Zwelling L A, Kerrigan D, Michaels S, Kohn K W
Biochem Pharmacol. 1982 Oct 15;31(20):3269-77. doi: 10.1016/0006-2952(82)90561-5.
The anticancer drug 4'-(9-acridinylamino)-methanesulfon-m-anisidide (m-AMSA) is known to bind to DNA by intercalation and to produce protein-associated DNA strand breaks in cells. Previous work [Zwelling et al., Biochemistry 20, 6553 (1981)] had shown that m-AMSA is in rapid equilibrium between extracellular and intracellular compartments, and that the DNA strand breaks exist in a steady state of rapid formation and resealing. The current work reports an unusual uptake phenomenon of m-AMSA by mouse leukemia L1210 cells that occurs at higher drug concentrations than previously studied. The new uptake phenomenon was characterized by cooperativity, hysteresis, irreversibility, saturability, slowness and temperature dependence. It is concluded that m-AMSA concentrations above a critical value can initiate the irreversible sequestration of m-AMSA into a new phase, probably in an extranuclear compartment of the cell, from which the drug has no access to the nuclear DNA and probably does not contribute to cytotoxicity.
抗癌药物4'-(9-吖啶基氨基)-甲磺酰基间茴香胺（m-AMSA）已知可通过嵌入作用与DNA结合，并在细胞中产生与蛋白质相关的DNA链断裂。先前的研究工作[兹韦林等人，《生物化学》20, 6553 (1981)]表明，m-AMSA在细胞外和细胞内区室之间处于快速平衡状态，并且DNA链断裂以快速形成和重新封闭的稳定状态存在。当前的研究报道了小鼠白血病L1210细胞对m-AMSA的一种异常摄取现象，该现象发生在比先前研究更高的药物浓度下。这种新的摄取现象具有协同性、滞后性、不可逆性、饱和性、缓慢和温度依赖性等特征。得出的结论是，高于临界值的m-AMSA浓度可引发m-AMSA不可逆地隔离到一个新的相，可能在细胞的核外区室中，药物无法从该相进入核DNA，并且可能对细胞毒性没有贡献。
