Characterization of a clonal human colon adenocarcinoma line intrinsically resistant to doxorubicin

被引:30
作者
Dolfini, E
Dasdia, T
Arancia, G
Molinari, A
Calcabrini, A
Scheper, RJ
Flens, MJ
Gariboldi, MB
Monti, E
机构
[1] UNIV MILAN,INST PHARMACOL,APPL PHARMACOL SECT,I-20129 MILAN,ITALY
[2] UNIV MILAN,DEPT BIOL & GENET HLTH SCI,I-20133 MILAN,ITALY
[3] IST SUPER SANITA,DEPT ULTRASTRUCT,I-00161 ROME,ITALY
[4] FREE UNIV AMSTERDAM HOSP,DEPT PATHOL,NL-1081 HV AMSTERDAM,NETHERLANDS
关键词
intrinsic drug resistance; doxorubicin; colon adenocarcinoma; multidrug resistance-associated protein; lung resistance-related protein;
D O I
10.1038/bjc.1997.338
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Intrinsic low-level resistance to anti-cancer drugs is a major problem in the treatment of gastrointestinal malignancies. To address the problem presented by intrinsically resistant tumours, we have isolated two monoclonal lines from LoVo human colon adenocarcinoma cells: LoVo/C7, which is intrinsically resistant to doxorubicin (DOX); and LoVo/C5, which shows the same resistance index for DOX as the mixed parental cell population. For comparison, we have included in the study a LoVo-resistant line selected by continuous exposure to DOX and expressing a typical multidrug resistant (MDR) phenotype. In these cell lines we have studied the expression and/or activity of a number of proteins, including P-glycoprotein 170 (P-gp), multidrug resistance-associated protein (MRP), lung resistance-related protein (LRP), glutathione (GSH)-dependent enzymes and protein kinase C (PKC) isoforms, which have been implicated in anti-cancer drug resistance. Intracellular DOX distribution has been assessed by confocal microscopy. The results of the present study indicate that resistance in LoVo/C7 cells cannot be attributed to alterations in P-gp, LRP or GSH/GSH-dependent enzyme levels. Increased expression of MRP, accompanied by alterations in the subcellular distribution of DOX, has been observed in LoVo/C7 cells; changes in PKC isoform pattern have been detected in both intrinsically and pharmacologically resistant cells.
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页码:67 / 76
页数:10
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