2016-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/646146摘要：台灣每年約有1,100 人死於攝護腺癌，另外有數以千計的病人，則因診斷或治療造成併發症，生活品質嚴重受到影響。如果能預防攝護腺癌之發生，則可大幅改善生活品質，節省醫療費用支出。可惜到目前為止，沒有任何藥物被核准可以預防攝護腺癌。大多數流行病學研究指出，蕃茄或某些植物中的一些成分，包括茄紅素及其他多重類胡蘿蔔素（multi-carotenoids）可能可以降低攝護腺癌發生率，而且主要是降低致死性癌的發生率。先前研究中已發現，包含茄紅素在內的類胡蘿蔔素，具有降低攝護腺癌病人血漿中攝護腺特異性抗原（PSA）的作用。MCS是一種具有專利，富含類胡蘿蔔素之純植物配方。我們的團隊先前完成之第二期及第三期臨床試驗（美國FDA 及TFDA，結果正分析中），共約600 人的經驗顯示，未發現任何嚴重不良反應（SAE）。而且MCS可能可改善排尿症狀，PSA 升高之病人，也有降低PSA 的作用。因此，我們正啟動另一大型（N=702）臺灣多中心第二期隨機分組臨床試驗（MCS-8 計畫），希望研究MCS是否可降低攝護腺癌。高風險之受試者每人將接受2 年，分別每日口服30、15 及0（placebo）毫克之MCS（1:1:1），再比較2 年期滿期末切片，各組攝護腺癌之累積診斷率，及受試者血清中的類胡蘿蔔素含量變動。本計畫有一部分是附屬於MCS-8 之轉譯研究。受試者同意參加MCS-8 後，再邀請其參加本研究。每位受試者（A 組，約100 人，不論其隨機分組），在治療前、治療後第24、48、72 及104 週，每次捐出8 西西全血，及50 西西尿液，分析以下數種攝護腺可能的癌變生物標記，包括：8-OHdG、caspase-3、malondialdehyde（MDA）、PCA3、IL-6 及engrailed-2。如果受試者在研究期間或兩年期滿，有機會取得攝護腺組織，我們將以免疫組織染色，分析組織中之生物標記（Ki-67/PCNA）蛋白表現量。未參加或拒絕參加MCS-8 計畫者，我們也將邀請其參加本研究（B 組，約200 人），A 組及B 組總共約300位受試者。我們將前瞻性地研究以下三大特定目標（specific aims）：一、 哪些生物標記之變化，可以反映攝護腺的癌變？（生物標記表現與受試者累積癌症發生率之相關分析）二、 投與MCS是否可以改變這些生物標記的表現？（三組中是否存在劑量效應關係）三、 生物標記的變動是否與血清中之類胡蘿蔔素變動有關？本計畫是首次前瞻性的研究，化學預防藥物MCS可否改變攝護腺癌變的生物標記，生物標記的變動，是否與血清中之類胡蘿蔔素變動呈現相關，並且觀察那些生物標記，可忠實反映國人攝護腺的癌變狀況。因此，本計畫具有原創性，也具有高度學術價值及產業價值。<br> Abstract: In Taiwan, about 1,100 men die of prostate cancer each year. Besides, thousands of men areafflicted with complications from biopsy or treatment of prostate cancer, causing impaired quality oflife. If prostate cancer can be largely prevented, all the above can significantly be avoided. A largeamount of health care expenses can be saved. Unfortunately, not a single agent has ever beenapproved for prostate cancer chemoprevention.Many epidemiological studies have shown that nutrients or elements from tomato or otherplants, including lycopene and multi-carotenoids, may reduce the risk of prostate cancer, especiallythose of lethal cancer. Studies have also shown that multi-carotenoids may reduce serum PSAlevels in prostate cancer patients. MCS is a patented, multi-carotenoids-rich, purely botanic agent.Our previous Phase II and III clinical trials (US FDA and TFDA, 600 subjects, studies finished, datain analysis) have shown that there were no MCS-related serious adverse events (SAE). MCS　 mayrelieve urinary symptoms in men with BPH and PSA was reduced in men with elevated PSA. So, weare initiating a large multi-center phase II randomized study (MCS-8, N=702) in Taiwan, to study ifMCS　 can reduce the risk of prostate cancer. High risk patients will be assigned to take oral daily30, 15, and 0 (placebo) mg of MCS (1:1:1). We will compare the cumulative prostate cancerincidence among groups and the change from baseline in serum carotenoids levels.A part of the current project is the translational component of the MCS-8 clinical trial. Subjectswill be invited to join the study once they have consented to enroll to the MCS-8 study (Group A:~100 men, irrespective of randomization). Subjects will donate 8 ml whole blood and 50 ml urine atbaseline、24、48、72 and 104 weeks during the study period, for the analysis of a panel of prostatetumorigenesis biomarkers, which include 8-OHdG、caspase-3、malondialdehyde (MDA)、PCA3、IL-6 and engrailed-2. If by any chance during the 2-year time, subjects receive prostate surgeries(TURP or Prostate Bx), the surgical specimens will subject to immunochemical staining forKi-67/PCNA protein expressions. To increase the sample size, we will also invite those subjects whodid not sign up for the MCS-8 clinical trial (Group B: ~ 200 men). Both Groups A and B make a totalof 300 subjects for the study.By using the prospective approach, we will finish the following 3 major specific aims:1. Which of these biomarkers investigated may reflect the tumorigenic process in the prostate?(An association analysis linking biomarker expression and cumulative cancer incidence)2. Does MCS treatment modify the expression of these biomarkers favorably? (Anypossible dose-response relationship?)3. Do serum carotenoids levels correlate with the expression of these biomarkers?The current proposal is for the first time to prospectively investigate whether thechemopreventive agent, MCS, may favorably alter biomarker expression, whether serumcarotenoids levels are associated with biomarkers levels, and whether the alterations of biomarkerexpression may reflect the cancer risk as shown by cancer incidence at the end of the clinical trial.In summary, the study is of high originality and also of high academic and industrial values.類胡蘿蔔素攝護腺癌化學預防生物標記臨床試驗multi-carotenoidsprostate cancerchemopreventionbiomarkerclinical trial