Bertino J R, Mini E, Sobrero A, Moroson B A, Love T, Jastreboff M, Carmen M, Srimatkandada S, Dube S
Adv Enzyme Regul. 1985;24:3-11. doi: 10.1016/0065-2571(85)90066-4.
Strategies that are selective for eradicating methotrexate resistant cells are described. These strategies have been developed based on knowledge of the mechanism of drug resistance encountered in experimental systems and in the clinic. Drug resistance to methotrexate in experimental tumors is commonly due to either gene amplification (dihydrofolate reductase) or to impaired transport of methotrexate. While no effective drugs or methods to prevent gene amplification have been described, the concept of developing "pro drugs", i.e. a drug that is selectively reduced by dihydrofolate reductase to an inhibitor of another critical folate enzyme (thymidylate synthase, methionine synthetase, folylpolyglutamate synthetase) remains worthwhile. Second generation antifolates such as trimetrexate which are effective vs methotrexate transport resistant cells have already been developed and are in clinical trial.
本文描述了用于根除甲氨蝶呤耐药细胞的选择性策略。这些策略是基于对实验系统和临床中遇到的耐药机制的了解而开发的。实验性肿瘤对甲氨蝶呤的耐药通常是由于基因扩增（二氢叶酸还原酶）或甲氨蝶呤转运受损。虽然尚未描述预防基因扩增的有效药物或方法，但开发“前药”的概念，即一种被二氢叶酸还原酶选择性还原为另一种关键叶酸酶（胸苷酸合成酶、蛋氨酸合成酶、叶酰聚谷氨酸合成酶）抑制剂的药物，仍然是值得的。第二代抗叶酸药物，如三甲曲沙，对甲氨蝶呤转运耐药细胞有效，已经开发出来并正在进行临床试验。
