SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1) Haruo Seto
Institute of Applied Microbiology,
University of Tokyo

Sponsor and Host Institution:
Dr. Ven L. Narayanan National Cancer Institute
Dates of Visit: November 11 - November 28, 1991

Summary of Activities:
My main object was to study and obtain information on screening, development and application of antitumor substances in the United States. Especially important was to discuss with experts in the fields of cancer therapy and natural product chemistry on systems to be employed in my laboratory for screening of new antitumor substances. To achieve this purpose, I visited the following institutions and universities, and exchanged useful information with experts working in these places. In addition, I gave lectures at some places on the biologically active substances isolated in my laboratory.

1. SRI International at Menlo Park, California
I met Dr. M. Tanabe, Director of Life Science, who is an expert in medicinal chemistry, and made discussion on the chemical synthesis and derivatizations of naturally occurring antitumor substances. He also made useful suggestions on the chemical modifications of biologically active substances isolated in my laboratory.

2. MD Anderson Hospital in Houston, Texas
I met Dr. Raber and several other researchers and argued on the usefulness of compounds active to prevent metastasis. Some people were questionable on the effects of such substances for cancer therapy. The discussion with them was very useful for me to decide whether my group should start screening for compounds to prevent metastasis.

3. Dana-Farber Cancer Institute in Boston, Massachusetts.
Prof. L.B. Chen made explanation on the use of synthetic fluorescent compounds as antitumor substances and summarized his conclusion on the chemical structural features required to express antitumor activities. His theory on the structure-activity relationship seemed to be quite reasonable and gave me a good hint for development of a new screening systems for antitumor substances. His group was studying the features of a transformant of Bacillus Subtilis which showed multidrug resistance to cancer cells. This micro-organism possessed biological features similar to multidrug resistant cancer cells and seemed to be useful as a model for screening compounds to overcome multidrug resistance. My group has been supplied with this organism from him and is now using as an assay system for screening compounds to overcome multidrug resistance.

4. National Cancer Institute in Washington D.C.
Dr. Narayanan and his collaborators explained the assay systems employed for screening for antitumor substances at NCI. We made discussion on the handling procedure for the compounds isolated by my group and made necessary arrangement for testing new compounds. This arrangement enables to test the antitumor activities of compounds isolated in my laboratory prior to their patent application and publication.

5. Johns Hopkins University in Baltimore
I made discussion with Prof. C. Townsend on the biosynthesis of antitumor substances produced by microorganisms. We argued mainly focused on the role and effectiveness of the biosynthetic information for improving production yield of microbial metabolites including antitumor substances.

6. University of Hawaii
Prof. R. Moore explained about several very interesting antitumor substance isolated in his laboratory. Most of them were metabolites of blue green algae. He also showed me experimental facilities necessary for cultivating blue green algae. We made discussion on the advantages and disadvantages of the use of blue green algae as a microbial source, and I came to the conclusion that my laboratory should continue the screening for antitumor substances using soil microorganisms.
Through the visit to the several places mentioned above, I could obtain valuable information and hints on the screening systems for antitumor substances to be employed in my laboratory. In fact, I have already started a new screening system based on the useful information obtained through this visit and am planning to start another screening system near future.



(2) Yasuo Morishima
First Department of Internal Medicine, School of Medicine, Nagoya University

Sponsors and host institutions:
Prof. P. B. McGlave
Minnesota University School of Medicine
Prof. J. A. Hansen
Washington University School of Medicine and Fred Hutchison Cancer Research Center
Dates of visit: October 4 - 23, 1991.

Summary of activities:
I visited two institutions where human allogeneic bone marrow transplantation (BMT) and its researches were most extensively performed in the world.

The main purposes of my visit were following:
1. Comparison of the incidence and severity of acute graft versus host disease (GVHD) in HLA matched allogeneic bone marrow transplantation between U.S. and Japan.
2. To learn how to organize and coordinate the national bone marrow donor registry for unrelated bone marrow transplantation from U.S. registry: National Marrow Donor Program.

I visited to clinical BMT care units, took clinical round to see the patients clinical conditions including GVHD and discussed about the diagnosis, prophylaxis and therapy of GVHD and other clinical problems of BMT with two professors and many other physicians. I also had opportunities to talk with 14 doctors doing clinical or basic researches in the field of BMT especially GVHD.
As the histocompativility between donor and patient is recognized to be more important for unrelated BMT, I visited the laboratories of histocompatibility testing, and had many informations for future plan such as sequence specific oligo probe method for HLA DNA typing.
Finally, NMDP coordination center in Minnesota and NMDR donor center in Seattle were very welcome for my visit.
As a summary of my visit to U.S., it was honor for me to have a seminar for one hour in Oct. 18, 1991 at the auditorium of Fred Hutchinson Cancer Research Center, Seattle. Title of my talk was “Low incidence of acute greft versus host disease in Japanese leukemia patients received marrow from HLA compatible related or unrelated donors: Possible role of genetic homogenieties among Japanese”.
Later sentence of my title is exactly the conclusion of my study (purpose 1 in this program). That is, lower incidence of acute GVHD in unrelated BMT in Japan wm be due to lower disparities of not only minor histocompatibility antigens but also HLA class 1 and class 2 antigens between donor and recipient among Japanese. This result also indicates that unrelated BMT in Japan will have superior outcomes of patients’ survival.
The informations of U.S. donor registry for unrelated BMT is very helpful for the establishment of Japan registry that I am asked to participate.



(3) Takao Yamori
Japanese Foundation for Cancer Research

Sponsor and Host Institution:
Dr. R. Shoemaker Frederick
Cancer Research and Development Center
National Cancer Institute
Dates of visit: October 5 - 25, 1991

Summary of Activities:
I visited Dr. Shoemaker at Frederick Cancer Research and Development Center, NCI to learn the methodology of current disease-oriented anticancer drug screen (DOS).

1. Experimental system of DOS
Each compound is tested for its growth inhibitory or its cytotoxic activity against 60 human malignant cell lines. The tumor cells are seeded in 96-well plate. Sample compounds are added on the next day, and the number of surviving cells is measured 48 hr later by colorimetric analysis using sulforhodamine blue which is a protein-binding dye. The raw data are automatically transferred to a computer and analyzed. The cell lines include 13 lung cancers, 9 colon cancers, 9 renal cancers, 6 ovarian cancers, 8 brain tumos and 6 lenkemias/lymphomas. Most of these malignant cells are transplantable to nude mice. A compound which showed differential growth inhibition against the 60 cell line panel is further examined for its therapeutic efficacy in nude mice.

2. Data analysis by computer
The data analysis by computer is the most important part of DOS. A data base is specifically designed for the analysis using VAX computer system installed with Oracle data base. The computer draws a “Mean Graph” for each sample compound. One can visually understand differential growth inhibitory activity of sample compounds in the 60 cell line panel by their Mean Graphs. Each compound show a unique Mean Graph pattern, so that the pattern is called “Finger Print”. The most interesting part was “Compare” program, which compares a certain compound with others in the data base for the Mean Graph pattern. It has been shown that some of anticancer compounds which have a common mode of action show similar Mean Graph patterns. For example, DNA intercalators show ones with different characteristics. The Compare program may predict the mode of action of screened compounds depending on their Mean Graphs. I think that this data base is very informative.
The information on the methodology of DOS obtained during this visit should greatly help me to establish a similar anticancer screening system in our institute.