SUMMARY REPORTS OF EXCHANGE SCIENTISTS

(1) Yutaka Mishima
Kobe University School of Medicine

Sponsor and Host Institution:
Dr. A. Soloway Idaho
National Engineering Laboratories
Dr. J. Antoine Radiation Research Program
National Cancer Institute
Dates of Visit: March 6-9, 1990

Summary of Activities:
1. During March 6-9, 1990
I visited Idaho National Engineering Laboratories (INEL) in Idaho Falls, Idaho and National Cancer Institute in Bethesda, Maryland to fulfill previous requests from responsible investigators at these institutions, among others, to present on our selective boron neutron capture therapy (BNCT) of malignant melanoma.
The overall purpose of my visit, which was initiated and supported by members of leading U.S. BNCT research groups was to promote Japan-U.S. cooperation in the field of BNCT for malignant melanoma and other cancers. I was also accompanied by Masamitsu Ichihashi, M.D., Ph.D. as Associate Professor in my Department of Kobe University: Summary of activity is as follows:
1) INEL
Arriving in Idaho Falls at 2:30 pm on March 6, I was met by Merle Griebenow, Manager, BNCT Research Programs, and Phil Narmic,INEL Laboratory Director. At 3 pm I presented a seminar entitled, “Current Status and Future Prospects for Selective Melanoma Neutron Capture Therapy”, to INEL scientists involved in BNCT-related reactor research. The lecture's purpose as to inform and stimulate INEL researchers by reviewing our development of selective BNCT from basic to preclinical studies and detailing our 5 clinical cures. Special attention was given to applying reactor technology to actual clinical situations.
Presentation and discussion lasted approximately two hrs, and following this we drove from the research center to the Power Burst Facility (PBF) reactor site. After touring the facility and talking to scientists there about our work in designing a reactor to be used specifically for neutron capture therapy. I presented a copy of our 1989 Medical Reactor Design Report which was prepared in cooperation with Mitsubishi Heavy Industry under a Japanese governmental research grant. 2) NCI
Arrival in Washington was on the afternoon of March 7 with my NCI presentation scheduled for the following morning at 8:30 in Conference Room J, Executive Plaza North, NIH. Previous to this session, I met Dr. J. Antoine, Associate Director, Radiation Research Program, who had originally arranged for my presentation and invited relevant NCI specialists in oncology and radiation therapy to attend. Also participating were individuals and groups from Sloan-Kettering, MIT, Ohio State Univ., and Brookhaven National Lab., including leading U.S. BNCT researchers, Dr. Soloway and Dr. Fairchild. The meeting was approximately 4 hrs. during which I presented an overview of our selective BNCT of malignant melanoma from basic investigative studies to clinical trials. This was followed by constructive discussion for potential Japan-U.S, cooperative studies using BNCT to treat malignant melanoma and possibly other types of cancer.
As a result, I have already received a preliminary proposal from Dr. R. Fairchild of BMRR desiring to begin collaborative BNCT studies using their epithermal beam port. Dr. Kraemer of NIH who also attended the meeting, recently informed me that funding has been approved for researchers from MIT and Boston Univ. to begin metastatic melanoma NCT trials.


(2) Yoichi Hayakawa
Institute of Applied Microbiology University of Tokyo

Sponsor and Host Institution:
University of Texas and Texas A&M University
Washington University. St Louis
National Cancer Institute, Bethesda
Rockefeller University, New York
Indiana University, Indianapolis
Stanford University, SRI International, Sanford
University of Southern California, Los Angeles
Dates of Visit: September 18 - October 2

Summary of Activities:
The objective of this study was to investigate methods, instruments related to research for antitumor antibiotics in the U.S.
The laser desorption mass spectrometry developed by Dr. B. Chait and others at Rockefeller University ionizes efficiently macromolecules with limited fragmentation. It can detect the molecular ions of carboxypeptides Y (MW 61,000) and beta-galactosidase (MW 1 16,000) and can analyze a protein mixture. It will be also able to analyze a large-molecule antibiotics such as bleomycins and neocarzinostatin.
National Cancer Institute is implementing a new anticancerdrug-screening program using a disease-oriented panel of cultured human tumor cell lines. Fifty-eight cell lines used there include leukemia, lung cancer, colon central nerve system, melanoma, ovarian cancer and renal cancers. Screening sources are collected from tropical plants and marine organisms. The samples are extracted with dichloromethane-methanol (1:1) and water respectively. The extracts are evaporated and lyophilized to prepare the screening samples.
Dr. B. I. Sikic and others study on the multi-drug resistance (MDR) of tumor cells at Stanford University. They recently found that cyclosporin and cefoperazone conquered MDR. Cyclosporin seems to inhibit the transport of P-glycoprotein and it will be clinically noticeable from its low toxicity. Dr. M. Tanabe and others evaluate angiogenesis inhibitors and an approach to new anticancer drug at SRI International. They test the activity of steroid compounds using chick-embryo assay.
Dr. F. Muggia and others at University of Southern California study of liposome-daunomycin, which is 40 times more active and less toxic to skin, hair and heart than daunomycin. This selective toxicity can be explained from the transport of the drug by macrophages.



(3) Taketo Mukaiyama
Cancer Chemotherapy Center Japanese Foundation for Cancer Research

Sponsor and Host Institute:
Dr. Branimir I. Sikic Stanford University
Dr. Irving L. Weissman Stanford University
Dr. William I. Bensinger Fred Hutchinson Cancer Research Center
Dr. Karen Antman Dana-Farber Cancer Institute
Dr. Michael A Friedman National Cancer Institute
Dr. Antonio Tiot Fojo National Cancer Institute

Summary of Activities:
Dana-Farber Cancer Institute, Harvard Medical School
Dr. Antman and her colleague have developed high-dose chemotherapy with autologous bone marrow transportation (HD-CT with ABMT) for the treatment of solid tumors, which is named as STAMP (Solid Tumor Autologous Marrow Program). Alkylating agents were chosen for the STAMP, because alkylating agents exhibit a steep dose-response curve, broad anti-tumor spectrum and non-cell cycle specific cytotoxicity. Response rate in recurrent breast cancer after failing conventional treatment was high, however, the duration of response was short. Based on these results, they conducted to employ HD-CT with ABMT for the treatment of breast cancer early in the course of the illness after several courses of standard dose therapy, and they could yield very high complete response rate (68%). Furthermore, they amplified peripheral blood stem cell (PBSC) using GM-CSF combined with several courses of post-chemotherapy refound and PBSC were collected by leukoapheresis. Comparing with ABMT, PBSC transplantation (PBSCT) showed more rapid hematological reconstitution. These data suggest that PBSCT followed by GM-CSF administration may decrease the mobility due to infection and/or hemorrhage and the length of admissions for patients.

Fred Huchinson Cancer Research Center, University of Washington
Recent work at this center has focused on development of methods to isolate multipotent hematopoietic progenitor (CD34 antigen positive cell) free of contaminating tumor cells by positive selection.
Bone marrow cells from patients with breast cancer or neuroblastoma were incubated with biotin conjugated anti-CD34 monoclonal antibody followed by passage down an immunoadsorption column containing avidin-linked polyacrylamide gel. The CD34 positive adherent cells were recovered by mechanical agitation and frozen. Six pts with metastatic breast cancer and 2 pts with neuroblastoma were treated with high-dose chemotherapy and/or Total Body Irradiation followed by reinfusion of CD34 positive cells. The time to engraftment was shorter than that observed in the experiment using baboons. CD34 positive cell transplantation is useful for s6lid tumor with bone marrow involvement. Furthermore, in vitro CD34 positive cell expansion using several cytokines is very interesting field.

Stanford University
Dr. Sikik and his colleague are analyzing multi-drug resistance (MDR) phenomenon using molecular and cellular biological technique. They found that some of cephalosporin antibiotics enhance drug accumulation and overcome MDR in human MDR sarcoma cell. Comparing with calcium antagonists, cephalosporin antibiotics are less toxic, so these drugs are attractive candidates for MDR modifier in a clinical setting. They analysed P-glycoprotein gene (mdr-1) expression in adult acute leukemia cells and found highly significant correlation between mdr-1 expression and MDR phenomenon. They have just started the clinical study of MDR modifier, Cyclosporin A (CsA), which is well known to overcome MDR in vitro, was chosen as modifier and they administer CSA and VP-16 to the patients with refractory malignant lymphoma, breast cancer and ovarian cancer which express P-glycoprotein. Furthermore, they are planing the combined administration of two different MDR modifiers with VP-16 on refractory cancers. Dr. Weissman and his colleague are attempting to purify human multipotent stem cells. Their ultimate project is stem cell transplantation collaborating with Bone Marrow Transplant team. Using Severe Combined Immunodeficiency Syndrome (SCID) mouse, they are establishing SCID/hu mouse which has human immunological and hematological function to study in vivo experiment close to human situation.

National Cancer Institute
Dr. Friedman and his colleague are judging clinical studies in the U.S. Each clinical trial is required to fulfill many data os fundamental study and theoretical background. There is not such system in Japan, and we also have to establish good surveillance systems to good quality clinical study.
Dr. Fojo and his colleagues are studying P-glycoprotein (PgP) expression in clinical specimens using Northern blot analysis, in situ hybridization, reverse transcriptase-polymerase chain reaction, Western blot analysis and immunocytochemical analysis. They found that the differentiation agents such as sodium butyrate of retinoic acid increase the level of PgP in several colon cancer cell lines, but in some of these cell lines, high level of PaP are not accompanied by increased resistance and decreased accumulation of Adriamycin and Vincristin. These differentiating agents overcome MDR phenomenon and show synergism with verapamil against MDR cell lines. they have just started the clinical study of MDR modifier, R-verapamil, which is less toxic for cardiovascular systems. They administer R-verapamil and Adriamycin, Vincristin and VP-16 to the patients with refractory malignant lymphoma which express PgP.

Summary
To overcome and cure cancers, many clinical trials based on the data from fundamental experiment are actively introduced in the U.S. I feel that we need more active collaborations among fundamental and clinical researchers in Japan.