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P-glycoprotein-associated resistance to taxol and taxotere and its reversal by dexniguldipine-HCl, dexverapamil-HCl, or cyclosporin A.

Abstract：

:A series of different human MDR (multidrug-resistant) cell lines including a HeLa-MDR1 transfectant which exhibit high overexpression of the MDR1/P-glycoprotein gene, but no enhanced expression of the MRP (multidrug resistance associated protein) gene, showed different ratios of relative resistances to the taxanes taxol and taxotere. Using these cell lines the chemosensitizing efficacies of several structurally different chemosensitizers, i.e. the dihydropyridine dexniguldipine-HC1 (B8509-035), its main pyridine metabolite M1 (B8909-008), the cyclic peptide cyclosporin A, or the phenylalkylamine dexverapamil-HCl, were examined applying a 72 h tetrazolium based colorimetric MTT-assay, or a 96 h sulforhodamine B assay. Remarkably, we observed in some instances that the modulating efficacy of a particular chemosensitizer was strongly dependent on the cell line used for experimentation. Thus, dexniguldipine-HCl efficiently modulated taxane resistances of the ovarian carcinoma MDR cell line 2780AD in the submicromolar concentration range, whereas cyclosporin A and the other chemosensitizers were rather ineffective. Dexniguldipine-HCl or cyclosporin A, however, both showed a similarly strong modulating activity on the HeLa-MDR1 transfectant in clear contrast to the effects observed using the pyridine B8909-008, or dexverapamil-HCl, respectively, at the same final concentrations. Our results point to additional, as yet unidentified factors beyond the expression levels of P-glycoprotein which could contribute to the susceptibility of MDR cells to a combined treatment using taxanes and different chemosensitizing compounds. This result appears to be important considering the clinical application of chemosensitizers for combination therapy of tumors of different origin.

journal_name

Int J Oncol

journal_title

International journal of oncology

authors

Ise W,Heuser M,Sanders K,Beck J,Gekeler V

doi

10.3892/ijo.8.5.951

subject

Has Abstract

pub_date

1996-05-01 00:00:00

pages

951-6

issue

eissn

1019-6439

issn

1791-2423

journal_volume

pub_type

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P-glycoprotein-associated resistance to taxol and taxotere and its reversal by dexniguldipine-HCl, dexverapamil-HCl, or cyclosporin A.