Overcoming multidrug resistance in Chinese hamster ovary cells in vitro by cyclosporin A (Sandimmune) and non-immunosuppressive derivatives

Gavériaux, Claire; Boesch, Danielle; Boelsterli, J. J.; Bollinger, Pietro; Eberle, M. K.; Hiestand, Peter; Payne, Trevor; Traber, René; Wenger, Roland M.; Loor, Francis

doi:10.1038/bjc.1989.381

Cited by 61 publications

(31 citation statements)

References 20 publications

(16 reference statements)

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“…This model is also consistent with the finding that CsA, FK506, and rapamycin concentrations required to reverse MDR are significantly higher than those required for immunosuppression and may suffice to inhibit the abundant immunophilins (9,12,14). Furthermore, although some nonimmunosuppressive CsA and FK506 analogs reverse MDR (10,11,16), the ability of these analogs to bind and inhibit immunophilins has not yet been reported and might contribute to mdr reversing activity.…”

Section: Discussionmentioning

confidence: 99%

“…Several additional findings support this view. First, several nonimmunosuppressive CsA and FK506 analogs, at least some of which do not inhibit calcineurin, still reverse MDR (10,11,16,31,32). Second, phosphorylation is known to stimulate Pgp activity (66, 70 -72), and thus calcineurin inhibition should increase, rather than decrease, Pgp activity.…”

Section: Discussionmentioning

confidence: 99%

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Immunosuppressant Target Protein FKBP12 Is Required for P-Glycoprotein Function in Yeast

Hemenway

Heitman

1996

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Immunosuppressant Target Protein FKBP12 Is Required for P-Glycoprotein Function in Yeast

Hemenway

Heitman

1996

Journal of Biological Chemistry

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“…In vitro cytotoxicity studies Tumour cell growth and its drug-mediated inhibition were measured as described previously (Gaveriaux et al, 1989(Gaveriaux et al, , 1991Boesch et al, 1991a). The growth levels obtained without RMA and ACD, but with their solvents were taken as representing 100% growth.…”

Section: Tumour Cell Linesmentioning

confidence: 99%

“…The growth levels obtained without RMA and ACD, but with their solvents were taken as representing 100% growth. The ACD IC50s (Table I) were calculated from the dose-response curves obtained by plotting the measured growth vs the ACD concentration as described previously (Gaveriaux et al, 1989). Cultures performed in absence of ACD (but in the presence of its solvent) with the whole range of RMA concentrations allowed the construction of (RMA dose/cell growth response) curves and the determination of the RMA IC50s (Table I) (Boesch et al, 1991a;Gaveriaux et al, 1991 (Gaveriaux et al, 1991).…”

Section: Tumour Cell Linesmentioning

confidence: 99%

“…Cyclosporin research has generated over a number of years a large family of related molecules in order to find compounds with improved immunosuppressive specificity and decreased host-toxicity. Their screening for RMactivity allowed us (Gaveriaux et al, 1989) to clearly separate the two known properties of the cyclosporin molecule, i.e. its immunosuppressive activity, possibly mediated through its interaction with cyclophilin (Takahashi et al, 1989), and its MDR-reversing activity, possibly mediated through its interaction with Pgp (Foxwell et al, 1989) and led to the identification of SDZ PSC 833, a cyclosporin derivative endowed in vitro with the near maximally achievable MDR-reversing potency (Gaveriaux et al, 1991).…”

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confidence: 99%

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SDZ 280-446, a novel semi-synthetic cyclopeptolide: in vitro and in vivo circumvention of the P-glycoprotein-mediated tumour cell multidrug resistance

Loor

Boesch²,

Gavériaux³

et al. 1992

Br J Cancer

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Summary SDZ 280-446 is a semi-synthetic derivative of a natural cyclic peptolide. Its ability to sensitise in vitro tumour cells whose resistance is due to P-glycoprotein-mediated anticancer-drug efflux was shown using four different pairs of parental drug-sensitive (Par-) and multidrug-resistant (MDR-) cell lines, from three different species (mouse, human, Chinese hamster) representing four different cell lineages (monocytic leukaemia, nasopharyngeal epithelial carcinoma, colon epithelial carcinoma, ovary fibroblastoid carcinoma), and using four different drug classes (colchicine, vincristine, daunomycin/doxorubicin and etoposide). By measuring its capacity to restore normal drug sensitivity of MDR-cells in culture in vitro, it appeared that SDZ 280-446 belongs to the same class of very potent chemosensitisers as the cyclosporin derivative SDZ PSC 833: both are about one order of magnitude more active than cyclosporin A (CsA), which is itself about one order of magnitude more active than other known chemosensitisers (including verapamil, quinidine and amiodarone which have already entered clinical trials in MDR reversal). Low concentrations of SDZ 280-446 could also restore cellular daunomycin retention in MDR-P388 cells to the levels found in the Par-P388 cells. SDZ 280-446 was also effective as a chemosensitiser when given orally in vivo. In a syngeneic mouse model, combined therapy with vinca alkaloids given i.p. and SDZ 280-446 given per os for 5 consecutive days significantly prolonged the survival of MDR-P388 tumour-bearing mice, when compared with mice receiving vinca alkaloids alone. Another protocol, using three cycles of i.p. doxorubicin at 4 day intervals, could also not increase MDR-P388 tumour-bearing mouse survival unless the mice received SDZ 280-446 orally 4h before each doxorubicin injection. Though only very few combined therapy treatment protocols have been tested so far, clear increases in survival time of MDR-tumour-bearing mice were regularly obtained, leaving hope for major improvement of the therapy using other dosing schedules.

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Reversal activity of cyclosporin A and its metabolites M1, M17 and M21 in multidrug-resistant cells

et al. 1997

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Cyclosporin A (CSA) is an effective inhibitor of the P-glycoprotein (P-gp) activity and has been shown to modulate multidrug resistance (MDR) in in vitro experimental models. During degradation of CSA, the metabolites arising from the parental compound reach high levels in the serum of patients, and it is not clear whether these metabolites maintain the reversal activity of the parental compound, like the metabolites of verapamil. In an in vitro experimental model, we compared the reversal activity of CSA and 3 CSA metabolites (M1, M17, and M21) in the range of concentrations obtained in whole blood during a clinical trial with CSA used as a revertant agent. As experimental model we used LoVo-resistant cells. Our in vitro studies indicated that the metabolic hydroxylation and demethylation of CSA lead to molecules that greatly differ from the parent drug in their reversal activity. In the range of concentration detected in the whole blood of the patients (1-3 microM), CSA had a significant reversal activity. It decreased the IC50 of antineoplastic drugs involved in MDR (vincristine, taxol, doxorubicin and etoposide) but not the IC50 of platinum or methotrexate. CSA increased intracellular doxorubicin content and inhibited P-gp 3[H]azidopine photolabeling. Conversely, CSA metabolite concentrations superimposable to those observed in the patients (0.5-2.2 microM) had no sensitizing effects on the cytotoxicity of MDR-related anti-neoplastic drugs, nor did they affect 3[H]azidopine photolabeling or doxorubicin uptake. This study demonstrates that, during degradation of CSA, metabolite derivatives arise that have a very different reversal activity from that of the parental compound.

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Overcoming multidrug resistance in Chinese hamster ovary cells in vitro by cyclosporin A (Sandimmune) and non-immunosuppressive derivatives

Cited by 61 publications

References 20 publications

Immunosuppressant Target Protein FKBP12 Is Required for P-Glycoprotein Function in Yeast

Immunosuppressant Target Protein FKBP12 Is Required for P-Glycoprotein Function in Yeast

SDZ 280-446, a novel semi-synthetic cyclopeptolide: in vitro and in vivo circumvention of the P-glycoprotein-mediated tumour cell multidrug resistance

Reversal activity of cyclosporin A and its metabolites M1, M17 and M21 in multidrug-resistant cells

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