EXPERIMENTAL THERAPEUTICS

实验治疗

• 批准号: 6203324
• 负责人: MALCOLM A. MOORE
• 金额: $ 15.02万
• 依托单位: GERON CORPORATION
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-17 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203324
• 关键词: cell growth regulation; clone cells; cooperative study; disease /disorder model; dosage; drug discovery /isolation; drug metabolism; enzyme activity; enzyme inhibitors; human tissue; laboratory mouse; leukemia; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; nucleic acid hybridization; pharmacokinetics; telomerase; telomere; xenotransplantation

Malignant growth leads to an unremitting increase in tumor burden despite treatment with antineoplastic agents. Treatment advances have been largely empirical, with improvements in surgical technique and the delivery of radiation therapy, leading to combined modality therapies that have improved outcomes for many patients. Loss of normal growth regulatory mechanisms and infinite replicative capacity are common features of many human malignancies. Successful targeting of the process whereby malignant cells become or maintain an immortal state should be an effective strategy for a number of cancers. Telomerase inhibition represents a new paradigm for, the treatment of human malignancies. As stated in Specific Aim 3, we will select and characterize human tumor cell lines and pathologic tumor samples from patients with representative tumor types of different stages for telomerase activity and telomere length. In Specific Aim 6, an in vitro evaluation of compounds identified in the high throughput screen will be examined against normal, tumor, and leukemia cell lines representative of the clinical profile studied in Specific Aim 3 to complement in vitro studies that will be conducted at Geron. Specifically, experiments will be conducted using cell lines and cultured primary tumors to examine the effects of a telomerase inhibitor on growth kinetics, telomerase activity, and telomere length. In Specific Aim 7 an assay will be developed for the detection of a candidate telomerase inhibitor(s) in biological materials. Pharmacology, drug metabolism, and pharmacokinetic studies will be conducted in order to optimize the bioavailability and activity of the compound in anticipation of performing animal experiments. In Specific Aim 8 we will select compounds showing in vitro efficacy and evaluate their effects on normal, and immunocompromised mice transplanted with tumor cell lines, primary tumors, or leukemias. Dosing schedules will be optimized and different routes of administration (p.o., i.v,, i.p., s.c.) will be evaluated. The capacity of telomerase inhibitors to block the development of tumors, to regress established tumors with or without chemotherapy, and/or to prevent metastasis will be measured. Quantitative measurements of tumor burden and residual disease will be determined by sensitive serologic, fluorescence, chromophilic, or molecular techniques. Telomerase levels and telomere length will be measured in control and treated tumors as a function of growth rate and time.

恶性生长导致肿瘤负担持续增加 尽管接受了抗肿瘤药物治疗。治疗方面的进展 在很大程度上是经验的，手术技术和 放射治疗的提供，导致了联合治疗 对许多患者有改善效果的治疗方法。损失 正常的生长调控机制和无限的复制能力 是许多人类恶性肿瘤的共同特征。成功锁定目标 恶性细胞变成或维持永生细胞的过程 国家应该是治疗一些癌症的有效策略。 端粒酶抑制代表了一种新的治疗方法 人类的恶性肿瘤。如具体目标3所述，我们将选择和 人类肿瘤细胞系和病理肿瘤标本的特征 不同分期具有代表性的肿瘤类型患者 端粒酶活性和端粒长度。在特定的目标6中，一个在 高通量筛选鉴定化合物的体外评价 将针对正常、肿瘤和白血病细胞系进行检测 在具体目标3至3中研究的临床概况的代表性 将在Geron进行的补体体外研究。 具体地说，将使用细胞系和 培养原发肿瘤以检测端粒酶的作用 抑制生长动力学、端粒酶活性和端粒 长度。在特定的目标7中，将开发一种检测方法 生物材料中的一种候选端粒酶抑制物(S)。 药理学、药物代谢和药代动力学研究将 为了优化生物利用度和活性而进行的 预期进行动物实验的化合物。具体而言 目的8筛选具有体外药效的化合物并进行评价 它们对正常和免疫低下小鼠移植的影响 肿瘤细胞系、原发肿瘤或白血病。配药计划将 优化不同的给药途径(P.O.、I.V.、I.P.、 S.C.)将会被评估。端粒酶抑制物抑制端粒酶活性 阻断肿瘤的发展，以消退已建立的肿瘤 或不进行化疗，和/或防止转移 量过了。肿瘤负荷和残留量的定量测量 疾病将通过敏感的血清学、荧光、 亲色性，或分子技术。端粒酶水平与端粒 长度将在对照组和治疗组肿瘤中作为函数进行测量 增长速度和时间的关系。