MECHANISM OF ACTION OF FOLATE ANTAGONISTS

叶酸拮抗剂的作用机制

• 批准号: 3163294
• 负责人: JOSEPH Rocco BERTINO
• 金额: $ 29.59万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-12-01 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3163294
• 关键词: antineoplastics; carboxypeptidase; chemical structure function; dihydrofolate reductase; dogs; drug metabolism; enzyme inhibitors; folate; folate antagonist; genetic manipulation; guinea pigs; human subject; human therapy evaluation; laboratory mouse; leukemia; lymphoma; methionine; methotrexate; neoplasm /cancer chemotherapy; polyglutamates; thymidylate synthase; triazines; tritium

The further characterization and study of 3 important enzymes that are targets for chemotherapeutic agents is proposed. By using techniques of recombinant DNA technology, we propose to generate sufficient amounts of two of these enzymes (dihydrofolate reductase and thymidylate synthase) and altered forms of these enzymes for detailed studies of structure, characterization, and interaction with inhibitors. The regulation of thymidylate synthetase will be further studied. Based on this and other information, new approaches to drug development, in particular inhibition of polyglutamate synthetase are planned. Strategies for prevention and eradication of drug resistant cells, based on concurrent or alternating therapy with folate contagonists have been formulated, and will be tested using tumor cells propagated in vitro, and with murine tumors propagated in vivo.

3种重要酶的进一步表征和研究 提出了化疗药物的目标。 通过使用以下技术 重组DNA技术，我们建议产生足够量的 其中两种酶（二氢叶酸还原酶和胸苷酸合成酶）和 改变这些酶的形式以进行结构的详细研究， 表征以及与抑制剂的相互作用。 的监管 胸苷酸合成酶将得到进一步研究。 基于此信息和其他信息，药物开发的新方法 计划特别抑制聚谷氨酸合成酶。 策略 用于预防和根除耐药细胞，基于并发 或已经制定了叶酸拮抗剂的交替疗法，并且 将使用体外繁殖的肿瘤细胞和小鼠进行测试 肿瘤在体内繁殖。