Clonal variation in multidrug resistant human cell populations

摘要: Heterogeneity within an adriamycin-selected multidrug resistant (MDR) human squamous lung carcinoma, DLKP-A, was examined by establishing and characterising nine clones of the cell line. MDR variants same line were established selecting with VP-16. The resulting lines, DLKP/VP-3 DLKP/VP-8, characterised their resistance profiles mechanisms compared DLKP-A line. All subpopulations found to possess profile, but their adriamycin spanned a 9-fold concentration range. VP-16 selected cells were also MDR. All lines vincristine, but not to 5-fluorouracil VP-16-selected cells hyper-sensitive cisplatin. rank order of similar in all lines. observed cell line pertaining cells’ drug- radiation-sensitivity, doubling time biochemical alterations associated acquisition profile. MDR, induced exposure of DLKP adriamycin, did not confer cross-resistance radiation. Alternatively, irradiation result could be mixed generate population toxicity profile original DLKP-A population. All exhibited biochemical alterations; P-glycoprotein expression increased mdrl mRNA levels overexpressed lines. Adriamycin accumulation reflective P-glycoprotein levels and completely reversible circumventing agents, verapamil cyclosporin A. These agents enhanced chemotherapeutic drugs DLKP variants. In addition, topoisomerase II altered drug A significant decrease enzyme level DLKP/VP-8 other cells exhibiting slight decrease. alterations due the a subunit these modifications confirmed analysis. Metabolic co-operation line. While functional gap junctions intercellular adriamycin transfer occur general, junction inhibitors enhance cells’ sensitivity drug. Sensitivity be densitydependent phenomenon. Conditioned medium from highly variant DLKP-A enhanced adriamycin-sensitivity low variant. This suggests that factor, secreted whose secretion and/or production presence of adriamycin, could modify sensitivity