TUMOR BIOLOGY

肿瘤生物学

• 批准号: 3773504
• 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/3773504
• 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.

计划 4 - 肿瘤生物学是名为“DNA”的项目的一部分 结肠癌的拓扑异构酶 I 靶向治疗'。高活性 拓扑异构酶 I 抑制剂，在程序 2 和 3 中鉴定并合成 计划 1 提供的足够数量，将使用异种移植物进行测试 系统。 最优先考虑的是高级研究 喜树碱类似物对结肠癌具有前所未有的功效 异种移植（参见总体研究计划、初步研究）。 每一份努力 将致力于将这些类似物带入早期临床试验。 我们的方法 分为几个步骤： 1. 收到用于评估的每种化合物都将进行急性和 裸鼠慢性毒性。 2. 将在体外屏幕中对新模拟进行初步测试 对两个异种移植肿瘤系进行的研究，以及对两个异种移植肿瘤系的高级药物研究 额外的线路。 总体毒性，以及肠道、骨髓 并将监测膀胱毒性。 端点包括 预防肿瘤生长、延​​迟生长、肿瘤消退/再生。 3.人工肝、肺或脑转移及盲肠的治疗 植入物将成为先进药物测试的一部分。 数据将是 评估并确定其统计显着性。 4. 将尝试识别具有从头耐药性的肿瘤 开发一种或多种具有获得性耐药性的人类结肠肿瘤系 喜树碱类似物。 耐药性研究将密切进行 与计划 3 的合作。 5. 荷瘤小鼠体内的药物分布研究将测试如下 皮下、静脉或股静脉给药、药物血浆 水平、通过泌尿道和肝胆道以及组织的处置 分配。