Rapid recovery of a functional MDR phenotype caused by MRP after a transient exposure to MDR drugs in a revertant human lung cancer cell line

Manzano, Ramón González; Versanvoort, C.; Wright, KarenA; Twentyman, Peter R.

doi:10.1016/s0959-8049(96)00263-8

Cited by 12 publications

(7 citation statements)

References 11 publications

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“…However, the possibility that selection had occurred could not be excluded (reviewed in Manzano et al, 1996), as drug-induced MDR1 expression usually occurred after a 72-h exposure to sublethal concentrations of cytotoxics and was associated with the appearance of visible morphological cell damage.…”

Section: Discussionmentioning

confidence: 99%

Induction of MDR1 gene expression by anthracycline analogues in a human drug resistant leukaemia cell line

Slater

Rischin

et al. 1999

Br J Cancer

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SummaryThe effects of 4-demethoxydaunorubicin (idarubicin, IDA) and MX2, a new morpholino-anthracycline, on up-regulation of the MDR1 gene in the low-level multidrug resistant (MDR) cell line CEM/A7R were compared at similar concentrations (IC 10 , IC 50 and IC 90 ) over a short time exposure (4 and 24 h). The chemosensitivity of each drug was determined by a 3-day cell growth inhibition assay. Compared with epirubicin (EPI), IDA and MX2 were 17-and eightfold more effective in the CEM/A7R line respectively. No cross-resistance to 5-FU was seen in the CEM/A7R line. Verapamil (5 µM) and PSC 833 (1 µM), which dramatically reversed resistance to EPI in the CEM/A7R line, had no sensitizing effect on the resistance of this line to MX2, but slightly decreased resistance to IDA. The sensitivity to 5-FU was unchanged by these modulators. The induction of MDR1 mRNA expression by IDA, MX2 and 5-FU was analysed by Northern blotting and semiquantitatively assessed by scanning Northern blots on a phosphorimager. The relative level of MDR1 expression was expressed as a ratio of MDR1 mRNA to the internal RNA control glyceraldehyde-3-phosphate dehydrogenase (GAPDH). IDA, MX2 and 5-FU differentially up-regulated MDR1 mRNA in the CEM/A7R line in a dose-dependent manner. Both IDA and MX2 induced MDR1 expression within 4 h. 5-FU up-regulated MDR1 expression only when drug exposure was prolonged to 24 h. Based on MRK 16 binding, flow cytometric analysis of P-glycoprotein (Pgp) expression paralleled the increase in MDR1 mRNA levels. For the three anthracyclines, the increase in MDR1 expression was stable in cells grown in the absence of drug for more than 3 weeks after drug treatment. The induction of MDR1 expression by 5-FU was transient, associated with a rapid decrease in the increased Pgp levels which returned to baseline 72 h after the removal of 5-FU. This study demonstrates that MDR1 expression can be induced by analogues of anthracyclies not pumped by Pgp, and that this induction appears to be stable despite a 3-week drug-free period.

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Section: Discussionmentioning

confidence: 99%

Induction of MDR1 gene expression by anthracycline analogues in a human drug resistant leukaemia cell line

Slater

Rischin

et al. 1999

Br J Cancer

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“…Other reports of MRP1 modulation in response to drug treatment have shown increases only after longer treatment times. MRP1 expression was increased after 30 hr of treating the ''revertant'' HL60/R-CP subline with cisplatin or arsenite (Ishikawa et al, 1996) and in the ''revertant'' COR-L23/Rev subline 3 to 4 days after treatment with cytotoxic levels of doxorubicin or with vincristine for 2 to 3 days (Manzano et al, 1996). Also, in these cases, MRP1 modulation was in cells that were originally highly resistant with high levels of MRP1 expression but had substantially lost their MRP1 expression during extended periods of growth in the absence of drug.…”

Section: Discussionmentioning

confidence: 99%

Induction of broad drug resistance in small cell lung cancer cells and its reversal by paclitaxel

Davey

1998

Int. J. Cancer

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The H82 “variant” and the H69 “classic” small cell lung cancer (SCLC) cell lines were treated with low levels of epirubicin (69 and 14 nM) which caused little cell death but produced the H82/E8 and H69/E8 extended‐multidrug resistant sublines. Both were resistant to drugs associated with multidrug resistance (MDR), and to chlorambucil (9.5‐ and 5.6‐fold, respectively) and cisplatin (2.3‐ and 8.5‐fold, respectively). There was increased expression of the multidrug resistance‐associated protein (MRP1) in the H82/E8 subline while P‐glycoprotein expression was not detected in any cells or sublines. Treatment of the H82 cells for 1 hr with 69 nM epirubicin increased MRP1‐mRNA expression within 4 hr and this was associated with an increase in the resistance to epirubicin, chlorambucil, cisplatin and paclitaxel. Further, a 1 hr treatment with non‐cytotoxic doses of chlorambucil (2.5 μM), cisplatin (1.3 μM) or paclitaxel (13 nM), drugs not normally associated with MRP1‐mediated MDR, also increased MRP1‐mRNA expression in the H82 cells with paclitaxel causing the highest increase (4.5‐fold). For chlorambucil treatment, this increased MRP1‐mRNA expression was accompanied by increased drug resistance while paclitaxel treatment had no effect on drug resistance in the H82 cells. For the drug resistant H82/E8 subline, these drug treatments had no effect on the MRP1‐mRNA expression and little effect on increasing the subline drug resistance. However, pre‐treatment with paclitaxel sensitised the H82/E8 subline to chlorambucil and cisplatin returning the subline to the sensitivity of the H82 cell line. We conclude that treatment with low levels of MDR and non‐MDR drugs can induce extended‐multidrug resistance in SCLC cells, a process that probably involves the co‐ordinate upregulation of MRP1 and other resistance mechanisms. The results also suggest paclitaxel may have a role as a response modifier in the treatment of refractory SCLC. Int. J. Cancer 76:702–708, 1998.© 1998 Wiley‐Liss, Inc.

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“…Although several attempts have been made to demonstrate that Pgp expression can be up-regulated, these studies have generally required long exposure times (72 h or more). Consequently, the selection of Pgp-expressing cells could not be ruled out from these studies (Manzano et al, 1996).However, we have demonstrated that a rapid induction of the MDR1 gene can occur after the exposure of cells to anthracyclines in a human MDR cell line (CEM/A7R) known to express lowlevel MDR1 mRNA and P-glycoprotein (Hu et al, 1995). The induction of MDR1 was dose and time related and correlated with an increase in Pgp expression and drug resistance.…”

mentioning

confidence: 96%

“…The level of MDR1 gene expression in acute leukaemia is commonly increased after chemotherapy (Grogan et al, 1993;Nooter and Sonneveld, 1994). In addition, there appears to be a direct correlation between expression of the MDR1 gene de novo and outcome (survival) in this disease (Poeta et al, 1996).Although the mechanisms underlying the effect of cytotoxic drugs on MDR1 gene expression and in turn the multidrug resistant (MDR) phenotype remain poorly understood, the acquisition of Pgp-mediated drug resistance during chemotherapy is usually thought to be due to the selection of drug-resistant cells (Chaudhary and Roninson, 1993;Gekeler et al, 1994;Manzano et al, 1996). Sikic and colleagues have clearly demonstrated this in a cell line model (Beketic-Oreskovic et al, 1994;Chen et al, 1994;Dumontet et al, 1996), under conditions in which up-regulation of Pgp was prevented.…”

mentioning

confidence: 99%

“…Although the mechanisms underlying the effect of cytotoxic drugs on MDR1 gene expression and in turn the multidrug resistant (MDR) phenotype remain poorly understood, the acquisition of Pgp-mediated drug resistance during chemotherapy is usually thought to be due to the selection of drug-resistant cells (Chaudhary and Roninson, 1993;Gekeler et al, 1994;Manzano et al, 1996). Sikic and colleagues have clearly demonstrated this in a cell line model (Beketic-Oreskovic et al, 1994;Chen et al, 1994;Dumontet et al, 1996), under conditions in which up-regulation of Pgp was prevented.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Induction of MDR1gene expression by anthracycline analogues in a human drug resistant leukaemia cell line

Hu¹,

Slater²,

Rischin³

et al. 1999

Br J Cancer

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The effects of 4-demethoxydaunorubicin (idarubicin, IDA) and MX2, a new morpholino-anthracycline, on up-regulation of the MDR1 gene in the low-level multidrug resistant (MDR) cell line CEM/A7R were compared at similar concentrations (IC10, IC50and IC90) over a short time exposure (4 and 24 h). The chemosensitivity of each drug was determined by a 3-day cell growth inhibition assay. Compared with epirubicin (EPI), IDA and MX2 were 17- and eightfold more effective in the CEM/A7R line respectively. No cross-resistance to 5-FU was seen in the CEM/A7R line. Verapamil (5 μM) and PSC 833 (1 μM), which dramatically reversed resistance to EPI in the CEM/A7R line, had no sensitizing effect on the resistance of this line to MX2, but slightly decreased resistance to IDA. The sensitivity to 5-FU was unchanged by these modulators. The induction of MDR1 mRNA expression by IDA, MX2 and 5-FU was analysed by Northern blotting and semiquantitatively assessed by scanning Northern blots on a phosphorimager. The relative level of MDR1 expression was expressed as a ratio of MDR1 mRNA to the internal RNA control glyceraldehyde-3-phosphate dehydrogenase (GAPDH). IDA, MX2 and 5-FU differentially up-regulated MDR1 mRNA in the CEM/A7R line in a dose-dependent manner. Both IDA and MX2 induced MDR1 expression within 4 h. 5-FU up-regulated MDR1 expression only when drug exposure was prolonged to 24 h. Based on MRK 16 binding, flow cytometric analysis of P-glycoprotein (Pgp) expression paralleled the increase in MDR1 mRNA levels. For the three anthracyclines, the increase in MDR1 expression was stable in cells grown in the absence of drug for more than 3 weeks after drug treatment. The induction of MDR1 expression by 5-FU was transient, associated with a rapid decrease in the increased Pgp levels which returned to baseline 72 h after the removal of 5-FU. This study demonstrates that MDR1 expression can be induced by analogues of anthracyclies not pumped by Pgp, and that this induction appears to be stable despite a 3-week drug-free period. © 1999 Cancer Research Campaign

show abstract

Rapid recovery of a functional MDR phenotype caused by MRP after a transient exposure to MDR drugs in a revertant human lung cancer cell line

Cited by 12 publications

References 11 publications

Induction of MDR1 gene expression by anthracycline analogues in a human drug resistant leukaemia cell line

Induction of MDR1 gene expression by anthracycline analogues in a human drug resistant leukaemia cell line

Induction of broad drug resistance in small cell lung cancer cells and its reversal by paclitaxel

Induction of MDR1gene expression by anthracycline analogues in a human drug resistant leukaemia cell line

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