氧化砷治癌及抗藥性機轉之研究

Abstract

砷元素廣泛的散佈在自然界中。長期 的暴露在過量的砷會引起各種疾病，包括 皮膚病變、神經病變及臺南沿海常見的烏 腳病等等，也會增加得到皮膚癌、肺癌、 膀胱癌等癌症的機會。最近中國大陸的哈 爾濱醫科大學發現，氧化砷是治療急性前 骨髓型白血病非常有效的藥物，使得這個 古老的藥物又重新被科學界認識。在哈爾 濱、大連及上海的血液科醫師分別發現， 氧化砷能治療對化學治療、全反式維生素 甲酸完全沒有效用的急性前骨髓型白血病 病人，並無交互抗藥性。大陸學者後來也 發現，有一部分一開始使用氧化砷治療有 效的病人，繼續治療仍產生抗藥性，使白 血病無法控制。 在先前計畫中，我們發現氧化砷對膀 胱癌及白血病細胞有極高毒性，對卵巢癌 及腸胃癌症的細胞毒性為中等，對其他癌 症之效果則不佳。氧化砷對癌細胞之毒性 似乎是經由引起細胞凋亡之機轉。氧化砷 應可應用在固態腫瘤治療之臨床試驗。 本計畫的目的在探討癌細胞對氧化砷 抗藥性的可能機轉。 在本計畫中，我們測試氧化砷在對化學 治療敏感的細胞及多重抗藥癌細胞株的細 胞毒性及這些細胞中Glutathione-stransferase pi(GST-pi)，GSH 及multidrug resistance-associated protein (MRP1)蛋白質 的表現，並和細胞毒性比對。此外也用GSH 的抗藥逆轉劑buthionine sulfoximine (BSO)，嘗試增強氧化砷對癌細胞的毒殺能 力。結果發現細胞中GSH 的升高或MRP1 的高度表現都能使多重抗藥癌細胞產生抗 藥性。使用BSO 使GSH 下降可使這兩株 抗藥細胞的氧化砷敏感度提高。氧化砷應 可應用在固態腫瘤治療之臨床試驗。由於 高GSH 往往引起細胞的抗藥性，使用BSO 可能可以加強治療的效果。本研究支持氧 化砷必須和GSH結合才能由MRP1 排到細 胞外的假說。

Arsenic trioxide is a novel anticancer agent, which has been found to induce remission in acute promyelocytic leukemic patients following daily intravenous administration. The therapeutic value of arsenic trioxide in other cancers is still largely unknown. Our previous study showed that bladder cancer, acute promyelocytic leukemic and gastrointestinal cancer cells were the most sensitive to arsenic trioxide. Cellular glutathione system plays an important role in arsenic detoxification in mammalian cells. Cancer cells that were intrinsically sensitive to arsenic trioxide contained lower levels of glutathione whereas resistant cancer cells contained higher levels of glutathione. On the other hand, there was no association of glutathione-s-transferase-pi or multidrug resistance-associated protein 1 levels with arsenic sensitivity in these cancer cells. In the present study we have shown that multidrug resistant cancer cells that were cross-resistant to arsenic contained higher levels of glutathione or multidrug-resistance associated protein 1 than their drug-sensitive parental cells. Cancer cells become more sensitive to arsenic after depletion of cellular glutathione with L-buthionine sulfoximine. We concluded that cellular glutathione level is the most important determinant of arsenic sensitivity in cancer cells. Cellular glutathione level and its modulation by buthionine sulfoximine should be considered in designing clinical trials using arsenic in solid tumors.