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研究生： 王鏈嘉
Wang, Lien-Chia
論文名稱： 5-Aminolevulinic Acid在基底細胞癌 之代謝與光毒性作用
Metabolism and Phototoxicity of 5-Aminolevulinic Acid in Basal Cell Carcinoma
指導教授： 蔡瑞真
Tsai, Jui-Chen
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床藥學研究所
Institute of Clinical Pharmacy
論文出版年： 2002
畢業學年度： 90
語文別： 中文
論文頁數： 156
中文關鍵詞： 代謝 、光毒性 、基底細胞癌
外文關鍵詞： 5-Aminolevulinic Acid, Basal Cell Carcinoma
相關次數： 點閱：155  下載：1 
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    • 中文摘要
    5-Aminolevulinic acid（ALA）應用在光化學動力療法（photodynamic therapy, PDT）用以治療腫瘤，於過去10年內引起相當廣泛之討論及研究。而以ALA-PDT治療黑色素瘤以外的皮膚癌（如superficial squamous cell carcinoma，sSCC）時，能得到約90 %以上的治療效果；但是如用在治療皮膚基底細胞瘤（basal cell carcinoma, BCC）時，無論是初次治療或是復發率方面，皆不如其他的皮膚癌有效，如對nodular basal cell carcinoma僅有約10 ~ 50%之療效，且復發率高達100 %。且過去對於基底細胞瘤之研究主要著重於臨床治療，並無直接關於ALA用於皮膚基底細胞瘤細胞株的研究報告。
    過去本實驗室以正常之裸鼠皮膚作為研究之模式，發現不論是在表皮或是真皮內PpIX的體內蓄積量隨著體外ALA經皮穿透速率之增加而漸趨飽和，顯示PpIX之蓄積量主要受限於細胞內將ALA代謝為PpIX之能力。
    因此本研究之目的乃以細胞層級來探討ALA本身對BCC細胞株及人類株化角質細胞HaCaT的毒性（cytotocixity）、細胞產生PpIX之動力學、照光後細胞的存活率及鐵離子螯合劑對於兩細胞株內PpIX生成的影響。期望能藉由本研究的結果提供一最適當之ALA給藥劑量、光照時間及劑量用於BCC之治療。
    研究結果顯示，投予0.2 ~ 5 mM ALA 24小時後，BCC仍保有約50%的存活率，而ALA對於HaCaT則較不具毒性。ALA培養 24小時內，兩種細胞所產生的PpIX量，除了5 mM之外，皆會隨著給藥濃度及時間而增加，而以BCC相對於HaCaT所產生之最大比例值在各濃度分別為：0.2 mM為24小時，0.5 mM為2小時，而1、2、5 mM為0.5小時，且最大之比例值出現在0.2 mM培養24小時。接著評估分別以ALA培養2 及4小時除藥後之PpIX動力學時，發現產生最大PpIX量及兩種細胞間最大之PpIX比值的時間，會隨著所投予的藥品濃度增加而增加，而最大之比值則出現在以0.5 mM ALA培養4小時後4小時。雖然BCC細胞株達到PpIX最高量的時間比HaCaT細胞株慢，但是就PpIX生成之最高量（PpIXmax）及AUC值來看，BCC細胞株皆大於HaCaT細胞株，顯示BCC細胞株生合成PpIX之能力大於HaCaT細胞株。
    當兩細胞株分別以0.2至5 mM ALA培養4小時後，再以不同劑量LED光源（波長630 nm）於不同時間照射後，可得到BCC相對於HaCaT之存活率最低出現於以0.5 mM和1 mM ALA培養後4小時施以60 J/cm2之照光，且以0.5 mM不影響HaCaT之存活率。此結果亦顯示細胞內PpIX之含量為影響照光後存活率主要之因素。
    繼續探討鐵離子螯合劑desferrioxamine （DFO）對兩細胞株PpIX生成之影響，研究結果顯示，兩細胞株皆會因DFO作用之故，而有PpIX蓄積及減緩排除的現象，間接指出兩者可能都有ferrochelatase酵素的存在，而以HaCaT細胞株較易受到DFO的作用而使細胞內PpIX含量較快達到飽和。但添加DFO後，BCC細胞株相對於HaCaT細胞株之PpIX含量比值則降低，顯示DFO反而不利於應用ALA-PDT對於BCC之選擇性。

    Abstract
    5-Aminolevulinic acid (ALA)-based photodynamic therapy to treat cancers has been widely discussed and investigated in the last decade. The application of ALA-PDT for the treatment of non-melanoma skin cancers, such as superficial squamous cell carcinoma, resulted in satisfied, complete response. However, the therapeutic outcomes of ALA-PDT in basal cell carcinoma (BCC) were not as good as in other skin cancers. Despite extensive clinical experience and reports on ALA-PDT for the treatment of BCCs, none has addressed the PpIX generation kinetics and phototoxicity in cultured BCC cells. Previous study has demonstrated that saturable correlations exist between PpIX accumulation in both the epidermis and dermis in vivo and its transdermal flux in vitro, indicating PpIX accumulation is mainly limited by metabolic capacity of the skin.
    The objectives of the study were to investigate ALA toxicity, protoprophyrin IX (PpIX) generation kinetics, cell survival ratio after light irradiation, and the influences of iron chelator, desferrioxamine (DFO) in PpIX generation following ALA incubation in basal cell carcinoma cells (BCC/KMC-1) and human immortalized keratinocytes (HaCaT). The ultimate goal was to optimize ALA-PDT in BCC.
    Cultured BCC and HaCaT were incubated with 0.2 to 5 mM ALA for various lengths of time. After 24 hours incubation of ALA, only 50 % BCC survived, but HaCaT were not affected. In general, the PpIX content in both cells increased with incubation time at all ALA concentration except 5 mM. The ratio of PpIX content in BCC vs. HaCaT decreased with increasing concentration during 24 hours ALA incubation. The time of maximal ratio was 24, 2, 0.5, 0.5 and 0.5 h from 0.2 to 5 mM, respectively, with the greatest ratio occurring at 24 h incubation 0.2 mM ALA. The time to reach peak PpIX content post 2 h and 4 h ALA-incubations in both cells and the time of maximal ratio increased with ALA concentration. The greatest ratio appeared at 4 h post 4 h-incubation of 0.5 mM ALA. Although the time to reach peak PpIX content in BCC was slower than HaCaT, the peak PpIX content and area under the PpIX content-concentration curve were greater in BCC than HaCaT, indicating higher biosynthetic capacity of PpIX in BCC than HaCaT.
    When both cells were irradiated by different doses of LED light at 0-24 h post 4 h-incubation of 0.2-5 mM ALA, the results demonstrated that the relative survival ratio of BCC vs. HaCaT was the lowest at 4 h post incubation of 0.5 and 1 mM ALA with light irradiation of 60 J/cm2 at 630 nm, with HaCaT survival not influenced by 0.5 mM ALA. The results also suggested cellular PpIX content as the major determinant for cytotoxity in both cells.
    Finally, the addition of iron chelator, desferrioxamine (DFO), resulted in enhanced PpIX accumulation and delayed clearance, suggesting the presence of ferrochelatase in both cells. The cellular PpIX content has reached plateau in HaCaT at a lower DFO concentration than BCC. However, the ratio of PpIX content in BCC vs. HaCaT was decreased with DFO in comparison with ALA only, indicating lower selectivity of ALA-PDT in BCC vs. HaCaT.

    目錄 中文摘要 i 英文摘要 iv 致謝 vi 目錄 vii 表目錄 ix 圖目錄 xi 縮寫表 xiii 第壹章 緒論 1 第貳章 文獻回顧 2 第一節 光化學動力療法簡介 2 第二節 光感前趨物質ALA之特性 9 第三節 PpIX生合成機轉及作用 13 第四節 調控PpIX生成之酵素及相關因素 16 第五節 光化學動力療法應用於基底細胞瘤之臨床治療 18 第參章 研究目的 22 第肆章 研究方法 24 第一節 實驗細胞 24 第二節 藥品、儀器裝置及分析原理 26 第三節 ALA對細胞之毒性試驗 45 第四節 ALA培養期間細胞內PpIX含量之經時變化 47 第五節 ALA培養後細胞內PpIX含量之經時變化 51 第六節 光照對ALA培養後細胞之影響 53 第七節 鐵離子螯合劑對ALA培養後細胞內PpIX含量 56 經時變化之影響 第伍章 研究結果 62 第一節 ALA對細胞之毒性試驗 62 第二節 ALA培養期間細胞內PpIX含量之經時變化 69 第三節 ALA培養後細胞內PpIX含量之經時變化 77 第四節 光照對ALA培養後細胞之影響 87 第五節 鐵離子螯合劑對ALA培養後細胞內PpIX含量 113 經時變化之影響 第六章 討論 130 第一節 ALA對細胞的毒性影響與培養期間細胞內PpIX 130 經時變化之相互關係 第二節 ALA培養後細胞內PpIX含量之經時變化 132 第三節 細胞內之PpIX含量與光照對ALA培養後細胞之影響 138 第四節 鐵離子螯合劑對ALA培養後細胞內PpIX動力學研究 141 第五節 結論 148 參考文獻 149 自述 156 表目錄 表2 - 1 細胞株之比較 25 表2 - 2 細胞培養用物品 27 表2 - 3 分析用化學試藥 30 表2 - 4 測量用儀器設備 31 表5 – 1 ALA水溶液之pH值 64 表5 - 2 BCC以ALA培養24小時期間之存活率 65 表5 - 3 HaCaT以ALA培養24小時期間之存活率 65 表5 - 4 以ALA培養24小時期間BCC相對於HaCaT之存活率比值 67 表5 - 5 BCC細胞株以ALA培養24小時期間內PpIX含量變化 73 表5 - 6 HaCaT細胞株以ALA培養24小時期間內PpIX含量變化 73 表5 - 7 ALA培養24小時期間細胞株內PpIX含量之比較: BCC相對於HaCaT 75 表5 - 8 BCC細胞株以ALA培養2小時後PpIX含量經時變化 79 表5 - 9 HaCaT細胞株以ALA培養2小時後PpIX含量經時變化 79 表5 - 10 以ALA培養2小時後細胞內PpIX含量之比較: BCC相對於HaCaT 81 表5 - 11 BCC細胞株以ALA培養4小時後PpIX含量之經時變化 83 表5 - 12 HaCaT細胞株以ALA培養4小時後PpIX含量之經時變化 83 表5 - 13 以ALA培養4小時後細胞內PpIX含量之比較: BCC相對於HaCaT 85 表5 - 14 細胞在僅受照光下之存活率 92 表5 - 15 0.2 mM ALA培養4小時後接受不同之光照劑量之細胞存活率 94 表5 – 16 0.5 mM ALA培養4小時後接受不同之光照劑量之細胞存活率 96 表5 – 17 1 mM ALA培養4小時後接受不同之光照劑量之細胞存活率 98 表5 – 18 2 mM ALA培養4小時後接受不同之光照劑量之細胞存活率 100 表5 – 19 5 mM ALA培養4小時後接受不同之光照劑量之細胞存活率 102 表5 – 20 細胞以0.2 mM ALA培養後照光之存活率比較: BCC相對於HaCaT 104 表5 – 21 細胞以0.5 mM ALA培養後照光之存活率比較: BCC相對於HaCaT 104 表5 – 22 細胞以1 mM ALA培養後照光之存活率比較: BCC相對於HaCaT 106 表5 – 23 細胞以2 mM ALA培養後照光之存活率比較: BCC相對於HaCaT 106 表5 – 24 細胞以5 mM ALA培養後照光之存活率比較: BCC相對於HaCaT 108 表5 – 25 BCC及HaCaT細胞株照光後存活率排序 110 表5 – 26 細胞存活率比值排序 112 表5 – 27 DFO溶液於加ALA前後之pH值變化 117 表5 – 28 不同濃度之DFO對細胞株的存活率影響 118 表5 – 29 不同濃度之DFO對細胞株內PpIX含量之影響 120 表5 – 30 不同濃度之DFO對細胞株內PpIX含量之比較: BCC相對於HaCaT 122 表5 – 31 以不同濃度DFO培養後細胞株內PpIX含量相較於單獨以ALA培養時增加之比值 122 表5 – 32 以1 mM DFO及ALA培養後細胞內之PpIX含量經時變化 124 表5 – 33 以1 mM DFO及ALA培養後細胞內PpIX含量之比較: BCC相對於HaCaT 126 表5 – 34 細胞株以不同濃度DFO培養後接受照光之細胞存活率 128 表6 – 1 細胞株以ALA培養2或4小時所得之PpIXmax, Tmax, AUC 134 表6 - 2 細胞株以ALA及DFO培養4小時所得之PpIXmax, Tmax, AUC 144 圖目錄 圖2 – 1 PpIX與血紅素生合成路徑 21 圖5 – 1 BCC以ALA培養24小時期間之細胞存活率 66 圖5 – 2 HaCaT以ALA培養24小時期間之細胞存活率 66 圖5 – 3 以ALA培養24小時期間BCC相對於HaCaT之存活率比值圖 68 圖5 – 4 PpIX校正曲線 71 圖5 – 5 蛋白質校正曲線 72 圖5 – 6 BCC以ALA培養24小時期間細胞內PpIX含量之經時變化 74 圖5 – 7 HaCaT以ALA培養24小時期間細胞內PpIX含量之經時變化 74 圖5 – 8 以ALA培養24小時期間BCC相對於HaCaT之細胞內PpIX含量比值 76 圖5 – 9 BCC以ALA培養2小時後細胞內之PpIX含量經時變化 80 圖5 – 10 HaCaT以ALA培養2小時後細胞內之PpIX含量經時變化 80 圖5 – 11 以ALA培養2小時後BCC相對於HaCaT之細胞內PpIX含量比值 82 圖5 – 12 BCC以ALA培養4小時後細胞內之PpIX含量經時變化 84 圖5 – 13 HaCaT以ALA培養4小時後細胞內之PpIX含量經時變化 84 圖5 – 14 以ALA培養4小時後BCC相對於HaCaT之細胞內PpIX含量比值 86 圖5 – 15 BCC在僅受照光下之細胞存活率 93 圖5 – 16 HaCaT在僅受照光下之細胞存活率 93 圖5 – 17 光照對以0.2 mM ALA培養後之BCC細胞株存活率之變化 95 圖5 – 18 光照對以0.2 mM ALA培養後之HaCaT細胞株存活率之變化 95 圖5 – 19 光照對以0.5 mM ALA培養後之BCC細胞株存活率之變化 97 圖5 – 20 光照對以0.5 mM ALA培養後之HaCaT細胞株存活率之變化 97 圖5 – 21 光照對以1 mM ALA培養後之BCC細胞株存活率之變化 99 圖5 – 22 光照對以1 mM ALA培養後之HaCaT細胞株存活率之變化 99 圖5 – 23 光照對以2 mM ALA培養後之BCC細胞株存活率之變化 101 圖5 – 24 光照對以2 mM ALA培養後之HaCaT細胞株存活率之變化 101 圖5 – 25 光照對以5 mM ALA培養後之BCC細胞株存活率之變 103 圖5 – 26 光照對以5 mM ALA培養後之HaCaT細胞株存活率之變化 103 圖5 – 27 照光對以ALA培養後之細胞存活率比值：BCC相對於HaCaT 105 圖5 – 28 照光對以ALA培養後之細胞存活率比值：BCC相對於HaCaT 105 圖5 – 29 照光對以ALA培養後之細胞存活率比值：BCC相對於HaCaT 107 圖5 – 30 照光對以ALA培養後之細胞存活率比值：BCC相對於HaCaT 107 圖5 – 31 照光對以ALA培養後之細胞存活率比值：BCC相對於HaCaT 109 圖5 – 32 BCC以DFO培養24小時期間內存活率經時變化 119 圖5 – 33 HaCaT以DFO培養24小時期間內存活率經時變化 119 圖5 – 34 不同濃度DFO及0.5 mM ALA培養後之細胞PpIX含量變化 121 圖5 – 35 BCC與HaCaT以DFO培養後細胞內PpIX含量增加之比值 123 圖5 – 36 以不同濃度DFO及 0.5 mM ALA培養後BCC相對於HaCaT之細胞內PpIX含量比值 123 圖5 – 37 BCC以1mM DFO及不同濃度ALA培養後之PpIX經時變化 125 圖5 – 38 HaCaT以1mM DFO及不同濃度ALA培養後之PpIX經時變化 125 圖5 – 39 以1mM DFO及不同濃度ALA培養後BCC相對於HaCaT之細胞內PpIX含量比值 127 圖5 – 40 BCC細胞株在以不同濃度DFO培養後接受照光之存活率 129 圖5 – 41 HaCaT細胞株在以不同濃度DFO培養後接受照光之存活率 129 圖6 – 1 ALA濃度與細胞株產生最大PpIX量（PpIXmax）之關係圖 136 圖6 – 2 ALA濃度與細胞株產生最大PpIX量時間點（Tmax）之關係圖 136 圖6 – 3 ALA濃度與兩細胞株間PpIX AUC值之關係圖 137 圖6 – 4 ALA濃度與細胞株產生最大PpIX量（PpIXmax）之關係圖 146 圖6 – 5 ALA濃度與細胞株產生最大PpIX量時間點（Tmax）之關係圖 146 圖6 – 6 ALA濃度與兩細胞株間PpIX AUC值之關係圖 147

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