TUMOR BIOLOGY

肿瘤生物学

• 批准号: 3751186
• 负责人: BEPPINO C GIOVANELLA
• 金额: --
• 依托单位: NEW YORK UNIVERSITY
• 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/3751186
• 关键词: DNA topoisomerases; antineoplastics; athymic mouse; camptothecin; cell growth regulation; clone cells; colon neoplasms; dosage; drug adverse effect; drug design /synthesis /production; drug resistance; drug screening /evaluation; enzyme inhibitors; human subject; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer transplantation; neoplastic cell; nonhuman therapy evaluation; statistics /biometry; xenotransplantation

PROGRAM 4 - TUMOR BIOLOGY is part of the Project entitled: 'DNA Topoisomerase I-Targeted Therapy of Colon Cancer'. Highly active topoisomerase I inhibitors, identified in Program 2 and 3 and synthesized in adequate quantities by Program 1, will be tested using the xenograft system. The highest priority has been given to advanced studies of camptothecin analogs with unprecedented efficacy against colon cancer xenografts (See Overall Research Plan, Preliminary Studies). Every effort will be made to bring these analogs to early clinical trials. Our approach follows several steps: 1. Each compound received for evaluation will be tested for acute and chronic toxicity in nude mice. 2. Initial testing of a new analog, active in in-vitro screens, will be done on two xenograft tumor lines, and the advanced drug studies on two additional lines. The overall toxicity, as well as intestinal, bone marrow and urinary bladder toxicities will be monitored. The endpoints include tumor growth prevention, delay in growth, tumor regression/regrowth. 3. The treatment of artificial liver, lung, or brain metastases and cecal implants will be part of the advanced drug testing. The data will be evaluated and their statistical significance established. 4. Attempts will be made to identify tumors with de-novo resistance and develop one or several human colonic tumor lines with acquired resistance to camptothecin analogs. Studies of drug resistance will be done in close collaboration with Program 3. 5. Drug distribution studies in tumor-bearing mice will test, following subcutaneous, intravenous or femoral drug administration, drug plasma levels, disposition via urinary and hepatobiliary tract, as well as tissue distribution.

方案4--肿瘤生物学是名为‘DNA’的项目的一部分 拓扑异构酶I靶向治疗结肠癌‘。高度活跃 程序2和3中确定并合成的拓扑异构酶I抑制剂 将使用异种移植物进行测试 系统。对以下方面的高级研究给予了最高优先 喜树碱类似物对结肠癌具有前所未有的疗效 异种移植(见总体研究计划，初步研究)。尽一切努力 将使这些类似物进入早期临床试验。我们的方法 遵循以下几个步骤： 1.接受评估的每一种化合物都将进行急性和 对裸鼠的慢性毒性。 2.一种在体外筛选中活跃的新类似物的初步测试将是 在两个异种移植瘤系上进行了研究，并对两个 更多的行。总的毒性，以及肠道、骨髓 并对膀胱毒性进行监测。终端包括 防止肿瘤生长、延缓生长、肿瘤消退/再生长。 3.人工肝、肺或脑转移瘤及盲肠的治疗 植入物将成为先进药物测试的一部分。数据将是 对其进行评估，并建立其统计意义。 4.将尝试识别具有去新生抵抗的肿瘤和 建立一个或多个具有获得性耐药的人结肠肿瘤细胞系 喜树碱类似物。耐药性研究将在近距离进行 与计划3协作。 5.药物在荷瘤小鼠中的分布研究将进行测试，如下 皮下、静脉或股动脉给药，药物血浆 水平、通过尿路和肝胆管以及组织的处置 分发。