摘要
本研究探讨MDR细胞内药物积聚减少究竟决定其抗药性的多大比例。MDR细胞K562/Dox来源于反复用Dox处理人红白血病细胞株K562细胞。经MTT法测定,k562/Dox对长春新碱等7种抗癌药的抗性提高了1200~11倍不等。k562/Dox可枝抗人P-gp单抗JSB-1标记,表明其有P-gp高表达。细胞内药物积聚试验显示,K562/Dox细胞内3种蒽坏类药阿霉素、表阿霉素和柔红霉素的积聚均显著低于其药敏细胞K562(P<001)。当K562/Dox与1.72μmol/L或8.62μmol/L的阿霉素(表阿霉素或柔红霉素)温育时,可使其细胞内的药物积聚饮复正常的Ver浓度分别为6μmol/L或12μmol/L,提示使MDR细胞内药物积聚恢复依赖于Ver与药物的相对浓度。然而,当Ver浓度为6μmol/L时,K562/Dox对Epi和Dau的抗性仍保持5.8和>6.6倍,很显然这部分抗药性与细胞内药物积聚改变无直接关系,即与P-gp过表达无关。
Abstract The
purpose of this study was to determine what proportion of drug
resistance of MDRcell variant K562 / Dox was attributed to the
reduced steady state intracellular drug accumula-tion related to
overexpression of P-glycoprotein. K 562 / Dox was derived from
repeated expo-sure of human ervthroleukaemic cell line K562 cell to
doxorubicin. As assessed with MTTassay, the resistance of K 562/Dox
to 7 cytotoxic drugs increased variably in the range between1200 and
11 folds,K562 / Dox cells were positively stained with anti-human
p-glycoproteinmonoclonal antibody JSB-1, indicating overexpression of
P-gp. Intracellular drug accumula-tion in K562 / Dox,though
significantly reduced as compured with that in K562 cells,
wasmaximally restored by concurrent exposure of cells to 6 μmol / L
verapamil and 1.72 μmol / Leither of the doxorubicin,epirubicin or
daunorubicin..Similar results were obtained by exposureof cells to 12
μmol / L verapamil and 8.62 μmol/L drug, indicating that
restoration ofintracellular drug accumulation in MDR cells was
dependent on the relative concentrations ofverapamil to drug.
However,the resistances of K562/Dox cells to epirubicin and
daunorubicinstill remained for about 5.6 and > 6.6
folds,respectively, even at verapamil concentration of 6μmol / L,
suggesting at least a relatively big fraction of drug resistance was
not directly relatedto the altered cellular pharmacokinetics
associated with overexpression of P-glycoprotein.
出处
《中华肿瘤杂志》
CAS
CSCD
北大核心
1995年第2期85-88,共4页
Chinese Journal of Oncology
基金
国家"八.五"攻关项目和浙江省自然科学基金