PRECLINICAL AND CLINICAL PHARMACOLOGY/EXPERIMENTAL THERAPEUTICS

临床前和临床药理学/实验治疗

• 批准号: 2456841
• 负责人: J GREM
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2456841
• 关键词: adenocarcinoma; antineoplastics; camptothecin; clinical research; clinical trial phase I; colorectal neoplasms; dosage; drug administration rate /duration; drug screening /evaluation; fluorouracil; gastrointestinal neoplasms; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; pharmacokinetics; tissue /cell culture

Innovative strategies are needed to improve the prognosis of patients with advanced adenocarcinomas arising in the gastrointestinal tract. We have tested several approaches to biochemically modulate fluorouracil (FUra), and are studying the interaction of other agents with FUra in vitro to define optimal sequences for potential clinical use. The identification of new agents such as the camptothecin analogs that display potent in vitro and in vivo activity against GI adenocarcinomas is of paramount importance. Studies designed to elucidate the optimal schedule of administration and mechanism of action of such agents are vital to facilitate their rational clinical use. We implement Phase I clinical trials that incorporate clinical pharmacokinetic, biochemical and/or molecular endpoints. New analytic assay methods are developed to measure the pharmacokinetics and intracellular pharmacodynamics of the anticancer agents. Colorectal cancer cells appear to have an extraordinary capacity to recover from the metabolic and/or genotoxic stress imposed during a transient cytotoxic insult. The refractory nature of human colorectal cancer may be attributed to differences in the cellular response to genotoxic stress such as DNA synthetic inhibition and/or DNA damage, and an impaired ability to undergo programmed cell death. These molecular phenotypes result from mutations in several key genes including p53, ras, and genes coding for proteins involved in DNA mismatch repair. Our ultimate goal is to develop new agents and drug combinations for patients with GI adenocarcinomas and to develop strategies to selectively target cancer cells with genomic instability and/or impaired programmed cell death pathways.

需要创新的策略来改善慢性粒细胞白血病患者的预后 发生在胃肠道的晚期腺癌。我们有 测试了几种生化调节氟尿嘧啶(Fura)的方法， 并正在研究其他制剂与富拉在体外的相互作用 确定潜在临床使用的最佳序列。身份识别 一系列新的药物，如喜树碱类似物，在 体外和体内抗胃肠腺癌活性至关重要 重要性。旨在阐明最优时间表的研究 这类机构的管理和行动机制对 促进其在临床上的合理应用。我们实施I期临床 结合临床药代动力学、生化和/或 分子端点。发展了新的分析测试方法来测量 抗癌药物的药代动力学和细胞内药效学 探员们。结直肠癌细胞似乎具有非凡的能力。 从新陈代谢和/或基因毒性应激中恢复 短暂的细胞毒性侮辱。人类结直肠癌的难治性 癌症可能归因于细胞反应的不同 基因毒性应激，如DNA合成抑制和/或DNA损伤，以及 细胞程序性死亡的能力受损。这些分子 表型是由几个关键基因的突变引起的，其中包括p53，ras， 以及编码参与DNA错配修复的蛋白质的基因。我们的 最终目标是为患者开发新的药物和药物组合 与胃肠腺癌的关系，并制定选择性靶向治疗的策略 基因组不稳定和/或编程细胞受损的癌细胞 死亡之路。