Futscher B W, Campbell K, Dalton W S
Arizona Cancer Center, University of Arizona, Tucson 85724.
Cancer Res. 1992 Sep 15;52(18):5013-7.
We have examined the effects of the nitrosoureas, streptozotocin (STZ) and 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), on a human multiple myeloma cell line, RPMI 8226, and its drug-resistant variants. Cell lines selected for doxorubicin (DOX) resistance alone displayed a STZ and BCNU cytotoxicity profile similar to that of the parent cell line. In contrast, two of the drug-resistant variants selected with DOX plus verapamil, an agent which inhibits P-glycoprotein-mediated multidrug resistance, displayed a collateral sensitivity to STZ and BCNU. Verapamil was included in the selection protocol because it has been shown to inhibit the P-glycoprotein-mediated multidrug resistance phenotype and is now in clinical trials as a chemosensitizing agent. The collateral sensitivity to these nitrosoureas seen in the DOX plus verapamil-selected cell lines is due to the functional loss of a DNA repair molecule, O6-Methylguanine DNA methyltransferase (MGMT). The functional loss of MGMT is secondary to the loss of MGMT gene expression. The loss of MGMT gene expression is not due to loss or gross rearrangement of the MGMT-coding region. If this selection pressure applied in vitro reflects the in vivo situation, then new chemotherapeutic strategies may be devised to exploit this phenomenon. These cell lines will serve as useful models for delineating mechanisms which govern MGMT expression.
我们研究了亚硝基脲类药物链脲佐菌素（STZ）和1,3-双（氯乙基）-1-亚硝基脲（BCNU）对人多发性骨髓瘤细胞系RPMI 8226及其耐药变体的影响。仅对阿霉素（DOX）耐药的细胞系表现出与亲本细胞系相似的STZ和BCNU细胞毒性特征。相比之下，用DOX加维拉帕米（一种抑制P-糖蛋白介导的多药耐药性的药物）筛选出的两个耐药变体对STZ和BCNU表现出协同敏感性。在筛选方案中加入维拉帕米是因为它已被证明能抑制P-糖蛋白介导的多药耐药表型，并且目前作为一种化学增敏剂正处于临床试验阶段。在DOX加维拉帕米筛选的细胞系中观察到的对这些亚硝基脲类药物的协同敏感性是由于DNA修复分子O6-甲基鸟嘌呤DNA甲基转移酶（MGMT）功能丧失所致。MGMT功能丧失继发于MGMT基因表达丧失。MGMT基因表达丧失并非由于MGMT编码区的缺失或严重重排。如果体外施加的这种选择压力反映了体内情况，那么或许可以设计新的化疗策略来利用这一现象。这些细胞系将作为描绘调控MGMT表达机制的有用模型。
