Chemoprevention

3.    Ulrich, C. M. (2007) Folate and cancer prevention: a closer look at a complex picture. The American journal of clinical nutrition 86, 271-3. 一刀二刃。 (pdf 4100)   

4.    Berdasco, M., and M. Esteller. (2010) Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell 19, 698-711. (pdf 2904  Must Read. (was referred by Hanahan and Weinberg))    Appropriate patterns of DNA methylation and histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases, such as cancer. Our aim here is to provide an overview of how epigenetic factors, including genomic DNA methylation, histone modifications, and microRNA regulation, contribute to normal development, paying special attention to their role in regulating tissue-specific genes. In addition, we summarize how these epigenetic patterns go awry during human cancer development. The possibility of “resetting” the abnormal cancer epigenome by applying pharmacological or genetic strategies is also discussed.

5.    Feil, R., and M. F. Fraga. (2011) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13, 97-109. (pdf 3200.)    Epigenetic phenomena in animals and plants are mediated by DNA methylation and stable chromatin modifications. There has been considerable interest in whether environmental factors modulate the establishment and maintenance of epigenetic modifications, and could thereby influence gene expression and phenotype. Chemical pollutants, dietary components, temperature changes and other external stresses can indeed have long-lasting effects on development, metabolism and health, sometimes even in subsequent generations. Although the underlying mechanisms remain largely unknown, particularly in humans, mechanistic insights are emerging from experimental model systems. These have implications for structuring future research and understanding disease and development.

6.    Crider, K. S., T. P. Yang, R. J. Berry, and L. B. Bailey. (2012) Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role. Adv Nutr 3, 21-38. (pdf 4146 in BB_Cancer Epigenomics.)    DNA methylation is an epigenetic modification critical to normal genome regulation and development. The vitamin folate is a key source of the one carbon group used to methylate DNA. Because normal mammalian development is dependent on DNA methylation, there is enormous interest in assessing the potential for changes in folate intake to modulate DNA methylation both as a biomarker for folate status and as a mechanistic link to developmental disorders and chronic diseases including cancer. This review highlights the role of DNA methylation in normal genome function, how it can be altered, and the evidence of the role of folate/folic acid in these processes.

7.    Gut, P., and E. Verdin. (2013) The nexus of chromatin regulation and intermediary metabolism. Nature 502, 489-98. (pdf 3881.)    Living organisms and individual cells continuously adapt to changes in their environment. Those changes are particularly sensitive to fluctuations in the availability of energy substrates. The cellular transcriptional machinery and its chromatin-associated proteins integrate environmental inputs to mediate homeostatic responses through gene regulation. Numerous connections between products of intermediary metabolism and chromatin proteins have recently been identified. Chromatin modifications that occur in response to metabolic signals are dynamic or stable and might even be inherited transgenerationally. These emerging concepts have biological relevance to tissue homeostasis, disease and ageing.

8.    Zenobi, R. (2013) Single-cell metabolomics: analytical and biological perspectives. Science 342, 1243259. (Zenobi, R 2013 Dec 6;342(6163):1243259. )    There is currently much interest in broad molecular profiling of single cells; a cell’s metabolome-its full complement of small-molecule metabolites-is a direct indicator of phenotypic diversity of single cells and a nearly immediate readout of how cells react to environmental influences. However, the metabolome is very difficult to measure at the single-cell level because of rapid metabolic dynamics, the structural diversity of the molecules, and the inability to amplify or tag small-molecule metabolites. Measurement techniques including mass spectrometry, capillary electrophoresis, and, to a lesser extent, optical spectroscopy and fluorescence detection have led to impressive advances in single-cell metabolomics. Even though none of these methodologies can currently measure the metabolome of a single cell completely, rapidly, and nondestructively, progress has been sufficient such that the field is witnessing a shift from feasibility studies to investigations that yield new biological insight. Particularly interesting fields of application are cancer biology, stem cell research, and monitoring of xenobiotics and drugs in tissue sections at the single-cell level.
   In recent years, there has been a surge in the development and application of single-cell molecular profiling [for reviews with a focus on metabolomics, see (2–8)].

9.    Fanidi, A., C. Relton, P. M. Ueland, O. Midttun, S. E. Vollset, R. C. Travis, A. Trichopoulou, P. Lagiou, D. Trichopoulos, H. B. Bueno-de-Mesquita, M. Ros, H. Boeing, R. Tumino, S. Panico, D. Palli, S. Sieri, P. Vineis, M. J. Sanchez, J. M. Huerta, A. Barricarte Gurrea, L. Lujan-Barroso, J. R. Quiros, A. Tjonneland, J. Halkjaer, M. C. Boutron-Ruault, F. Clavel-Chapelon, C. Cadeau, E. Weiderpass, M. Johansson, E. Riboli, P. Brennan, and M. Johansson. (2014) A prospective study of one-carbon metabolism biomarkers and cancer of the head and neck and esophagus. Int J Cancer (Pdf 4093.)    Experimental and epidemiological data suggest that factors of one-carbon metabolism are important in the pathogenesis of several cancers, but prospective data on head and neck cancer (HNC) and esophagus cancer are limited. The European Prospective Investigation into Cancer and Nutrition (EPIC) study recruited 385,747 participants from 10 countries who donated a blood sample. The current study included 516 cancer cases of the head and neck and esophagus and 516 individually matched controls. Plasma levels of vitamins B2, B6, B9 (folate), B12, and methionine and homocysteine were measured in pre-diagnostic plasma samples and analyzed in relation to HNC and esophagus cancer risk, as well as post-diagnosis all-cause mortality. After controlling for risk factors, study participants with higher levels of homocysteine had elevated risk of HNC, the odds ratio (OR) in conditional analysis when comparing the top and bottom quartiles of homocysteine [ORQ4vs.Q1] being 2.13 (95% confidence interval [95% CI] 1.13-4.00, P for trend 0.009). A slight decrease in HNC risk was also seen among subjects with higher levels of folate (ORQ4vs.Q1 0.63, 95% CI 0.35-1.16, P for trend 0.02). Subgroup analyses by anatomical sub-site indicated particularly strong associations with circulating homocysteine for oral cavity and gum cancer (P for trend 8×10-4 ), as well as for oropharynx cancer (P for trend 0.008). Plasma concentrations of the other investigated biomarkers did not display any clear association with risk or survival. In conclusion, study participants with elevated circulating levels of homocysteine had increased risk of developing squamous cell carcinoma of the head and neck. (c) 2014 Wiley Periodicals, Inc.

10.    Galeone, C., V. Edefonti, M. Parpinel, E. Leoncini, K. Matsuo, R. Talamini, A. F. Olshan, J. P. Zevallos, D. M. Winn, V. Jayaprakash, K. Moysich, Z. F. Zhang, H. Morgenstern, F. Levi, C. Bosetti, K. Kelsey, M. McClean, S. Schantz, G. P. Yu, P. Boffetta, Y. C. Amy Lee, M. Hashibe, C. La Vecchia, and S. Boccia. (2014) Folate intake and the risk of oral cavity and pharyngeal cancer: A pooled analysis within the INHANCE Consortium. Int J Cancer (Pdf 4092.)    There are suggestions of an inverse association between folate intake and serum folate levels and the risk of oral cavity and pharyngeal cancers (OPC), but most studies are limited in sample size, with only few reporting information on the source of dietary folate. This study aims to investigate the association between folate intake and the risk of OPC within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. We analyzed pooled individual-level data from 10 case-control studies participating in the INHANCE consortium, including 5,127 cases and 13,249 controls. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were estimated for the associations between total folate intake (natural, fortification and supplementation) and natural folate only, and OPC risk. We found an inverse association between total folate intake and overall OPC risk (the adjusted OR for the highest versus the lowest quintile was 0.65, 95% CI: 0.43-0.99), with a stronger association for oral cavity (OR=0.57, 95% CI: 0.43-0.75). A similar inverse association, though somewhat weaker, was observed for folate intake from natural sources only (OR=0.64, 95% CI: 0.45-0.91). The highest OPC risk was observed in heavy alcohol drinkers with low folate intake as compared to never/light drinkers with high folate (OR=4.05, 95% CI: 3.43-4.79); the attributable proportion due to interaction was 11.1%(95% CI: 1.4-20.8%). The present project of a large pool of case-control studies supports a protective effect total folate intake on OPC risk. (c) 2014 Wiley Periodicals, Inc.

1.    Moyers, S. B., and N. B. Kumar. (2004) Green tea polyphenols and cancer chemoprevention: multiple mechanisms and endpoints for phase II trials. Nutrition reviews 62, 204-11. (pdf 3214 in BB2011June. Green Tea Polyhenols and Cancer Prevention)    Among the numerous polyphenols isolated from green tea, the catechin EGCG predominates and is the target of anticancer research. But studies suggest that EGCG and other catechins are poorly absorbed and undergo substantial biotransformation to species that include glucuronides, sulfates, and methylated compounds. Numerous studies relate the antioxidant properties of the catechins with anticancer effects, but recent research proposes other mechanisms of action, including those involving methyl transfers that are subject to allelic variability in the enzyme catechol O-methyl transferase. However, preclinical research is promising and EGCG appears to be ready for further study in phase II and III trials.

2.    Shin, D. M. (2009) Oral cancer prevention advances with a translational trial of green tea. Cancer Prev Res (Phila) 2, 919-21. (Preview of pdf 3226 in BB2011June. Green Tea for PMD Phase II trial (pdf 3226, Tsao et al 2009). HNSCC.)    This perspective on Tsao et al. (beginning on p. 931 in this issue of the journal) discusses green tea extract, which was shown for the first time to have dose-dependent effects in a clinical chemopreventive setting (oral premalignant lesions). This translational trial provides important data on angiogenesis and other biomarkers on which to base future clinical research, which should include trials of green tea extract or polyphenols combined with other natural or synthetic compounds to enhance chemopreventive effects.

3.    Tsao, A. S., D. Liu, J. Martin, X. M. Tang, J. J. Lee, A. K. El-Naggar, I. Wistuba, K. S. Culotta, L. Mao, A. Gillenwater, Y. M. Sagesaka, W. K. Hong, and V. Papadimitrakopoulou. (2009) Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila) 2, 931-41. (pdf 3226 in BB2011June. HNSCC.)   Epidemiologic and preclinical data support the oral cancer prevention potential of green tea extract (GTE). We randomly assigned patients with high-risk oral premalignant lesions (OPL) to receive GTE at 500, 750, or 1,000 mg/m(2) or placebo thrice daily for 12 weeks, evaluating biomarkers in baseline and 12-week biopsies. The OPL clinical response rate was higher in all GTE arms (n = 28; 50%) versus placebo (n = 11; 18.2%; P = 0.09) but did not reach statistical significance. However, the two higher-dose GTE arms [58.8% (750 and 1,000 mg/m(2)), 36.4% (500 mg/m(2)), and 18.2% (placebo); P = 0.03] had higher responses, suggesting a dose-response effect. GTE treatment also improved histology (21.4% versus 9.1%; P = 0.65), although not statistically significant. GTE was well tolerated, although higher doses increased insomnia/nervousness but produced no grade 4 toxicity. Higher mean baseline stromal vascular endothelial growth factor (VEGF) correlated with a clinical (P = 0.04) but not histologic response. Baseline scores of other biomarkers (epithelial VEGF, p53, Ki-67, cyclin D1, and p16 promoter methylation) were not associated with a response or survival. Baseline p16 promoter methylation (n = 5) was associated with a shorter cancer-free survival. Stromal VEGF and cyclin D1 expression were downregulated in clinically responsive GTE patients and upregulated in nonresponsive patients at 12 weeks (versus at baseline). An extended (median, 27.5 months) follow-up showed a median time to oral cancer of 46.4 months. GTE may suppress OPLs, in part through reducing angiogenic stimulus (stromal VEGF). Higher doses of GTE may improve short-term (12-week) OPL outcome. The present results support longer-term clinical testing of GTE for oral cancer prevention.

4.    Yang, C. S., X. Wang, G. Lu, and S. C. Picinich. (2009) Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer 9, 429-39. (pdf 3623 in BB2013Mar)    Extracts of tea, especially green tea, and tea polyphenols have been shown to inhibit the formation and development of tumours at different organ sites in animal models. There is considerable evidence that tea polyphenols, in particular (-)-epigallocatechin-3-gallate, inhibit enzyme activities and signal transduction pathways, resulting in the suppression of cell proliferation and enhancement of apoptosis, as well as the inhibition of cell invasion,angiogenesis and metastasis. Here, we review these biological activities and existing data relating tea consumption to human cancer risk in an attempt to understand the potential use of tea for cancer prevention.

5.    Kim, J. W., A. R. Amin, and D. M. Shin. (2010) Chemoprevention of head and neck cancer with green tea polyphenols. Cancer Prev Res (Phila) 3, 900-9. (pdf 3123 in BB2011June. Emory U. HNSCC SPORE.)    Recently, squamous cell carcinoma of the head and neck chemoprevention research has made major advances with novel clinical trial designs suited for the purpose, use of biomarkers to identify high-risk patients, and the emergence of numerous molecularly targeted agents and natural dietary compounds. Among many natural compounds, green tea polyphenols, particularly (-)-epigallocatechin-3-gallate (EGCG), possess remarkable potential as chemopreventive agents. EGCG modulates several key molecular signaling pathways at multiple levels and has synergistic or additive effects when combined with many other natural or synthetic compounds. This review will provide an update of the potential of green tea polyphenols, particularly EGCG, for the chemoprevention of squamous cell carcinoma of the head and neck.

6.    Crew, K. D., P. Brown, H. Greenlee, T. B. Bevers, B. Arun, C. Hudis, H. L. McArthur, J. Chang, M. Rimawi, L. Vornik, T. L. Cornelison, A. Wang, H. Hibshoosh, A. Ahmed, M. B. Terry, R. M. Santella, S. M. Lippman, and D. L. Hershman. (2012) Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor-Negative Breast Cancer. Cancer Prev Res (Phila) 5, 1144-54. (pdf not yet)    Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor-negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade >/=II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals. Cancer Prev Res; 5(9); 1144-54. (c)2012 AACR.

7.    Hsu, W. L., W. H. Pan, Y. C. Chien, K. J. Yu, Y. J. Cheng, J. Y. Chen, M. Y. Liu, M. M. Hsu, P. J. Lou, I. H. Chen, C. S. Yang, A. Hildesheim, and C. J. Chen. (2012) Lowered risk of nasopharyngeal carcinoma and intake of plant vitamin, fresh fish, green tea and coffee: a case-control study in Taiwan. PLoS One 7, e41779. (no pdf yet. 陳建仁老師group.)    BACKGROUND: A case-control study was conducted to evaluate the role of adult diet on nasopharyngeal carcinoma (NPC) in Taiwan. METHODS: A total of 375 incident NPC cases and 327 controls matched to the cases on sex, age, and residence were recruited between July 1991 and December 1994. A structured questionnaire inquiring complete dietary history, socio-demographic characteristics, and other potential confounding factors was used in the personal interview. Unconditional logistic regression analysis was used to estimate multivariate-adjusted odds ratio (OR(adj)) with 95% confidence interval (CI) after accounting for known risk factors. RESULTS: Fresh fish (OR(adj), 0.56; 95% CI, 0.38-0.83 for the highest vs. lowest tertile of intake), green tea (OR(adj), 0.61; 95% CI, 0.40-0.91 for drinking >/=1 times/week vs. never) and coffee (OR(adj), 0.56; 95% CI, 0.37-0.85 for drinking >/=0.5 times/week vs. never) were inversely associated with the NPC risk. No association with NPC risk was observed for the intake of meats, salted fish, fresh vegetables, fruits and milk. Intake of vitamin A from plant sources was associated with a decreased NPC risk (OR(adj), 0.62; 95% CI, 0.41-0.94 for the highest vs. lowest tertile). CONCLUSION: The study findings suggest that certain adult dietary patterns might protect against the development of NPC.

8.    Wu, A. H., D. Spicer, F. Z. Stanczyk, C. C. Tseng, C. S. Yang, and M. C. Pike. (2012) Effect of 2-month controlled green tea intervention on lipoprotein cholesterol, glucose, and hormone levels in healthy postmenopausal women. Cancer Prev Res (Phila) 5, 393-402. (EGCG)    There have been no controlled intervention studies to investigate the effects of green tea on circulating hormone levels, an established breast cancer risk factor. We conducted a double-blind, randomized, placebo-controlled intervention study to investigate the effect of the main green tea catechin, epigallocatechin gallate (EGCG), taken in a green tea extract, polyphenon E (PPE). Postmenopausal women (n = 103) were randomized into three arms: placebo, 400-mg EGCG as PPE, or 800-mg EGCG as PPE as capsules per day for 2 months. Urinary tea catechin and serum estrogen, androgen, lipid, glucose-related markers, adiponectin, and growth factor levels were measured at baseline and at the end of months 1 and 2 of intervention. On the basis of urinary tea catechin concentrations, compliance was excellent. Supplementation with PPE did not produce consistent patterns of changes in estradiol (E2), estrone (E1), or testosterone (T) levels. Low-density lipoprotein (LDL)-cholesterol decreased significantly in both PPE groups but was unchanged in the placebo group; the change in LDL-cholesterol differed between the placebo and PPE groups (P = 0.02). Glucose and insulin levels decreased nonsignificantly in the PPE groups but increased in the placebo group; statistically significant differences in changes in glucose (P = 0.008) and insulin (P = 0.01) were found. In summary, green tea (400- and 800-mg EGCG as PPE; approximately 5-10 cups) supplementation for 2 months had suggestive beneficial effects on LDL-cholesterol concentrations and glucose-related markers.

9.    Hu, Y., G. H. McIntosh, R. K. Le Leu, L. S. Nyskohus, R. J. Woodman, and G. P. Young. (2013) Combination of selenium and green tea improves the efficacy of chemoprevention in a rat colorectal cancer model by modulating genetic and epigenetic biomarkers. PLoS One 8, e64362. (pdf not yet)    Dietary supplementation of selenium and green tea holds promise in cancer prevention. In this study, we evaluated the efficacies of selenium and green tea administered individually and in combination against colorectal cancer in an azoxymethane (AOM)-induced rat colonic carcinogenesis model and determined the underlying mechanisms of the protection. Four-week old Sprague-Dawley male rats were fed with diets containing 0.5% green tea extract, 1ppm selenium as selenium-enriched milk protein, or combination of 1ppm selenium and 0.5% green tea extract. Animals received 2 AOM (15 mg/kg) treatments to induce colonic oncogenesis. Rats were killed 8 or 30 wk later after the last AOM to examine the effect of dietary intervention on aberrant crypt foci (ACF) formation or tumor development. On sacrifice, colons were examined for ACF and tumors, the mRNA levels of SFRP5 and Cyclin D1, and the proteins levels of ss-catenin, COX-2, Ki-67, DNMT1 and acetyl histone H3. The combination of selenium and green tea resulted in a significant additive inhibition of large ACF formation, this effect was greater than either selenium or green tea alone, P<0 .01="" a="" accompanied="" acetylation="" additive="" agent="" all="" alone.="" alone="" also="" and="" associated="" biomarkers="" by="" carcinogenesis.="" cell="" colonic="" colorectal="" combination="" crypts.="" cyclin="" d1="" data="" diet="" div="" dnmt1="" effect="" effective="" either="" endpoints="" epigenetic="" expression="" fed="" first="" for="" genetic="" greater="" green="" h3="" had="" histone="" implicated="" in="" incidence="" induction="" inhibition="" is="" marked="" more="" mrna="" multiplicity="" normal-appearing="" nuclear="" of="" on="" oncogenesis="" or="" p="" preventive="" proliferation.="" rats="" reduced="" reduction="" regulation="" restoration="" selenium="" sfrp5="" show="" showed="" significant="" significantly="" size="" ss-catenin="" suppressing="" tea="" than="" that="" the="" these="" time="" translocation="" tumor="" was="" were="" which="" with="">

中央社訊息服務20131218 13:38:13)中國醫藥大學副校長葛應欽教授研究檳榔成癮的成果登上美國有線電視新聞網CNN了！

『回眸一笑：亞洲的致命成癮檳榔；』（Nothing to smile about: Asia’s deadly addiction to betel nuts）是CNN專題報導的標題，由派駐緬甸記者希拉里•懷特曼（Hilary Whiteman）採訪台灣中國醫藥大學葛應欽講座教授發表在知名國際期刊的檳榔研究成果，揭露亞洲族群對檳榔依賴性之盛行率，及嚼檳榔會引發口腔潛在惡 性病變，增加致癌風險，提醒檳榔族能提高警覺。

現任中國醫藥大學副校長葛應欽是國際檳榔研究的翹楚，以環境醫學為核心，長期致力國人特定盛行疾病其成因及分子機轉之研究，並率先證明單獨嚼食檳榔與口腔癌、咽癌、喉癌及癌前病變之相關，研究發現嚼食者如有基因變異，則交互作用增加致癌的危險。

亞洲檳榔研究聯盟計畫主持人葛應欽講座教授，最近在知名國際期刊發表多篇嚼食檳榔相關研究論文，受到國際學術界及媒體關注；諸如：國際癌症雜誌（IJC）刊 登研究論文『亞洲檳榔研究聯盟：在南亞，東南亞和東亞地區檳榔盛行及相關口腔癌前病變與患病率』Intercountry prevalences and practices of betel-quid use in south, southeast and eastern Asia regions and associated oral preneoplastic disorders: An international collaborative study by Asian betel-quid consortium of south and east asia。(PMID: 21128235 / 2011-Oct)

成癮雜誌（Addiction）刊登研究論文『亞洲多國証據顯示：檳榔依賴性之內容與症狀』Betel-Quid Dependence Domains and Syndrome Associated with Betel-Quid Ingredients Among Chewers: An Asian Multi-Country Evidence。(PMID: 24650227 / 24903294  2014-July)

英國精神病學雜誌（BJPsych）刊登研究論文『六個亞洲國家對檳榔成癮與口腔潛在惡性病變』Betel-quid dependence and oral potentially malignant disorders in six Asian countries。(PMID: 22995631 / 2012-Nov)

美國公共衛生雜誌（American Journal of Public Health）刊登研究論文『亞洲檳榔聯合研究：南亞，東南亞和東亞的檳榔使用之群眾負荷』Population Burden of Betel-Quid Abuse and It’s Relation to Oral Premalignant Disorders in South, Southeast, and East Asia: An Asian Betel-Quid Consortium Study。(PMID: 22390524 / 2012-Mar)

吃多少粒檳榔才會有健康危險？美國有線電視新聞網CNN採訪葛應欽講座教授的研究成果『以每天一顆為基礎，吃得愈多風險愈高；』。榮獲國科會傑出研究獎的葛應欽講座教授說，在台灣吃檳榔人口逐漸下降約150萬人，嚼檳榔會上癮占42%，即戒除不易，由於檳榔添加物有大量的石灰，會促進檳榔鹼釋放，增強成癮及潛在的病變之效應，檳榔依賴性者之風險高於非依賴性者，尤其是，檳榔與香菸有加成作用，其致癌危險為一般人的123倍。

榮獲第九屆有庠科技 講座獎、第十屆王民寧獎—傑出貢獻獎表揚的葛應欽講座教授，投入檳榔口咽癌研究與防治成果績效斐然，在教育部鼓勵下，於99年以環境醫學研究計畫名義拓展區域性的國際合作，邀請印尼、馬來西亞、斯里蘭卡、尼泊爾及中國大陸等六國成立『亞洲檳榔研究聯盟』，促使台灣成為國際檳榔研究重鎮。

此外，中國醫藥大學也成立全國第一個《國家級成癮醫學研究暨風險評估中心》對於「成癮」疾病，期能導入中、西醫新型替代戒治療法。

訊息來源： 中國醫藥大學

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1.背景(請說明欲解決的問題及目標)
        第二期癌症研究計畫之目標，在於降低口腔癌的發生率與死亡率。目前對口腔癌相關研究很多，較少對口腔癌前病變進行研究。根據最近國際癌症研究中心的報告，台灣口腔癌標準化發生率為十萬分之26，男性為十萬分之48，皆位居世界第一位，為世界平均值5 倍，男性更高逹7 倍。依據我們先前的研究，台灣口腔癌歸因比檳榔佔80％，主要的口腔癌前病變則為白斑症（OL）及口腔黏膜下病變（OSF）歸因比各佔73％（OL）及85％（OSF）。而較惡性之OL 與OSF 可能惡轉成口腔癌，惡轉率5/100 人年以上，口腔癌同時存在癌前病變更佔40％－50%。因此若能考慮口腔癌前病變的病因學，充分研究其惡性轉化與治療，提早控制其發生與發展，將可有效降低口腔癌發生率。  目標（補充口腔癌前病變研究缺口如下）：
(1) 多中心臨床試驗（第二期）：對於老藥新用的候選標靶藥物（如Celecoxib 等），先以人類口腔細胞與裸鼠癌前病變異殖模式證實其藥效，並進行臨床試驗，以預防性治療口腔癌前病變復發與惡化，降低口腔癌發生率。
(2) 進一步探討分子病因學：了解口腔癌前病變致病基因與蛋白質之致病機轉，以利後續發展新穎標靶及蛋白質藥物，降低口腔癌前病變復發及惡性轉化為口腔癌。

       口腔癌前病變在口腔癌發生及發展扮演重要角色，但過去的研究很少探討其復發與惡性轉化之分子機轉與特異性標誌，以應用於化學預防劑開發及預防式治療。本單位於衛生福利部第二期癌症研究計畫，與高雄醫學大學、中山醫學大學及彰化基督教醫院合作，進行順利。
於主軸研究“降低口腔癌的發生率和死亡率”執行四項分項計劃，包括兩個老藥新用的臨床試驗

(1)針對檳榔成癮者與癌前病變者之戒斷評估與檳榔相關抗憂鬱藥物臨床戒斷試驗
(2)以COX-2 抑制劑針對口腔癌新療法臨床試驗

(3)口腔癌前期病變篩檢追蹤，探討其分子成因與分子機轉，並探討與檳榔交互作用組成基因群條碼以開發新穎生物標記

(4)口腔癌具有第二原發癌症及早期口腔癌表觀體學變化之預防標記開發。

        我們建立已知病因的口腔癌細胞株，發現選擇性COX-2 抑制劑能有效抑制口腔癌癌細胞的細胞活性、增生、遷移與侵犯。目前仍以五株市售口腔癌細胞株進行驗證，目前完成度約70%。而選擇性COX-2 抑制劑在裸鼠口腔癌腫瘤異殖模式亦進入試驗階段。過去所建立許多口腔癌研究模式，將可應用於本計畫之口腔癌前病變研究，例如以人類齒齦纖維正常細胞模式，篩選並確認包括COX－2 等十餘個基因標誌可能與口腔癌前病變形成有關。

3.初步構想(作法)，並請簡述與各合作機構之實質分工
本研究計畫將完成的執行內如下：
(1).多中心臨床試驗：以老藥新用的候選標靶藥物進行口腔癌前病變之臨床試驗(phase II)，該藥物經台灣藥物食品管理署核准應用於其他新適應症之學術研究，本校IRB 已通過對口腔癌之臨床試驗，而本計畫對於口腔癌前病變之藥物臨床試驗目前進行審查中。
(2).細胞與動物模式：探討候選標靶藥物在已知檳榔與/或吸菸成因培養的原代口腔癌前病變細胞的藥效作用，並以裸鼠腫瘤異殖方式進行藥物臨床前導試驗與其分子機轉探討。
(3).分子病因探討：以已知檳榔及/或吸菸發生臨床口癌前病變個案之配對組織進行篩選與驗證具潛力性的未知候選基因，並探討其疾病成因的訊息傳導路徑。
(4).次世代定序 (Next Generation Sequencing, NGS) 與蛋白質體分析：對於口腔癌，我們已完成NGS 篩檢及驗證，發現體細胞突變點之致癌基因。利用已建立之基礎，預計將收集口腔癌前病變配對組織300例左右來進行體細胞突變與蛋白質表現差異分析

         利用已建立之模式，本申請計畫將針對口腔癌前病變（以口腔黏膜下纖維化症與白斑症為優先）進行選擇性COX-2 抑制劑的臨床試驗與相關分子機轉之探討，與新適應症的療效評估。以整合口腔癌前病變的多中心臨床試驗將可補強國人口腔癌早期預防與治療的進展，並可有效從早期口腔癌前病變的復發及惡化之預防來進一步降低口腔癌之發生率。

         本團隊彼此互動良好，跨過本院口腔外科、耳鼻喉科、病理科、醫學遺傳學、臨床流行病學、生物資訊組成，並邀請高雄醫學大學附設中和紀念醫院口腔顎面外科（陳中和教授）與高雄醫學大學健康科學院公共衛生學系（李建宏教授）參與執行（皆已同意合作）。目前亦與國家衞生研究院洽談合作事宜，若有需要將擴大合作醫院與研究學者參與。

4.計畫執行後之重大影響
        以老藥新用方式進行臨床試驗，因藥物本身對於人體的副作用與使用劑量為已知，較具安全性。新適應症的臨床實務應用將可縮短口腔癌前病變患者漫長等待之時間。本計畫目標具體，且有可行性，並可符合衛福部國家政策及國衛院任務，造福民眾健康。

Randomized double-blind placebo-controlled trial of celecoxib for oral mucositis in patients receiving radiation therapy for head and neck cancer. (PubMed)

Conclusion: Daily use of a selective COX-2 inhibitor, during period of RT for H&NC, did not reduce the severity of clinical OM, pain, dietary compromise or use of opioid analgesics. These findings also have implications for celecoxib use in H&NC treatment regimens (NCT00698204).

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