臺灣博碩士論文加值系統

不同種族間對於藥物的療效以及毒性都不盡相同，近年來許多研究也發現，個人間的基因差異會對用藥的質與量產生不同影響，因此本研究探討了八個基因多型性在台灣地區大腸直腸癌患者中的分佈情形並與其他種族比較，來探討是否因為基因型的頻率有差異才導致此現象。這八個基因多型性分別會影響三種大腸直腸癌化療藥物之藥物相關代謝機轉、藥物標的活性以及藥物抵抗性，而這三種化療藥物為：5-FU、Irinotecan(CPT-11)和Oxaliplatin。在藥物相關代謝機轉中，吾人探討了DPYD、MDR1、UGT1A1、GSTP1這四種基因；在藥物標的活性方面，選擇了5-FU的藥物標的基因，TS；另外再加上5-FU藥物作用的輔因子，MTHFR；在藥物抵抗性方面，則探討了有關DNA修復系統的基因，包括有XRCC1以及XPD。吾人利用聚合酶連鎖反應結合限制酶切割片段長度多型性分析(PCR-RFLP)更進一步以去氧核醣核酸定序此方法，來分析這八個基因多型性在台灣地區201位大腸直腸癌病患中的分佈情形。這些基因多型性的分佈頻率(%)分別為，TS(3R/3R：66.8、3R/2R：29.7、2R/2R：3.5)；MTHFR C677T(CC：60.9、CT：35.6、TT：3.5)；DPYD IVS14+ 1G>A(GG：100)；UGT1A1 TA repeat(6/6：76.2、6/7：23.8、7/7：0 )；MDR1 C3435T(CC：34.6、CT：52.0、TT：13.4)；XRCC1 Arg399Gln(Arg/Arg：61.9、Arg/Gln：31.7、Gln/Gln：6.4)；XPD Lys751Gln(Lys/Lys：87.6、Lys/Gln：11.9、Gln/Gln：0.5)；GSTP1 Ile105Val (Ile/Ile：64.3、Ile/Val：32.7、Val/Val：3.0)。與其他國家比較後發現，這些基因多型性的分佈情形在台灣地區族群與高加索人中是有所差異的，這個結果或許可解釋此不同種族對於藥物的療效及毒性不同。此研究結果也可提供台灣地區大腸直腸癌患者化療相關基因型之分子流行病學探討，並作為未來基因型相關研究之參考。

Different drug response and toxicity were found between different races and countries. Recently, many researches have found that the different genotypes from person to person may affect drug responsiveness. In this study, we investigated eight functional genetic polymorphisms which are related to three chemotherapy agents for colorectal cancer(CRC), 5-FU, irinotecan(CPT-11), and oxaliplatin involving in drug target, metabolic pathway and DNA repair systems. Our aim was to analyze the prevalence of these genetic polymorphisms in CRC patients in Taiwan and compare with other races. Genotyping of metabolizing genes dihdropyrimidine dehydrogenase(DPYD), uridine diphosphate glucuronosyltransferase(UGT1A1), multidrug resistance 1(MDR1), glutathione S-transferase P1(GSTP1), DNA repair genes X-ray cross-complementing 1(XRCC1) and xeroderma pigmentosum group D(XPD), drug target gene thymidylate synthase(TS), and co-factor gene methylenetetrahydrofolate reductase(MTHFR) were performed in 201 CRC patients using a polymerase chain reaction restriction fragment length polymorphism(PCR-RFLP) technique and DNA sequencing. Results: The frequencies of 3R/3R, 3R/2R, and 2R/2R genotypes of TS polymorphism were 67.2%, 29.3%, and 3.5%; the frequencies of CC, CT, and TT genotypes of MTHFR C677T polymorphism were 60.7%, 35.8%, 3.5%, respectively; the frequencies of GG genotypes of DPYD IVS14 + 1G>A polymorphism were 100%, and no patients with mutations; the frequencies of 6/6 and 6/7 genotypes of UGT1A1 TA repeats were 76.1% and 23.9%, respectively; the frequencies of CC, CT, and TT genotypes of MDR1 C3435T were 34.8%, 51.8%, and 13.4%; the frequencies of Arg/Arg, Arg/Gln, Gln/Gln genotypes of XRCC1 Arg399Gln were 61.7%, 31.8%, and 6.5%, respectively; the frequencies of Lys/Lys, Lys/Gln, Gln/Gln genotypes of XPD Lys751Gln were 87.6%, 11.9%, and 0.5%; the frequencies of Ile/Ile, Ile/Val, Val/Val genotypes of GSTP1 Ile105Val polymorphism were 64.2%, 32.8%, and 3.0%, respectively. The present study showed that these variants frequencies were similar to frequencies observed in other oriental populations but have difference between Taiwanese and Caucasian. The results may explain the different drug response and toxicity between different races and offer an epidemiological discussion and can be a reference of relevant research in the future.

論文合格通過證明
致謝
中文摘要 4
英文摘要 6
緒論 8
研究策略與材料方法 17
一、研究策略流程圖 17
二、材料與方法 18
結果 23
一、本實驗族群臨床病理資料 23
二、基因型分析結果 23
三、基因型與臨床病理資料間的關係 25
討論 26
結論與未來展望 32
參考文獻 34
附錄 42
ㄧ、圖與表 42

Ando, Y., Saka, H., Ando, M., Sawa, T., Muro, K., Ueoka, H., Yokoyama, A., Saitoh, S., Shimokata, K., and Hasegawa, Y. (2000). Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis. Cancer Res 60, 6921-6926.
Andre, N., and Schmiegel, W. (2005). Chemoradiotherapy for colorectal cancer. Gut 54, 1194-1202.
Bae, S. Y., Choi, S. K., Kim, K. R., Park, C. S., Lee, S. K., Roh, H. K., Shin, D. W., Pie, J. E., Woo, Z. H., and Kang, J. H. (2006). Effects of genetic polymorphisms of MDR1, FMO3 and CYP1A2 on susceptibility to colorectal cancer in Koreans. Cancer Sci 97, 774-779.
Bagley, P. J., and Selhub, J. (1998). A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proc Natl Acad Sci U S A 95, 13217-13220.
Beckman, K. B., and Ames, B. N. (1997). Oxidative decay of DNA. J Biol Chem 272, 19633-19636.
Becouarn, Y., Ychou, M., Ducreux, M., Borel, C., Bertheault-Cvitkovic, F., Seitz, J. F., Nasca, S., Nguyen, T. D., Paillot, B., Raoul, J. L., et al. (1998). Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 16, 2739-2744.
Berger, R., Stoker-de Vries, S. A., Wadman, S. K., Duran, M., Beemer, F. A., de Bree, P. K., Weits-Binnerts, J. J., Penders, T. J., and van der Woude, J. K. (1984). Dihydropyrimidine dehydrogenase deficiency leading to thymine-uraciluria. An inborn error of pyrimidine metabolism. Clin Chim Acta 141, 227-234.
Berrino, F., Gatta, G., Chessa, E., Valente, F., and Capocaccia, R. (1998). The EUROCARE II study. Eur J Cancer 34, 2139-2153.
Bosma, P. J., Chowdhury, J. R., Bakker, C., Gantla, S., de Boer, A., Oostra, B. A., Lindhout, D., Tytgat, G. N., Jansen, P. L., Oude Elferink, R. P., and et al. (1995). The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert''s syndrome. N Engl J Med 333, 1171-1175.
Braithwaite, E., Wu, X., and Wang, Z. (1999). Repair of DNA lesions: mechanisms and relative repair efficiencies. Mutat Res 424, 207-219.
Caldecott, K. W., McKeown, C. K., Tucker, J. D., Ljungquist, S., and Thompson, L. H. (1994). An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III. Mol Cell Biol 14, 68-76.
Chen, J., Hunter, D. J., Stampfer, M. J., Kyte, C., Chan, W., Wetmur, J. G., Mosig, R., Selhub, J., and Ma, J. (2003). Polymorphism in the thymidylate synthase promoter enhancer region modifies the risk and survival of colorectal cancer. Cancer Epidemiol Biomarkers Prev 12, 958-962.
Cohen, V., Panet-Raymond, V., Sabbaghian, N., Morin, I., Batist, G., and Rozen, R. (2003). Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy. Clin Cancer Res 9, 1611-1615.
Curtin, K., Bigler, J., Slattery, M. L., Caan, B., Potter, J. D., and Ulrich, C. M. (2004). MTHFR C677T and A1298C polymorphisms: diet, estrogen, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 13, 285-292.
Efferth, T., and Volm, M. (2005). Pharmacogenetics for individualized cancer chemotherapy. Pharmacol Ther 107, 155-176.
Evans, W. E., and Relling, M. V. (1999). Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286, 487-491.
Frosst, P., Blom, H. J., Milos, R., Goyette, P., Sheppard, C. A., Matthews, R. G., Boers, G. J., den Heijer, M., Kluijtmans, L. A., van den Heuvel, L. P., and et al. (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10, 111-113.
Gatta, G., Faivre, J., Capocaccia, R., and Ponz de Leon, M. (1998). Survival of colorectal cancer patients in Europe during the period 1978-1989. Eur J Cancer 34, 2176-2183.
Gebhardt, F., Zanker, K. S., and Brandt, B. (1999). Modulation of epidermal growth factor receptor gene transcription by a polymorphic dinucleotide repeat in intron 1. J Biol Chem 274, 13176-13180.
Gill, S., Loprinzi, C. L., Sargent, D. J., Thome, S. D., Alberts, S. R., Haller, D. G., Benedetti, J., Francini, G., Shepherd, L. E., Francois Seitz, J., et al. (2004). Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much? J Clin Oncol 22, 1797-1806.
Goldberg, R. M. (2005). Advances in the treatment of metastatic colorectal cancer. Oncologist 10 Suppl 3, 40-48.
Gonzalez-Baron, M., Feliu, J., de la Gandara, I., Espinosa, E., Colmenarejo, A., Martinez-Martinez, B., Blanco, E., Garcia-Giron, C., Juarez, F., Garrido, P., and et al. (1995). Efficacy of oral tegafur modulation by uracil and leucovorin in advanced colorectal cancer. A phase II study. Eur J Cancer 31A, 2215-2219.
Gonzalez Baron, M., Feliu, J., Garcia Giron, C., Espinosa, J., Martinez, B., Blanco, E., Crespo, M. C., Ordonez, A., Espinosa, E., de Castro, J., et al. (1997). UFT modulated with leucovorin in advanced colorectal cancer: Oncopaz experience. Oncology 54 Suppl 1, 24-29.
Heidelberger, C., Chaudhuri, N. K., Danneberg, P., Mooren, D., Griesbach, L., Duschinsky, R., Schnitzer, R. J., Pleven, E., and Scheiner, J. (1957). Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 179, 663-666.
Hoffmeyer, S., Burk, O., von Richter, O., Arnold, H. P., Brockmoller, J., Johne, A., Cascorbi, I., Gerloff, T., Roots, I., Eichelbaum, M., and Brinkmann, U. (2000). Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 97, 3473-3478.
Hong, Y. C., Lee, K. H., Kim, W. C., Choi, S. K., Woo, Z. H., Shin, S. K., and Kim, H. (2005). Polymorphisms of XRCC1 gene, alcohol consumption and colorectal cancer. Int J Cancer 116, 428-432.
Horie, N., Aiba, H., Oguro, K., Hojo, H., and Takeishi, K. (1995). Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5''-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 20, 191-197.
Hsiao, H. H., Yang, M. Y., Chang, J. G., Liu, Y. C., Liu, T. C., Chang, C. S., Chen, T. P., and Lin, S. F. (2004). Dihydropyrimidine dehydrogenase pharmacogenetics in the Taiwanese population. Cancer Chemother Pharmacol 53, 445-451.
Iyer, L., King, C. D., Whitington, P. F., Green, M. D., Roy, S. K., Tephly, T. R., Coffman, B. L., and Ratain, M. J. (1998). Genetic predisposition to the metabolism of irinotecan (CPT-11). Role of uridine diphosphate glucuronosyltransferase isoform 1A1 in the glucuronidation of its active metabolite (SN-38) in human liver microsomes. J Clin Invest 101, 847-854.
Johnston, P. G., Lenz, H. J., Leichman, C. G., Danenberg, K. D., Allegra, C. J., Danenberg, P. V., and Leichman, L. (1995). Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res 55, 1407-1412.
Kafka, A., Sauer, G., Jaeger, C., Grundmann, R., Kreienberg, R., Zeillinger, R., and Deissler, H. (2003). Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer. Int J Oncol 22, 1117-1121.
Kawakami, K., Salonga, D., Park, J. M., Danenberg, K. D., Uetake, H., Brabender, J., Omura, K., Watanabe, G., and Danenberg, P. V. (2001). Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin Cancer Res 7, 4096-4101.
Kawakami, K., and Watanabe, G. (2003). Identification and functional analysis of single nucleotide polymorphism in the tandem repeat sequence of thymidylate synthase gene. Cancer Res 63, 6004-6007.
Kim, D. H., Ahn, Y. O., Lee, B. H., Tsuji, E., Kiyohara, C., and Kono, S. (2004). Methylenetetrahydrofolate reductase polymorphism, alcohol intake, and risks of colon and rectal cancers in Korea. Cancer Lett 216, 199-205.
Kitagawa, C., Ando, M., Ando, Y., Sekido, Y., Wakai, K., Imaizumi, K., Shimokata, K., and Hasegawa, Y. (2005). Genetic polymorphism in the phenobarbital-responsive enhancer module of the UDP-glucuronosyltransferase 1A1 gene and irinotecan toxicity. Pharmacogenet Genomics 15, 35-41.
Komoto, C., Nakamura, T., Sakaeda, T., Kroetz, D. L., Yamada, T., Omatsu, H., Koyama, T., Okamura, N., Miki, I., Tamura, T., et al. (2006). MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal cancer and esophageal cancer. Drug Metab Pharmacokinet 21, 126-132.
Kurzawski, M., Drozdzik, M., Suchy, J., Kurzawski, G., Bialecka, M., Gornik, W., and Lubinski, J. (2005). Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients. Eur J Clin Pharmacol 61, 389-394.
Lima, J. J., Thomason, D. B., Mohamed, M. H., Eberle, L. V., Self, T. H., and Johnson, J. A. (1999). Impact of genetic polymorphisms of the beta2-adrenergic receptor on albuterol bronchodilator pharmacodynamics. Clin Pharmacol Ther 65, 519-525.
Longley, D. B., Harkin, D. P., and Johnston, P. G. (2003). 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3, 330-338.
Lunn, R. M., Helzlsouer, K. J., Parshad, R., Umbach, D. M., Harris, E. L., Sanford, K. K., and Bell, D. A. (2000). XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 21, 551-555.
Macdonald, J. S. (1999). Adjuvant therapy of colon cancer. CA Cancer J Clin 49, 202-219.
Marcuello, E., Altes, A., Menoyo, A., Del Rio, E., Gomez-Pardo, M., and Baiget, M. (2004). UGT1A1 gene variations and irinotecan treatment in patients with metastatic colorectal cancer. Br J Cancer 91, 678-682.
Marsh, S., Collie-Duguid, E. S., Li, T., Liu, X., and McLeod, H. L. (1999). Ethnic variation in the thymidylate synthase enhancer region polymorphism among Caucasian and Asian populations. Genomics 58, 310-312.
Massacesi, C., Terrazzino, S., Marcucci, F., Rocchi, M. B., Lippe, P., Bisonni, R., Lombardo, M., Pilone, A., Mattioli, R., and Leon, A. (2006). Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy. Cancer 106, 1007-1016.
Mathijssen, R. H., van Alphen, R. J., Verweij, J., Loos, W. J., Nooter, K., Stoter, G., and Sparreboom, A. (2001). Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). Clin Cancer Res 7, 2182-2194.
Moscow, J. A., Fairchild, C. R., Madden, M. J., Ransom, D. T., Wieand, H. S., O''Brien, E. E., Poplack, D. G., Cossman, J., Myers, C. E., and Cowan, K. H. (1989). Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors. Cancer Res 49, 1422-1428.
Park, D. J., Stoehlmacher, J., Zhang, W., Tsao-Wei, D. D., Groshen, S., and Lenz, H. J. (2001). A Xeroderma pigmentosum group D gene polymorphism predicts clinical outcome to platinum-based chemotherapy in patients with advanced colorectal cancer. Cancer Res 61, 8654-8658.
Pazdur, R., Lassere, Y., Rhodes, V., Ajani, J. A., Sugarman, S. M., Patt, Y. Z., Jones, D. V., Jr., Markowitz, A. B., Abbruzzese, J. L., Bready, B., and et al. (1994). Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma. J Clin Oncol 12, 2296-2300.
Piedbois, P., Buyse, M., and Rustum, Y. (1992). Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 10, 896-903.
Pignon, J. P., and Ducreux, M. (2001). Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 344, 306; author reply 306-307.
Pullarkat, S. T., Stoehlmacher, J., Ghaderi, V., Xiong, Y. P., Ingles, S. A., Sherrod, A., Warren, R., Tsao-Wei, D., Groshen, S., and Lenz, H. J. (2001). Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 1, 65-70.
Raida, M., Schwabe, W., Hausler, P., Van Kuilenburg, A. B., Van Gennip, A. H., Behnke, D., and Hoffken, K. (2001). Prevalence of a common point mutation in the dihydropyrimidine dehydrogenase (DPD) gene within the 5''-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls. Clin Cancer Res 7, 2832-2839.
Raymond, E., Buquet-Fagot, C., Djelloul, S., Mester, J., Cvitkovic, E., Allain, P., Louvet, C., and Gespach, C. (1997). Antitumor activity of oxaliplatin in combination with 5-fluorouracil and the thymidylate synthase inhibitor AG337 in human colon, breast and ovarian cancers. Anticancer Drugs 8, 876-885.
Raymond, E., Faivre, S., Woynarowski, J. M., and Chaney, S. G. (1998). Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 25, 4-12.
Saltz, L. B., Leichman, C. G., Young, C. W., Muggia, F. M., Conti, J. A., Spiess, T., Jeffers, S., and Leichman, L. P. (1995). A fixed-ratio combination of uracil and Ftorafur (UFT) with low dose leucovorin. An active oral regimen for advanced colorectal cancer. Cancer 75, 782-785.
Shirao, K., Hoff, P. M., Ohtsu, A., Loehrer, P. J., Hyodo, I., Wadler, S., Wadleigh, R. G., O''Dwyer, P. J., Muro, K., Yamada, Y., et al. (2004). Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV. J Clin Oncol 22, 3466-3474.
Simmonds, P. C. (2000). Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. Colorectal Cancer Collaborative Group. Bmj 321, 531-535.
Sohn, K. J., Croxford, R., Yates, Z., Lucock, M., and Kim, Y. I. (2004). Effect of the methylenetetrahydrofolate reductase C677T polymorphism on chemosensitivity of colon and breast cancer cells to 5-fluorouracil and methotrexate. J Natl Cancer Inst 96, 134-144.
Stoehlmacher, J., Ghaderi, V., Iobal, S., Groshen, S., Tsao-Wei, D., Park, D., and Lenz, H. J. (2001). A polymorphism of the XRCC1 gene predicts for response to platinum based treatment in advanced colorectal cancer. Anticancer Res 21, 3075-3079.
Stoehlmacher, J., Park, D. J., Zhang, W., Groshen, S., Tsao-Wei, D. D., Yu, M. C., and Lenz, H. J. (2002). Association between glutathione S-transferase P1, T1, and M1 genetic polymorphism and survival of patients with metastatic colorectal cancer. J Natl Cancer Inst 94, 936-942.
Stoehlmacher, J., Park, D. J., Zhang, W., Yang, D., Groshen, S., Zahedy, S., and Lenz, H. J. (2004). A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer. Br J Cancer 91, 344-354.
Sung, P., Bailly, V., Weber, C., Thompson, L. H., Prakash, L., and Prakash, S. (1993). Human xeroderma pigmentosum group D gene encodes a DNA helicase. Nature 365, 852-855.
van der Logt, E. M., Bergevoet, S. M., Roelofs, H. M., van Hooijdonk, Z., te Morsche, R. H., Wobbes, T., de Kok, J. B., Nagengast, F. M., and Peters, W. H. (2004). Genetic polymorphisms in UDP-glucuronosyltransferases and glutathione S-transferases and colorectal cancer risk. Carcinogenesis 25, 2407-2415.
van Kuilenburg, A. B., Muller, E. W., Haasjes, J., Meinsma, R., Zoetekouw, L., Waterham, H. R., Baas, F., Richel, D. J., and van Gennip, A. H. (2001). Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin Cancer Res 7, 1149-1153.
Vidal, A. E., Boiteux, S., Hickson, I. D., and Radicella, J. P. (2001). XRCC1 coordinates the initial and late stages of DNA abasic site repair through protein-protein interactions. Embo J 20, 6530-6539.
Watson, M. A., Stewart, R. K., Smith, G. B., Massey, T. E., and Bell, D. A. (1998). Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution. Carcinogenesis 19, 275-280.
Wei, X., Elizondo, G., Sapone, A., McLeod, H. L., Raunio, H., Fernandez-Salguero, P., and Gonzalez, F. J. (1998). Characterization of the human dihydropyrimidine dehydrogenase gene. Genomics 51, 391-400.
Wein, A., Riedel, C., Bruckl, W., Kastl, S., Reingruber, B., Hohenberger, W., and Hahn, E. G. (2001). Weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) with folinic acid (FA) in adjuvant therapy of colon cancer. Z Gastroenterol 39, 153-156.
Yamaguchi, K., Arai, Y., Kanda, Y., and Akagi, K. (2001). Germline mutation of dihydropyrimidine dehydrogenese gene among a Japanese population in relation to toxicity to 5-Fluorouracil. Jpn J Cancer Res 92, 337-342.
Yeh, C. C., Hsieh, L. L., Tang, R., Chang-Chieh, C. R., and Sung, F. C. (2005a). Vegetable/fruit, smoking, glutathione S-transferase polymorphisms and risk for colorectal cancer in Taiwan. World J Gastroenterol 11, 1473-1480.
Yeh, C. C., Sung, F. C., Tang, R., Chang-Chieh, C. R., and Hsieh, L. L. (2005b). Polymorphisms of the XRCC1, XRCC3, & XPD genes, and colorectal cancer risk: a case-control study in Taiwan. BMC Cancer 5, 12.
Yin, G., Kono, S., Toyomura, K., Hagiwara, T., Nagano, J., Mizoue, T., Mibu, R., Tanaka, M., Kakeji, Y., Maehara, Y., et al. (2004). Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study. Cancer Sci 95, 908-913.
行政院衛生署2005年健康統計 Department of Health, Executive Yuan, ROC: Health Statistics. 2005.