Preclinical Study of Ar senic Tr ioxide in the Treatment of Solid Tumor

砷元素廣泛的散佈在自然界中。長期 的暴露會引起各種疾病，也會增加得到皮 膚癌、肺癌、膀胱癌等癌症的機會。但自 古以來，砷就被用來治療多種疾病，包括 關節炎、氣喘及白血病等癌症。 最近在哈爾濱及上海的血液科醫師分 別發現，注射氧化砷能治療對化學治療、 全反式維生素甲酸失效的急性前骨髓型白 血病病人。效果很好，毒性也可接受。 氧化砷可抑制細胞生長，它可干擾蛋白 質硫氫基(-SH)及磷酸化的功能，從而抑制 細胞代謝、結構。砷也可以破壞 DNA、改 變細胞的染色體。我們發現，氧化砷在病 人身上可達到的濃度下，即可抑制癌細胞 的生長，可能有臨床應用價值。 本計畫的目的在探討氧化砷用在各種 癌症治療的可行性，以及初步瞭解氧化砷 毒殺癌細胞及癌細胞抗藥性的可能機轉。 在本計畫中，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。由於高 的GSH 往往引起細胞的抗藥性，使用BSO 可能可以將加強治療的效果。Arsenic is a ubiquitous element in environment. Chronic exposure of arsenic compound may cause various diseases and is also associated with increased risk of skin cancer, lung cancer, bladder cancer. Despite these chronic toxicity, arsenic is an ancient medication and was used widely in both western and Chinese medicine. It has been used to treat asthma, arthritis and several types of cancer, including leukemias. Arsenic trioxide has revived after the revelation that it is very effective in the treatment of acute promyelocytic leukemia patients who were refractory to both chemotherapy and all-trans retinoic acid. Our preliminary cytotoxicity results indicated that at concentrations attainable in patient plasma, As2O3 may inhibit the growth of some solid tumor cell lines. The objective of this project is to test feasibility of using As2O3 in the treatment of solid tumors. The secondary aim is to find out mechanisms of toxicity and resistance of tumor cells to arsenic compounds. In this study, we found that As2O3 is very cytotoxic to bladder cancer and APL cells. It is moderately active in ovarian and gastrointestinal cancer cells. Other types of cancer are resistant to As2O3. As2O3 seems to kill tumor cells through induction of apoptosis. Our results indicate that it is warranted to use As2O3 in clinical trials to treat solid cancer patients, especially for bladder cancer. High GSH content was associated with intrinsic arsenic resistance in cancer cells. BSO may be considered to enhance cytotoxicity of arsenic treatment