IN VITRO CORRELATES OF DRUG SENSITIVITY IN LUNG CANCER

肺癌药物敏感性的体外相关性

• 批准号: 3423784
• 负责人: BONNIE S GLISSON
• 金额: $ 5.02万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1994-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3423784
• 关键词: DNA topoisomerases; antineoplastics; drug resistance; drug screening /evaluation; enzyme activity; enzyme inhibitors; human subject; human therapy evaluation; lung neoplasms; molecular oncology; neoplasm /cancer pharmacology; quinoline analog; tissue /cell culture

Lung cancer is the leading cause of death from cancer in both American men and women with 147,000 estimated deaths in 1991. Although surgical treatment (and in the case of small cell lung cancer, chemotherapy and radiation) is effective in very early stage disease, only a small minority of patients present in this way, and even these maintain significant risk of recurrence in the five years following diagnosis. Although radiotherapy and chemotherapy can be applied to treat regionally extensive and metastatic disease, few major advances have been forthcoming in the past decade, and five year survival for patients with lung cancer overall remains quite low at 134. Thus, drug resistance represents a major obstacle to progress in the therapy of lung cancer. While in vitro models have identified the mechanisms operative in some forms of drug resistance, the causes of the resistance we encounter in the patient with lung cancer remain obscure. The overall objective of this proposal is to enhance insight into determinants of therapeutic response by evaluating pertinent in vitro correlates of drug sensitivity. We will focus on topotecan, the first topoisomerase I-targeted drug to be tested extensively in the clinic in the U.S. This drug arrives in the clinical arena with much already established regarding its mechanism of action and factors which influence cellular response. We plan prospective evaluation of critical parameters of topotecan sensitivity including topoisomerase I content, topotecan-induced cleavable complex formation, and proliferative fraction, in fresh tumor tissue of patients with lung cancer who will be treated with the drug. The long-term goal is to obtain significant correlations of these in vitro parameters with clinical outcome, both to predict response and understand resistance. However, due to the small number of patients we will be able to study initially, our immediate goals are to develop methodology, establish feasibility, and identify trends on which to base further study.

肺癌是两名美国男性癌症死亡的主要原因 和1991年估计死亡147,000人的妇女。 治疗（以及小细胞肺癌，化学疗法和 辐射）在非常早期的疾病中有效，只有少数 以这种方式出现的患者，甚至这些患者都保持了重大风险 诊断后的五年复发。 虽然放疗 并且化学疗法可用于治疗区域广泛，并且 转移性疾病，过去很少有重大进展 整体肺癌患者的十年和五年生存 在134时保持很低。因此，耐药性代表了一个主要 肺癌治疗进展的障碍。 同时体外模型 已经确定了某些形式的耐药性的机制， 我们在肺癌患者中遇到的抵抗的原因 保持晦涩。 该提议的总体目的是增强 通过评估相关性来洞悉治疗反应的决定因素 药物敏感性的体外相关性。 我们将专注于拓扑丹（Toopotecan） 第一个在诊所进行广泛测试的topoisomerase i靶向药物 在美国，这种药物已经到达临床领域 建立了有关其行动机制和影响因素的影响 细胞反应。 我们计划对关键参数的预期评估 拓调蛋白酶敏感性，包括拓扑异构酶I含量， 拓平诱导的可裂解的复合物形成和增殖分数， 在肺癌患者的新鲜肿瘤组织中 药物。 长期目标是获得明显的相关性 这些具有临床结局的体外参数，都可以预测反应 并了解抵抗。 但是，由于患者数量少 最初将能够学习，我们的近期目标是发展 方法论，确定可行性并确定以此为基础的趋势 进一步研究。