Cellular pharmacology of lipophilic anthracyclines in human tumor cells in culture selected for resistance to doxorubicin

Bennis, S.; Fauré, Philippe; Chapey, C.; Yp, Hu; Fourche, J.; J, El Yamani; Robert, Jacques

doi:10.1097/00001813-199707000-00009

Cited by 15 publications

(9 citation statements)

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“…those of the breast and lung [7,8]. Compared to the lower intracellular accumulation and significantly decreased potency of other antimitotic drugs in hypoxic-acidic environments, DOX is used to treat glioblastoma due to its preserved efficacy in extreme metabolic conditions [9,10]. However, the significant hematological, gastrointestinal and cardiac toxicity of this drug has limited its therapeutic applicability.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Multidrug-Resistance-Associated P-Glycoprotein in Human U-87 MG and HUV-ECC Cells with Antisense Oligodeoxynucleotides to MDR1 mRNA

Rittierodt¹,

Tschernig

Harada

2004

Pathobiology

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Objective: Glioblastoma is the highest dedifferentiated form of astrocytic brain tumors, and it is refractory to chemotherapy in most cases. To improve the clinical outcome of such tumors, new therapeutic strategies are needed. While malignancy is mainly associated with a nonfunctional apoptotic pathway, the lack of chemotherapeutic success correlates with overexpression of the multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp). Previous investigations have shown that not only glioblastoma cells but also endothelial cells are important in the response to chemotherapy. The aim of the present investigations was to reduce the expression of P-gp in the human glioblastoma cell line U-87 MG and in the human endothelial cell line HUV-ECC. Methods: Therefore, these cells were treated with antisense oligodeoxynucleotides (asn-ODN) directed against the P-gp mRNA in order to increase the intracellular retention of doxorubicin (DOX) which had been given previously. Results: Flow cytometry revealed about 4-fold increased intracellular retention of DOX in both asn-ODN-treated cell lines as compared to asn-ODN non-treated cell lines. Conclusion: These results suggest that asn-ODN-mediated inhibition of P-gp expression is an efficient way to increase intracellular retention of DOX.

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Section: Introductionmentioning

confidence: 99%

Modulation of Multidrug-Resistance-Associated P-Glycoprotein in Human U-87 MG and HUV-ECC Cells with Antisense Oligodeoxynucleotides to MDR1 mRNA

Rittierodt¹,

Tschernig

Harada

2004

Pathobiology

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“…The object of this study was to assess interaction between multidrug-resistance modulators (Klohs et al 1986;Bennis et al 1997;Ramu et al 1984;Tsuruo 1983) within the membrane of anionic liposomes. Apart from the importance of these molecules in cancer therapy, they have an additional theoretical interest by reason of the high cooperativity of their dose-response curves.…”

Section: Discussionmentioning

confidence: 99%

“…The spatial positioning of these molecules in the binding site may vary according to their sizes and shapes, and according to their hydrophobicity and electric charge (Castaing et al 2003(Castaing et al , 2005. We therefore set out to assess the possibility of synergy between multidrug resistance modulators in terms of drug-membrane interactions, by testing the ability of verapamil to induce dye leakage from anionic liposomes, alone (Klohs et al 1986) and in combination with other modulators, diltiazem (Klohs et al 1986), quinine (Bennis et al 1997), thioridazine (Ramu et al 1984) and clomipramine (Tsuruo 1983). We derived an equation that allows all the data to be explained simultaneously in terms of cooperative binding of the separate drugs as well as synergistic interactions between them.…”

Section: Introductionmentioning

confidence: 99%

Synergy between verapamil and other multidrug-resistance modulators in model membranes

Castaing¹,

Loiseau

Cornish‐Bowden

2007

J Biosci

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Various cationic lipophilic compounds can reverse the multidrug resistance of cancer cells. Possible interaction between these compounds, which are known as modulators, has been assessed by measuring leakage of Sulphan blue from anionic liposomes, induced both by verapamil alone and by verapamil in combination with diltiazem, quinine, thior idazine or clomipramine. An equation was derived to quantify the permeation doses and Hill coefficients of the drugs and mixtures between them by simultaneous fitting of the experimental data. The interaction was tested by two methods, the competition plot and the isobole method; both showed synergy between verapamil and each of diltiazem, qui nine and thioridazine. The dose factor of potentiation for verapamil determined within membranes was 4.0 ± 0.4 with diltiazem, 3.2 ± 0.4 with quinine and 2.4 ± 0.3 with thior idazine. The results suggest that the effectiveness of reversing multidrug resistance may be increased with modulators such as verapamil and diltiazem that have a much greater ef fect in combination than what would be expected from their effects when considered sep arately.

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“…Idarubicin is a lipophilic drug widely distributed in body fluids that reaches high intracellular concentrations. 15 In vitro studies have shown that idarubicin is more effective than daunorubicin in tumor cell lines displaying the MDR phenotype; 16,17 these data suggest that idarubicin can be noncross-resistant with epirubicin. Moreover, cellular pharmacology of idarubicin and its metabolite idarubicinol suggests that idarubicin has antitopoisomerase II activity.…”

Section: Discussionmentioning

confidence: 99%

High-dose consolidation chemotherapy with Idarubicin and alkylating agents following induction with gemcitabine–epirubicin–paclitaxel in metastatic breast cancer: a dose finding study

Bengala¹,

Danesi²,

Guarneri³

et al. 2003

Bone Marrow Transplant

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Summary:Preliminary randomized studies have failed to show a survival benefit of high-dose chemotherapy with alkylators in advanced breast cancer. Idarubicin is an active agent in breast cancer and is suitable for dose escalation. We designed a dose finding study with escalating high-dose idarubicin (HD-Ida) followed by fixed high-dose thiotepa+melphalan (HD-TM) with peripheral blood progenitor cells (PBPC) in MBC patients with stable disease or in partial response after six courses of induction chemotherapy with gemcitabine 1000 mg/m 2 days 1 and 4, epirubicin 90 mg/m 2 day 1, taxol 175 mg/m 2 day 1 (GET). Aims of the study were to identify the maximum tolerated dose (MTD) of idarubicin, to evaluate the cardiac safety and activity of HD-Ida and HD-TM after GET and to study the pharmacokinetic profile of idarubicin and idarubicinol. A total of 14 patients were treated. Idarubicin was administered as a 48 h continuous i.v. infusion at the following dose levels: 40 mg/m 2 (three patients), 50 mg/m 2 (three patients), 60 mg/m 2 (five patients) and 70 mg/m 2 (three patients). Mucositis was the dose-limiting toxicity and the MTD was 60 mg/m 2 . C max of Idarubicin and idarubicinol were 7.772.0 and 26.379.7 ng/ml at 40 mg/ m 2 and increased to 14.8+3.0 and 47.4+12.6 ng/ml at 70 mg/m 2 . AUCt 0-264 of idarubicin and idarubicinol increased from 423.27111.6 and 25817606 hng/ml at 40 mg/m 2 to 732.87140.2 and 459071258 hng/ml at 70 mg/m 2 . Conversion rates after HD-Ida and HD-TM were 28.6 and 38.5%, respectively. No episodes of cardiac toxicity were observed. We conclude that HD-Ida followed by HD-TM is feasible and devoid of cardiac toxicity. Moreover, the activity of HD-Ida after a epirubicin-containing regimen suggests incomplete crossresistance between the two drugs. High-dose chemotherapy (HDC) with autologous hemopoietic support has been used as intensification/consolidation treatment in advanced breast cancer responsive to standard chemotherapy. However, despite encouraging preclinical data and phase II results, preliminary data from phase III randomized trials have failed to show any survival benefit. 1-4 Most of the randomized trials have used four to six courses of induction chemotherapy followed by late intensification with a single course of HDC. High-dose regimens usually have included alkylating agents because of their steep dose-response curve, non-cell cycle specificity and broad clinical activity. 5 Attempts to improve these disappointing results include the development of more active induction regimens, the upfront use of HDC and sequential administration of high-dose drugs or regimens.Our group has shown that the combination of gemcitabine+epirubicin+paclitaxel (GET) is very active with an overall response rate of 92% and a complete response rate of 31%; 6 the administration of high-dose thiotepa followed by high-dose melphalan as consolidation of GET induces an improvement in quality of response in 44% of patients. 7 On the basis of the promising activity and acceptable toxicity observed in this study...

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Cellular pharmacology of lipophilic anthracyclines in human tumor cells in culture selected for resistance to doxorubicin

Cited by 15 publications

References 0 publications

Modulation of Multidrug-Resistance-Associated P-Glycoprotein in Human U-87 MG and HUV-ECC Cells with Antisense Oligodeoxynucleotides to MDR1 mRNA

Modulation of Multidrug-Resistance-Associated P-Glycoprotein in Human U-87 MG and HUV-ECC Cells with Antisense Oligodeoxynucleotides to MDR1 mRNA

Synergy between verapamil and other multidrug-resistance modulators in model membranes

High-dose consolidation chemotherapy with Idarubicin and alkylating agents following induction with gemcitabine–epirubicin–paclitaxel in metastatic breast cancer: a dose finding study

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