ARSENIC TRIOXIDE TREATMENT OF LYMPHOPROLIFERATIVE DISORD

As 2 O3，通过经验设计的静脉输注给药， 中国，已成为一种新的治疗药物的选择，在治疗 难治性急性早幼粒细胞白血病（APL）。这是一个不寻常的代理，因为它 对化疗耐药的APL患者有效， 1-2 M的表观治疗浓度诱导临床缓解， 最小骨髓毒性。类似于全反式视黄酸，As 2 O3可以是 在治疗APL中是独特有效的，因为它可以诱导分化， 在体外和体内APL细胞凋亡。As 203是否可以作为 癌症治疗仍有待确定。我们决定扩大使用 As 203与淋巴组织增生性疾病（LPD）有关。轶事，未发表的报告 来自中国和美国最近的病例报告表明，As 203 可能是治疗LPD的有效方法。与此相一致的是我们的观察 As 2 O3（1-2 M）处理LPD（B细胞）的细胞系和原代培养物 淋巴瘤，CLL，ALL，多发性骨髓瘤，但不是T细胞淋巴瘤）的原因 显著的生长抑制和在一些细胞中可测量的凋亡类似 NB 4细胞（t（15：17）APL细胞系）。AS 303也很吸引人，因为它 有效抑制恶性细胞的生长并诱导细胞凋亡， 突变型p53，在淋巴瘤细胞中，t（14：18）过度表达Bcl-2， 在P388淋巴瘤细胞中显示对紫杉醇和阿霉素的交叉耐药性 表达MDR-1。As 203可能有多种影响，有助于 依赖于剂量、细胞类型或细胞环境诱导细胞死亡。 在体外，一些细胞中的As 2 O3增加了H2 O2的积累，这作用于细胞内的H2 O2。 线粒体诱导caspase依赖性细胞凋亡。但这些 体外观察结果应谨慎解释，因为细胞 谷胱甘肽和H2 O2的水平可以在组织培养中人为地改变 培养基中，并且可能不同于体内的细胞。知之甚少 关于1-2 M As 2 O3体内暴露的后果及其对 人类恶性细胞我们将在体外和体内进行比较和对比 As 203处理LPD细胞系和LPD细胞原代培养物的作用 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谱和积累的重要性， H2 O2和砷对As 2 O3诱导的细胞生长抑制和细胞凋亡的影响; 2） 使用cDNA在mRNA水平表征对As 203的细胞反应 在从用As 2 O3治疗的患者获得的LPD细胞中的微阵列中; 3）设计 体外和体内联合治疗以提高LPD的敏感性 4）我们设计了一项II期试点研究，以评估0.25 治疗中的As 203（浓度比APL中使用的浓度高2-1/2） 复发性和难治性惰性LPD患者。本研究旨在 鉴定As 2 O3活性潜在替代标记物。我们的实验室 通过研究确定增强对As 203反应的药剂或时间表，我们将 使用它们来适当修改初始II期试点研究。

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 Anecdotal, unpublished reports from China and more recent case reports in the United States suggest that As203 may be an effective treatment of LPD.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.