2012-08-012024-05-14https://scholars.lib.ntu.edu.tw/handle/123456789/660608摘要：泌尿上皮癌(urothelial carcinoma)的發生率為每十萬人中11.6，是台灣地區第十大常見的惡性腫瘤。台灣與巴爾幹半島地區同為全世界上泌尿道(腎盂及輸尿管)泌尿上皮癌發生率最高的地區，且數倍於歐美等西方國家。許多台灣學者發現較之於國外的上泌尿道泌尿上皮癌患者，台灣的患者有較高比率為女性（男女比：1：1.1）。多數歐美國家的上泌尿道泌尿上皮癌可歸因於吸菸，但台灣地區的女性患者僅有百分之四以下有吸菸史；因此，吸菸這一個危險因子只能解釋一半男性患者的成因，對於大多數女性患者並不適用。換言之，約有四分之三的台灣上泌尿道泌尿上皮癌病人原因不明。西元一九九二年，數十名比利時布魯塞爾的年輕婦女被發現皆因間質性腎炎導致腎臟衰竭，終致造成末期腎病。進一步研究發現，這些婦女全都在同一間診所服用相同的減肥中藥配方。自從西元一九九0年後，部分該配方被取代為belladonna extract、Magnolia officinalis和Stephania tetrandra。香港中文大學進一步發現在出口至比利時的Stephania tetradra 實為富含Aristolochic acid 的Aristolochia fangchi。Nortier教授發現39位準備接受腎移植的Chinese herb nephropathy病患先行接受原腎臟預防性摘除，18位有泌尿上皮癌，19位有中度至重度的泌尿上皮異常，但僅有兩位的泌尿上皮是正常的。因此，Aristolochic acid 不僅是一個nephrotoxic agent也是一個carcinogenic agent。台灣大學公衛系王榮德教授根據台灣健保局於西元1997年至西元2003年七年間國人的用藥資料庫，隨機抽取其中200,000人的資料分析。他發現此七年期間核可使用之中藥材中，竟有12%含有馬兜鈴酸，如關木通、廣防己、青木香、天相藤及馬兜鈴等至少十七種藥材。而選取分析的此200,000人中，有53%曾於此七年內因不同的原因服用中藥配方。更令人震驚的是78,000 (39%)人服用了含馬兜鈴酸的中藥材。這樣的結果說明台灣人長期處於馬兜鈴酸的環境中。而我們在最近的實驗中，也發現了超過60%的上泌尿道泌尿上皮癌患者的腎實質中含有aristolochic acid-DNA adduct，表示我們的患者中有超過一半曾有馬兜鈴酸的暴露。於此同時，與台灣同樣有高發生率的巴爾幹半島也發現，原來在他們主食作物的旁邊也有含馬兜鈴的植物，在收成時往往也會被採收而混入了當地人的主食中。所以，經過了多年的實驗，不管是位於歐洲的巴爾幹半島或是位於遠東的台灣島上，馬兜鈴酸均已被證實為上泌尿道泌尿上皮癌發生的一大致癌物質。雖然衛生署於2003正式禁止了多數含馬兜鈴酸藥材的進口與銷售，然而依據過去環境汙染對人體影響的經驗，其造成的後續影響仍會持續數十年。據此，本計畫預定藉由過去幾年的研究基礎，區分台灣上泌尿道泌尿上皮癌的致病因，並研究馬兜鈴酸所致腫瘤的特異臨床表現型、特異基因型、以及對藥物治療的反應情況。對於發生在台灣民眾的此特別上泌尿道泌尿上皮癌，研究成果將有助於預測其臨床表現與反應，並改善治療成效。<br> Abstract: Urothelial carcinoma is the 10th leading malignancy in Taiwan, and theincidence is about 11.6/100,000 person-year. Both Taiwan and Balkan areashad the highest incidence of urothelial carcinoma of the upper urinary tract(ureter and renal pelvis) around the world. Several Taiwanese investigatorsdiscovered that the sex ratio of the upper urinary tract urothelial carcinoma (UUC)was mild female-predominant (1.1:1), but that in other western countries wasmale dominant. In western countries, cigarette smoking is a major risk factor fordeveloping UUC, but less than 4% of Taiwanes female patients and 40% of malepatients had smoking histories. In other word, the causes of at least 75% of ourUUC patients was still not well-known.In 1992, Vanherweghem discovered several young Belgium womendeveloped acute exacerbation of renal function with the same histological pattern,interstitial nephritis. In the further investigations, these women took similarChinese slimming regimen from the same clinic. A part of the contents had beenreplaced with belladonna extract, Magnolia officinalis and Stephania tetrandrraafter 1990. In addition, other investigators found that Stephania tetradra (fangji)exported to Belgium had been replaced with Aristolochia fangchi whichcontained aristolochic acid. Professor Nortier discovered 18 UUC and 19 severeurothelial dysplasia within 39 patients who underwent prophylactic nativenephrectomies before receiving kidney transplantation. Till this time, aristolochicacid was not only a nephrotoxic but also a carcinogenic agent.In Taiwan, Professor Grollman et al. discovered 12% of all licensed Chineseherbal regimens contained aristolochia from 1997 to 2003. According to the200,000 random people extracted from the national health reimbursementdatabase at the same duration, he also noted 53% had taken Chinese herbs and39% of this cohort had taken aristolochia-containing Chinese herbal regimens,suggesting that a large part of Taiwanese populations had been exposed toaristolochia before 2003. In our recent study, we also discoveredaristolactum-DNA adduct could be detected in the renal cortex of more than halfof our UUC patients. Similarly, aristolochia could be noted in the grain growingaround the villages with endemic nephropathy and UUC in Balkan.Aristolochia-DNA adducts were also detected in their patients. Hence,aristolochic acid was proven to cause UUC, regardless of Balkan and Taiwan.Although Department of Health in Taiwan had abandoned the sales andimport of most aristolochia-containing herbs officially in 2003, the adverse effectof aristolochia contamination might exist for several decades according to theprevious experience. Accordingly, we plan to raise this proposal to investigatethe unique clinical phenotype, genotype, and response to chemotherapeutic andtarget therapeutic agents under the basis of our previous work on the detectionof aristolactum-DNA adduct and p53 signature mutation. For Taiwanese UUCcases, the achievement of this proposal will help to expect the clinical responseand improve the treatment outcome.馬兜鈴酸上泌尿道泌尿上皮癌中藥腎病變基因型臨床表現型廣防 己關木通aristolochiaupper urinary tract urothelial carcinomaChinese herb nephropathygenotypephenotypeGuangfungjiGuanmutong