Sakata K, Kwok T T, Gordon G R, Waleh N S, Sutherland R M
Department of Cell and Molecular Biology, SRI International, Menlo Park, CA 94025-3493.
Int J Cancer. 1994 Oct 15;59(2):282-6. doi: 10.1002/ijc.2910590222.
The ability of verapamil to overcome resistance to adriamycin in a multidrug-resistant derivative of the V79 cell line (LZ), grown as multicellular spheroids or as monolayers, was examined. Verapamil was much less effective in overcoming resistance to adriamycin in spheroids than in monolayers. Verapamil increased the adriamycin content of cells grown as monolayers, but had no significant effect on the drug content of spheroids. This occurred in spite of the same mdr-I mRNA and protein levels in monolayers and spheroids. When the surviving fraction of cells was normalized to the cellular adriamycin content, cells both in monolayers and spheroids treated with verapamil were still more sensitive to adriamycin than their counterparts not treated with verapamil. The observed resistance of spheroids to adriamycin and verapamil sensitization may be caused by a drug-resistance mechanism that is functional only in spheroids, in addition to the activity of P-glycoprotein. Multicellular tissue architecture and cell-cell contact may play significant roles in this type of multidrug-resistance mechanism.
研究了维拉帕米在多药耐药的V79细胞系（LZ）的衍生物中克服对阿霉素耐药性的能力，该衍生物以多细胞球体或单层形式生长。维拉帕米在克服球体对阿霉素的耐药性方面比在单层细胞中效果差得多。维拉帕米增加了单层生长细胞的阿霉素含量，但对球体的药物含量没有显著影响。尽管单层细胞和球体中的mdr-1 mRNA和蛋白质水平相同，但仍出现这种情况。当将细胞的存活分数标准化为细胞阿霉素含量时，用维拉帕米处理的单层细胞和球体中的细胞对阿霉素仍比未用维拉帕米处理的对应细胞更敏感。除P-糖蛋白的活性外，观察到的球体对阿霉素的耐药性和维拉帕米致敏作用可能是由仅在球体中起作用的耐药机制引起的。多细胞组织结构和细胞间接触可能在这种多药耐药机制中起重要作用。
