POLYGLUTAMATION OF METHOTREXATE - IS METHOTREXATE A PRODRUG
POLYGLUTAMATION OF METHOTREXATE - IS METHOTREXATE A PRODRUG
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DOI：
10.1172/jci112088
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发表时间：
1985-01-01
影响因子：
15.9
通讯作者：
JOLIVET, J
中科院分区：
文献类型：
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作者：
CHABNER, BA;ALLEGRA, CJ;JOLIVET, J
强烈关注药物作用机制的第二个原因源于此类工作提供的有关正常生物过程的见解。例如，Schimke 及其同事对耐药肿瘤细胞的研究成果首次描述了哺乳动物细胞中的基因扩增 (1)，并认识到这种现象是对 DNA 合成抑制剂的反应 (2)。癌症药理学在阐明跨细胞膜主动运输 (MTX)(3)、核苷酸合成（5-氟尿嘧啶和阿拉伯胞嘧啶）(4) 的调节以及 DNA 修复（放射和烷化剂）(5) 过程中同样发挥着重要作用。因此，药物作用的研究具有相关性，不仅因为它们丰富了我们对细胞毒性机制的理解，而且因为它们使我们更好地了解正常细胞功能。然而，研究药物作用机制的最直接原因是这些知识对改善治疗的实际好处。许多实际应用源于对药物如何发挥作用、它们如何被正常和恶性细胞激活或降解以及它们攻击什么目标的理解。这些应用包括响应的预测、可以促进响应的更好代理的设计
A second reason for the intense concern with mechanisms of drug action stems from the insights such work provide re-garding normal biological processes. For example, the first descriptions ofgene amplification in mammalian cells (1) and the recognition of this phenomenon as a response to inhibitors of DNA synthesis (2) resulted from the work of Schimke and col-leagues with drug-resistant tumor cells. Cancer pharmacology has been equally instrumental in elucidating the processes of active transportacross cell membranes (MTX)(3), the regulation ofnucleotide synthesis (5-fluorouracil and cytosine arabinoside)(4), and DNA repair (radiation and alkylating agents)(5). Thus, investigations of drug action have relevance not only because they enrich our understanding ofthe mechanisms ofcytotoxicity, but also because they lead to a greater understanding of normal cell function.However, the most immediate reason for studying mecha-nisms of drug action is the practical benefit of such knowledge for improving therapy. A number of practical applications flow from the understanding of how drugs work, how they are acti-vated or degraded by normal and malignant cells, and what targets they attack. These applications includethe prediction of response, the design ofbetter agents that can facilitate response