ARSENIC TRIOXIDE TREATMENT OF LYMPHOPROLIFERATIVE DISORD

三氧化二砷，由一种经验性设计的静脉输液给予 中国，已成为治疗慢性阻塞性肺疾病的新的首选药物 难治性急性早幼粒细胞白血病(APL)。它是一种不同寻常的代理商，因为它 对耐化疗的急性早幼粒细胞白血病患者有效 表观治疗浓度1-2M可诱导临床缓解 最小的骨髓毒性。与所有反式维甲酸类似，As203可能是 在治疗APL方面独一无二有效，因为它可以诱导分化和 体外和体内APL细胞的凋亡。AS203是否可以扩展为 癌症的治疗方法仍有待确定。我们决定延长使用 As203为淋巴增生性疾病(LPD)。轶事般的、未发表的报告 来自中国和美国最近的病例报告表明，AS203 可能是治疗LPD的有效方法。与此一致的是我们的观察 As203(1-2M)对LPD(B细胞)细胞系和原代培养的作用 淋巴瘤、CLL、ALL、多发性骨髓瘤但不是T细胞淋巴瘤) 显著的生长抑制，在一些细胞中，可检测到的凋亡类似 对NB4细胞(t(15：17)APL细胞株)。AS303也很有吸引力，因为它 有效抑制肿瘤细胞生长并诱导其凋亡 突变的p53，在t(14：18)淋巴瘤细胞中过表达而不是 P388淋巴瘤细胞对紫杉醇和阿霉素的交叉耐药 表达MDR-1。As203可能有多个效应，这些效应有助于 诱导细胞死亡依赖于剂量、细胞类型或细胞环境。 在体外，As203在一些细胞中增加了H202的积聚，从而作用于 线粒体在诱导caspase依赖性细胞凋亡中的作用然而，这些 在体外进行的观察应该谨慎解释，因为细胞 组织培养中谷胱甘肽和H202水平可能被人为改变 与体内细胞的情况可能有所不同。鲜为人知 1-2M As_2O_3体内暴露的后果及其对机体的影响 人类的恶性细胞。我们将在体外和体内进行比较和对比 As203对LPD细胞系及原代培养LPD细胞的作用 从动物和病人身上获得。这些材料将用于：1) 评估细胞内氧化还原分布和积累的重要性 H202和砷对As203诱导的生长抑制和细胞凋亡；2) 用cDNA在mRNA水平上表征细胞对As203的反应 As203处理的LPD细胞中的微阵列；3)设计 体内外联合治疗提高LPD敏感性的研究 CELES到AS203；4)我们设计了一项第二阶段的先导研究，以评估0.25 As203(比APL使用的浓度高2-1/2)治疗 复发和难治性惰性LPD的患者。这项研究旨在 确定As203活性的潜在替代标记。我们的实验室是否应该 研究确定可增强对AS203响应的代理或时间表，我们将 使用它们来适当地修改初始阶段II试点研究。

As2O3, given by an intravenous infusion empirically designed in China, has become a new therapeutic agent of choice in the treatment of refractory acute promyelocytic leukemia (APL). It is an unusual agent since it is effective in APL patients that are chemotherapy-resistant and at the apparent therapeutic concentration of 1-2 M induces clinical remission with minimal myelotoxicity. Similar to all trans retinoic acid, As203 may be uniquely effective in treating APL since it can induce both differentiation and apoptosis in APL cells in vitro and in vivo. Whether As203 can be extended as a cancer treatment remains to be determined. We elected to extend the use of As203 to lymphoproliferative disorders (LPD). Anecdotal, unpublished reports from China and more recent case reports in the United States suggest that As203 may be an effective treatment of LPD. Consistent with this is our observation that As203 (1-2 M) treatment of cell lines and primary cultures of LPD (B-cell lymphoma, CLL, ALL, multiple myeloma but not T-cell lymphoma) causes significant growth inhibition and, in some cells, measurable apoptosis similar to NB4 cells (t(15:17) APL cell line). As303 is also appealing since it effectively inhibits growth and induces apoptosis in malignant cells with mutant p53, in lymphoma cells with t(14:18) that overexpress Bcl-2 and does not demonstrate cross resistance to taxol and doxorubicin in P388 lymphoma cells expressing MDR-1. As203 probably has multiple effects that contribute to the induction of cell death dependent on dose, cell type or cellular environment. In vitro, As203 in some cells increases H202 accumulation which acts on the mitochrondria to induce caspase dependent apoptosis. However, these observations made in vitro should be interpreted with caution since cellular levels of glutathione and H202 may be artifactually altered in tissue culture media and are likely to differ from that of cells in vivo. Little is known about the consequence of in vivo exposure of 1-2 M As203 and its effect on human malignant cells. We will compare and contrast in vitro and in vivo effects of As203 treatment of LPD cell lines and primary cultures of LPD cells obtained from animals and patients. These materials will be used: 1) to evaluate the importance of the intracellular redox profile and accumulation of H202 and arsenic to As203-induced growth inhibition and apoptosis; 2) to characterize the cellular responses to As203 at mRNA level using cDNA microarray in LPD cells obtained from patients treated with As203; 3) to design combination therapies in vitro and in vivo to improve the sensitivity of LPD cells to As203; 4) we have designed a phase II pilot study to evaluate 0.25 mg/kg/day As203 (2-1/2 higher concentration than used in APL) in the treatment of patients with relapsed and refractory indolent LPD. The study is designed to identify potential surrogate markers of As203 activity. Should our laboratory study identify agents or schedules that enhance the response to As203, we will use them to appropriately modify the initial phase II pilot study.