FOLYL- AND ANTIFOLYLPOLYGLUTAMATES IN COMBINATION CHEMOTHERAPY

叶酰和抗叶酰聚谷氨酸盐在联合化疗中的应用

• 批准号: 5206530
• 负责人: JOHN J MCGUIRE
• 金额: --
• 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/5206530
• 关键词: combination chemotherapy; cytotoxicity; dosage; drug administration rate /duration; drug interactions; drug metabolism; drug screening /evaluation; fluorine; fluorouracil; human tissue; laboratory rat; leucovorin; methotrexate analog; neoplasm /cancer chemotherapy; neoplastic cell; polyglutamates; stereoisomer; tissue /cell culture

The long term objective of this research is to improve chemotherapy of cancer by using novel antifolates or novel reduced-folate analogs for biochemical modulation to yield an increased therapeutic index. The approach to be used may also define the role of antifolyl- and folylpolyglutamate metabolites in cytotoxicity and selectivity. The antifolate methotrexate (MTX) is clinically effective in combination chemotherapy regimens, but its efficacy is often limited by resistance which cannot be overcome at higher doses because toxicity is reached, i.e., it is not selective enough. Polyglutamates of MTX are implicated in its cytotoxicity as a single agent, but their contribution to cytotoxicity and (particularly) selectivity in combinations using this agent are unknown. Exogenous reduced folates (as leucovorin (LV); 5-formyltetra- hydrofolate) are used to "rescue" from the cytotoxic effects of MTX and to augment the cytotoxicity of other drugs (e.g., 5-fluorouracil [FU]). The role of folylpolyglutamate synthesis in achieving these effects as well as in host toxicity and selectivity are unknown. This proposal will determine whether substitution of nonpolyglutamylatable analogs of MTX and LV in combination chemotherapy yields any therapeutic advantage. The analogs of MTX and LV will contain 4-fluoroglutamate instead of glutamate, a change sufficient to block polyglutamylation of the analog. The proposed studies of drug combinations will compare the biochemical, cytotoxic, and therapeutic effects of LV or MTX in a regimen with the same regimen containing these nonpolyglutamylatable "mimics". Cytotoxicity will be assessed by out-growth and/or clonogenic assays using the human leukemia cell line CCRF-CEM and an appropriate murine model (for extension to in vivo therapeutic studies); time and dose dependence will be investigated in detail. Where feasible the biochemical determinants of cytotoxicity will be explored. The regimens to be investigated are: sequential MTX/5FU, simultaneous LV/5-FU, and LV rescue of MTX cytotoxicity. MTX and LV and their respective fluorinated "mimics" will be compared to determine if they are biochemically equivalent, except for polyglutamylation. If the analogs are true "mimics, the results from the cytotoxicity and efficacy studies would yield basic knowledge about the role of polyglutamates in these combinations. It is hoped that the knowledge gained in these studies will provide a basis for more sophisticated therapy protocols with improved efficacy.

这项研究的长期目标是改善化疗， 通过使用新的抗叶酸剂或新的还原叶酸类似物 生物化学调节以产生增加的治疗指数。 的 使用的方法也可以定义antifolyl的作用， 叶酰聚谷氨酸代谢物的细胞毒性和选择性。 的 抗叶酸剂甲氨蝶呤（MTX）是临床有效的组合 化疗方案，但其疗效往往是有限的耐药性 其不能在较高剂量下克服因为达到毒性， 也就是说，它选择性不够。 MTX的多聚谷氨酸盐涉及 其作为单一药剂的细胞毒性，但它们对细胞毒性的贡献 和（特别是）选择性的组合使用该试剂是 未知 外源性还原叶酸（如甲酰四氢叶酸（LV）; 5-甲酰四氢叶酸） 氢叶酸）用于“拯救”MTX的细胞毒性作用， 增加其它药物的细胞毒性（例如，5-氟尿嘧啶[FU]）。 的 叶酸聚谷氨酸合成在实现这些效果中的作用，以及 在宿主中毒性和选择性是未知的。 这项建议会 确定MTX的非多聚谷氨酰化类似物和 LV联合化疗产生任何治疗优势。 的 MTX和LV的类似物将含有4-氟谷氨酸而不是谷氨酸， 足以阻断类似物的多聚谷氨酰化的变化。 的 建议的药物组合研究将比较生物化学， LV或MTX在使用其的方案中的治疗效果 含有这些非聚谷氨酰化的“模拟物”的方案。 细胞毒性 将通过使用人类的生长和/或克隆形成试验进行评估。 白血病细胞系CCRF-CEM和适当的鼠模型（用于扩展 体内治疗研究）;时间和剂量依赖性将是 详细调查。 在可行的情况下， 将探索细胞毒性。 待研究的方案为： MTX/5-FU序贯治疗、同时LV/5-FU治疗和MTX的LV补救治疗 细胞毒MTX和LV以及它们各自的氟化“模拟物”将在 比较以确定它们是否具有生物化学等效性，除了 多聚谷氨酰化 如果类似物是真正的“模拟物”，则来自 细胞毒性和疗效研究将产生关于 聚谷氨酸在这些组合中的作用 希望广大 在这些研究中获得的知识将为更多的 先进的治疗方案，提高疗效。