11TH NCI-JSPS JOINT STEERING COMMITTEE MEETING
Captain Cook Hotel, Anchorage, Alaska
June 23-24, 1988
The meeting was called to order by Dr. Richard Adamson at 9 a.m. He welcomed the members of the Joint Steering Committee for the 15th year of the US-Japan Cooperative Cancer Research Program. Dr. Adamson introduced the historical, cultural, geographical, and industrial background of the state of Alaska, the largest state in the U.S., which was purchased from Russia in 1867. The state is rich in natural resources such as oil, gas, timber, minerals, and marine products. The natural beauty of the mountains, glaciers, and rivers are well protected and are regarded as state treasures of Alaska. He introduced the U.S. participants and expressed sincere gratitude for Dr. Ihor Masnyk, who served as acting director of the Office of International Affairs, as well as supported this program for the past several years.
Dr. Sugimura introduced Dr. S. Nojima, professor emeritus and Dean of Teikyo University. Dr. Nojima, attending his first meeting, is Science Advisor for this program and was representing the JSPS in place of Dr. Sakai who could not attend. Dr. Nojima expressed his gratitude and excitement in participating in one of the most successful international cancer programs. Dr. Adamson and Dr. Kakefuda announced that the modified time schedule was compressed to one day, so that it would be possible to visit Dr. A. Lanier’s laboratory, Alaska’s Center for Disease Control, for discussions of cancers in Alaskan natives.
Dr. Miller asked whether the Science and Technology (S&T) Agreement between the U.S. and Japan recently signed by the President of the U.S. and the Japanese Prime Minister is involved In any way with the US-Japan Cancer Program. Dr. Adamson explained the fact that the cancer program is involved in the S&T Agreement in an overall sense, but the program operation would not be affected. Dr. Kakefuda outlined two new Japanese programs established recently by the JSPS and the Science and Technology Agency of Japan to encourage young foreign scientists to study in Japanese institutions. Dr. Sugano introduced the newly established NCI-JFCR (Japanese Foundation for Cancer Research) Research Training Program that will also support exchange of young scientists for up to two years in both countries.
Dr. Adamson proposed that a discussion to be included in this session, at a later time, to extend the program for the next five years since this was the last year of the five-year term.
Dr. Adamson reported first on the progress since the last reporting period in the Etiology Program Area. Four seminars were held in the U.S. The first seminar, “Development of New Medium Term Bioassay for Carcinogenesis” focused on new medium-term bioassay systems developed in both countries.
The assay system which requires only a short time (weeks to months) are of great advantage over the standard 2-year terms in rodents in terms of saving time and cost. The second seminar on “Cancer Cell Membrane: Aberrant Glycosylation and Other Critical Molecular Events” focused on aberrant glycosylation and other molecular changes expressed on the surface of cancer cells. The third seminar “Biology of Oncogenes” focused on new oncogenes, growth factors and their receptors. The fourth seminar, “Glutathione S-Transferase and Carcinogenesis” discussed the role of glutathione S-transferase on the genetic expression and regulation, carcinogenesis, and their involvement in drug resistance.
During this reporting period, four scientists from Japan and one scientists from the U.S. were exchanged. Several compounds were exchanged by or facilitated through the program and made available for scientists in both countries.
The seminar on “Development of New Medium Term Bioassay for Carcinogenesis was organized by Dr. J. Ward and Dr. N. Ito and was attended by seven participants from each country. Dr. Huff reported several long- and short-term in vivo assays in progress under the National Toxicology Program. Strain A mouse lung tumor assay, in vivo rat liver model, mouse bone marrow assay, erythrocyte micronucleus assay, and pre-weaning mouse liver assays were found to be the most sensitive methods.
Other assay systems were presented by other participants. Dr. Slaga presented the SENCAR inbred and outbred mouse skin tumor models, that may be of particular interest for the U.S. because of the prevalence of melanomas and skin cancer. Dr. Yoshizawa presented short-term screening systems for new TPA type and non-TPA type tumor promoters. It was generally agreed that most skin promoters were irritants but not all irritants were promoters.
Dr. Tsuda presented an assay of hepatocarcinogens by observation of the enhancement of DEN-initiated placental form of glutathione S-transferase positive foci after administration of test substance. The assay offers a valuable model for screening a large number of chemicals m a short time (8 weeks). Dr. Popp’s study indicated that there were two types of promoters; one which increases the number of foci, and the other which promotes focus growth, likely as a late stage promoter.
Dr. Ward reported a mouse endpoint bioassay for initiation and promotion of liver carcinogenesis. He also discussed the use of Zeiss stereology programs. Dr. Ito discussed a medium-term multi-organ bioassay for carcinogens by a wide spectrum initiation protocol. Combined initiator models appear to provide promising assays for detecting carcinogens of unknown organ specificity. Dr. Vesselinovitch introduced an infant mouse liver system. Leukemia was most rapidly induced in infant mice, while lung tumors may be more rapidly induced in adult mice. Dr. Mori introduced a medium-term assay which observes early changes in liver and preneoplastic mesenchymal cells in the stomach. Dr. Teramatsu and Dr. Ohgaki presented a medium-term bioassay for gastric carcinogens and promoters based on measurements of putative preneoplastic pepsinogen-decreased pyloric glands, and the proliferative zone of the pyloric epithelium of glandular stomach.
Dr. Stoner reported a new specific mutation occurring in K-ras codon in association with specific carcinogens. Dr. Longnecker reported atypical acinar cell nodules in pancreas as the phenotypic endpoint marker only four months after a single injection of a carcinogen. Dr. Hasegawa reported a 20-day bioassay for bladder carcinogens and promoters using a preneoplastic papillary or nodular hyperplasia and papilloma as markers.
Dr. Sugimura pointed out that the general trend of carcinogenesis test system is moving from long-term to medium and short-term test systems. The medium-term systems have been reasonably well established in liver and skin carcinogenesis, however, further studies are needed to establish medium-term systems for stomach, urinary bladder and lung. A pepsinogen gene has been cloned and will be available as a marker for early detection. The long-term rodent test can indicate the carcinogenicity of a given compound, but will not provide much information regarding the quantitative risk assessment. Medium-term assay systems would be extremely valuable to bridge between the long-term to short-term (such as the Salmonella system) for a proper evaluation of the carcinogenicity. He mentioned that a potent tumor promoter, okadaic acid, isolated from a black sponge will be available for U.S. scientists upon request through the Carcinogen Repository in the near future. Combination of test systems, combined application of carcinogens, effects of radiation and nutrition in human as well as experimental carcinogenesis studies, were discussed extensively.
The second seminar on “Cancer Cell Membranes: Aberrant Glycosylation and Other Critical Molecular Events” was held in Hawaii, organized by Dr. S. Hakomori and Dr. S. Hirohashi. The seminar focused on aberrant glycosylation and other changes which occur on the surface of cancer cells identified by monoclonal antibodies. Although many tumor-associated antigens defined by monoclonal antibodies have been identified as glycolipid, many of the same epitopes are also carried by mucin-type glycoproteins.
An IgM monoclonal antibody (LeoMel 3) directed to human melanoma could block IL-2stimulated LAK cell killing, showing that the LeoMel 3 antibody is directed to GD3 ganglioside. Thus, LAK cells are capable of recognizing GD3 at the target cells. Dr. Yamashita presented a method for production of monoclonal antibodies directed to glycoprotein carbohydrates. He was able to isolate a series of three classes of antibodies. Dr. Hirohashi described diagnostic application and functional aspects of normal differentiation antigens defined by monoclonal antibodies.
Dr. M. Iwamori discussed a human monoclonal antibody derived from the lymph node lymphocytes of a patient with endometrial cancer. The antibody defining endometrial carcinoma and germinal proliferation was directed to lactotetraosylcearmide, the precursor of various type I chain blood group antigens. As an important issue of disialosyl gangliosides as melanoma and neuroblastoma-associated antigens, Dr. Tai scrutinized monoclonal antibodies directed to GD2 and GD3 in order to define the specificities of the antibodies recognizing disialosyl structures.
The functional significance of glycosylation was discussed in the second session. A great deal of interest has been focused on ganglioside as protein kinase modulators, in relation to the physiological function of ganglioside in growth regulation and differentiation. Among the information presented, Dr. Nagai reported the critical requirement of GQ1b for differentiation and various protein kinase activities.
Dr. Hakomori reported striking promoting or inhibitory activities of GM1, GM3, and ganglioside on PDGF-dependent cell growth. The functional significance of glycoconjugates in defining malignancy, including metastatic potential was discussed. Dr. Osawa reported a modified sialic acid-nucleoside conjugate that inhibited sialyltransferase and mucin-type glycans and ganglioside. The compound inhibited the metastatic potential of NL-17 colon adenocarcinoma and tumor cell-dependent platelet aggregation.
Dr. Irimura reported a positive correlation between a higher degree of sialylation and metastatic potential in many human colon carcinomas. He defined a large amount of mucin-like sialoglycoprotein correlated with higher metastatic potential. Dr. Fukuda reported characteristic changes during differentiation from immature precursors to functionally-active, mature cells. Dr. Holmes presented enzymatic changes as a basis for the major aberrant glycosylation associated with human colonic cancer. The key enzyme for synthesis of an enhanced quantity of lacto-series glycans is a!!!
1 3 GlcNAC transferase which catalyzes chain elongation. Dr. Muramatsu presented data showing germ cell carcinomas contain a polylactosamine embryoglycan, which showed a great deal of homology with immunoglobulin. Studies on cell adhesion molecules and the possible application of such molecules in defining the metastatic potential of tumor cells were discussed. Dr. Yamada reviewed the structure of fibronectin, including the role of the R-G-D sequence in cell attachment. He presented data showing that another molecule of 50 amino acids is required. Dr. Martin reviewed the interaction of malignant tumor cells with basement membranes. A unique sequence, YIGS R (try-ile-gly-ser-arg) serves as a binding site for laminin receptor on the tumor cells. This YIGS R peptide showed antimetastatic activity in mice. Selective metastatic potential of cancer cells as related to various molecular parameters was presented by Dr. Nicolson.
Dr. Sugimura mentioned that the meeting was particularly meaningful because of the new subject and fresh people making a new type of cooperative discipline and linkage of scientists of both countries.
The third seminar on “Biology of Oncogenes” was held in Kauai Island on Hawaii organized by Drs. S. Aaronson and M. Terada. Dr. Adamson highlighted some of the topics presented in the meeting. Dr. Terada presented information on hst transforming genes, originally Isolated from noncancerous as well as cancerous portions from stomach cancer patients. The KS oncogene recently isolated from Kaposi’s sarcoma turned out to be hst. The hst has sequence homology to basic and acidic human fibroblast growth factors.
Among the information presented was the following: Dr. Aaronson described growth factor-activated pathways in the neoplastic process of sis proto-oncogene and PDGF-2. Dr. Yamamoto reported on new proto-oncogenes of tyrosine kinase family. Transgenic models for oncogenes was described by Dr. Hanahan who presented two examples of tumorigenesis in transgenic mice, one with BPV I genome, and the second with SV40 T antigen.
Dr. Aisawa also reported that ras induced lung adenomatous tumor, myc induced pre-B cell lymphomas and the SV40 T antigen induced tumors in transgenic mice. Molecular cloning of a serine-specific protein kinase activated by mitogenic stimuli was discussed in the next session. Dr. Shibuya reported that both tyrosine and serine/ tyrosine kinases have crucial roles in carcinogenesis in a tissue and stage-specific manner. Dr. McCormack presented evidence that GAP may be a ras effector. A point mutation in the putative effector region of ras p21 were insensitive to GAP. Dr. Nagao described induction of flat revertants by benzamid from oncogene-transfectants.
In a session on the recessive genes in human malignancy, Dr. Yokota described oncogene and chromosome abnormalities in human lung cancer. The heterogenous occurrence of myc family oncogene abnormalities in lung tumors was infrequent. Dr. Oshimura reported that introduction of single copy of a human chromosome 11 is sufficient to completely suppress tumorigenicity of HeLa and Wilms’ tumor cells, suggesting the “suppressor” gene(s) on chromosome 11 play a crucial role In a step of neoplastic development of the tumor cell lines tested.
Dr. Sugimura commented that the studies of oncogenes are growing rapidly in Japan. New unique eukaryotic vectors have been developed to produce gene products in large quantities just as fervently as the traditionally well studied silk worm systems in Japan. Dr. Yokota found 9 out of 10 small cell lung cancer cases with a lost chromosome, showed a loss of heterozygosity in chromosome 13q, which is close to the RB gene.
The fourth seminar on “Glutathione S-Transferase and Carcinogenesis” was held in Hawaii, organized by Dr. H. Pitot and Dr. K. Sato. The purpose of this seminar was to discuss the properties, regulation, genetic expression, and role of glutathione S-transferase (GST) and its related functions in carcinogenesis. drug resistance, and normal tissue expression. Dr. Sato described the placental form of GST appears during the early stage of hepatocarcinogenesis The human form of this enzyme appears to be a good marker in human cancer, except liver, and in premalignant conditions, e.g. colon and cervix.
Among the findings were: Dr. Muramatsu described the increased levels of the placental form of GST in 2-D electrophoresis of normal rat liver, neoplastic nodules, and carcinomas. He identified both enhancer and silencer sequences of the GST gene. Dr. Picket described several forms of GST including several subunit species. These genes construct including the Ya subunits, that resulted in more resistance to the toxicity of the anti-diolepoxide B(a)P. Transgenic experiments with a construct of the Ya subunit and SV40 promoter was also presented.
Dr. Saijo described studies on the mechanism of resistance of cells to cisplatin and its analogues. Drug resistance was associated with a high level of the placental form of GST. DNA repair and topoisomerase II seems to be involved as well. Dr. Tew described aspects of acquired and induced drug resistance involving various forms of GST, especially the placental form Studies on the GST inhibitors, prostaglandin synthesis, rapid chromatographic isolation of GST were also discussed.
Dr. Watabe described the stereochemistry of hydration and glutathione S-conjugation of mutagenic/carcinogenic epoxide enantiomers. Dr. Ito reported a significant correlation between hepatocarcinogenesis and placental form of GST. Dr. Kensler reported a similar result with aflatoxin B1 carcinogenesis. Dr. Ruddy described his studies on the carcinogenicity or peroxisome proliferating agents that are carcinogenic, but do not exhibit DNA-damaging effects or increase the placental form of GST. Dr. Konishi showed histochemical levels of the placental form of GST in rodent and human neoplasms.
Dr. Pitot described the expression of the placental form to GST and gamma-glutamyltranspeptidase (GGTP) in multistage carcinogenesis in the liver. The latter enzyme was a good marker for the stage of promotion for phenobarbital but not by peroxisome proliferating agents. Histochemical staining of the GGTP is reflected by an increased level of the mRNA of the gene product.
Dr. Sugimura commented on the discovery and developmental process of GST by Drs. Sato, Muramatsu, and Pitot and others in Japan and in the U.S., which turned out to be a crucial enzyme important in all stages of neoplastic development. The involvement of GST in drug resistance studies by Drs. Saijo and Tew are now a major subject of cancer research drawing much scientific attention. The report will be published in one of the journals for cancer research.
Four Japanese scientists visited the U.S., and one U.S. scientist visited Japan through the Exchange Scientist Program in the Etiology Program Area. Dr. Nam-ho Huh visited Drs. A. Pegg, C. Harris, and E. Huberman to discuss DNA repair and molecular epidemiology. Dr. Zacharias visited Dr. Hayatsu and discussed problems of DNA conformation. Dr. K Yaginuma visited Dr. J. Summers’ laboratory for exchange of information regarding hepatitis B and hepatocellular carcinoma of humans and ducks. Dr. Hirose visited Dr. H. Witschi for antioxidant carcinogenesis study. Dr. Y. Ishizawa visited Dr. A. Carrano to study molecular cloning in yeast.
Biology and Diagnosis Program Area
Dr. Hodes reported the activities in the Biology and Diagnosis Program Area. Two meetings were held, one of which was a large, jointly organized seminar. A meeting on “Molecular Mechanisms of Lymphoid Cell Activation and Application to Tumor Immunology” was organized by Drs. R. Hodes, S. Korsmeyer, T. Hamaoka, and T. Kishimoto. Fourteen Japanese and 13 U.S. scientists attended the four-day meeting.
In the first session on molecular events in lymphoid cell activation Dr. Kelly presented data showing gene induction in human peripheral T cells following mitogen activation. Dr. Perlmutter described a study of T cell lineage specific protein tyrosine kinases. The regulation of kinase lck gene during T cell activation has been characterized.
Dr. Yodoi discussed the increased expression of IL-2 receptor genes in HTLV-I transformed cells. ATL derived factor has been purified, and a monoclonal antibody has been generated against it. Dr. Okumura has accomplished the cDNA cloning of the mouse homolog of CD2. Dr. Sugimura has analyzed growth signal transduction in IL-2 dependent T cells. He has demonstrated that the HTLV-I pX gene product p40tax activates transcription of IL-2 and Il-2 receptor chains in the Jurkat cell line.
A number of presentations described protein kinase C and GTP binding proteins in the signaling growth factors. Dr. Sobue described the role of calmodulin binding proteins (cytocalbins) in its interaction with the cytoskeleton for regulation of the cytoskeleton. Dr. Yamamura presented transgenic mice as tools in the study of oncogenesis and autoimmune disease. He also reviewed his diabetic mouse model experiments suggesting that a MKC as well as non-MHC locus has contribution to insulinitis.
In the second session for “Ig and Ig Receptors” Dr. Sakano discussed the molecular mechanism of immunoglobulin DNA rearrangements. Dr. Korsemeyer presented data on the deregulation of the Bcl-2-immunoglobulin fusion gene in follicular lymphoma and a polymerase chain reaction which is capable of amplifying that breakpoint. Transfection of Bcl-2 constructs proved that is functioned as a proto-oncogene converting B cells to tumors in nude mice. Dr. Kishimoto discussed their recent information on regulation of the CD23 molecule which serves as the Fc receptor for IgE on B cells.
The third session dealt with “T Cell Receptor and its Structure and Function.” Dr. Klausner reviewed their extensive work on the CD3 molecule which is now possible to relate to the polymorphic changes of the T cell receptor. Dr. Brenner described their recent study on the gamma delta T cell receptor in human and other animals. Dr. Bluestone followed by presenting data concerning the expression of the gamma delta T cell receptor and its function in cytotoxic T cells.
The fourth session was devoted to “Lymphokines and Lymphokine receptors.” Dr. Uede discussed the affinity conversion of human Il-2 receptors. Dr. Takamatsu described the physiologic effect of IL-5 studies by using recombinant IL-5. An antigen primed B cell system revealed that IgA bearing B cells will respond to IL-5 as a maturational or help factor. IL-5 stimulated the growth and differentiation of pro-B lymphocytes. Dr. Hirano reviewed their extensive study on IL-6 and its receptor. IL-6 has wide ranging effects and serves as a growth and differentiation factor for hybridoma and plasmacytomas. Multiple myeloma cells were shown to make IL-6 in addition to having IL-6 receptors on their surface. This raises the intriguing possibility that an autocrine growth cycle might exist within such malignancies.
The fifth session dealt with “Molecular Mechanisms of T Helper Cell Activation and Function.” Dr. Hamaoka described la restricted B cell-B cell interactions and their relationship to the B cell repertoire. Dr. Janeway discussed the subpopulations of T helper cells classified based on the differential pattern of lymphokine secretion. TH2 cells function as specific helper cells for B cell responses, while the TH1 cells act as cytotoxic cells and mediators of inflammation. Dr. Hodes described two potential mechanisms contributing to specific T helper cell effector function in the activation of B cell responses. The TH2 cells contain cytoplasmic granules, and that exocytosis can be induced by stimuli derived through the T cell receptor, but not through the IL-2 receptor. The presence of an active factor in cell free supernatant from activated T helper cells suggests it is analogous to or identical to the cell surface T cell receptor structure mediating the T cell function. Dr. Schwartz discussed a number of issues involved in a system of non-responsiveness in TH1 cloned cells.
The sixth and final session dealt with “T Cell Function and Anti-tumor Immune Responses.” Dr. Hamaoka described antigen recognition mechanisms of anti-tumor T cell subsets involved in host tumor resistance. The roles of both CD4+ and CD8+ tumor immune cells in anti-tumor responses were characterized.
Dr. Greenberg described the role of T effector cells in host antitumor responses. It was demonstrated that combination of cytoxan and Immune T cells was required to establish long term cures.
A seminar on the “Molecular Biology of the Cancer Cell” was held in Kyoto, co-organized by Dr. S. Nakanishi and Dr. I. Pastan. Dr. Watanabe described studies of lymphocyte expression and differentiation controlled by a transcription factor isolated from B cell nuclei which is essential for expression of immunoglobulin heavy chains. Dr. Evans described the novel and powerful techniques to study regulation of steroid, hormone and vitamin A receptors. Dr. Yamamoto described the isolation and transforming potential of several proto-oncogenes.
Dr. Ariga described c-myc regulation of transcription. Dr. Adhya described studies on elements the produce and negative control of gene transcription. Dr. Honjo described his recent experiments on factors that control differentiation of B cells, indicating that a novel molecule, perhaps a new lymphokine, is involved in lymphocyte differentiation. Dr. Takeichi described the structure and function of cadherins and its possible role in tumor metastasis. Dr. Caron described catecholamine receptors.
Dr. Nakanishi reported a new method of cloning receptor genes for hormones and growth factors. This method involves the production of full length cDNA transcripts and microinjection of RNA into an oocyte. Dr. Ui described his studies using pertussis toxin to activate adenylate cyclase. Dr. U no has used a genetic approach to investigate second messenger systems including phosphoinositol and the PIP2 cascade in yeast.
Dr. Pastan described how pseudomonas exotoxin can be directed to EGF receptor bearing cells. The molecules bind to, enter and kill cells bearing EGF receptors. Dr. Tsuruo made monoclonal antibodies (MDR16) to a protein found on the surface of multidrug resistant cancer cells. He used this antibody to study drug resistance, and found that drug resistant cells have an increased sensitivity to drug after exposure to MRK16 suggesting its possible therapeutic use.
Dr. Gottesman concluded the meeting by presenting an overview of the ways in which cancer cells avoid being killed by cytotoxic chemotherapeutic drugs. The multidrug transporter (P170) is expressed in many kinds of multidrug-resistant cells MDR1 gene encoding the transporter has been cloned and sequenced.
Dr. Adamson asked about details of the cadherin. Dr. Sugano responded by saying that there are two different kinds of cadherins known, and the molecular structure and function were studied extensively. The cadherin converts highly metastatic cells adhered to each other to form cell clusters. Dr. Adamson pointed out that lung is not included in the list of organs producing MDR1. A question was raised whether MDR1 gene is smoke inducible. Dr. Sugimura mentioned that normal tissues from which cancers are originated with a high level of MDR1 expression, also show high multi drug resistance. Dr. Sugano mentioned that MDR1 transcription level is high in preneoplastic stage during experimental hepatocarcinogenesis.
Dr. Miller asked about Dr. Matsubara’s visit to the U.S. Dr. Sugano and Dr. Sugimura explained the rather unusual situation of the urgent necessity to send Dr. Matsubara to investigate the feasibility of studying the human genome, although his and Dr. Takanami’s collaboration had not been approved by the Steering Committee. It has generally been agreed to exclude the activity outside of this program in the report, however, the program channel could be used for cases of emergency or extraordinary importance, after mutual agreement of both sides has been reached.
Dr. M. Kimoto visited Dr. A. Singer for exchange of information on the regulation of immune response gene expression and visited the Mayo Clinic. Dr. H. Fujiwara visited Dr. M. Green to initiate collaborative studies of functional properties and physiological effects of the TSTGF and additional exchange information.
Dr. Ogawa initiated the report on the activities in the Treatment Program Area. The first seminar on “Role of Cytokines in Cancer Treatment” was organized by Dr. Ogawa and Dr. Friedman. Alpha Interferon treatment on hairy cell leukemia, chronic phase of CM L, renal cell cancer, melanoma, low grade NHL, lymphoma, mycosis fungoides and carcinoid were reported. Generally, slow growing tumors were responsive. High dose seemed more beneficial. Gamma interferon showed some anticancer activity, although various side effects were observed. Gamma interferon was effective on renal cell carcinoma, T cell leukemia, and myelodysplastic syndrome. However, the overall effect of gamma interferon was very disappointing. A confirming study of Dr. Rosenberg’s LAK-IL-2 treatment was carried out in Japan. Results of melanoma and colon cancer were similar to that of the U.S. reports, except the number of renal tumors that responded was about a half of the NCI report. Toxic side effects were also observed.
TNF was effective on hemangiosarcoma. With systemic administration of TNF alone less than 5 percent of solid tumors responded. Synergistic actions of more than two lymphokines were observed in in vitro studies. Low dose cyclophosphamide with IL-2 was particularly effective.
Dr. Adamson asked about any effect of interferon on skin cancer in xeroderma pigmentosum such as was reported by Dr. Kraemer and others. Not much treatment has been done with interleukin in Japan. Evaluation of LAK therapy and international comparison of the results have been difficult during the past years because of high cost and toxic side effects associated with the treatment. True evaluation of such treatment must await for future developments.
The second seminar on “New Agent Development” was organized by Dr. Friedman and Dr. Ogawa, and held in Hawaii. The purpose of this meeting is to discuss new methodology and new agents for cancer treatment. Every year, the methodology of drug screening is becoming more rational rather than random. Human cell lines are increasingly used for screening because of the relevance of human cancer.
The areas in which U.S. and Japanese scientists and other clinical investigators are interested in is the new platinum analogues. Dr. Rosencweig reviewed U.S. activities, and Dr. Ota reviewed Japanese hew platinum analogues. Dr. Gabrilove discussed her work with GCSF and GMCSF which stimulates all granulocytes and monocytes. Dr. Takatsu provided complimentary data from Japan about GCSF. Pharmacokinetics and pharmacodynamics of CBDCA were discussed with excellent prediction for future applications.
New anthracycline derivatives were discussed by Dr. Unezawa and Dr. Tsuruo. Dr. Ogawa and Dr. Taguchi reported new antibiotics and compounds developed in Japan. Inhibitors of topoisomerase II was also discussed. Antimetastatic agents were discussed by Dr. Sobel. Higher metastatic potential was noted in those cells with more laminin receptors.
Dr. Tsuruo described the mechanism of drug resistance and clinical application of agents that reduce drug resistance. Dr. Ogawa introduced new Japanese drugs which have no cross reacting resistance to anthracycline and adriamycin. A dramatic effect and potential risk of GCSF and GMCSF after bone marrow suppression, extensive chemotherapy, chronic application, and in leukemic and leukopenic patients were discussed by committee members.
The third meeting for the Treatment Program Area was on “Current Progress in Combined Modalities” co-organized by Dr. T. Phillips and Dr. M. Abe, and held in San Francisco. The meeting was participated in by a large number of attendants who were supported by this program as well as self-supported individuals and observers. Numerous handouts distributed to the participants and the NCI had excellent updated information of the activities covered by this meeting.
The equipment and preclinical rationale of hyperthermia in radiotherapy and combined modalities were discussed extensively. In the second session Dr. Brown and Japanese participants discussed biochemical rationale and clinical application of radiation sensitizers such as nitroimidazole and others. Dr. Coleman presented a talk on the mechanism of cross resistance against radiation and chemotherapy.
The final session of the second day was devoted to a review of high LET and particle radiotherapy. Intraoperative radiation therapies explored extensively in Japan and the U.S. were presented.
Dr. Sugimura mentioned that the meeting was successful in terms of the scientific merit received by the large number of participants, however, this is the first time having such a large seminar under the auspices of the US-Japan Cancer Program. The original idea of the program was to support small meetings to encourage discussion, rather than numerous presentations. Although a large meeting such as this would be more pertinent because of the type of subject, It should be considered to be an unusual opportunity in this program. Dr. Adamson agreed to keep the program fully controlled and maintain the original principle, but flexible enough to avoid intrusion of excessive bureaucracy.
Dr. Yamamura questioned the effectiveness of particle radiation therapy which was favorably reported by Japanese participants, whereas the U.S. studies do not indicate very convincing results with neutron therapy at this time. Dr. Friedman mentioned that only promising therapy with neutron radiation is with the salivary gland carcinoma. The lack of distinct cost efficiency over conventional therapy hinders the development of particle radiation therapy in the U.S.
Three scientists visited U.S. Iaboratories in the Treatment Program Area. Dr. O. Niwa visited Dr. I. Fidler for exchanging information regarding the current research on molecular biology of tumor metastasis. Dr. S. Fujimoto visited Drs. R. Shoemaker, E. Mihich, and F. Muggia to discuss current screening systems for new drug development. Dr. R. Ueda visited Dr. L. Old for exchange of information regarding the present status of the application of mouse and human monoclonal antibodies produced against human tumors for diagnosis and treatment.
Two meetings were held under the Interdisciplinary Program Area. A seminar on “Melanoma and Skin Cancer” was co-organized by Drs. A. Kukita, K. Jimbow, and T. Fitzpatrick, and was held in Tokyo. The seminar was organized along multidisciplinary lines ranging from pigment cells of fish to human melanoma cells and clinical aspects. The topics discussed were in the following five categories:
(1) Epidemiology and Comparative Aspects:
Dr. Tucker summarized the recent incidence rate of cutaneous malignant melanoma in Japan, U.S., and Australia. She mentioned that remarkably low incidence of the familial malignant melanoma and dysplastic nevi in Japanese compared with very high incidence of these syndromes in the U.S. Drs. Kukita and Ikeda described melanomas in pigmented races occurred frequently in non-exposed areas of the body with a low familial background.
(2) Cellular and Basic Biology of Melanoma:
This session was designed to clarify the regulatory factors responsible for proliferation and differentiation of epidermal cells, and to define the factors which might be relevant to prevention of skin cancer and melanoma.
(3) Pathogenesis:
Three major topics were discussed: a) pigment cells and tumors in fish; b) sun exposure and DNA damage; and c) immunology and oncogene on melanoma. Prince Masahito demonstrated how neural crest cells differentiate into pigment cells of fish, and the involvement of ras oncogene in transformation. Dr. Kimura discussed environmental factors on development of pigmented tumors in fish.
Dr. Adamson questioned whether environmental pollutants really produced the melanoma in fish, and whether there are any experimental model systems which have proven the epidemiological findings in Japan. Dr. Sugano answered that there is no direct experimental evidence supporting the epidemiological finding at this time.
(4) Biology of Precursor Lesions and Early Diagnosis:
The nature and significance or dysplastic nevi and giant melanocytic nevi were discussed. The Importance of high and low melanoma risk heterogeneity, periodic follow-up and clinical management at intervals dependent on the risk factors, biopsy and future studies aimed to define the significance of DMN were subject to extensive discussion.
(5) Methods of Control and Treatment:
This session was aimed at summarizing the clinical features of melanoma and skin cancer in the U.S. and Japan, and to discuss the results of the treatment which have been engaged in currently in both countries, and the possibility for development of rational and experimental approaches in the therapy. Various results from treatment with lymphokines, Immune-based tactics, chemotherapeutic approaches, and neutron capture therapy were reported and discussed extensively.
Dr. Miller pointed out that the subject of the seminar was an excellent choice because of the clear difference in epidemiology, genetic, familial, and environmental backgrounds, risk heterogeneity, different types of melanoma occurring at different portions of the body, precursor diseases in the U.S. and Japan. This meeting has prompted Dr. Tucker to visit Hiroshima to set up a new program to review photographs of Japanese atomic bomb survivors and other patients for epidemiological survey of skin abnormalities and malignant neoplasms. Active participation of Prince Masahito in this seminar was particularly appreciated and it was a great honor for all participants. Dr. Adamson suggested to set up an experimental system where environmental exposure to fish can be Investigated using normal and polluted environments in nature. He also asked about the sampling methods of the fish for study, and that would make a significant difference in the findings, as experienced by previous studies carried out by the Smithsonian Institute. It was answered by Dr. Sugano that it was an incidence survey carried out by 25 stations in the area.
Dr. Miller reported the workshop on “The Family Syndrome of Sarcoma, Breast Cancer, and other Neoplasms” which was organized by Drs. R. Miller, F. Li, and H. Sugano. The Li-Fraumeni family cancer syndrome (LFS) is of special interest because of the diverse cancers which aggregate among family members or as multiple primary neoplasia. To explore the nature of the disease as defined thus far in the U.S., and to search for affected families in Japanese registries or case-series, was the purpose of this workshop on the syndrome.
Dr. Tsunematsu presented data from the Japanese Childhood Cancer Registry and the Childhood Multiple Primary Cancer Registry. Of ten families, four were of unusual interest showing the elements of the syndrome. Dr. Sugano reported the family history of 2,810 breast cancer cases. Twenty-two of them reported the occurrence of sarcoma in a close relative. Dr. Watanabe reported 7,500 cases of breast cancers with 322 having another primary cancer.
Dr. Matsunaga reported the childhood cancer incidence data for Kanagawa Prefecture where the incidence of childhood sarcoma was less than 50 percent of that reported in SEER data for U.S. white children, but about the same as that of U.S. black children. Dr. Sugano pointed out that the incidence of breast cancer has doubled in 15 years among post-menopausal women in Japan. However, the overall rates remain below those for U.S. white women. thus the cancer family syndrome may be less common in Japan because its principle components, breast cancer and soft tissue sarcoma, occur less frequently in Japan.
Dr. Garber reported a case of hepatoblastoma with a family history of polyposis of the colon, which also commonly had black spots in their ocular fundi. Dr. Newton noted that of histological review of sarcomas in children may serve as markers of hereditary forms in addition to detailed family history. Dr. Koufos reported Wilms’ tumor associated with aniridia or other neoplasms showed a constitutional deletion of chromosome at specific locations.
In the general discussion it was noted that the goal in studying LFS is not to explain the cause of cancer in these rare families, but to uncover basic principles In human biology that can be applied to cancer in general. LFS involves a variety of cancers that are not explained by knowledge thus far of oncogenes or tumor suppressor genes. Adrenocortical carcinoma may provide a key because the neoplasm is rare except in cases of LFS, and a high proportion of ACC occurs in families or with other primary cancers. Opportunities were noted for further study of unusual histories of familial cancer described during the workshop, and it was suggested that an exchange of scientists between the two countries could be of benefit to both. One of the plans was to include Dr. Tsunematsu’s visit to Dr. Strong’s laboratory to study her highly sophisticated system.
Dr. Adamson asked how much of cytogenetic and follow up study has been done in familial cancers in Japan. Dr. Miller and Dr. Sugano answered that cytogenetic studies at chromosomal and molecular level are currently in progress in the U.S. and Japan.
Three scientists have been exchanged under the Interdisciplinary Program Area. Dr. E. Tahara visited Dr. M. Ryoji and Dr. Schlom for studies on the interaction between growth factors and oncogenes in human gastric cancer; and monoclonal antibodies against human cancers. Dr. K. Fukuda visited Dr. B. Henderson and Dr. H. Hayes for epidemiological studies of nasal sinus cancer and pancreatic cancer. Dr. M. Takanami visited numerous institutions for the feasibility of human gene analysis.
FUTURE PLANS
Twelve future workshops or symposia are envisioned, nine in the United States and three in Japan. Thirteen scientists will be in the Exchange Program. Mutagenic heterocyclic amines and okadaic acid will be sent from Japan to the U.S., and made available for U.S. scientists. Fecapentaene will be sent to the National Cancer Center in Japan for its carcinogenesis study.
Planned Seminars in the Etiology Program Area for FY 88: