussion of the site and dates for the Fourth Joint Meeting to be held in 1977. By general consensus, it was agreed that the next meeting will be held in Bethesda, Maryland, with the first choice of dates for November 1 and 2, 1977, and the second choice for November 8 and 9, 1977. The earlier date would permit several Japanese and American cancer virologists to attend the annual meeting of the NCI Viral Oncology Meeting held each year in the Washington area.
The matter of the Five-Year Report was brought up for discussion. The JSPS is required by the Government of Japan to submit a Five-Year Report in order to arrive at a decision to continue or terminate the U.S.-Japan Cooperative Cancer Research Program.
After considerable discussion, it was decided that a Second Report, covering years 1976-1977, be published by the NCI in the same manner as the First Report of the U.S.-Japan Cooperative Cancer Research Program, which was published this year by the JSPS. This Second Report would summarize the 1976 and 1977 activities and could be used as a substitute for the Five-Year Report in addition to a supplemental summary report for the 1978 activities, in order to provide justification for continuing the Program.
The Joint Scientific Groups agreed to have a special subcommittee write the Second Report and the Summary for the 1978 activities. The members of the subcommittee are as follows:
JSPS Scientific Group:
Dr. Takeshi Hirayama
Dr. Yoji Ikawa
Ms. Yuko Kitamura
NCI Scientific Group:
Dr. Glenn Sheline
Dr. Chester Herman
Dr. Robert Omata
The matter of the possibility of the continuation of the Program for another term beyond the initial five-year agreement was brought up for discussion.
Dr. Herman reported that the Cytology Program has been extraordinarily productive and highly stimulating for all concerned with the Program. He stated that he would strongly advocate the continuation of the Cytology Program with possible modification of the Program content.
Dr. Sugimura stated that from his vantage point, it has been a great asset to Japanese investigators in that they have learned very much from the U.S., particularly in the Carcinogenesis Program. He would strongly recommend the continuation of the Program.
Mr. Hara spoke from the viewpoint of the Japan Society for the Promotion of Science and heartily agreed with Dr. Sugimura. In the event that the Joint Scientific Group recommended the renewal and continuation of the Program, he felt that the JSPS would agree with the recommendation.
Dr. Newell stated his opinion that the Program in toto has proved to be highly productive, in spite of the initial lag phase to develop mutual cooperation and confidence. He would certainly urge the renewal and continuation in order to protect the initial investment of funds and manpower into the Program. He felt that as long as there is scientific productivity from the Program, the subsequent continuation need not be an all or nothing proposition. He emphasized that there is a great need for continuing review and evaluation of each of the Program Areas and then decide to either enlarge or constrict the number of Program Areas.
The subject of modification of the Program was brought up for discussion to the membership.
Dr. Sheline stated that the title Of the High LET Radiation Therapy should be changed in the future to Radiation Oncology, since the program content has been changing toward clinical trials and several other areas, such as hyperthermia and radiation sensitization, have been developing rapidly.
Dr. Ikawa stated that cancer research has become increasingly multidisciplinary and that there may be a need to merge certain program areas, particularly to hold certain special combined seminars and conferences on the basis of one per year or once every two years.
Dr. Newell expressed his opinion that such a merging of program interests has been emerging in the field of cancer treatment, and it is highly probable that there will be a “crossing-over” of research areas, particularly in the research based on organ sites.
Dr. Carter stated that Cancer Therapy is certainly one area of broad and mutual interest to several program areas. He expressed his opinion that in the event that there will be restrictions on travel funds on either one or both sides, there will be a need for increased coordination of areas of mutual or common interest. If a conference on cancer treatment were to be held, several program areas should coordinate ideas and look for areas of mutual agreement in order to save time and money by holding a larger meeting. The organ site area is a good example, and the program coordinators could arrange for a meeting of the minds for common areas of interest. This will permit the coordinators to draw from a large pool of talents and experts for a productive program.
Dr. Stansly suggested the formation of a coordinating subcommittee.
Dr. Terry agreed that there is already a certain amount of overlap of research interests. However, he negates the need for the formation of another committee and strongly urged the Program Coordinators to contact each other.
Dr. Carter strongly recommended the coordination of activities, particularly in the area of clinical trials, since it is one with many problems in the treatment of patients.
It was agreed that the next Joint Meeting should include a scientific session either on Clinical Trials and/or Anticarcinogenic Agents. These two subjects have a myriad of relationships to each program area and there will be a need to look for a common denominator or to identify areas of common interest.
Drs. Upton and Clayson suggested that at least a half-day session should be devoted to an important area of mutual concern in order to discuss the impact ramifications of the subject matter, such as cancer treatment.
Dr. Muggia suggested another area, the carcinogenic action of therapeutic agents, which demands some attention.
Dr. Newell felt that the session on Chemical Carcinogenesis covered the broad aspects of the area and had contributed to the general understanding of the purpose of the Program.
Dr. Herman and Dr. Hirayama suggested that cytology and epidemiology of cancer would be appropriate subjects.
Dr. Newell pointed out that the following topics should be considered for the next Joint Meeting: Clinical Trials, Cytology, and Epidemiology of Cancer.
Dr. Terry then asked for opinions on continuation and evaluation of the program areas, whether to add or drop a program area.
Dr. Miller suggested that, as Co-Chairmen, Drs. Sugano and Newell were in the best position to set the policy for modification. Dr. Ikawa suggested that a special subcommittee be formed to make recommendations for modification to the Joint Scientific Group for approval or disapproval.
Dr. Herman suggested that each program coordinator should look at the interests of his program area and should consider merging with another.
Dr. Sugimura recommended that the Program continue with the present set-up and organization. He also stated that if special topical items should arise, they could be included in one of the related existing program areas, which is more or less being done currently.
Dr. Stansly recommended that modification of the Program Areas be considered when the Five-Year Renewal of the Agreement will be discussed in 1978. Dr. Newell supported this and also recommended that the present program areas be retained, even though certain areas, such as Radiation Oncology, would provide broader coverage as suggested by Dr. Sheline.
Ms. Kitamura and Dr. Sugano stated that the specific program areas were agreed upon at the First Joint Meeting but the situation is changing.
Dr. Sheline stated that the High LET Radiation Therapy is an area of personal interest but the radiotherapists are moving into radiation diagnosis and other types of radiation therapy although they are related to high energy particle radiation studies.
Dr. Sugimura recommended that Dr. Sheline and Dr. Tsuya should continue as coordinators for the High LET Program Area and involve other areas of program interests.
Dr. Newell agreed that each program area should retain broad interest and should continue to encourage and develop the best areas which will be highly informative and productive for cooperative efforts. Therefore, he recommended that Drs. Tsuya and Sheline continue to cover a broad area for the time being.
The first session was adjourned at 5:10 p.m.
The Japan Society for the Promotion of Science hosted a dinner in honor of the American delegation at Kikusui Inn in the Nanzenji Temples compound.

October 13, 1976

At 9:00 a.m. the members of the NCI Scientific Group gathered in the lobby of the Miyako Hotel. Through the efforts and kindness of Professor Yohei Ito, special permission was obtained from the Imperial Household Agency allowing the participants to tour the famous Katsura Imperial Villa on the outskirts of Kyoto. The Katsura Villa is known for its beautiful gardens since it was first built during the Heran Period, some time during the 11th century. This excursion was a very esthetic divergence and enjoyed by all the members.
Dr. Newell hosted an informal buffet luncheon in honor of the Japanese delegation, prior to the afternoon session.
Dr. Haruo Sugano, as Chairman, called the meeting to order at 2:00 p.m. On behalf of the Japanese delegation, he expressed his appreciation to Dr. Newell and to the American delegation for the luncheon stating that it provided an additional opportunity to engage in personal and informal interaction.
Dr. Sugano then called on Dr. Yoji Ikawa, co-coordinator for the Breast Cancer Program Area, to present the Annual Report in the absence of Dr. Nathaniel I. Berlin. Dr. Sugano expressed his personal regrets that Dr. Berlin was unable to participate at this meeting due to prior commitments.

8. Breast Cancer Program Area: Dr. Haruo Sugano, Dr. Yoji Ikawa (co-coordinator), Dr. Nathaniel I. Berlin
Dr. Ikawa presented a brief summary of the Joint Seminar on Breast Cancer, which was held in Tokyo in March 1976. Some of the highlights were the following:
• Presentations of the breast cancer programs in the U.S. and Japan
• The possibilities for the use of ultrasound as a diagnostic tool for mass-screening for breast cancer
• The use of adjuvant chemotherapy for breast cancer and the need for collaboration in the treatment of breast cancer
• The joint cooperation in the use of estrogen receptor method for detection
• Relationship of diet and the epidemiology of breast cancer in Japan.
The exchange of scientists has provided opportunities for continuing cooperative and collaborative research in areas on hormone receptors and on mammary tumor viruses.
Since the inception of the U.S.-Japan Cooperative Cancer Research Program, the NCI Breast Cancer Task Force has invited and included several Japanese investigators in the BCTF meetings and workshops. In the ensuing years, this participation will be continued and encouraged. In addition, several members of the Japanese Breast Cancer Group have been invited to the White House Conference on Breast Cancer to be held in November 1976.
Dr. Ikawa reported that two important meetings are being planned during 1977 and 1978. These groups are meeting to discuss “The Relationship of Diet and the Epidemiology of Breast Cancer” and “Symposium on Hormone Receptors and Breast Cancer.”
After the formal presentation, Dr. Upton asked if there is a good reason why there is a rising incidence of breast cancer in Japan. Dr. Hirayama responded that the increase in incidence in Japan is real; however, the reasons are still unknown. Research will be started to study the risk factors and the incidence in the younger and older women. There is no answer to the mechanism or the etiology. There is a definite increase in the 52-54 age bracket and another peak in the 45-49 age group. There seems to be some similarity in the age groups.
Dr. Muggia initiated considerable discussion on the use of adjuvant therapy in Japan. It was reported that some comparative studies have been done on the use of surgery, surgery and chemotherapy versus postoperative radiotherapy; however, there appears to be no special difference in the survival rates among the treated groups. These are subjects that will require further collaborative clinical studies.

9. Cancer Immunology Program Area: Professor Yuichi Yamamura, Dr. William Terry
Dr. Terry reported on the last meeting, “The Present Status of Preclinical and Clinical Immunotherapy Research,” which was held in San Diego, California, in March 1976. The abstracts of the presentations have been included in the Annual Report. There were many topics discussed which are of considerable interest, such as preclinical studies, use of animal models for immunotherapy, function of T cells in cancer immunity, some newer materials being used in immunotherapy, and clinical studies using adjuvant immunological agents such as BCG cell-wall and Nocardial cell-wall. Much of the American studies are unpublished and there have been some problems associated with clinical research. The meeting was very successful since it provided the participants an opportunity to engage in serious exchange of information. The exchange of scientists and the exchange of research materials will be encouraged for collaborative studies.
The exchange of scientists this past year has been very successful. Dr. Terry reported that Dr. Charles Boone spent two months with Professor Hiroshi Kobayashi at Hokkaido University. The visit was an unqualified success since they both had been doing related research and no time was lost in doing collaborative studies. It has been a very productive experience for both the U.S. and Japanese side.
During the year, three Japanese investigators spent varying periods of time in U.S. laboratories and the collaboration has been extremely successful. These scientists will undoubtedly continue to pursue cooperative research in cancer immunology.
In the future, a meeting is being planned for September 1977, to be held in Japan. During the coming year, there will be an increased level of exchange of research materials, such as cell-wall preparations, for preclinical testing and model systems. Both preclinical and clinical data will be exchanged at a greater level. The coordinators plan to extend the group's activities more into basic immunology in the future.
Professor Yamamura reported that the field on cancer immunology has entered into a very critical stage as far as immunotherapy is concerned. It is becoming very well developed and there is a need to evaluate and review the clinical data. The immunology mechanism in cancer must be further investigated. There are several new immunopotentiating agents which must be researched. Time is rapidly approaching for initiating larger clinical trials on patients.
Dr. Herman asked if the Program Area was moving into immunodiagnosis. Dr. Terry responded that the Program Coordinators have not broadened into that field; however, there is already some informal cooperation between Japanese and American scientists in immunodiagnosis.
Drs. Terry and Yamamura stressed that current and future clinical trials in immunotherapy must be very carefully evaluated and scrutinized and that new clinical protocols will be carefully drawn up for cooperative clinical studies.

10. Lung Cancer Program Area: Professor Yuichi Yamamura, Dr. Takeshi Hirayama, Dr. Oleg Selawry
Dr. Selawry reported on the previous activities in the Lung Cancer Program Area by summarizing the meeting on “Morphology and Staging” and the meeting on “Early Diagnosis of Lung Cancer.” The meeting on “Morphology and Staging” enabled the Japanese and U.S. groups to arrive on common criteria for the morphology and staging which may be adopted in the revision of the WHO Lung Cancer Program.
The meeting on “Early Diagnosis of Lung Cancer,” held in Japan in November 1975, advanced this bilateral program into technology and review of clinical data on diagnostic methods. The newly developed Ikeda fibro-optics has been introduced into the U.S. and has been used in several U.S. centers. In addition, chest films and cytological specimens have been utilized extensively for early diagnosis. There has been great progress made and productive interchange of information and clinical data.
Dr. Hirayama reported that in ten years, with the incidence of lung cancer increasing at the present rate, lung cancer may become the highest form of cancer in Japan. The incidence has already increased to this level in the U.S.
Dr. Yamamura succeeded Dr. Hirayama as Program Coordinator during the year. He reported that the Japanese are very much interested in the advancement of lung cancer treatment and they have already accomplished a great deal in early diagnosis. He stated that he hopes to promote better cooperation in the field of treatment and therapy.
In March 1977, the Lung Cancer Program will sponsor a meeting on the multidisciplinary approach to the therapy of lung cancer, with therapy stressed on the early stages of lung cancer. The subject of anticarcinogenic agents may be introduced at this meeting.
Future exchange of scientists will be very selective based on special skills and specific program interests. Thus far, the exchange of personnel and information has been very successful.

11. Cancer Therapy Program Area: Dr. Yoshio Sakurai, Dr. Stephen Carter
Dr. Carter first expressed the appreciation of the U.S. group for the contributions made by Dr. Kiyoji Kimura, Dr. Hamao Umezawa and Dr. Sakurai in advancing the Program Area. He then introduced Dr. Franco Muggia as co-coordinator.
He stated that informal cooperation began in 1970-71 when the Chemotherapy Liaison Office was established at the Japanese Cancer Chemotherapy Center at the Cancer Institute in Tokyo. This made it possible for the NCI and groups of Japanese investigators to cooperate on the screening and testing of drugs and the exchange of new developmental drugs. He stated that Japan was one of the leaders in the development of antitumor drugs and antibiotics.
During the past year, meetings were held to discuss the therapeutic values of nitrosoureas and Bleomycin, which was discovered by Dr. Umezawa. There are new derivatives of these drugs and antibiotics being produced and introduced into clinical research. There was good exchange of information on the effectiveness of the nitrosoureas. He expressed his hope for more future collaboration and the sharing of new information forthcoming from the clinical trials.
A major thrust was made during the past year on the therapy of gastric cancer. A team of American investigators led by Dr. Carter, engaged in an in-depth survey of the method of treatment of gastric cancer in Japan with many of their Japanese colleagues. It has been learned that the treatment methods in Japan provided a high degree of success, which may be due to the effective mass screening program, although there is a higher incidence of gastric cancer in Japan. The success with surgery has been comparable on both sides. In advanced cases, there has been comparability in results with the combination of surgery and chemotherapy.
The Japanese Cancer Therapy Group has been invited to participate in the U.S. Gastrointestinal Tumor Study Group in Boston and to visit several U.S. cancer centers. Dialogue has been developed to explore areas for collaborative studies as a result of these meetings.
The concept of team visits of scientists has proved to be very successful.
Future plans are being made to hold a meeting in San Francisco, California, in May 1977, to review and evaluate preclinical and clinical drug trials.
Dr. Sakurai stated that the main goal of the Cancer Therapy Program is to make rapid progress in the treatment of gastric cancer. The meeting on the treatment of gastric cancer was extremely important in developing common protocols to initiate cooperative clinical trials. The concept of combined modality for the treatment of cancer should progress well. The smooth cooperation in clinical research can be possible with advanced planning, since there are differences in the Japanese and American systems in the treatment of patients. He put special emphasis and stress on the importance of personnel exchange to nurture greater understanding between the investigators from both sides.
Dr. Sakurai stated that he and his team enjoyed and appreciated the opportunity to participate at the recent Gastrointestinal Tumor Study Group meeting. It was particularly important to learn more about the investigations on methods and planning treatment protocols.
Dr. Muggia expressed his interest in the U.S.-Japan Cooperative Cancer Research Program and stated that he appreciated the opportunity to become involved in the Program. He stated that the Division of Cancer Treatment, NCI, is holding a meeting on therapy in Annapolis, Maryland, and several Japanese investigators will be invited as participants.
Dr. Newell then introduced Dr. Carter and Dr. Sakurai as moderators for the scientific session on cancer therapy. Other participants in the session were Dr. Hamao Umezawa, Dr. Franco Muggia, and Dr. Kimura. Many points were brought out during the presentations and there were very active and lively discussions (see page 75 for a summary of the session by Drs. Sakurai and Carter).
During the closing session, it was agreed that the administrative staff of the NCI and JSPS would prepare the Minutes and distribute the information. There was unanimous agreement to endorse the activities of all of the Program Areas and to encourage the Program Coordinators to promote and further the objectives and goals of the U.S.-Japan Cooperative Cancer Research Program.
Dr. Newell stated that the Program has continued to be very successful through the devoted efforts of the Program Coordinators. He expressed his high opinion of the return accrued from the NCI investment of funds and the many benefits towards the advancement of cancer research in Japan and the U.S. He also stated that he was extremely grateful to the Japanese hosts and the JSPS staff for their warm hospitality and generosity, and genuine friendship, and looks forward with enthusiasm to the next Annual Joint Meeting in Bethesda, Maryland in November 1977.
Dr. Sugano closed the meeting with remarks that the presentations during the two days were ample evidence of the good progress and friendly cooperation that has evolved in the two and one-half years since the establishment of the Program. He expressed his appreciation to the moderators and invited speakers for the two excellent scientific sessions. He also thanked Dr. Robert Miller for making the recommendation to hold scientific sessions.
On behalf of the JSPS Scientific Group, Dr. Sugano sent his best wishes to Dr. Frank J. Rauscher, Jr., Director, National Cancer Program, who was soon to leave the National Cancer Institute to become Vice-President of the American Cancer Society. Dr. Sugano drew special attention to Dr. Rauscher for initiating the U.S.-Japan Cooperative Cancer Research Program and for his strong sustained support of the Program. He expressed his heartiest thanks to Dr. Rauscher and hoped that he would give continued support to the Program in his new position. Finally, he thanked all of the participants for their efforts in producing a successful cooperative program.
The meeting was adjourned at 6:00 p.m.

Respectively submitted,

Robert R. Omata, Ph.D.
Executive Secretary
U.S.-Japan Cooperative
Cancer Research Program

Summary of Scientific Session on Chemical Carcinogenesis

The first scientific session to be presented at the Third Joint Meeting was convened to report progress in the Chemical Carcinogenesis Program Area. Dr. H. Sugano introduced Drs. Upton and Sugimura as the moderators. Dr. David Clayson, Deputy Director, Eppley Institute, University of Nebraska, Omaha, Nebraska, and Professor Sohei Kondo, Faculty of Medicine, Osaka University, Osaka, Japan, were introduced as invited guests.
The session opened with the following presentations: Dr. David Clayson, “Modern Concepts Concerning the Mode of Action of Carcinogens”; Dr. Takashi Sugimura, “Mutagenic Activity of Carcinogens as Assayed in Microbial Systems”; and Dr. Arthur Upton, “Ramifications of Current Cancer Research, and Importance of Research on Multistage Processes of Carcinogenesis.” These presentations of the latest progress in chemical carcinogenesis were extremely beneficial to the participants.
The audience was especially impressed with the presentation by Dr. Sugimura which included a discussion of the refinement of a microbial assay system of carcinogens, and the observation of highly mutagenic activity of smoke condensates from broiled fish and meat as identified as a tryptophan pyrolysis product for a proximate substance.
In contrast to the emphasis of initiation of carcinogenesis by the two speakers, Dr. Upton presented a broad overview of current research in chemical carcinogenesis, and stressed the necessity of research on factors involving multistage processes of cancerization from initiation to clinical appearance. In a “Symposium of the General Meeting of the Japanese Cancer Association” held several weeks before the Third Joint Meeting, Dr. Upton discussed the epigenetic aspects of cancer.
Summaries of the presentations at the scientific session follow.
Dr. Clayson surveyed highlights of the mainstream of modern concepts concerning the mode of action of chemical carcinogens, as related to the design of animal studies and short-term carcinogenicity tests. He pointed out that with most chemical carcinogens the induction of cancer could be divided into three phases: (1) the metabolic activation of a relatively inert precarcinogen to a highly reactive, positively charged (electrophilic) form; (2) the interaction of this electrophile with critical cellular targets, which are probably in the nuclear DNA; and (3) the development of the consequently altered cell, or cells, ultimately into a clinically apparent cancer, which occurs under a wide variety of still poorly understood influences, including cell proliferation, immune factors, hormonal status, and so on.
With some chemical carcinogens, such as the highly reactive biological alkylating agents, he pointed out that the metabolic activation stage is not necessary, and with other carcinogens, such as asbestos, the agent may act only on the third phase. The binding of carcinogens to DNA, in the second of the above presumed phases, is reversible, pre-replicative DNA repair being inferred to restore the DNA to its original state, whereas post-replicative DNA repair tends to lock induced errors into the genome, as does semiconservative DNA synthesis.
In the design of animal experiments in chemical carcinogenesis, Dr. Clayson noted that it is important to differentiate influences which affect the metabolic activation of carcinogens from those which affect the other phases. Since the pattern of metabolic activation depends on the enzymic profile of each experimental species, its modification (for example, by the induction of specific enzymes) may not be directly relevant to man. The separation of the time of administration of the carcinogen from that of the modifying factor is one way of eliminating confusion as to the phase of carcinogenesis affected by a modifying factor.
Short-term microbial tests for carcinogenesis were noted to present two special problems concerning metabolic activation. First, the disruption of cellular metabolizing systems for their utilization in vitro may affect the balance or spatial distribution of the component metabolizing or detoxifying enzymes. This could, for example, be the reason why aflatoxin B₁ has low hepatocarcinogenicity in hamsters, despite the fact that hamster microsomes are highly efficient in activating the mycotoxin in vitro. Second, in vitro systems do not possess clearance mechanisms, such as biliary or urinary excretion, so that weakly reactive electrophiles may remain in vitro for sufficient time to react with critical biological targets, while this does not happen in vivo.
Dr. Sugimura then reviewed studies analyzing the mutagenic activity of various known and suspected carcinogens, as determined in microbial assays. The mutagenicity assay system used for this purpose was a modification of the procedure developed by Bruce Ames, employing Salmonella typhimurium histidine requiring auxotroph strains grown in the presence of a metabolic activation enzyme system derived from rat liver. To date more than 400 chemicals have been tested in this laboratory for mutagenicity with this technique. Of 140 such chemicals which had been reported to be carcinogenic, 121 (or 87 percent) were found to be mutagenic; and of 69 such chemicals which had been reported to be noncarcinogenic, 53 (or 73 percent) were found to be nonmutagenic. Chemicals which had been reported to be carcinogenic in animals but which did not show mutagenic activity included chlorinated hydrocarbons, thioacetamide, thiourea, and some mycotoxins. Since, however, the mutagenicity of certain chemicals was observed to vary, depending on the microbial tester strain and oxidative enzyme system utilized in the assay, it may be expected that refinement of carcinogenicity and mutagenicity screening techniques will resolve some of the presently existing discrepancies and ultimately improve the consistency of the correlation.
Noteworthy among compounds showing mutagenicity is AF-2, which had been widely used as a food preservative in Japan from 1965 until 1974. When AF-2 was discovered in 1973 to be more mutagenic for Salmonella typhimurium TA-100 than any other compounds tested, including aflatoxin B₁, its carcinogenicity had not been detected. Further testing, prompted by the evidence of its mutagenicity, subsequently disclosed carcinogenic activity for the forestomach of the mouse and led to its banning as a food preservative in 1974. As in the case of some other chemicals, the mutagenicity of AF-2 was not detectable in certain Salmonella tester strains (e.g., the Salmonella typhimurium TA-1535 series), indicating the importance of using more than one microbe or assay system in evaluating mutagenic activity.
Other compounds demonstrating mutagenicity include the majority (155/205) of hair dyes heretofore commercially available in Japan; various mycotoxins, which have been found to contaminate food stocks; coltsfoot, a favorite natural food in Japan; cycasin; smoke condensates from tobacco and from cooked foods, as discussed below; and other chemicals of diverse forms.
Particularly noteworthy is the observation that smoke condensates derived from tobacco, broiled meat, and broiled fish contain fractions that are highly mutagenic when activated metabolically. In each case, the available data imply that the highest activity resides in a tryptophan pyrolysis product, which is roughly two orders of magnitude more mutagenic than Benzo[a]pyrene.
Dr. Sugimura concluded that the evidence points to man's exposure during everyday life to chemicals from a variety of sources which are mutagenic and presumably also carcinogenic, and which can therefore be designated as “mutacarcinogens.” Viewed in historical perspective, exposure to one class of such chemicals goes back to the earliest times, since the chemicals of this class occur naturally in man's environment and his food chain. A second important class of such mutacarcinogens, the importance of which has been hitherto underestimated, includes compounds formed during the cooking of food and in the burning of vegetable matter and fossil fuels. The third class, most recently introduced into man's environment, include the myriads of new chemicals resulting from advanced technology and organic synthesis. To cope adequately with the problems posed by these compounds, the relationship between mutagenic potency and carcinogenic potency will need to be evaluated further. The relationship may not necessarily be either qualitative or quantitative, in view of the possible influence of various cofactors. Criteria for evaluating test results and methods for detecting and characterizing the influence of cofactors (cocarcinogens; promoting agents; anticarcinogens; differences in host susceptibility) are urgently called for. Also among the more obvious and immediate approaches warranting investigation, with the ultimate aim of cancer prevention, are further studies on mutacarcinogens in reference to the development of improved diets and cooking procedures.
Dr. Upton then surveyed briefly some of the broader ramifications of current research in carcinogenesis, reemphasizing the point, stressed earlier by Drs. Clayson and Sugimura, that neoplasia is generally envisioned as a multistage process, in which the outcome at each succeeding stage is dependent on a complex interaction of factors. The criteria for distinguishing the successive stages and for identifying and characterizing the factors influencing their development and fate are still poorly understood. It is evident, however, that the process can be affected in different ways at various stages in its evolution and at various levels of biological organization.
The evidence that mutagenesis may be postulated to play an important role in the initiation of cell transformation, and the development of rapid and sensitive mutagenicity assay techniques, has made it feasible to screen the environment more effectively than heretofore, for the purpose of detecting potentially carcinogenic agents. At the same time, however, the evidence that certain types of carcinogens and cocarcinogens (e.g., hormones as a class) may exert their effects through nonmutagenic (i.e., epigenetic) mechanisms, obliges us to broaden our approach in seeking methods for the detection and control of cancer-inducing agents. In this connection, the biological interaction of chemicals of various types, physical agents (e.g., ionizing and ultraviolet radiations), and viruses constitutes a subject calling for intensified study, especially since human populations are seldom ever exposed to any one such agent alone. In seeking to evaluate the risks to human populations of agents that have been found to be mutagenic or carcinogenic in experimental screening systems, experience with ionizing radiation can provide helpful guidelines. Since, with penetrating ionizing radiation the dose to every cell of the body can be specified relatively precisely, irrespective of the species exposed, the situation is vastly simpler in many respects from that encountered with chemicals, where pharmacological variations in uptake, distribution, metabolism, and excretion complicate extrapolations from one species to another. Even with radiation, however, as yet unexplained differences in carcinogenic response preclude the derivation of quantitative risk estimates for man from observations in experimental animals. In the case of the relative carcinogenicity of different radionuclides for man, on the other hand, tentative inferences can presumably be drawn from studies of the relative carcinogenicities of such nuclides (e.g., plutonium-239, strontium-90, and cesium-137) in a series of animal species appropriately selected for the metabolism of the elements in question. Nevertheless, even in man himself, there appear to be large quantitative variations among the sensitivities of different organs of the body to radiation carcinogenesis, which remain to be accounted for. Hence, although a tentative approach to numerical risk estimates for radiation carcinogenesis is now feasible, the approach is as yet highly empirical and heavily dependent on quantitative dose-incidence data from epidemiological studies of human populations. These features underscore the difficulties involved in any efforts to arrive at quantitative risk estimates for microbial or animal data.
In concluding, Dr. Upton voiced regret that limited time had permitted mention of only a few of the many cogent questions that were identified in advance for possible consideration. He expressed the hope that the list of topics tabulated below might serve as a basis for future discussion.

Summary of Scientific Session on Cancer Therapy

Drs. Stephen K. Carter and Professor Yoshio Sakurai presented a scientific session in which the following topics were discussed: (1) the rationale for combined modality therapy for cancer; (2) the development of multimodality therapy at the U.S. National Cancer Institute (NCI); (3) the history of cancer therapy in Japan; and (4) the U.S.-Japan Cooperative Cancer Therapy Program.
For many solid tumors, surgical treatment and/or radiation therapy are effective in controlling the local cancer. Unfortunately, they do not always control the primary tumor and generally fail when there is dissemination to distant sites. Chemotherapy, used in conjunction with radiotherapy or surgery, may aid in control of the primary tumor and potentially may eradicate small metastatic foci. It has been established experimentally that chemotherapy agents are most effective when the tumor cell population is small. An inverse relation between tumor cell population and chemotherapeutic cure rate has been demonstrated for mouse leukemia and solid tumor systems. Thus, the chance for cure is greater when all visible tumor has been surgically excised than after subtotal or no resection. The optimum time to administer chemotherapeutic agents is immediately after eradication or removal of the primary tumor.
The therapeutic strategy developed by the NCI Division of Cancer Treatment (DCT) utilizes the sequence: (1) test promising new drugs and drug combinations in patients with advanced disease; (2) using the best drugs from step 1, determine the optimum chemotherapy regimen for treatment of disseminated disease; and (3) integrate this regimen into a combined modality treatment of local and regional disease. Thus, new drugs and drug combinations are tested in advanced disease and those that show positive results are used in the primary treatment of disseminated disease and as part of a combined modality treatment of local and regional disease.
Several studies using surgery and adjuvant chemotherapy for the initial treatment of operable breast cancer were described. In one study, a single postoperative course of thiotepa was found to decrease the recurrence rate in premenopausal women who had had four or more positive axillary lymph nodes at the time of mastectomy. This study has shown a 20 percent improvement in survival at five and ten years postresection. More recently, melphalan has been shown to reduce the local recurrence rate at two years postsurgery for premenopausal women; recurrence occurred in 1 of 30 patients who had received melphalan compared with 11 of 37 who had surgery alone. In another study (Bonadonna et al., under contract to NCI), the relapse rate was I percent for patients receiving adjuvant CMF (cyclophosphamide, methotrexate, 5-fluorouracil), as compared with 12 percent for those with surgery alone.
In Japan, the study of antitumor agents began in 1943 with the establishment of the Yoshida sarcoma, a rat ascites tumor. Shortly thereafter it was observed that nitrogen mustard produced morphologic changes in Yoshida sarcoma cells and that tumor-bearing rats treated with nitrogen mustard survived longer than nontreated rats. Using Yoshida sarcoma for screening, an improved analogue of nitrogen mustard, nitrogen mustard N-oxide, was discovered in 1950. The early testing of cyclophosphamide by German researchers also made use of the Yoshida sarcoma. The first antitumor antibiotic discovered in Japan was sarcomycin; the test tumor in this case was Ehrlich carcinoma.
The second stage of cancer chemotherapy development in Japan was promoted by the introduction of a series of rat ascites hepatomas. These hepatomas exhibit characteristic individually specific sensitivities to various antitumor agents. Some are sensitive to alkylating agents but others are not. One hepatoma is sensitive to Bleomycin but not to other antitumor drugs. The series of hepatomas provides a spectrum of response and represents a valuable screening system for antitumor agents. Since the host animals are not available outside of Japan, use of this screening system is limited to Japan.
Active collaboration between Japanese and U.S. scientists working on cancer chemotherapy began in 1957. In 1961 the United States-Japan Committee on Scientific Cooperation was established by an agreement between the governments of the two countries. Under this agreement, a panel for cancer chemotherapy screening was recommended in 1962 and the L1210 screening system was introduced into Japan in 1964. Adoption of the L1210 system provided a common base for comparison of results. Because of failure of the L1210 system to predict the activity of some compounds (e.g., Bleomycin), P388 mouse leukemia, B16 melanoma, and Lewis lung cancer were subsequently added. In 1973 the Japanese Cancer Chemotherapy Center, under contract with the NCI, instituted a screening service utilizing the L1210 and P388 systems. The Japanese screening station now conducts experiments with the same tumor lines and animals used at the NCI. This cooperative effort permits a valuable data interchange.
In Japan there is an interest in development of analogues of known active anticancer agents. The intent is to find agents with improved antitumor activity but lower toxicity. Analogues of promise include: (1) cyclocytidine and N4-behenoyl-cytosine arabinoside, analogues of cytocin arabinoside; (2) ACNU, a water-soluble pyrimidine derivative of nitrosourea which has less bone marrow toxicity than the lipophilic nitrosoureas; (3) 4-perhydroxy isofamide, an analogue of cyclophosphamide; (4)cyclohexal-carbamoyl-5-fluorouracil, an analogue of 5-FU; and (5) Aclacynomycin A, which is related to Adriamycin but has less cardiotoxicity and myelotoxicity. These agents are currently being studied in animal test systems or in various phases of clinical trials. The development and testing of such analogues is actively promoted under the U.S.-Japan Cooperative Cancer Research Program.
The Cancer Chemotherapy Scientific Program concluded with a discussion of the collaborative efforts on antitumor antibiotic research. Among the antitumor antibiotics which have been investigated are Macromycin, Neothramycin, and Bleomycin. Macromycin is an acidic peptide which inhibits Ehrlich carcinoma, sarcoma 180, Gardner lymphosarcoma, and L1210; it was identified as an active agent by the L1210 screening system. Neothramycin, a member of the benzodiazepine antibiotic family prolongs survival of mice inoculated with L1210 and inhibits Yoshida rat sarcoma; in the L1210 and Yoshida rat sarcoma test systems it has the lowest toxicity and highest therapeutic index of the benzodiazepine antibiotics. Bleomycin has attracted a great deal of clinical interest and investigation. It is active against Hodgkin’s disease and, in combination with irradiation, it has been used for treatment of squamous cell carcinomas. Various Bleomycin analogues differ in the terminal amine moiety and in renal and pulmonary toxicity.

THIRD ANNUAL JOINT MEETING UNITED STATES-JAPAN COOPERATIVE CANCER RESEARCH PROGRAM
Miyako Hotel, Kyoto, Japan October 12-13, 1976

AGENDA

PARTICIPANTS

UNITED STATES

Dr. Guy R. Newell, Chairman
Deputy Director
National Cancer Institute

Dr. Arthur C. Upton
Professor of Pathology
School of Basic Health Science, State University of New York at Stony Brook

Dr. William D. Terry
Associate Director for Immunology
Division of Cancer Biology and Diagnosis National Cancer Institute

Dr. Stephen K. Carter
Director
Northern California Cancer Program

Dr. Robert W. Miller
Chief
Epidemiology Branch, Division of Cancer Cause and Prevention, National Cancer Institute

Dr. Oleg S. Selawry
Deputy Director for Intramural Affairs
Comprehensive Cancer Center for the State of Florida at the University of Miami School of Medicine-Jackson Memorial Medical Center

Dr. George T. Bryan
Professor
Clinical Oncology and Surgery University of Wisconsin

Dr. Glenn E. Sheline
Professor and Vice-Chairman
Division of Radiation Oncology University of California, San Francisco

Dr. Chester J. Herman
Head, Quantitative Cytology Section
Laboratory of Pathology, Division of Cancer Biology and Diagnosis, National Cancer Institute

Dr. Philip G. Stansly
Program Director for Viral Oncology
Division of Cancer Research Resources and Center, National Cancer Institute

Dr. Franco M. Muggia
Associate Director
Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute

Dr. David Clayson
University of Nebraska School of Medicine, Eppley Institute

Dr. Robert R. Omata
Executive Secretary
United States-Japan Cooperative Cancer Research
Program, Office of International Affairs National Cancer Institute


JAPAN

Dr. Haruo Sugano, Chairman
Director, Cancer Institute
Japanese Foundation for Cancer Research

Dr. Takeshi Hirayama
Head, Division of Epidemiology
National Cancer Center Research Institute

Dr. Yoji Ikawa
Head, Laboratory of Viral Oncology
Cancer Institute, Japanese Foundation for Cancer Research

Dr. Yohei Ito
Professor
Department of Microbiology School of Medicine, Kyoto University

Dr. Kiyoji Kimura
Deputy Director
National Cancer Center Hospital

Dr. Yoshio Sakurai
Director, Cancer Chemotherapy Center
Japanese Foundation for Cancer Research

Dr. Haruo Sato
Professor
Research Institute for Tuberculosis, Leprosy and
Cancer, Tohoku University

Mr. Toru Sawada
Deputy Director-General
Science and International Affair’s Bureau, Ministry of Education, Science and Culture

Dr. Takashi Suginrura
Director
National Cancer Center Research Institute

Dr. Akira Tsuya
Head, Department of Radiation Therapy
Cancer Institute Hospital, Japanese Foundation for Cancer Research

Dr. Hamao Umezawa
Director
Institute of Microbial Chemistry

Dr. Tadashi Yamamoto
Director
Institute of Medical Science
The University of Tokyo

Dr. Yuichi Yamamura
Professor, Department of Internal Medicine School of Medicine, Osaka University

Dr. Osamu Yoshida
Professor, Department of Urology School of Medicine, Kyoto University

Dr. Sohei Kondo
Professor, School of Medicine
Osaka University

Mr. Kunio Sato
Senior Specialist
International Science Division, Science and International Affair’s Bureau, Ministry of Education, Science and Culture


JSPS Members

Dr. Isao Amagi
Director-General

Mr. Genkichi Hara
Head, Science Department

Mr. Nagahide Onozawa
Head, Scientific Cooperation Division Science Department

Miss Yuko Kitamura
Scientific Cooperation Division, Science Department