(1) Masaaki Ishizuka
Institute For Chemotherapy
Microbialchemistry Research Foundation

Dr. Ronald B. Luftig, Medical Center,
Louisiana State University
Dr. James E. Talmadge, Medical Center,
University of Nebraska
Dr. Mary L. Stracke, Laboratory of Pathology,
National Cancer Institute
DATES OF VISITS: October 17–30, 1993

Cancer chemotherapy has been developed by the discovery of new substances with a specific mechanism of action. I have engaged in searching antitumor agents involving cytotoxic and cytostatic substances, and immunomodulators in microbial products. In order to explore new antitumor substance, a new target based on the up-to-date results of fundamental and clinical observations is needed. Using this opportunity, I intended to find the target for searching antitumor substance and the direction of our study on cancer chemotherapy in the future. At the Louisiana State University Medical Center, I visited Prof. Luftig and gave the seminar titled "Bioactive Compound Produced by Microorganisms–Cytokine Inducer and ECM Antagonist" in the department of Microbiology, Immunology and Parasitology. In this seminar, most of the attendants were interested in conagenin which was found as a cytokine inducer of activated T cells exclusively. It also increased the number of platelets in peripheral blood of mice given antitumor substances such as cyclophosphamide and mitomycin C through enhancement of the production of megakaryocytes in bone marrow cells. Dr. Thompson, immunologist, pointed out that conagenin might be effective in dieting because of the suppressive effect on monokine production by macrophages. It will be suggested for action of conagenin in future. Prof. Luftig and a co-worker developed E. coli (E. coli BL21(DE3)/ pT7Q10H1N) encoded plasmid of HIV aspartic proteinase. Using this strain, the inhibitory activity of HIV proteinase can be assayed easily without virus and lymphocyte cultures. It will be a valuable tool for searching for inhibitors of the proteinase.
At the University of Nebraska Medical Center, I visited Prof. Talmadge and gave a seminar titled "Bio-Active Compound Produced by Microorganisms-Cytokine Inducer, ECM antagonist and Immunosuppressant" in the department of Pathology and Microbiology. Since most attendants were students of the graduate school, Ph. D's and M. D.'s in the Medical School, they were interested in screening methods, purification and determination of structure. Conagenin was also a topic of the seminar. In this visit, I learned about Peripheral Stem Cell Transplantation (PSCT). In the retrospective study, PSCT has been effective in prolonging the survival periods of patients with lymphomas and leukemias at the Medical Center. Ubenimex, which we found as a chemotherapeutic agent for leukemia and other tumors, has been used in clinical trials in Japan and is in phase study for PSCT conducted by Dr. Talmadge in this facility. I also introduced the activity of ubenimex in the seminar. It was interesting that the clinical trial of 14P53 antisense will be conducted by Dr. Iverson's group. They are also looking at its feasibility as a chemotherapeutic agent of antisenses of plasminogen activator, collagen IV and cathepsin D for incurable diseases. Drs. Bierman, Gross and Klassen with whom I had discussions, were anxious about toxicity of antitumor substances and immunosuppressants which are now in clinical trials, although the first choice for chemotherapy is cytotoxic agents. They want a new cytotoxic substance for cancer treatment. Thus, we should be continuing to search new cytotoxic and cytostatic substances for new targets.
At NCI, I visited Dr. Stracke who is studying the Autocrine Mobilizing Factor (AMF) produced by melanoma, and we discussed AMF and tumor metastases, since we are looking for antimetastatic agents among ECM antagonists. It was very helpful for our future studies. Dr. Kohn, who is engaged in a phase study of a cytostatic agent, suggested that new cytostatic agents for the new target should be valuable for cancer treatment.
Considering the remarks of all the scientists I met in the United States, it is urgent to develop new cytotoxic and cytostatic antitumor substances. Though new targets are still obscure, some molecular targets in stromal cells are to be found in connection with cell to cell interactions and paracrines.
Comment for the program:
During my 2-week stay, the scientists I visited were very hospitable, and as a result of this program, I have learned many things. I hope that this program will be continued.

(2) Mine Harada
First Department of Internal Medicine
Faculty of Medicine, Kyushu University

Dr. Robert Peter Gale, Salick Health Care Inc.
Dr. James O. Armitage, University of Nebraska Medical Center
Dr. Rainer Storb, Fred Hutchinson Cancer Research Center
DATES OF VISITS: January 12–February 1, 1994

In order to know the current status of autologous peripheral blood stem cell transplantation (PBSCT) for the treatment of malignancies and the possibility of allogeneic PBSCT in the United States, I visited the Fred Hutchinson Cancer Research Center (FHCRC) and University of Nebraska Medical Center (UNMC). I attended the symposium on Advances and Controversies in Bone Marrow Transplantation moderated by Drs. Gale and Champlin. Autologous PBSCT has been increasingly used for the treatment of hematologic malignancies and solid tumors including breast cancer, neuroblastoma and small cell lung cancer. At FHCRC, low dose stem cell factor plus high dose G-CSF showed most efficient mobilization of PBSC (by Dr. Richard Nash) in a dog model. Dr. Joachim Deeg and I discussed our data suggesting that soluble IL-2 receptor may be a good marker of acute GVHD. Dr. Beverly Torok-Storb commented on a possible mechanism for G-CSF induced mobilization of not only myeloid but also erythroid progenitors in our data. Dr. Rainer Storb demonstrated that a gene marked PBSC can differentiate into a lymphoid lineage in a dog model. Dr. Dean Buckner presented the first successful case of allogeneic PBSCT in FHCRC. These are very encouraging for clinical application of allo-PBSCT in Japan.
At UNMC, information about cytokine mobilization, use of autologous PBSCT for the treatment of malignant lymphoma and breast cancer, and comparison of autologous PBSCT and autologous bone marrow transplantation was obtained. I discussed our clinical results of PBSCT for acute leukemia with Drs. Kessiner, Bierman, and Bishop. I visited the Apheresis Room where several protocols of PBSC mobilization are ongoing. They explained data showing that PBSC mobilization by G-CSF alone is very effective. Interestingly, Dr. Sharp showed that Epo could mobilize progenitor cells. As a result, I feel that autologous bone marrow transplantation will be replaced by autologous PBSCT in the near future. I attended the symposium on "Advances and controversies in bone marrow transplantation". Many exciting data were presented. The problem of allogeneic bone marrow transplantation versus chemotherapy for the treatment of acute leukemia was extensively discussed; again, there was no significant difference. Also, there is critical discussion concerning interferon therapy versus allogeneic bone marrow transplantation for the treatment of CML. Gene therapy, including gene marking, is one of the major topics; but there are several problems to be solved. Since the frequency of the marked cells was low, it is still difficult to interpret the data, when relapsed leukemia cells contained a small number of marked cells. At least 20 cases of allogeneic PBACT were presented and the outcome seemed to be encouraging. It is surprising to know that the incidence of severe acute GVHD was not so high, though a number of mature T cells infused were I to 2 log greater than those in allogeneic bone marrow transplantation. Furthermore, earlier granulocyte and platelet recovery was documented with fewer days of infection, lower transfusion requirements, and a shorter hospital stay. These observations suggest that allogeneic bone marrow transplantation may be replaced by allogeneic PBSCT. It is also suggested that by reducing the risk associated with marrow aspiration under general anesthesia, the potential will exist to expand the unrelated donor pool for allogeneic transplants. As a whole, the symposium was very helpful to deepen my understanding of issues and problems in the field of stem cell transplantation.

(3) Masato Seto
Aichi Cancer Center Research Institute

Dr. Riccardo Dalla-Favera, Department of Pathology
College of Physicians & Surgeons Columbia University
DATE OF VISIT: February 17–March 5, 1994

Objectives of Visit:
Aim 1. To gain information for new approaches and directions for the research of hematopoietic malignancies .
Aim 2. To discuss recent data obtained in both research groups.
Aim 3. To initiate a new collaborative study based on the recent data discussed during this program.
For aim 1:
To understand molecular mechanisms involved in malignant transformation it is important to know molecular interactions. For Burkitts' lymphoma, it is well known that Myc translocation with immunoglobulin genes plays an important role for lymphomagenesis Prof. Dalla-Favera is now working on proteins having association with myc protein. A recent approach is the so called two-hybrid system in Yeast system. His group is using the system but he recommended proving such interactions by some other methods in addition to the two hybrid system because of the false positive reactions.
For aim 2:
A one-hour seminar entitled "Translocation-associated genes on chromosome 11 :BCL1/PRAD1 at 11ql3 and MLL at 11q23", at NIH (Department of Hematology), Massachusetts General Hospital (Endocrine Unit), University of Michigan School of Medicine (Department of Pathology) and Washington University School of Medicine (Howard Hughes Medical Institute).
For aim 3:
(1) A new collaborative research regarding 11q23 region was proposed by Dr. Andrew Arnold who found that overexpression of PTH in ovarian cancer cells of a patient possibly caused by translocation of PTH gene to 11q23 region He knew through my seminar that m group made a precise physical map at 11q23 region.
(2) I have shown the reactivity of monoclonal antibody produced against recombinant PRAD1/cyclin D1 product in my seminar and discussions, and Dr. I. Berbard Weinstein (Columbia University), Dr. Andrew Arnold and Dr. Stanley J. Korsemeyer were interested in the antibody. I have agreed to send the antibody on request as a collaborative work.
Comments for the exchange program: This exchange program was very helpful for my group and I am very grateful to the members of this exchange program. My request is that this program be more available to younger people who may not have a tenure position.