CANCER MODELS FOR DNA-INTERACTING DRUGS

DNA 相互作用药物的癌症模型

• 批准号: 3166577
• 负责人: HERBERT S SCHWARTZ
• 金额: $ 12.44万
• 依托单位: ROSWELL PARK CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-01-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3166577
• 关键词: DNA directed DNA polymerase; adenosinetriphosphatase; allopurinol; anthracyclines; brain neoplasms; combination chemotherapy; cyclic AMP; cyclic GMP; daunorubicin; doxorubicin; drug adverse effect; drug metabolism; enzyme induction /repression; human therapy evaluation; human tissue; hydroxyapatites; laboratory mouse; mathematical model; microsomes; mitochondria; neoplasm /cancer pharmacology; neoplasm /cancer therapy; neoplastic cell; steroid glycoside aglycone; thin layer chromatography; thymidine; tissue /cell culture; xanthine oxidase

This project is intended to improve therapeutic efficacy of anthracyclines (Adriamycin, daunorubicin, etc.), AZQ, and related agents by altering their metabolic transformations in animals. In tumor bearing mice, anthracycline drugs will be given in combination with allopurinol which inhibits xanthine oxidase, an enzyme that converts the anthracyclines to aglycones. The same system also metabolizes AZQ and it will be tested in combination with allopurinol in mice with tumors (L1210, P388, etc.). AZQ specifically designed for chemotherapy of brain tumors, will be tested in animals with rescue agents that inactivate the drug systemically (to reduce host toxicity) but have little or no effect on AZQ in brain tumors. Associated with these studies, the effects of rescue agents in bone marrow cells with be tested by spleen colony assays. The pharmacokinetics and metabolism of AZQ in animals will be described. The interactions of labile intermediary products of biotransformation of anthracyclines, AZQ, and similar agents with DNA will be investigated with respect to cross-links and interstrand damage. These effects on DNA will be evaluated with DNA polymerase alpha.

该项目旨在提高治疗效果 蒽环类药物（阿霉素、柔红霉素等）、AZQ 及相关药物 通过改变动物体内的代谢转化来调节药物。 在 荷瘤小鼠给予蒽环类药物 与抑制黄嘌呤氧化酶的别嘌呤醇组合， 将蒽环类药物转化为糖苷配基的酶。 相同 系统也代谢AZQ，并将进行组合测试 在患有肿瘤（L1210、P388 等）的小鼠中使用别嘌呤醇。 AZQ 专为脑肿瘤化疗而设计，将 使用灭活药物的救援剂在动物身上进行测试 全身性（以减少宿主毒性）但影响很小或没有影响 AZQ 治疗脑肿瘤。 与这些研究相关， 救援剂对骨髓细胞的影响可通过以下方法进行测试 脾集落测定。 药代动力学和代谢 将描述动物中的AZQ。 不稳定的相互作用 蒽环类药物生物转化的中间产物， AZQ 和类似的 DNA 制剂将被研究 关于交联和链间损伤。 这些影响对 DNA 将使用 DNA 聚合酶 α 进行评估。