INVITRO SCREENING OF BIOCHEMICAL-ACTIVITY OF FOLIC-ACID ANTAGONISTS IN SKIN

[摘要] Dihydrofolate reductase (DHFR) inhibitors, which differ from the classical folate antagonists in physicochemical and pharmacologic parameters such as lipid solubility and mechanisms of cellular transport, were screened for DHFR inhibitory activity and biologic activity in newborn rat skin. The most effective drugs from this screen were tested for their effects on de novo DNA synthesis in psoriatic epidermis in vitro. Of the 24 compounds studied, methotrexate (MTX) was the most potent inhibitor of rat skin DHFR (I50 = 8.6 .times. 10-9 M). Methotrexate-dimethylester, methasquin-diethylester, DDEP (2,4-diamino-5-(3'',4''-dichlorophenyl)-6-ethylpyrimidine), and Baker''s triazine antifolate (NSC 139105), while less effective than MTX as DHFR inhibitors, were more effective than MTX as inhibitors of de novo DNA synthesis in rat skin in vitro. Baker''s antifolate was the only compound tested which was considerably more effective than MTX as an inhibitor of de novo DNA synthesis in psoriatic epidermis in vitro.