SIMULATED TUMOR THERAPY WITH AN IN VITRO MODEL

体外模型模拟肿瘤治疗

• 批准号: 3175581
• 负责人: RALPH E. DURAND
• 金额: $ 11.64万
• 依托单位: BRITISH COLUMBIA CANCER AGENCY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3175581
• 关键词: 5 fluorouridine; antineoplastics; biological models; carmustine; cellular oncology; cis platinum compound; combination cancer therapy; combination chemotherapy; doxorubicin; drug resistance; lomustine; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; radiation sensitivity; respiratory oxygenation; tissue /cell culture

Most human malignancies will respond to current chemotherapeutic treatment regimens, yet few neoplasms can be cured by chemotherapy alone. Development of more effective drugs is thus necessary, but we believe that a high priority should also be placed on optimizing the use of available agents, which in turn requires a better understanding of the factors which modulate drug activity in a tumor. While drug 'resistance' is generally implicated as the cause of treatment failure, it is seldom possible to know when, where, or why resistant cells appear in the tumor mass. This information can, however, be determined in certain laboratory models, like V79 multicell spheroids in tissue culture. We thus intend to evaluate several clinically-used chemotherapeutic agents in spheroids, emphasizing regional and temporal variations in cytotoxicity; our results will suggest ways to use each agent more effectively, and provide additional criteria for selecting (and using) drug combinations. Regional variations in drug efficacy will be studied in spheroids stained with slowly-penetrating, non-toxic fluorescent dyes. Since the dyes are retained in disaggregated cells, a fluorescence- activated cell sorter can be used to select subpopulations with specified stain intensities; the clonogenicity of these sorted cells then defines the drug toxicity throughout the spheroid. The location, timing and degree of resistance to each drug will suggest useful combinations, as well as indicating ways to improve single- agent efficacy. In subsequent multidrug studies, therapeutically useful interactions, including differential (complementary) toxicity, reoxygenation, cell cycle perturbations, metabolic alterations, and/or direct interaction of lesions, will be identified and quantified. The resulting information will supplement that already available for these clinically effective drugs, so promising combinations, doses and sequences and can be evaluated in patients without delay.

大多数人类恶性肿瘤都会回应当前 化学治疗治疗方案，但很少有肿瘤可以 仅通过化学疗法治愈。 发展更有效 因此，必须使用毒品，但我们认为高度优先级应该 还放置在优化可用代理的使用中，其中 转弯需要更好地了解这些因素 调节肿瘤中的药物活性。 而毒品的“抗药性”是 通常被认为是治疗失败的原因，是 很少可能知道何时，何地或为什么要抗性细胞 出现在肿瘤质量中。 但是，这些信息可以是 在某些实验室模型中确定，例如V79 Multicell 组织培养中的球体。 因此，我们打算评估几个 球体中临床中使用的化学治疗剂，强调 细胞毒性的区域和时间变化；我们的结果将会 建议更有效地使用每个代理的方法，并提供 选择（和使用）药物组合的其他标准。 将在球体中研究药物疗效的区域变化 用缓慢渗透的无毒荧光染料染色。 由于染料保留在分解的细胞中，因此 活化的单元格拉刀可用于选择与 指定的污渍强度；这些分类细胞的克隆发育性 然后定义整个球体的药物毒性。 这 位置，时间和对每种药物的抵抗力 有用的组合，并指示改善单一组合的方法 代理功效。 在随后的多药研究中，在治疗上 有用的相互作用，包括差分（互补） 毒性，重氧，细胞周期扰动，代谢 病变的改变和/或直接相互作用将被识别 并量化。 由此产生的信息将补充 已经可用于这些临床有效的药物，因此很有希望 组合，剂量和序列，可以评估 患者毫不延迟。