Ishitsuka K, Hanada S, Uozumi K, Utsunomiya A, Arima T
2nd Department of Internal Medicine, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
Leuk Lymphoma. 2000 May;37(5-6):649-55. doi: 10.3109/10428190009058521.
A novel therapeutic potential for acute promyelocytic leukemia using arsenic trioxide (As(2) O(3) ) has been reported. Recent in vitro studies demonstrated that As(2) O(3) effectively inhibits the growth of some cell lines derived from patients with malignant lymphoma, chronic lymphocytic leukemia and multiple myeloma. Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T-cell origin caused by human T-cell leukemia virus type-I (HTLV-I) the prognosis of which still remains very poor. A possible role of As(2) O(3) for the treatment of ATL is demonstrated from evidence that As(2) O(3) significantly inhibits the growth of HTLV-I infected T-cell lines and induces apoptosis in fresh ATL cells at clinically achievable concentration of the agent. The growth inhibition of As(2) O(3) treated HTLV-I infected T-cell lines was induced by both apoptosis and G(1) phase accumulation. Cleaved bcl-2 protein and an enhanced expression of bak protein in the cells were coincidentally observed during As(2) O(3) treatment. A broad spectrum caspase inhibitor, z-Val-Ala-DL-Asp-fluoromethylketone inhibited the apoptosis induced by As(2) O(3). Increased expression of p53, Cip1/p21 and Kip1/p27, and dephosphorylation of retinoblastoma protein (pRb) were detected in the As(2) O(3) treated cells. In conclusion, As(2) O(3) might become a new therapeutic tool in the treatment of ATL as As(2) O(3) induces apoptosis by destruction of the bcl-2 protein and enhancement of the bak protein production proceeding to activate caspases, and also induces G(1) phase accumulation by enhancement of p53, Cip1/p21, Kip1/p27 and dephosphorylation of pRb to HTLV-I infected T-cell lines.
已有报道称三氧化二砷（As₂O₃）对急性早幼粒细胞白血病具有新的治疗潜力。最近的体外研究表明，As₂O₃能有效抑制一些源自恶性淋巴瘤、慢性淋巴细胞白血病和多发性骨髓瘤患者的细胞系的生长。成人T细胞白血病（ATL）是一种由I型人类T细胞白血病病毒（HTLV-I）引起的成熟T细胞来源的侵袭性肿瘤，其预后仍然很差。As₂O₃在治疗ATL方面的潜在作用可从以下证据得到证明：在临床可达到的药物浓度下，As₂O₃能显著抑制HTLV-I感染的T细胞系的生长，并诱导新鲜ATL细胞凋亡。As₂O₃处理的HTLV-I感染的T细胞系的生长抑制是由凋亡和G₁期积累共同诱导的。在As₂O₃处理过程中，同时观察到细胞中裂解的bcl-2蛋白和bak蛋白表达增强。一种广谱半胱天冬酶抑制剂z-Val-Ala-DL-Asp-fluoromethylketone可抑制As₂O₃诱导的凋亡。在As₂O₃处理的细胞中检测到p53、Cip1/p21和Kip1/p27表达增加，以及视网膜母细胞瘤蛋白（pRb）去磷酸化。总之，As₂O₃可能成为治疗ATL的一种新的治疗工具，因为As₂O₃通过破坏bcl-2蛋白和增强bak蛋白产生来诱导凋亡，进而激活半胱天冬酶，并且还通过增强p53、Cip1/p21、Kip1/p27以及使pRb去磷酸化，从而诱导HTLV-I感染的T细胞系G₁期积累。
