MECHANISMS OF ANTIFOLATE EFFICACY

抗叶酸功效的机制

• 批准号: 6112863
• 负责人: SARAH LUISE MORGAN
• 金额: $ 2.95万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6112863
• 关键词: adenosine; clinical research; clinical trials; combination chemotherapy; folate; folate antagonist; human subject; human therapy evaluation; methotrexate; neurotransmitter metabolism; rheumatoid arthritis; tetrahydrofolates

Low-dose methotrexate therapy suppresses autoimmune arthritis in human and animal models. It is our hypothesis that the effect of methotrexate in the treatment of rheumatoid arthritis is due to the inhibition of aminoimidazole-carboxamide ribotide transformylase, a folate-dependent enzyme which catalyzes the last step in the de novo biosynthesis of inosine monophosphate. The resulting accumulation of aminoimidazole carboxamide riboside inhibits adenosine deaminase, therefore, interfering with normal adenosine metabolism. It is well known that children with adenosine deaminase deficiency have severe-combined-immunodeficiency syndrome. This suggests that adenosine deaminase activity is key to immune competence and is associated with the mechanism of efficacy in methotrexate therapy of rheumatoid arthritis. Several studies indicate that supplemental folinic acid (5-formytetrahydrofolate) used in large doses during low-dose methotrexate therapy for rheumatoid arthritis causes a flare in joint inflammation. However, supplemental folic acid (pteroylglutamic acid) does not lessen the efficacy of the therapy. We further hypthesize that if methotrexate efficacy is driven by aminoimidazole carboxamide ribotide transformylase inhibition, folic acid supplementation should not alter urinary levels of aminoimidazole carboxamide, adenosine, and deoxyadenosine, while folinic acid supplementation should prevent the accumulation of these compounds. Our hypotheses will be tested both in patients with rheumatoid arthritis and in Lewis rat adjuvant arthritis. Objectives include: A) to deterine if the dose level of methotrexate which is clinically optimal in the treatment of Lewis rat adjuvant arthritis interferes with normal adenosine metabolism; B) to determine the effectiveness of drugs which interfere with adenosine metaboism (deoxycoformycin, aminioimidazole carboxamide, and aminoimidazole carboxamide with a suboptimal dose of methotrexate) in Lewis rat adjuvant arthritis; and C) to determine whether supplemental folic acid and folinic acid during methotrexate therapy normalize adenosine metabolism in patients with rheumatoid arthritis. The information from this research will enhance the understanding of the biochemical action of antifolates/antimetabolites that are effective in the treatment of human and animal arthritis. The GCRC protocol will discuss only the human portion of the research.

低剂量甲氨蝶呤治疗在人类和动物模型中抑制自身免疫性关节炎。 我们假设甲氨蝶呤治疗类风湿性关节炎的作用是由于抑制氨基咪唑-羧酰胺核苷酸转化酶，这是一种叶酸依赖性酶，催化肌苷一磷酸从头生物合成的最后一步。 由此产生的氨基咪唑甲酰胺核苷的积累抑制腺苷脱氨酶，因此，干扰正常的腺苷代谢。 众所周知，腺苷脱氨酶缺乏的儿童患有严重的联合免疫缺陷综合征。 这表明腺苷脱氨酶活性是免疫能力的关键，并与甲氨蝶呤治疗类风湿关节炎的疗效机制有关。几项研究表明，在类风湿关节炎的低剂量甲氨蝶呤治疗期间，大剂量补充亚叶酸（5-甲酰四氢叶酸）会导致关节炎发作。然而，补充叶酸（蝶酰谷氨酸）不会降低治疗的疗效。 我们进一步推测，如果甲氨蝶呤的疗效是由氨基咪唑甲酰胺核苷酸转化酶抑制驱动的，叶酸补充剂不应该改变氨基咪唑甲酰胺，腺苷和脱氧腺苷的尿水平，而亚叶酸补充剂应该防止这些化合物的积累。我们的假设将在类风湿性关节炎患者和刘易斯大鼠佐剂性关节炎中进行检验。 目标包括：A）确定在治疗刘易斯大鼠佐剂性关节炎中临床上最佳的甲氨蝶呤剂量水平是否干扰正常的腺苷代谢; B）确定干扰腺苷代谢的药物的有效性（脱氧共形霉素，氨基咪唑甲酰胺，氨基咪唑甲酰胺与次优剂量的甲氨蝶呤）在刘易斯大鼠佐剂性关节炎;和C）确定在甲氨蝶呤治疗期间补充叶酸和亚叶酸是否使类风湿性关节炎患者的腺苷代谢正常化。 这项研究的信息将增强对抗叶酸剂/抗代谢物的生物化学作用的理解，这些抗叶酸剂/抗代谢物可有效治疗人类和动物关节炎。 GCRC方案将仅讨论研究的人体部分。