Futscher B W, Micetich K C, Barnes D M, Fisher R I, Erickson L C
Department of Medicine, Loyola University of Chicago, Stritch School of Medicine, Maywood, IL 60153.
Cancer Commun. 1989;1(1):65-73. doi: 10.3727/095535489820875444.
In this report we present evidence which suggests that pretreatment of a highly nitrosourea-resistant human colon tumor cell line with non-cytotoxic doses of streptozotocin (STZ) prior to, or simultaneously with, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) exposure produces synergistic increases in cytotoxicity of several logs over the cytotoxicity produced by exposure to BCNU alone. STZ pretreatment or simultaneous treatment with BCNU allowed BCNU-induced DNA interstrand crosslinks to form in this cell line, in which BCNU alone did not induce DNA interstrand-crosslinks. Reversal of the schedule (i.e., STZ following BCNU) was less effective in producing synergistic cell kill or increased DNA interstrand crosslinking. Replacement of BCNU with fresh BCNU was not effective in producing increased cell kill and produced no observable interstrand crosslinking. Direct assays for guanine O6-DNA alkyltransferase activity confirmed that more than 75% inhibition of this important DNA repair system occurred following exposure to 2.5 mM STZ and that the inhibition was virtually complete when STZ pretreatment was combined with BCNU exposure.
在本报告中，我们提供的证据表明，在暴露于1,3-双（2-氯乙基）-1-亚硝基脲（BCNU）之前或同时，用无细胞毒性剂量的链脲佐菌素（STZ）预处理一种高度耐亚硝基脲的人结肠肿瘤细胞系，会使细胞毒性协同增加几个对数，超过单独暴露于BCNU所产生的细胞毒性。STZ预处理或与BCNU同时处理能使BCNU诱导的DNA链间交联在该细胞系中形成，而单独使用BCNU时不会诱导DNA链间交联。颠倒处理顺序（即BCNU之后使用STZ）在产生协同细胞杀伤或增加DNA链间交联方面效果较差。用新鲜的BCNU替代BCNU在增加细胞杀伤方面无效，且未产生可观察到的链间交联。对鸟嘌呤O6-DNA烷基转移酶活性的直接检测证实，暴露于2.5 mM STZ后，该重要的DNA修复系统受到超过75%的抑制，当STZ预处理与BCNU暴露相结合时，抑制几乎完全。
