EXPERIMENTAL THERAPEUTICS

恶性生长导致肿瘤负荷持续增加 尽管使用了抗肿瘤药物治疗。治疗的进步 随着手术技术的改进， 放射治疗的实施，导致联合治疗 这些疗法改善了许多患者的预后。损失 正常的生长调节机制和无限的复制能力 是许多人类恶性肿瘤的共同特征。成功靶向 指恶性细胞变成或保持永生的过程 国家应该是一个有效的战略，对一些癌症。 端粒酶抑制代表了一种新的治疗模式， 人类恶性肿瘤如具体目标3所述，我们将选择和 表征人肿瘤细胞系和病理肿瘤样品， 具有不同阶段的代表性肿瘤类型的患者， 端粒酶活性和端粒长度。在具体目标6中， 在高通量筛选中鉴定的化合物的体外评价 将针对正常、肿瘤和白血病细胞系进行检查 代表特定目标3至 补充将在Geron进行的体外研究。 具体地，将使用细胞系和 培养原发性肿瘤来检测端粒酶的作用 生长动力学、端粒酶活性和端粒抑制剂 长度在具体目标7中，将开发一种检测方法， 生物材料中候选端粒酶抑制剂的研究。 将进行药理学、药物代谢和药代动力学研究。 进行，以优化生物利用度和活性的 化合物，预期进行动物实验。在特定 目的8我们将选择在体外表现出功效的化合物并进行评价 它们对正常和免疫功能低下的小鼠的影响， 肿瘤细胞系、原发性肿瘤或白血病。给药方案将 优化和不同的给药途径（p.o.，静脉注射，腹腔注射， （单位：秒）将被评估。端粒酶抑制剂的能力， 阻断肿瘤的发展，使已建立的肿瘤消退， 或不使用化疗，和/或预防转移， 测定了肿瘤负荷和残留的定量测量 疾病将通过敏感的血清学，荧光， 或分子技术。端粒酶水平和端粒 将在对照和治疗的肿瘤中测量长度作为函数 增长速度和时间。

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.