Takimoto C H, Allegra C J
Oncology Branch Bethesda Naval Hospital, Maryland, USA.
Oncology (Williston Park). 1995 Jul;9(7):649-56, 659 DISC 660, 662, 665.
Numerous new antifolate drugs have been developed in an attempt to overcome the potential mechanisms of tumor cell resistance to methotrexate, which can include decreased drug transport into cells; decreased polyglutamation, leading to increased drug efflux from cells; decreased drug affinity for folate-dependent enzymes; mutations of dihydrofolate reductase (DHFR), a key enzyme required for the maintenance of adequate intracellular reduced folate levels that is inhibited by methotrexate; and increased expression of the DHFR protein. Promising antifolate compounds undergoing clinical testing as anticancer agents include trimetrexate (which was recently approved by the FDA for the treatment of Pneumocystis carinii pneumonia), edatrexate, piritrexim, Tomudex, and lometrexol. The mechanisms of action, dosage, pharmacokinetics, clinical toxicity, and antitumor activity of these drugs are profiled.
为克服肿瘤细胞对甲氨蝶呤产生耐药性的潜在机制，人们已研发出多种新型抗叶酸药物，这些潜在机制包括药物进入细胞的转运减少；多聚谷氨酸化减少，导致药物从细胞内流出增加；药物对叶酸依赖性酶的亲和力降低；二氢叶酸还原酶（DHFR）发生突变，DHFR是维持细胞内足够的还原型叶酸水平所需的关键酶，可被甲氨蝶呤抑制；以及DHFR蛋白表达增加。正在作为抗癌药物进行临床试验的有前景的抗叶酸化合物包括三甲曲沙（最近被美国食品药品监督管理局批准用于治疗卡氏肺孢子虫肺炎）、依达曲沙、吡利曲辛、托莫昔芬和洛美曲唑。文中概述了这些药物的作用机制、剂量、药代动力学、临床毒性和抗肿瘤活性。
