COMBINED MODALITY THERAPY TO SUPPRESS PHILADELPHIA CHROMOSOME CELLS IN CML

该项目涉及临床研究的战略，以改善 CML的化疗和生物治疗的结果。目标1建立在 该计划在确定α干扰素活性方面的成功 治疗慢性粒细胞白血病以及最近的干扰素和阿糖胞苷联合治疗。我们 将检验干扰素-α， 与干扰素相比，阿糖胞苷和全反式维甲酸可改善预后， α/阿糖胞苷治疗。目标2是评估一个 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，以确定它是否会导致重大和持久的抑制， 慢性期晚期CML和/或干扰素α中的Ph阳性细胞 （IFN-A）抗性CML疾病。这种药剂对DNA的影响 甲基化将被研究，并与表观遗传学的评价有关。 9号工程改造。目的3和4是针对评价新颖的 生物制剂在对以下药物无重大反应的患者中 干扰素目标3开发治疗方法以克服耐药性 干扰素-α通过抑制细胞产生 白细胞介素-1受体拮抗剂白细胞介素-1-β评价。在aim中 4.目的是鉴定改善细胞遗传学的生物制剂， 对干扰素的反应在一项初步研究中，干扰素- α和GM-CSF在干扰素治疗中产生了显著的细胞遗传学应答 耐药患者;将在更大的II期临床试验中研究该联合用药。 试验以评估其潜在功效。该项目相互作用 在这个提案中广泛地涉及基础科学项目， 特别是，项目5（p210 Bcr-Abl阳性的分子致敏 细胞治疗），项目4（敏感性和 项目9（CML中的表观遗传改变）。

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).