DIFFERENTIATING AGENTS IN HEMATOLOGIC MALIGNANCIES

血液系统恶性肿瘤的分化剂

• 批准号: 3184353
• 负责人: DONALD W. KUFE
• 金额: $ 25.19万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1990-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3184353
• 关键词: 1,25 dihydroxycholecalciferol; 13 cis retinoate; cell differentiation; cyclosporines; cytogenetics; cytosine arabinoside; flow cytometry; formamide; gene expression; genetic manipulation; hexamethonium compound; human tissue; immunosuppressive; interferons; molecular cloning; monoclonal antibody; myelogenous leukemia; neoplasm /cancer transplantation; oncogenes; surface antigens

The proposed studies represent an integrated program consisting of basic research interfaced with concurrent clinical trails of differentiating agents in the treatment of hematologic malignancies. The proposal is comprised of 4 interrelated areas. The basic studies encompass two areas that will monitor changes in expression of cell surface antigens and proto-oncogenes during differentiation. Each of these approaches is now applicable to clinical samples. The basic approaches will be used to monitor differentiation of leukemic blasts transplanted into cyclosporine-treated mice. The fourth area of emphasis will be clinical investigation. In addition to ongoing studies with low-dose cytosine arabinoside and 13-cis-retinoic acid, protocols are being developed for the study of interferon-gamma, hexamethylene bisacetamide, N-methylformamide and 1,25(OH)2D3. Combination trials will be directed by preclinical findings. The available resources will thus allow us to integrate molecular biology, immunology and in vivo pharmacology with clinical trials. The specific aims are: 1) to monitor expression of cell surface differentiation antigens, self-renewal capacity and cytogenetics of leukemic blast progenitors following treatment with differentiating agents; 2) to monitor proto-oncogene expression as a measure of in vitro and in vivo differentiation of leukemic blasts and leukemic progenitor cells; 3) to determine the effects of differentiating agents alone and in combination on induction of leukemic blasts using an in vivo model; 4) to perform clinical trials with differentiating agents in which outcome is correlated with cell surface differentiation antigens, proto-oncogene expression and differentiation of blasts in vitro and in the in vivo model. These approaches, taken together, should provide new and relevant information regarding the induction of differentiation as clinical therapy.

拟议的研究代表了一个综合计划，包括基本的 研究与并发临床试验相结合 治疗血液系统恶性肿瘤的药物。 该提案是 由 4 个相互关联的领域组成。 基础研究涵盖两个领域 将监测细胞表面抗原表达的变化 分化过程中的原癌基因。 这些方法中的每一种现在都 适用于临床样本。 基本方法将用于 监测移植到的白血病细胞的分化 环孢素治疗的小鼠。 第四个重点领域是临床 调查。 除了正在进行的低剂量胞嘧啶研究外 阿拉伯糖苷和 13-顺式视黄酸，正在制定方案 干扰素-γ、六亚甲基双乙酰胺、N-甲基甲酰胺的研究 和1,25(OH)2D3。 联合试验将由临床前指导 发现。 因此，可用资源将使我们能够整合 分子生物学、免疫学和体内药理学及临床试验。 具体目的是：1）监测细胞表面的表达 分化抗原、自我更新能力和细胞遗传学 用分化剂治疗后的白血病原始细胞； 2) 监测原癌基因的表达作为体外和体内的测量 白血病原始细胞和白血病祖细胞的体内分化； 3） 确定单独和组合的差异化药物的效果 使用体内模型诱导白血病细胞； 4）执行 具有相关结果的差异化药物的临床试验 与细胞表面分化抗原、原癌基因表达和 体外和体内模型中原始细胞的分化。 这些 综合起来，各种方法应提供新的相关信息 将诱导分化作为临床治疗。