Document Detail

Comparison of mechanisms responsible for resistance to idarubicin and daunorubicin in multidrug resistant LoVo cell lines.
MedLine Citation:
PMID:  7986198     Owner:  NLM     Status:  MEDLINE    
Two human colon carcinoma drug resistant clones (LoVo-IDA-1 and LoVo-IDA-2) were selected by continuous pressure of LoVo parent cell lines to idarubicin (IDA). Both cell sublines exhibited a typical multidrug resistance (MDR) phenotype but, despite IDA selection, the resistance index (RIext) was higher for daunorubicin (DAU) (RIext = 101-112) than for IDA (RIext = 20-23). A similar pattern of cross-resistance was also observed in two (DOX) doxorubicin-selected LoVo cell lines (LoVo-DOX-1 and LoVo-DOX-2). All the MDR cell lines exhibited decreased drug accumulation and increased intracellular drug tolerance as evidenced by the greater intracellular amount of drug required to cause a 50% growth inhibition (IC50int) compared to their parent cell line. The differences between DAU and IDA RIext exhibited by MDR cells were a function of intracellular resistance. DAU IC50int was 13.9 and 14.9 times higher in LoVo-IDA-1,2 and 6.4 and 6.2 in LoVo-DOX-1,2 cell lines, respectively, than in LoVo-sensitive cells, whereas IDA IC50int was only 3.6 and 3.2 times higher in LoVo-IDA-1,2 and 2.2 and 2.3 in LoVo-DOX-1,2 cell lines, respectively. Conversely, variations in IDA accumulation between resistant and sensitive cells were similar to those observed for DAU [the ratios between DAU uptake in sensitive and resistant cells were almost identical (P = NS) to those observed for IDA]. Differences between IDA and DAU intracellular distribution accounted for the relatively higher DAU intracellular resistance. In fact nuclear/cytoplasmic (N/C) DAU fluorescence ratio was higher (P < 0.01) in sensitive (N/C = 3.4 +/- 2.7) than in MDR cells (N/C ranging from 0.31 +/- 0.2 to 0.41 +/- 0.1). In contrast, no significant (P = NS) differences were observed in IDA N/C ratios between sensitive and MDR cells (N/C ranging from 0.16 +/- 0.1 to 0.20 +/- 0.1). In MDR cells, 1-hr VER (10 microM) treatment partially reverted both DAU N/C ratios and intracellular DAU resistance but neither changes in IDA N/C ratios nor variation in intracellular IDA resistance were observed following VER exposure. In conclusion, the greater intracellular drug tolerance that MDR cells show for DAU compared to IDA makes IDA more effective than DAU in MDR cells overexpressing P-glycoprotein (P-gp).
G Toffoli; F Simone; M Gigante; M Boiocchi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  48     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  1994 Nov 
Date Detail:
Created Date:  1994-12-30     Completed Date:  1994-12-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1871-81     Citation Subset:  IM    
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano (PN), Italy.
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MeSH Terms
Affinity Labels
Biological Transport
Cell Membrane / metabolism
Cell Nucleus / enzymology
Clone Cells
Colonic Neoplasms / drug therapy,  metabolism,  pathology*
DNA Topoisomerases, Type II / metabolism
Daunorubicin / metabolism,  pharmacology*
Drug Resistance, Multiple* / genetics
Idarubicin / metabolism,  pharmacology*
P-Glycoprotein / metabolism
Tumor Cells, Cultured
Reg. No./Substance:
0/Affinity Labels; 0/Azides; 0/Dihydropyridines; 0/P-Glycoprotein; 20830-81-3/Daunorubicin; 58957-92-9/Idarubicin; 90523-31-2/azidopine; EC Topoisomerases, Type II

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