The Role of Nutrition in Cancer Treatment and Prevention-From Bench to Clinic. New concepts for nutraceutical application in

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1 2017 年營養醫學研討會活動日期 :106 年 11 月 26 日營養醫學在癌症預防與治療扮演的角色 - 從實驗室到臨床 The Role of Nutrition in Cancer Treatment and Prevention-From Bench to Clinic 時間課程主題及內容綱要授課講師引言人 08:20-09:00 報到 09:00-09:20 開場 - 理事長致詞 貴賓致詞 台灣營養醫學推廣協會理事長陳伯中教授臺北醫學大學臺北癌症中心院長彭汪嘉康院士 台灣營養學會理事長貴賓致詞王果行教授 New concepts for nutraceutical application in 台灣營養醫學推廣協會 09:20-09:50 cancer. 創會暨榮譽理事長 夏滉博士 The clinical application of coenzyme Q10 中山醫學大學 09:50-10:35 supplements in hepatocellular carcinoma 健康管理學院營養學系 patients after surgery. 林娉婷副教授 10:35-10:50 交流時間 The synergistic effect and mechanism of total 臺北榮民總醫院 10:50-11:35 nutrition supplement with radiation in lung 腫瘤醫學部放射腫瘤科主任 cancer bearing mice. 劉裕明醫師 基隆長庚醫院血液腫瘤科主任王正旭醫師台灣營養醫學推廣協會理事長陳伯中理事長亞東紀念醫院放射腫瘤科主任熊佩韋主任 11:35-12:00 綜合座談 Q & A 夏滉博士 / 林娉婷副教授 / 劉裕明主任 12:00-13:00 午餐 Dietary supplementation with a special 弘光科技大學 國立臺灣海洋大學 13:00-13:45 nutritional formula protects lipolytic and 營養系暨營養醫學研究所食品科學系特聘教授 thermogenic deplation of adipose in cachectic 王涵助理教授吳彰哲教授 mice treated with erlotinib. 13:45-14:30 Combination of selenium yeast and fish oil reverses the gefitinib resistance of HCC827GR human lung cancer cells. 萬芳醫學中心教學研究部醫學研究員姚智榮博士 萬芳醫學研究中心副院長賴基銘醫師 The effectiveness of combining nutraceutical 弘光科技大學 台灣營養學會理事長 14:30-15:15 supplement with chemotherapy or targeted 營養醫學研究所王果行教授 therapy on reducing tumor progression in 郭志宏教授 triple-negative breast cancer-bearing mice. 15:15-15:30 交流時間

2 15:30-16:15 16:15-17:00 17:00-17:30 The synergistic and protection effects of total nutrition supplement to pelvic radiation in cancer bearing mice. 臺北榮總放射腫瘤科主任劉裕明醫師 亞東紀念醫院放射腫瘤科主任熊佩韋主任 Recent advance of demethylation agent in cancer 萬芳醫學研究中心副院長 臺北醫學大學 therapy-the role of nutritional medicine. 賴基銘醫師 臺北癌症中心院長 彭汪嘉康院士 綜合座談 Q & A 夏滉博士 / 王涵助理教授 / 姚智榮博士 / 郭志宏教 授 / 劉裕明主任 / 賴基銘副院長

3 課程摘要 講師 姓名 夏滉博士 課程題目 New concepts for nutraceutical application in cancer. 課程摘要 Nutraceutical is a term derived from nutrition and pharmaceu tical. Increasing studies and clinical trials have been done and show promising beneficial results for various diseases. In recent years nutraceutical received considerable interest due to safe, nutritional benefits, promising side effect reduce and high therapeutic properties in many diseases. Good nutrition support during cancer treatment can make quality of life better, keep up patient s strength and energy, better weight menagement(cachexia). Lower risk of infection, heal and recover faster. More and more data show integrate, chemotherapy, radiation therapy, hyperthermia, immunotherapy (monoclonal antibodies, immune checkpoint inhibitors, cancer vaccines, and non-specific immunotherapies) and nutraceutical will possible form a new era for cancer treatment. From cell to human studies, nutraceutical also give promising data for cancer prevention and after treatment benefits for patients. 根據世界衛生組織及臺灣衛生福利部資料顯示, 肝細胞癌 林娉婷 輔酶 Q10 補充劑於肝癌術後之臨床應用 (The clinical application of coenzyme Q10 supplements in hepatocellular carcinoma patients after surgery) (hepatocellular carcinoma) 佔癌症死亡的第二位 手術是目前治療肝癌主要治癒性方法 肝癌病人接受手術切除治療可能影響其氧化壓力及發炎反應, 進而影響術後併發症與預後 因此給予肝癌病人抗氧化或抗發炎營素輔助癌症治療是一個值得思考的營養照護策略 輔酶 Q10 為參與粒線體電子傳遞 鏈生成三磷酸腺苷中重要脂溶性營養素, 已被證實具很好的抗

4 氧化及抗發炎功效 我們利用觀察性實驗, 發現肝癌病人 (n = 71) 在術前之血漿輔酶 Q10 濃度 ( 中位數 0.32 M) 有較低 的情形 ( 低於正常值 : μM), 且術後輔酶 Q10 濃度 較術前濃度更為下降 ( 中位數 0.28 M,p < 0.01) 且術後發 炎指標 ( 高敏感度 C- 反應蛋白 腫瘤壞死因子 -α 及介白素 -6) 濃度顯著較手術前上升 有鑑於肝癌病人有較低血漿輔酶 Q10 濃度及較高發炎反應, 我們進一步利用介入型試驗, 給予手術 後肝癌病人 (n = 41) 輔酶 Q10 補充劑 (300 mg/d) 對其 氧化壓力及發炎之影響 給予肝癌病人輔酶 Q10 補充劑 (300 mg/d), 介入 12 週後, 也發現可顯著降低肝癌病人脂質過氧 化物質 (MDA) 及抗氧化酵素活性 (SOD CAT 及 GPx) 除了降低氧化壓力, 我們也發現, 輔酶 Q10 補充劑介入後 4 週後即校正受試者原本較低輔酶 Q10 濃度 ( 中位數 0.27 M 上升至 1.35 μm) 在發炎指標方面, 輔酶 Q10 補充劑介入 12 週後肝癌病人之發炎指標 (hs-crp 及 IL-6) 濃度顯著較 介入前降低 64.3 % 及 14.1 % 因此, 本研究發現肝癌病人接 受手術治療時會有較低的輔酶 Q10 濃度及較高的發炎反應 ; 肝癌術後病人可藉由輔酶 Q10 補充劑 ( 每日 300 毫克 ) 以增 加其抗氧化力 降低氧化壓力與發炎指標濃度

5 劉裕明 A 王涵 The synergistic effect and mechanism of total nutrition supplement with radiation in lung cancer bearing mice Dietary supplementation with a special nutritional formula protects lipolytic and thermogenic deplation of adipose in cachectic mice treated with erlotinib Lung cancer is one of the deadly malignancies with high mortality now a day. Concurrent chemoradiotherapy (CCRT) is now recommended as a standard treatment for locally advanced unresectable or inoperable disease. Cisplatin is the major chemotherapeutic drug most widely used for CCRT for lung cancer. However, the associated bone marrow, renal toxicity and resistance to this drug remain major concerns. Therefore, novel and potent regimens that can control or ameliorate both local and distant tumor progression are urgently needed. As fish oil and selenium enriched nutrition supplement had been reported to enhance anti-tumor immunity for cancer patients, total nutrition support is the tendency now a day. The purpose of this study was to evaluate the radiation enhancement effects of total nutrition formula (TNuF) on the Lewis lung cancer cells bearing BALC/c mice. Tumor growth delay and cachexia status were measured. Our results showed the oral TNuF could enhance the tumor growth delay, decrease distant metastasis, increasing body weight gain, and keep Gluteal muscles weight, without bone marrow suppression during the treatment. Our total nutrition formula might enhance the radiation anti-tumor effect on Lewis lung cancer cells bearing BALC/c mice and decrease malignancy cause cachexia. The possible mechanism might include apoptosis and inhibit EGFR, VEGF, TNF-α and IL-6 expression. Lung cancer is the leading cause of cancer-related death worldwide. Erlotinib can treat advanced non-small-cell lung cancer (NSCLC) to a certain extent, but a proportion of patients who could receive a survival benefit is still limited. Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. This systemic syndrome, termed cancer-associated cachexia (CAC) is still no successful pharmacological treatment, and is responsible for approximately 20% of total deaths in cancer patients. Therefore, new therapeutic targets for cachexia prevention and treatment are urgently needed. One key characteristic of cachexia is elevated resting energy expenditure, which has been linked to increased brown fat thermogenesis. Here, using a Lewis

6 姚智榮 併用酵母硒與魚油逆轉 lung carcinoma model of cancer cachexia, we show that Erlotinib inhibited tumor size and metastatic node number, but failed to affect the weight of adipose tissues. However, supplementary treatment with special nutritional formula significantly preserved PTHrP-triggers adipose tissue browning and IL-6-induces lipolysis. Furthermore, nutrition supplement reduced inflammation and a shift in macrophage polarization. These results reveal Erlotinib in combination with specific nutritional formula might hold promise for improving therapeutic effect and ameliorating cachectic symptoms in cancer patient. adenocarcinoma cell line, which has an mutation in the EGFR HCC827GR 人類肺癌細胞之 tyrosine kinase domain (E746-A750 deletion). At dose of 1 M, gefitinib 抗藥性 Combination of selenium yeast and fish oil reverses the gefitinib resistance of HCC827GR human lung cancer cells Non-small cell lung cancer (NSCLC) constitutes more than 80% of lung cancers. A subset of NSCLC carrying specific genetic mutations of epidermal growth factor receptor (EGFR) can be effectively treated by tyrosine kinase inhibitors (TKIs)-mediated targeted therapy. However, the drug resistance leads to the inevitable relapse from prior effective therapy. How to overcome this obstacle is very important for the successful treatment of NSCLC. In this study, we established a gefitinib-resistant subline (HCC827GR) from gefitinib-sensitive HCC827 human lung gefitinib reduced HCC827GR cell number to 87.4% of control after 96 h of treatment. Combine gefitinib (1 M) with selenium yeast 500 ng/ml and fish oil 75 M DHA, the cell number reduced to 28.3%. In comparison to parental HCC827, the HCC827GR subline has much higher stemness (CD44) and mesenchymal (N-cadherin, vimentin) and lower epithelial (E-cadherin) markers. Furthermore, we found the HCC827GR subline possesses significant higher cytoprotective (glucose-regulated protein 78, GRP78) and lower proapoptotic (C/EBP homologous protein, CHOP) endoplasmic reticulum (ER) stress markers. The effects of selenium yeast and fish oil on the above stemness, EMT (epithelial-mesenchymal transition) and ER stress markers of HCC827GR cells will be investigated with regard to the enhancement of geftinib sensitivity.

7 郭志宏 劉裕明 B The Effectiveness of Combining Nutraceutical Supplement with Chemotherapy or Targeted Therapy on Reducing Tumor Progression in Triple-negative Breast Cancer-bearing Mice The synergistic and protection effects of total nutrition supplement to pelvic radiation in cancer bearing mice Breast cancer is the most commonly cause of cancer-related death among women. The percentage of seventy to eighty of all patients are positive for estrogen or progesterone receptors (ER and PR). In contrast, 10-15% of patients, triple-negative for ER, PR, and human epidermal growth factor receptors (HER2), is associated with a worse prognosis, and higher recurrence and majority of deaths in the first three to five years after the initial treatment. Therefore, it is important to develop new therapeutic strategy and avoid the development and metastatic progression of triple-negative breast cancer patients to increase their life expectancy. Line of evidence have shown that the redox homeostasis plays a pivotal role in the occurrence of the cancer progression. In recent studies, chemotherapy efficacy of certain anti-oxidant micronutrients for breast cancer have also been documented. Furthermore, these micronutrient distribution were well known to be involved in induction of apoptosis, inflammation and immune-mediation, as well as inhibition of angiogenesis and metastatic progression in cancer patients. The purpose of our present investigation was to determine the difference of chemotherapy drugs (Taxol and Adriamycin) or targeted therapy (Avastin) along with/without nutraceutical supplementations on oxidative stress and inflammatory status, cachexia, as well as apoptosis, angiogenesis and metastatic progression in BALB/cByJNarl mice bearing triple-negative 4T1 mammary carcinoma. In the last few decades radiotherapy was established as one of the primary treatment modalities for certain tumors. Concurrent chemoradiotherapy with regimens of cisplatin is now recommended as a standard treatment for locally advanced pelvic tumor in gynecological and urologic malignancy. However, pelvic radiation could cause damage to surrounding non-cancerous tissues resulting in disruption of normal physiological functions and symptoms such as diarrhea, tenesmus, incontinence, and bleeding. The purpose of this study was to evaluate the possibilities of the radiation enhancement and normal tissue protection effects from total nutrition formula (TNuF) engagement on the Lewis lung cancer cells bearing BALC/c mice with pelvic irradiation. Our results showed the oral TNuF

8 could enhance the tumor growth delay in tumor volume, decrease distant metastasis, increasing body weight gain, keep Gluteal muscles weight, reduce intestine mucosa damage and without bone marrow suppression during the treatment. The results also showed pretreatment with TNuF had better GI mucosa protection and less distant metastasis than concurrent TNuF treatment. Total nutrition formula might enhance the radiation anti-tumor effect on Lewis lung cancer cells bearing BALC/c mice, decrease malignancy cause cachexia and radiation caused GI toxicity. The possible mechanism of radiation enhancement might include apoptosis and inhibit EGFR, VEGF, TNF-α and IL-6 expression. 許多研究顯示, 抑癌基因啟動子 (promoter) 的異常甲基化會 使其蛋白表現沉默, 即所謂表觀遺傳調控 (epigenetic modification), 與癌症的形成密切相關 DNA 甲基轉移酶 (DNA methyltransferase, DNMT) 過度表達, 已發現在下列 賴基銘 腫瘤去甲基化療法的最新 進展 --- 營養醫學的角色 Recent Advance of Demethylation Agent in Cancer Therapy-The Role of Nutritional Medicine 癌症包括 : 肺 肝 乳 胃 大腸 攝護腺 膀胱 胰臟 腎 食道及血癌等 去甲基化會抑制腫瘤的成長, 誘導腫瘤細胞的良性分化, 並清除癌幹細胞及調整免疫細胞的功能, 因此研發去甲基化藥物已成為癌症藥物開發的重要方向 已開發的藥物中包括 : 三氧化二砷 ( 砒霜 ) 維甲酸 維他命 D3 Azacitidine(Vidaza) Decitabine SAHA 及 CDA-2( 人 尿萃取物 ), 已分別透過臨床試驗證實有效控制 : 血癌 骨髓 增生分化不良症 (MDS) 皮膚 T 細胞淋巴瘤及其它實體瘤 ( 如 :

9 肝 腎 惡性腦瘤 乳 肺 甲狀腺 神經母細胞瘤及腸胃道 基質瘤 ) 不過目前已上市的去甲基化藥物, 其化學結構與細胞之核酸相 近, 易產生副作用而限制其應用 因此, 科學家們也從食物中 找尋具有去甲基化活性的營養成分, 例如食物中的多酚 (polyphenols) 茶葉中的 (-)-epigallocatechin-3-gallate (EGCG) 黃豆中的 genistein 硒 (Se) 等, 都被報導有抑制 DNMT 的活性 此外, 最新的研究顯示, 對甲基化的調控有提 升免疫細胞活性的潛力, 去甲基化可使衰竭的 T 細胞再次回春 (rejuvenation) 因此, 如何善用具調控去甲基化活性的營養 成分, 以適當地調控癌細胞與免疫細胞的甲基化, 是當今防癌 與抗癌的一重要課題 結論 : 基因甲基化是表觀遺傳調控的關鍵, 去甲基化會甦醒抑 癌基因的表達 誘導癌細胞的良性分化 抑制腫瘤成長的信號 通路 清除癌幹細胞及提升免疫細胞的功能 去甲基化藥劑的 開發與應用, 其重要性與日俱增, 營養醫學的介入, 將提升癌 症治療成功的機會 此外, 合併去甲基化療法會強化放療及化

10 療的療效, 尤其是未來在免疫療法 ( 免疫檢查點抑制劑 ) 的應 用, 將是癌症整合療法發展的新趨勢 講師學經歷 編號講師姓名講師學經歷

11 現職 ( 含單位 / 職稱 / 年資起迄 ) 台灣營養醫學推廣協會 / 創會理事長 /2007~ 迄今 1 夏滉 學歷 ( 含校名 / 系所 / 年屆起迄 ) 加州大學爾灣分校 / 核醫療及放射化學博士 /1980~1985 經歷 ( 含單位 / 職稱 / 年資起迄 ) 弘光科技大學 / 營養醫學研究所兼任副教授 /2007 年 ~2015 現職 ( 含單位 / 職稱 / 年資起迄 ) 中山醫學大學 / 健康管理學院營養學系 / 副教授 / 民國 102.2~ 迄 今 2 林娉婷 Ping-Ting Lin 學歷 ( 含校名 / 系所 / 年屆起迄 ) 1. 中山醫學大學 / 營養學科學研究所 / 博士 / 民國 91.9~ 中山醫學大學 / 營養學科學研究所 / 碩士 / 民國 89.9~91.6 經歷 ( 含單位 / 職稱 / 年資起迄 ) 1. 中山醫學大學營養學系 / 專任助理教授 / 民國 98.8~ 中州技術學院保健營養系 / 專任助理教授 / 民國 96.3~98.7

12 3. 真理大學餐旅管理學系 / 兼任講師 / 民國 95.8~96.7 現職 ( 含單位 / 職稱 / 年資起迄 ) 1. 台北榮總 / 放射腫瘤科主任 /2012~ 迄今 2. 國立陽明大學 / 醫學系助理教授 學歷 ( 含校名 / 系所 / 年屆起迄 ) 3 劉裕明 1. 成大醫學系 / 台大化工一 /1983 經歷 ( 含單位 / 職稱 / 年資起迄 ) 台北榮總 / 放射腫瘤科主治醫師 /1997~ 現職 ( 含單位 / 職稱 / 年資起迄 ) 弘光科技大學營養系暨營養醫學所 / 助理教授 /2014,8~ 迄今 4 王涵 學歷 ( 含校名 / 系所 / 年屆起迄 ) 國立台灣海洋大學 / 食品科學系 / 博士 /2007,9~2012,6 經歷 ( 含單位 / 職稱 / 年資起迄 ) 1. 環球科技大學 / 講師 /2011,11~2014,7

13 2. 國立台灣海洋大學食品科學系 / 國科會博士後研究員 /2012,9~2014,7 (grant NSC B ) 現職 ( 含單位 / 職稱 / 年資起迄 ) 1. 萬芳醫院教研部 / 研究員 /2009~ 迄今 2. 臺北醫學大學醫學系 / 內科學科兼任助理教授 /2010.2~ 迄今 學歷 ( 含校名 / 系所 / 年屆起迄 ) 5 姚智榮 國立台灣大學 / 毒理學研究所 / 博士 經歷 ( 含單位 / 職稱 / 年資起迄 ) 1. 國家衛生研究院癌症研究所 Everlife Biotechnology Ltd./ 產學計畫博士後研究員 2. Everlife Biotechnology Ltd. 育成中心研究部主任 3. 國家衛生研究院 / 癌症研究所博士 / 後研究員

14 現職 ( 含單位 / 職稱 / 年資起迄 ) Prof. of the Institute of Biomedical Nutrition & Department of Nutrition, Hung Kuang University (2013.8~ 迄今 ) 學歷 ( 含校名 / 系所 / 年屆起迄 ) Ph.D. in Nutrition, Fu Jen Catholic University, 郭志宏 經歷 ( 含單位 / 職稱 / 年資起迄 ) 1. Editorial Board, SM Journal of Hepatitis Research and Treatment. 2. Director of the Institute of Biomedical Nutrition & Chair of the Department of Nutrition, Hung Kuang University, Taiwan. 3. Consultant, Department of Medical Research, China Medical University Hospital, Taiwan. 4. AD, Taiwan Nutraceutical Association, Taipei, Taiwan. 5. Advisory Committee of Food Safety, Health Bureau, Taichung, Taiwan 6. Advisory Committee of Dietary Reference of Intakes zinc (7th ed.), Department of Health, Executive Yuan, Taiwan.

15 7 賴基銘 (Gi-Ming Lai) 現職 ( 含單位 / 職稱 / 年資起迄 ) 1. 臺北市立萬芳醫院 / 癌症中心主任 /2017.8~ 迄今 Director, Cancer Center of Wan Fang Hospital, Taipei Medical University 2. 中華民國癌症醫學會會員 / 推廣委員會委員 /2017.5~ 迄今 Membership Promotion Committee Member of Taiwan Oncology Society 3. 臺北醫學大學醫學院 / 醫學系內科學科教授 /2017.2~ 迄今 Professor, College of Medicine, Taipei Medical University 4. 台灣營養醫學推廣協會 / 副理事長 /2016.3~ 迄今 Deputy chairman, Taiwan Nutraceutical Association 5. 國家衛生研究院癌症研究所 / 兼任副研究員級主治醫師 /2016.1~ 迄今 Adjunct Associate Investigator and Attending Physician, National Institute of Cancer, Research, National Health Research Institutes (NHRI) 6. 臺北市立萬芳醫院 / 檢體保存庫生物醫學主管 / ~ 迄 今 Supervisor of Human Biobank, Wan Fang Hospital, Taipei Medical University 7. 世界華人腫瘤醫師協會 / 副會長 /2015.9~ 迄今 Vice President of World Chinese Oncologist Association 8. 世界華人臨床營養醫師協會 / 委員 /2015.9~ 迄今 Committee Member of the World Association of Chinese Physicians in Nutrition 9. 台灣臨床腫瘤醫學會 / 理事 /2004~ 迄今 Councilor, Taiwan Clinical Oncology Society 10. 台灣癌症基金會 / 執行長 /1997~ 迄今 Chief Executive Officer, Formosa Cancer Foundation 學歷 ( 含校名 / 系所 / 年屆起迄 ) 台灣大學 / 醫學院醫學士 /1971~1978 M.D., School of Medicine, College of Medicine, National Taiwan University

16 經歷 ( 含單位 / 職稱 / 年資起迄 ) 1. 臺北市立萬芳醫院 / 研究副院長 /2015.2~ Vice Superintendent, Wan Fang Hospital, Taipei Medical University 2. 臺北市立萬芳醫院 / 血液腫瘤科主任 /2011.3~ Director, Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University 3. 臺北市立萬芳醫院 / 教研部主任 /2010.9~ Director, Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University 4. 署立雙和醫院 / 血液腫瘤科主任 /2009.6~ Director, Department of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University 5. 國家衛生研究院癌症研究所 / 合聘副研究員級主治醫師 / ~ Associate Investigator and Attending Physician, National Institute of Cancer, Research, National Health Research Institutes (NHRI) (joint appointment) 6. 臺北市立萬芳醫院 / 癌症中心副主任 /2008.9~ Deputy Director, Cancer Center of Wan Fang Hospital, Taipei Medical University 7. 臺北醫學大學醫學院 / 醫學系內科學科副教授 /2008.9~ Associate Professor, Department of Medicine, Taipei Medical University 8. 中藥全球化聯盟台灣分會 / 執行秘書 /2005~2008 Executive Secretary, Taiwan Local Chapter of Consortium for Globalization of Chinese Medicine (CGCM) 9. 國家衛生研究院癌症研究所 / 副研究員級主治醫師 /2004.6~ Associate Investigator and Attending Physician, National Institute of Cancer Research, National Health Research Institutes (NHRI) 10. 國家衛生研究院 / 行政處處長 /2004.6~ Director, Department of Administration, National Health Research Institutes (NHRI) 11. 國家衛生研究院 / 癌症研究組副研究員 /1997~2002 Associate Investigator, National Institute of Cancer Research, National Health Research Institutes (NHRI) 12. 國家衛生研究院 / 台灣癌症臨床研究合作組織主任 ~ Director, Taiwan Cooperative Oncology Group, NHRI

17 13. 長庚大學醫學院 / 內科副教授 /1990~1996 Associate Professor of Medicine, Chang Gung Medical College 14. 美國國家衛生研究院 / 癌症研究所協同研究員 /1987~1989 Visiting Associate, Experimental Therapeutics Section, Medicine Branch, COP, DCT, NCI, NIH, U.S.A 15. 美國國家衛生研究院 / 癌症研究所客座研究員 /1986~1987 Guest Researcher, Experimental Therapeutics Section, Medicine Branch, COP, DCT, NCI, NIH, U.S.A