The antifolates.
The antifolates.
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DOI：
10.1016/j.hoc.2012.02.002
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发表时间：
2012-06
影响因子：
2.4
通讯作者：
Goldman, I. David
中科院分区：
文献类型：
--
作者：
Visentin, Michele;Zhao, Rongbao;Goldman, I. David
关键词：
抗叶酸剂是65年前进入临床的第一类抗代谢药。其作用机制是由于代谢途径的破坏，需要一个碳部分提供的B9叶酸维生素，他们类似。虽然骨髓和肠道的更新组织也是叶酸依赖性的，并且是抗叶酸剂毒性的部位，但抗叶酸剂的临床效用是通过确定剂量和给药时间表来确定的，所述剂量和给药时间表提供足够的选择性以使这些药物有效治疗癌症以及炎性病症。许多早期的关键临床前研究定义了这类药物的药理学特性和治疗策略，这些研究是在体外和小鼠体内使用小鼠白血病细胞系1，2进行的。临床上的第一种抗叶酸剂是氨基蝶呤。1948年6月，《新英格兰医学杂志》3首次报道了它的引入，当这种药物首次被证明能缓解儿童急性淋巴细胞白血病时，人们对它产生了极大的热情。虽然这些缓解是短暂的，但这种药物的活性确定了这种疾病是可治疗的，并乐观地认为这种疾病和其他恶性疾病将在未来被癌症化疗药物征服。由于未完全理解的原因，但归因于氨基蝶呤的不可预测的毒性，该药物在20世纪50年代早期被甲氨蝶呤（MTX）取代，甲氨蝶呤是一种抗叶酸剂，其效力低于氨基蝶呤，但被认为是更有利的治疗指数2。
The antifolates were the first class of antimetabolites to enter the clinics 65 years ago. Their mechanism of action is due to the disruption of the metabolic pathways that require onecarbon moieties supplied by the B9 folate vitamins which they resemble. While renewing tissues of the bone marrow and intestinal tract are also folate-dependent and are sites of antifolate toxicity, the clinical utility of antifolates was established with the identification of doses and schedules of administration that provided sufficient selectivity to make these drugs effective in the treatment of cancer as well as inflammatory disorders. Many of the early key preclinical studies that defined the pharmacological properties of this class of drugs, and treatment strategies, were conducted in vitro and, in vivo in mice, using murine leukemia cell lines 1, 2.The first antifolate in the clinic was aminopterin. Its introduction, as first reported in the New England Journal of Medicine in June 1948 3, was greeted with great enthusiasm when this agent was shown to produce, for the first time, remissions in children with acute lymphoblastic leukemia. While these remissions were short-lived, the activity of this agent established that this disease was treatable and provided optimism that this and other malignant diseases would be conquerable with cancer chemotherapeutics in the future. For reasons not fully understood, but attributed to the unpredictable toxicity of aminopterin, this drug was replaced with methotrexate (MTX) in the early 1950s, an antifolate less potent that aminopterin but with what was considered to be a more favorable therapeutic index 2.
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5.7
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