Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

U Vanhoefer; M R Müller; R A Hilger; B Lindtner; U Klaassen; N Schleucher; Y M Rustum; S Seeber

doi:10.1038/sj.bjc.6694384

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Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

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Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines

U Vanhoefer, M R Müller, R A Hilger, B Lindtner, U Klaassen, N Schleucher, Y M Rustum and S Seeber

British journal of cancer, Vol.81(8), pp.1304-1310

12/01/1999

DOI: 10.1038/sj.bjc.6694384

PMCID: PMC2362978

PMID: 10604726

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Abstract

Recent data suggest that expression of the membrane P 170 -glycoprotein (P-gp) may confer resistance to the topoisomerase- I-interactive agent topotecan. The present study describes the cellular effects of a new dihydropyridine analogue, PAK-200S, on P-gp-mediated resistance to topotecan in human breast and ovarian tumour cells. PAK-200S at a non-cytotoxic concentration of 2.0 μ M completely reversed resistance to topotecan in P-gp-expressing MCF-7/adr (breast) and A2780/Dx5 (ovarian) tumour cells, respectively, with no effects on parental cells. Cellular pharmacokinetic studies by reversed-phase high-performance liquid chromatography analysis showed significantly lower cellular drug concentrations of the pharmacologically active closed-ring lactone of topotecan in multidrug-resistant cells than in parental cells. PAK-200S was effective in restoring the cellular lactone concentrations of topotecan in resistant MCF-7/adr cells to levels comparable to those obtained in parental cells. Furthermore, exposure of MCF-7/adr cells to topotecan in the presence of PAK-200S significantly increased the induction of protein-linked DNA breaks. PAK-200S did not alter nuclear topoisomerase I-mediated ex vivo pBR322 DNA plasmid unwinding activity and topoisomerase-I protein expression. These results suggest that reversal of P-gp-mediated resistance to topotecan by PAK-200S was related to the restoration of cellular drug concentrations of the active lactone form of topotecan rather than a direct effect on topoisomerase-I function. © 1999 Cancer Research Campaign

breast cancer

multidrug resistance

ovarian cancer

PAK-200S

Regular

topotecan

Details

Title: Subtitle: Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines
Creators: U Vanhoefer - German Cancer Research Center
M R Müller - Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen, Germany
R A Hilger - Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen, Germany
B Lindtner - Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen, Germany
U Klaassen - Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen, Germany
N Schleucher - Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen, Germany
Y M Rustum - Roswell Park Cancer Institute
S Seeber - Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Essen, Germany
Resource Type: Journal article
Publication Details: British journal of cancer, Vol.81(8), pp.1304-1310
DOI: 10.1038/sj.bjc.6694384
PMID: 10604726
PMCID: PMC2362978
NLM abbreviation: Br J Cancer
ISSN: 0007-0920
eISSN: 1532-1827
Publisher: Nature Publishing Group
Language: English
Date published: 12/01/1999
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984360149802771

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