COMBINED MODALITY THERAPY TO SUPPRESS PHILADELPHIA CHROMOSOME CELLS IN CML

该项目涉及临床研究，以改进策略 慢性粒细胞白血病的化疗和生物治疗结果。目标1建立在 该计划在确定干扰素-α活性方面的成功 对于慢性粒细胞白血病，以及最近干扰素和阿糖胞苷的联合治疗。我们 将检验这样一种假设，即干扰素-α的组合， 与干扰素相比，阿糖胞苷和全反式维甲酸可改善预后- 阿尔法/阿糖胞苷治疗。目标2旨在评估 地西他滨，一种具有独特作用机制的新型化疗药物 采取行动确定它是否能显著和持久地抑制 慢性粒细胞白血病晚期和/或干扰素α中的Ph阳性细胞 (干扰素-A)耐药的CML疾病。该试剂对DNA的影响 甲基化将被研究并与表观遗传学的评估相关 项目9中的修改。目标3和4旨在评估小说 生物制剂在患者身上未能产生重大反应 干扰素。目标3开发克服耐药性的治疗方法 通过抑制细胞产生干扰素-α 白介素1受体拮抗剂对白介素1-β的评价。在AIM 4、目标是确定能改善细胞遗传学的生物制剂 对干扰素的反应。在一项先导性研究中，干扰素- Alpha和GM-CSF在干扰素中产生了显著的细胞遗传学反应 耐药患者；这种组合将在更大的II期进行研究 进行试验以评估其潜在疗效。此项目将与 在这项提案中广泛地涉及基础科学项目， 特别是，项目5(p210 bcr-Abl阳性的分子敏化 治疗的细胞)，项目4(干细胞敏感性和预测者 慢性粒细胞白血病耐药)和项目9(慢性粒细胞白血病表观遗传学改变)。

This project involves clinical investigation of strategies to improve results of chemotherapy and biologic treatment of CML. Aim 1 builds upon the success of the program in defining the activity of interferon-alpha for CML and more recently the combination of interferon and cytarabine. We will test the hypothesis that the combination of interferon-alpha, cytarabine and ATRA improves outcome compared to interferon- alpha/cytarabine treatment. Aim 2 is directed to evaluation of a decitabine, a novel chemotherapeutic agent with a unique mechanism of action to determine if it an induce significant and durable suppression of the Ph-positive cells in late chronic phase CML and/or in interferon alpha (IFN-A) resistant CML disease. The effects of this agent on DNA methylation will be studied and related to the evaluation of epigenetic alterations in Project 9. Aims 3 and 4 are directed to evaluating novel biologic agents in patients failing to have a major response to interferon. Aim 3 develops therapeutic approaches to overcome resistance to interferon-alpha via the inhibition of cellular production of interleukin 1-beta evaluation of interleukin-1 receptor antagonist. In aim 4, the objective is to identify biologics which improve cytogenetic response to interferon. In a pilot study, the combination of interferon- alpha and GM-CSF has produced marked cytogenetic responses in interferon resistant patients; this combination will be studied in a larger phase II trial to evaluate its potential efficacy. This project interacts extensively with he basic science projects within this proposal, particularly, Project 5 (Molecular Sensitization of p210 Bcr-Abl Positive Cells to Therapy), Project 4 (Stem Cell Prognosticators of Sensitivity & Resistance in CML) and Project 9(Epigenetic Alterations in CML).