TREATMENT PROGRAM AREA

REPORTS ON SEMINARS

(1) Seminar on “New Antitumor Agents and Novel Therapeutic Approaches”
May 20-21, 1998-Dana Point, California

The focus of the Dana Point seminar May 20 - 21, 1998, was the information exchange and discussion of promising new anticancer agents and novelherapeutic approaches. Following introductory remarks by Drs. Ogawa and Christian, the seminar was carried out on the following three topics.
1. Angiogenesis.
In solid tumors, cancer cells induce angiogenesis and newly organized blood vessels in turn supply the cancer cells with nutrient and growth factors to support the growth of the tumors. Based on these situations, it has been postulated that inhibition of angiogenesis would lead to blockade of tumor growth.
The first speaker, Dr. Pluda, summarized his research progress at NCI on inhibitory drugs of angiogenesis. Among the drugs under clinical trials at present were thalidomide and Col-3 (NSC683551), as he listed. In addition, he mentioned that Angiostatin was under preclinical study.
Next, Dr. Ono reported the preclinical studies on Irsogladine and OPB-3206, both of which were under development in Japan. As advantageous properties of such inhibitors, she gave several points, including wide spectrum of their efficacy against cancers, lack of drug resistance, low toxicity, and synergistic effects when combined with classical anticancer drugs.
Finally, Dr. Grochow reviewed the methodology in perspective of clinical evaluation for these angiogenesis inhibitors. In usual cases of the evaluation for classical anticancer drugs, the most important factors have been elongation of survival periods and improvement of QOL of patients. However, since it seems to be difficult to simply apply such determinants to the evaluation system for angiogenesis inhibitors, some alternative strategies are required to adequately evaluate the efficacy of these inhibitors. It is obvious that evaluation by monitoring changes in the amounts of known tumor markers has its own limit to apply because such markers do not always reflect the disease status of patients. Dr. Grochow therein exemplified a candidate approach for adequate evaluation for efficacy of angiogenesis inhibitors. Among them were histological examinations on changes in various enzymes or changes in the blood vessels which surrounded tumors. Actually, however, the final evaluation when applied in combination with classical anticancer drugs would again focus on elongation of patients’ survival periods with or without a relapse.
2. Cdk inhibitors and mechanisms for drug resistance in solid tumors.
Cyclin-dependent kinases (Cdk) and their inhibitory proteins, such as p16INK4, are functionally involved in punctual progression and quiescence of cell cycle. Since disruption of the Cdk inhibitory pathways is associated with wide ranges of carcinogenesis, restoration of these pathways by Cdk inhibitory drugs is one probable strategy for a novel anticancer chemotherapy.
Dr. Schwartz reported the combination therapy of Cdk inhibitors, including Safingol and Flavopirial, with classical anticancer drugs. He mentioned that his group had performed a phase I trial for Safingol in combination with Doxorubicin. However, he confessed, Safingol was so expensive that he could not have helped suspending the trial. At present, instead, he is trying a combination therapy of Flavopirial with Taxol. So far, he has observed a case of complete remission in the phase I trial for an esophagus cancer, to which patient Taxol was administrated in advance and then Flavopirial was administrated later.
Meanwhile, Dr. Tsuruo reported his recent research progress on mechanisms for natural drug resistance in solid tumors. In general, solid tumors are resistant to chemotherapy. As probable mechanisms for such resistance, he suggested G1 arrest of the cell cycle and decrease in intracellular amounts of topoisomerase II, both of which involved certain stress proteins in the solid tumor cells.
3. High-dose chemotherapy.
The afternoon session began with a subject on high-dose chemotherapy. Dr. Shea reviewed status quo in United States on high-dose chemotherapy that was supported by transplantation of hematopoietic stem cells. Historically, allogenic bone marrow transplantation has been widely applied to acute leukemia or chronic myeloid leukemia patients. Recently, as an alternative strategy, allogenic transplantation of peripheral blood stem cells has been applied more frequently than ever. Just similar to these situations, to date, autotransplantation of bone marrow has been largely replaced by that of peripheral blood stem cells, which is used for high-dose chemotherapy of breast tumors and malignant lymphomas. So far, however, it is a high frequency of chronic GVHD that makes troubles in transplantation of peripheral blood stem cells.
4. Various new anticancer drugs.
Dr. Taguchi summarized the preclinical and clinical studies on a 5FU analogue, S1, that had been developed in Japan. According to his report, S1 exhibited a high effective ratio against stomach cancers (more than 40%). He added that this drug was also effective against colon cancers with effective ratios of 17 to 35%.
Dr. Fukuoka reported the preclinical and phase I studies on a new antimetabolite, DMDC. Meanwhile, Dr. Sasaki reported the phase I study on a topoisomerase inhibitor, Top-53, that had been developed in Japan. He increased the administration dose of Top-53 by monitoring its blood concentration in the patients. Finally, he identified depression of neutrophils as a limiting factor for administration dose of this new drug to a patient.
In the next morning session, Dr. Christian, as the first speaker, suggested the examined patients’ demerits, which might be caused by the situation that many phase I studies on anticancer drugs had been performed with much lower initial doses than required for actual cure. In order to avoid such demerits, he referred to the results of the phase I trials obtained at NCI and discussed the methodology for more efficient phase I studies.
Dr. LoRusso reported the phase I study on KRN5500, that had been developed in Japan. He demonstrated that the limiting factor for its administration dose was hepatotoxicity. He also determined the dose of maximal tolerance as 6 mglm2. Based on these observations, his group is now planning the phase II trial at the administration dose of 4.3 mg/m2.
Meanwhile, Dr. Eguchi reported the preclinical and on-going phase I studies on a novel pyrazoloacridone derivative anticancer drug, KW-2170, that had been developed in Japan.
The last speaker was Dr. Ogawa, who summarized the preclinical and clinical studies on Amrubicin, a completely synthetic anthracycline derivative. He demonstrated that Amrubicin exhibited high efficacy against malignant lymphoma and lung cancers (small cell and non-small cell).

PARTICIPANTS

UNITED STATES

Dr, Michaele Christian
Associate Director
National Cancer Institute
Executive Plaza, North, Room 742
Rockville, Maryland 20892

Dr. Patricia LoRusso
Wayne State University
Harper Hospital
6990 John R Street, Room 530 5-Hudson
Detroit Michigan 48201-2018

Dr. James Pluda
National Cancer Institute
Executive Plaza, North/Room 715
Rockville, Maryland 20892

Dr. Louise Grochow
oncologu 1-109
Johns Hopkins Oncology Center
600 N. Wolf Street
Baltimore, Maryland 21287-0002

JAPAN

Dr. Takashi Tsuruo
Laboratory Research Department of Clinical Biology
Institute of Molecular and Cellular Bioscience
University of Tokyo
1-1-1 Yayoi-cho, Bunkyo-ku, Tokyo 162

Dr. Tetsuo Taguchi
Japan Society for Cancer Chemotherapy
No. 505 1-18-35, Edobori, Nishi-ku
Osaka 550

Dr. Masahiro Fukuda
Internal Medicine 4
Kinki University School of Medicine
377-2 Ohono-higashi
Osaka-sayama 589

Dr. Yasutsuna Sasaki
Division of Oncology/Hematology
National Cancer Center Hospital East
6-5-1 Kashiwanoba, Kashiwa-city
Chiba 227

Dr. Mayumi Ono
Department of Biochemistry
Kyushu University School of Medicine
1-1-3 Umade Higashi-ku
Fukuoka 812-82

Dr. Kenji Eguchi
Department of Internal Medicine
National Shikoku Cancer Center
Horinouchi, 13, Matsuyama
Ehime 790