SUMMARY REPORTS OF EXCHANGE SCIENTISTS
(1) Gang-Hong Lee
Department of Pathology
Asahikawa Medical College
SPONSOR AND HOST INSTITUTION:
Dr. Allan Balmain
ONYX Pharmaceuticals
Dr. Norman R. Drinkwater
McArdle Laboratory for Cancer Research
University of Wisconsin
Dr. Takashi Kojima
Albert Einstein College of Medicine
Dates of Visit: January 16 - February 1, 1998
SUMMARY OF ACTIVITIES:
The major objectives of visit were restricted to exchanging mutual data and planning collaborative projects with US scientists because of the limitation of time. I believe that the objectives were satisfactorily achieved. I presented my works in seminars and also tried communicating with “non-host” scientists to know the most recent advances in the field of chemical carcinogenesis.
We have been working on a murine resistance gene to urethane-induced lung carcinogenesis, namely Par2, which was chromosomally mapped and characterized with its biological functions, but not yet cloned. To clone the Par2 gene, we need to finely map it by establishing YAC-or BAC-transgenic mouse lines. However, we lack enough space for animals and techniques for making transgenic mice. Dr. Balmain and I talked about feasibility of a collaboration to clone the gene. Dr. Balmain was extremely interested in our project and willing to help us in terms of space for animals and making the transgenics. I also talked with young scientists working with him. Mechanisms of malignant progression in skin papillomas developing in TGFâL1-transgenic mice were enthusiastically investigated.
Dr. Drinkwater in McArdle Laboratory and I have been collaborating in making chromosomal region-specific congenic mice for the hepatocarcinogen resistance gene, Hcr, and the ovarian teratoma susceptibility gene, Ots1. The congenic mice are essential for finely mapping the genes and finally cloning them. Dr. Drinkwater said that the congenic mice would be available for experiments in about a year. I also talked with several young scientists working in Dr. Dove’s laboratory in McArdle. I was informed of their recent achievements on the analyses of the Min and Mom1 gene, which are respectively sensitivity and resistance gene for murine intestinal carcinogenesis. They demonstrated that the Pla2g2 gene may be identical to the Mom1 gene using a transgenic mouse model.
Dr. Kojima, Albert Einstein College of Medicine, is using a murine hepatocyte cell line, CHST8, showing temperature-dependent growth. The CHST8 cell line was established by us and provided for him to study relationship between hepatocytic growth and connexin gene expression. He found that the connexin 43 expression correlated with growth arrest and differentiation of the CHST8 cells. He also informed me of his recent data obtained with connexin 32-knockout mice. In these mice, both spontaneous and chemically-induced hepatocarcinogenesis were promoted. His findings suggest that the connexin genes are suppressor genes for liver tumors.
(2) Kei Nakachi
Saitama Cancer Center Research Institute
SPONSOR AND HOST INSTITUTION:
The University of Texas, MD. Anderson Cancer Center
Dates of Visit: March24 - April 13, 1998
SUMMARY OF ACTIVITIES:
Purpose of Visit:
We have been investigating the cancer-preventive effects of green tea in terms of a prospective cohort study, followed by a Phase I trial using green tea extract among a Japanese healthy population. In addition to numerous laboratory studies on the inhibitory effects of green tea or its main constituent (EGCG) on carcinogenesis, the results of our epidemiological study contributed much to the Phase I clinical trial using green tea extract, which started at MD. Anderson Cancer Center in August, 1997, after the approval of IND from U.S. FDA. Since their Phase I trial is ending in April 1998, it is needed to overview the results of trial and discuss future strategies. The purpose of my visit is then to participate in those overviewing and discussion at MD. Anderson Cancer Center and also to discuss the mutual cooperation in achieving cancer chemoprevention using green tea extract.
Research Activities:
1. Participated in staff meeting on the clinical trial using green tea extract at MD. Anderson Cancer Center and studied the results on individual patients including clinical and pathological changes and adverse effects associated with different dose levels of green tea extract; MTD was determined.
2. Discussed another protocol of applying green tea extract, which will be conducted as a next step to determine MTD in a different way of application.
3. To avoid adverse effects ascribed to caffeine in green tea extract, we, Japanese-side researchers, will develop low-caffeine extract of green tea without using any chemical agents. Explained and discussed the methodology of producing the low-caffeine extract.
4. Discussed and investigated possible compliance biomarkers and surrogate biomarkers, which will be measured using stored serum and urine samples of the patients. Experience of our (Japanese-side) Phase I trials conducted in Japan using green tea extract helped much to determine compliance biomarkers, As for possible surrogate biomarkers for the trial, both U.S. and Japanese researchers are required to make a further effort. Japanese side will also conduct a clinical trial to develop reliable surrogate biomarkers, which are able to estimate the efficacy of green tea in reduction of cancer risk.
5. Discussed the schedule of subsequent Phase II trial as well as selection of participants (patients), targeting precancerous lesions, and protocol.
6. Apart from clinical trials using green tea, discussed about our other research project with a research group studying the same subject at MD. Anderson Cancer Center: clinical significance of IGF (Insulin Growth Factors) and IGFBP (Insulin Growth Factor Binding Protein). Although our research group investigated it using surgical materials of breast cancer from a clinicoepidemiological standing point, and U.S.. group investigated using cancer cell lines, both the groups can find a possibility of developing research by cooperation. Also discussed on abnormal transcripts of FHIT gene in cancer with other research group as a common target of research.
To summarize, I studied much about the protocol and actual procedures of clinical trials using chemopreventives at MD. Anderson Cancer Center. This knowledge is very needed for clinical research in Japan using chemopreventives, since there has been no good paradigm for clinical trials in Japan. At the same time, our experience on green tea contributed much to the determination of biomarkers and selection of participants and targeting precancerous lesions, although researchers in both US and Japan need to develop adequate surrogate markers. My visit to MD. Anderson Cancer Center was very fruitful for both US and Japanese research groups to deepen the mutual cooperation for cancer chemoprevention using green tea extract.