PRECLINICAL DEVELOPMENT OF A GLUTATHIONE BASED CANCER DRUG

描述（由申请人提供）：该A2修订I期STTR的目标是将学术团队的专业知识与Novelos Therapeutics Inc.的资源相结合，研究一种新的可注射小分子衍生物，该衍生物是氧化谷胱甘肽（GSSG）的专有和稳定配方，称为NOV-002。在俄罗斯完成的现有临床试验结果表明，该药物对癌症患者的治疗作用，美国的临床试验正处于规划阶段。为了获得FDA的新药批准，需要临床前数据，本申请中提出的方法是推进这一议程的唯一手段。本STTR的目的是促进临床前药代动力学研究，并确定NOV-002治疗可能的药效学终点。该计划包括鉴定药物诱导的谷胱甘肽化蛋白，这些蛋白可能作为似是而非的血浆标记物和骨髓细胞中的靶蛋白，可能与药物疗效和作用机制有关。这些蛋白质的鉴定将使用s -谷胱甘肽化残基特异性抗体和免疫印迹技术、蛋白质组学检查和质谱分析来实现。为了进一步研究NOV-002的骨髓增殖活性，药物治疗小鼠的骨髓细胞将被用于研究细胞因子和生长因子表达上游的信号通路。这些研究应该有助于理解影响氧化还原平衡的药物如何影响血液增殖参数。这些目标与公司驱动的临床试验相一致，应该为增强最终药物注册的势头提供动力。

DESCRIPTION (provided by applicant): The goal of this A2 revised Phase I STTR is to combine the expertise of an academic team with the resources of Novelos Therapeutics Inc. to study a new injectable small molecule derivative of a proprietary and stabilized formulation of oxidized glutathione (GSSG) called NOV-002. Existing clinical results from trials completed in Russia suggest therapeutic activity of the drug in cancer patients and US clinical trials are in the planning stages. To gain FDA approval of a new drug, preclinical data are required and the approaches proposed in this application are the sole means to advance this agenda. The aims of this STTR are designed to facilitate preclinical pharmacokinetic studies and identify possible pharmacodynamic endpoints of NOV-002 treatment. The plans include identification of drug-induced glutathionylated proteins that may serve as plausible plasma markers and target proteins in bone marrow cells that may be relevant to drug efficacy and mechanism of action. Identification of these proteins will be achieved using antibodies specific for S-glutathionylated residues and immunoblot techniques, proteomic work-up and mass spectrometry. As a further interrogation of the myeloproliferative activity of NOV-002, bone marrow cells from drug treated mice will be used to study the signaling pathways that may be upstream of cytokine and growth factor expression. Such studies should aid in understanding how agents that influence redox balance impact on parameters of hematological proliferation. These aims, in concert with company driven clinical trials, should provide the impetus to enhance the momentum towards eventual drug registration.