Rhodes T, Barrand M A, Twentyman P R
MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Cambridge, UK.
Br J Cancer. 1994 Jul;70(1):60-6. doi: 10.1038/bjc.1994.250.
We have investigated the effects of H(+)-ATPase inhibitors, bafilomycin A1 and 7-chloro-4-nitro-benz-2-oxa-1,3 diazole (NBD), and the Golgi inhibitor, brefeldin A, on daunorubicin accumulation and doxorubicin intracellular distribution in the non-P-glycoprotein-mediated multidrug-resistant cell line COR-L23/R. This cell line overexpress a 190 kDa protein which is probably the product of the MRP gene and shows an anthracycline accumulation defect and a drastically altered intracellular anthracycline distribution from the parental cell line COR-L23/P. We found that all three agents could selectively increase the cellular accumulation of daunorubicin in resistant cells. However, these effects were only seen at doses of the modifiers which were equal to or greater than the IC50 of the modifier alone. Effects of the modifiers on the intracellular distribution of doxorubicin fluorescence could, however, be seen at doses lower than those required to produce significant effects on daunorubicin accumulation. However, when used in a continuous MTT chemosensitivity assay none of the agents, used at maximum non-toxic doses, was able to sensitise COR-L23/R cells to doxorubicin or to colchicine. Although these lead compounds are unlikely to be useful as clinical modifiers, development of more selective analogues may prove useful in the modification of non-P-glycoprotein-mediated multidrug resistance.
我们研究了H(+)-ATP酶抑制剂巴弗洛霉素A1和7-氯-4-硝基苯并-2-恶唑-1,3-二氮杂茂（NBD）以及高尔基体抑制剂布雷菲德菌素A对柔红霉素蓄积和阿霉素在非P-糖蛋白介导的多药耐药细胞系COR-L23/R内细胞分布的影响。该细胞系过度表达一种190 kDa的蛋白，它可能是多药耐药相关蛋白（MRP）基因的产物，与亲代细胞系COR-L23/P相比，表现出蒽环类药物蓄积缺陷以及细胞内蒽环类药物分布的显著改变。我们发现，这三种药物均可选择性增加耐药细胞中柔红霉素的细胞蓄积。然而，只有当修饰剂的剂量等于或大于其单独使用时的半数抑制浓度（IC50）时，才会出现这些效应。不过，修饰剂对阿霉素荧光细胞内分布的影响在低于对柔红霉素蓄积产生显著效应所需的剂量时即可观察到。然而，在连续的MTT化学敏感性试验中，以最大无毒剂量使用这些药物时，没有一种药物能够使COR-L23/R细胞对阿霉素或秋水仙碱敏感。尽管这些先导化合物作为临床修饰剂可能并无用处，但开发更具选择性的类似物可能对非P-糖蛋白介导的多药耐药的修饰有用。
