(1) Toshiwo Andoh
Aichi Cancer Center Research Institute
SPONSORS AND HOST INSTITUTIONS:
Hosts:
Dr. J.L. Nitiss
Department of Pediatrics, Children’s Hospital of Los Angeles
University of Southern California
Dr. J.C. Wang
Department of Biochemistry and Molecular Biology
Harvard University
Dr. M. Potmesil
Department of Radiology
New York University School of Medicine
Date of Visits: October 18 - November 3, 1992
SUMMARY OF ACTIVITIES:
Through this program I aimed at extending a joint project with investigators in the US and exchanging information and ideas on biological function of DNA topoisomerases (topo) and its application to chemotherapy.
I visited Drs. John L. Nitiss at University of Southern California in Los Angeles and James C. Wang at Harvard University in Boston, with whom I have been conducting joint work for the preceding several months on molecular targets of a new antitumor drug MST-16 in a yeast system, taking advantage of various types of topo mutants. We were able to establish unequivocally the molecular target of the drug being DNA topoisomerase II within the living cells.
I then attended the 4th International Symposium on "DNA Topoisomerases in Therapy", held in New York University. The symposium consisted of the following 5 sessions.
1. Mechanistic, Genetic and Biological Topics
2. Quinoline Inhibitors of DNA Gyrase
3. Clinical Studies of DNA Topoisomerase I Inhibitors
4. Resistance to DNA Topoisomerase I Inhibitors
5. Studies of Drugs Inhibiting DNA Topoisomerase II
The symposium focused on basic biology of DNA Topoisomerases and on its application to chemotherapy of cancer and infectious diseases. The important progress in the former are two fold. In one of the multicellular higher eukaryotes, Drosophila, DNA topoisomerase I was demonstrated to be essentially involved in embryonic development. Secondly, part of the well-studied type II Topoisomerase, gyrase, was crystallized and analyzed, which disclosed and established tertiary structure of the part of the functional domains of the enzyme. In the latter topics, progress was made in clinical development of camptothecin variety of tumors including, breast, lung, colon, cervix and ovary, most of which are generally refractory to chemotherapy. One of the important problems of chemotherapy is the development of resistance of tumor cells to chemotherapeutic agents. Mechanism of resistance to the above mentioned CPT-11 was disclosed, i. e. that mutations in DNA topoisomerase I gene, lead to the production of altered enzyme within the cells which is resistant to the drug and protect cells from being killed by the drug. I presented my talk on this topic.
I obtained full information on DNA topoisomerases, which helps to further develop fundamental aspect of he biological functions of the enzymes and the development of new inhibitors of DNA topoisomerases.
(2) Shousnke Kawanishi
Department of Public Health
Faculty of Medicine
Kyoto University
SPONSORS AND HOST INSTITUTIONS:
Hosts:
Dr. Lawrence A. Loeb
Department of Pathology SM-30
School of Medicine
University of Washington
Dr. W. David Wilson
Department of Chemistry
Georgia State University
Dr. Arthur P. Grollman
Department of Pharmacological Sciences
State University of New York
Health Sciences Center
Date of Visits: November 16 - December 6, 1992
SUMMARY OF ACTIVITIES:
I am studying (1) DNA damage induced by oxygen radicals and (2) amplifier of anticancer drugs (chemical compounds which amplify the action of bleomycin, neocarzinostatin, etc.) In order to develop my research project, I visited the following laboratories in USA.
I visited Dr. W. David Wilson at Georgia State University and discussed problems relating to amplifiers of anticancer drugs and other topics of common interest. I agreed with Dr. Wilson's opinion that an important approach to improve cancer chemotherapy is to find compounds (amplifiers) that enhance the anticancer drugs-mediated DNA cleavage. We also agreed to the cooperative research concerning amplifiers. Dr. Wilson et al. will synthesize compounds which have a conformationally flexible, unfused polyaromatic system and cationic side chain in the molecules and bind specifically with DNA. We will examine whether these DNA ligands amplify anticancer drugs-mediated DNA cleavage most efficiently not only in vitro but also in cultured cells. In addition, I have had the opportunity to give a seminar talk on my work. After that, we discussed with Dr. Baumstark, Dr. Dixson, Dr. Netzel, and Dr. Kennedy the various problems involved in the mechanisms of anticancer drugs-mediated DNA cleavage. It was very stimulating discussion.
I visited Dr. Arthur P. Grollman at the State University of New York at Stony Brook and discussed the structural and biological investigations of DNA damage induced by oxygen radicals and studies on the mechanism of action of bleomycin and neocarzinostatin. Dr. Grollman was involved early in the research on the amplifiers of bleomycin. I gave a research seminar for the students and faculty in Graduate Program in Molecular and Cellular Pharmacology at the State University of New York at Stony Brook. I found it most valuable to talk with Dr. Johnson, Dr. Iden, Dr. Takeshita, Dr. Shibutani, and Dr. Moriya.
I visited Dr. Lawrence A. Loeb at University of Washington and discussed problems relating to the effects of "amplifiers" on free radical-induced DNA damage and other topics of common interest. I gave a seminar talk on my work. I found it most valuable to talk with Dr. Juchau, Dr. Monnat, Dr. Fukuchi and Dr. Loeb's associates.
(3) Yoshiro Niitsu
Department of Internal Medicine, Section 4
Sapporo Medical College
SPONSOR AND HOST INSTITUTION:
Host: Dr. Jayanta Roy Chowdhury
Albert Einstein College of Medicine
Date of Visits: October 23 - November 12, 1992
SUMMARY OF ACTIVITIES:
In this study, the current state of cancer gene therapy in the US was investigated by discussing with several leading scientists who were deeply engaged in this project in the US. Dr. Rosenberg at Nm, Surgery Branch, kindly provided me an opportunity to attend his ward round, and research and clinical meetings. He and his colleague were pursuing adoptive immunotherapy combined with gene therapy and adoptive immunotherapy using TIL transduced with TNF gene.
Results so far obtained were not so satisfactory, as initially expected, but such a pioneering work will certainly provides valuable information to similar studies in this field. At the second institute I visited, Albert Einstein College of Medicine, I had a rather practical discussion with Dr. Roy Chowdry regarding the new strategy for gene transfection, namely in vivo gene targeting. Via receptor for asialogycoprotein which is specifically expressed in the liver, they have tried to transduce genes for!!
!-glucronidase and lipoprotein lipase receptor in his laboratory for the past few years. Similar experiments were carried out in the laboratory of Dr. George Wu. Although experiments were still at the preclinical stage, the strategy appeared to be promising for future clinical trials. In particular, this approach could be applicable for gene delivery in vivo to the tumor tissue so that such antiproliterative genes as antioncogene, antisense of oncogene and herpes simples virus thymdin kinase (HSV-TK) can be transferred specifically to tumor cells via tumor specific antigen or receptor.
With Dr. Mulligan at White Head Institute, I had a discussion concerning the feasibility of vaccine therapy utilizing cytokine-gene modified tumor. Their finding was that the tumor cells transduction with GM-CSF and IL2 genes were most potent to induce antitumor activity in tumor bearers. They are presently expanding their initial observations to the clinical trials by collaboration with affiliate hospitals.
Over the discussion with these scientists, in a conclusion, I found that gene therapy bears high potentiality for the treatment of certain types of cancers.