PRECLINICAL DEVELOPMENT OF A GLUTATHIONE BASED CANCER DRUG

描述(由申请人提供)：这项A2修订的第一阶段STTR的目标是将学术团队的专业知识与Novelos治疗公司的资源相结合，研究一种名为NOV-002的氧化谷胱甘肽(GSSG)专利稳定配方的新的可注射小分子衍生物。在俄罗斯完成的现有临床试验结果表明，该药物对癌症患者具有治疗活性，美国的临床试验正处于规划阶段。为了获得FDA对新药的批准，需要临床前数据，而本申请中提出的方法是推进这一议程的唯一手段。这项STTR的目的是促进临床前药代动力学研究，并确定NOV-002治疗的可能药效终点。这些计划包括鉴定药物诱导的谷胱甘肽基化蛋白，这些蛋白可能作为可信的血浆标志物，以及骨髓细胞中可能与药物疗效和作用机制相关的靶蛋白。这些蛋白质的鉴定将使用针对S谷胱甘肽残基的抗体和免疫印迹技术、蛋白质组学工作和质谱学。作为对NOV-002骨髓增殖活性的进一步询问，来自药物处理的小鼠的骨髓细胞将被用于研究可能是细胞因子和生长因子表达上游的信号通路。这样的研究应该有助于理解影响氧化还原平衡的因素如何影响血液学增殖参数。这些目标与公司主导的临床试验相结合，应该会推动最终实现药物注册的势头。

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.