同半胱胺酸、葉酸、維生素B-6、氧化壓力及抗氧化能力與大腸直腸癌危險性的關係

大腸直腸癌是人類常見的腫瘤，也是目前台灣十大癌症死亡原因的第三名。微量營養素是一種有機複合物，少量存在人體內但卻提供了正常細胞代謝與生理機能的需求。其中，低濃度的葉酸與維生素B-6，以及因低濃度葉酸與維生素B-6而導致的高同半胱胺酸濃度、高氧化壓力及低抗氧化能力被認為在大腸直腸癌形成中扮演重要角色。但是有關葉酸、維生素B-6、同半胱胺酸、氧化壓力以及抗氧化能力在大腸直腸癌患者體內的相互間關係卻尚未有完整的研究。 本論文的第一個目的在探討並釐清大腸直腸癌患者體內葉酸、維生素B-6、同半胱胺酸、氧化壓力及抗氧化能力的相關性，以及這些因素對罹患大腸直腸癌的影響。以病例-對照研究模式於台中榮民總醫院大腸直腸外科募集168位大腸直腸癌患者，另外於健康管理中心募集188位經大腸鏡檢查後確認健康的受試者。結果發現大腸直腸癌患者的葉酸及同半胱胺酸，與氧化壓力及抗氧化能力間沒有顯著相關性；但是調整相關干擾因子後，維生素B-6與穀胱甘肽硫轉移酶活性呈顯著正相關。受試者的低葉酸及維生素B-6濃度與罹患大腸直腸癌的危險對比值沒有顯著相關性；但若有較高的同半胱胺酸濃度會獨立於葉酸、維生素B-6、氧化壓力及抗氧化能力的因素外顯著增加罹患大腸直腸癌的危險對比值。 雖然本論文的第一個研究顯示葉酸與罹患大腸直腸癌的危險性無顯著相關性，但是葉酸被發現在癌化過程中有可能因為扮演雙重角色而改變與罹患大腸直腸癌危險性的關係。因此本論文的另一目的是要探討葉酸在健康受試者、大腸直腸腺瘤性息肉(可能演化成大腸直腸癌)患者以及大腸直腸癌患者的營養狀況以及與罹患大腸直腸腺瘤性息肉及大腸直腸癌的關係。以病例-對照研究模式於台中榮民總醫院大腸直腸外科募集156位大腸直腸癌患者，另外於健康管理中心募集70位經大腸鏡檢查及病理檢驗後確認為大腸直腸息肉的受試者，以及182位健康的受試者。將大腸直腸息肉及大腸直腸癌患者的葉酸濃度分層為四分位數後，若葉酸濃度位於第三個四分位數 (OR, 3.46; 95% CI, 1.16 - 10.34; p = 0.03) 與第四個四分位數(OR, 4.86; 95% CI, 1.42 - 16.58; p = 0.01)會顯著增加罹患大腸直腸癌的危險對比值，但是同樣的結果卻未在大腸直腸癌患者與健康受試者之間觀察到。 綜合前述的2個研究結果，同半胱胺酸濃度是獨立於低葉酸及維生素B-6、高氧化壓力及低抗氧化能力外顯著的增加罹患大腸直腸癌的風險；而大腸直腸腺瘤性息肉患者若有高葉酸濃度會增加罹患大腸直腸癌的風險，但是健康受試者的葉酸營養狀況與罹患大腸直腸癌風險則無顯著相關性。

Colorectal cancer is one of the most frequent neoplastic diseases and is now the third leading cause of cancer-related deaths in Taiwan. Micronutrients are required by humans to orchestrate a range of physiological functions and normal metabolism. Among micronutrients, low folate and vitamin B-6, increased homocysteine concentration and oxidative stress and decreased antioxidant capacities which are caused by low folate and vitamin B-6 are thought to play important roles in the carcinogenesis. However, the associations of folate, vitamin B-6, homocysteine, oxidative stress and antioxidant capacities in patients with colorectal cancer are unclear and not been studied simutaneneously. The first purpose of this dissertation was to elucidate the relationships among folate, vitamin B-6, homocysteine, oxidative stress and antioxidant capacities in patients with coloreclta cancer; and further to analyze their relationships with respect to risk for colorectal cancer. This was a case-control design study. We recruited 168 patients with colorectal cancer at the division of colorectal surgery of Taichung Veterans General Hospital, Taiwan, and 188 healthy subjects were recruited from the physical examination unit of Taichung Veterans General Hospital. Results showed no significant associations among folate, homocysteine, oxidative stress and antioxidant capacities in patients with colorectal cancer. However, vitamin B-6 positively correlated with glutathione S-transferase activities after adjusting for potential confounders in pateints with colorectal cancer. Subjects with higher plasma homocysteine concentration significantly increased the risk of colorectal cancer independently of folate, vitamin B-6, oxidative stress and antioxidant capacities. The associations of folate and vitamin B-6 with the risk of colorectal cancer were not observed when potential confounders were adjusted. Althoug we did not observe the significant association between serum folate and the risk of colorectal cancer, folate might possess dual modulatory effects on the development and progression of colorectal cancer. Therefore, the second purpose of this dissertation was to investigate the association between serum folate and the risk of colorectal cancer in subjects with colorectal cancer or colorectal adenomatous polyps (a precursor of CRC), and healthy subjects. This was a case control study. We recruited 156 patients with colorectal cancer from the division of colorectal surgery of Taichung Veterans General Hospital, Taiwan; and 70 patients with colorectal adenomatous polys and 182 healthy subjects were recruited from the physical examination unit of Taichung Veterans General Hospital. The risk of CRC was significantly increased in the third (OR, 3.46; 95% CI, 1.16 – 10.34; p = 0.03) and fourth (OR, 4.86; 95% CI, 1.42 – 16.58; p = 0.01) quartiles of serum folate concentration after adjusting for potential confounders among subjects with colorectal adenomatous polyps or colorectal cacner. However, serum folate had no significant effect on the risk of colorectal cancer among subjects in the control and CRC groups.Based on the results of two studies, increased plasma homocysteine concentration was associated with the increased risk of colorectal cancer independently of low folate and vitamin B-6, increased oxidative stress and decreased antioxidant capacities. In addition, patients with colorectal adenomatous polyps had high serum folate concentration might increase the risk of colorectal cancer; however, serum folate concentation in healthy subjects played no significant role in the risk of colorectal cancer.