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Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines.
Br J Cancer. 1999 Dec; 81(8):1304-10.BJ

Abstract

Recent data suggest that expression of the membrane P170-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 microM 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.

Authors+Show Affiliations

Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10604726

Citation

Vanhoefer, U, et al. "Reversal of MDR1-associated Resistance to Topotecan By PAK-200S, a New Dihydropyridine Analogue, in Human Cancer Cell Lines." British Journal of Cancer, vol. 81, no. 8, 1999, pp. 1304-10.
Vanhoefer U, Müller MR, Hilger RA, et al. Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines. Br J Cancer. 1999;81(8):1304-10.
Vanhoefer, U., Müller, M. R., Hilger, R. A., Lindtner, B., Klaassen, U., Schleucher, N., Rustum, Y. M., Seeber, S., & Harstrick, A. (1999). Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines. British Journal of Cancer, 81(8), 1304-10.
Vanhoefer U, et al. Reversal of MDR1-associated Resistance to Topotecan By PAK-200S, a New Dihydropyridine Analogue, in Human Cancer Cell Lines. Br J Cancer. 1999;81(8):1304-10. PubMed PMID: 10604726.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reversal of MDR1-associated resistance to topotecan by PAK-200S, a new dihydropyridine analogue, in human cancer cell lines. AU - Vanhoefer,U, AU - Müller,M R, AU - Hilger,R A, AU - Lindtner,B, AU - Klaassen,U, AU - Schleucher,N, AU - Rustum,Y M, AU - Seeber,S, AU - Harstrick,A, PY - 1999/12/22/pubmed PY - 1999/12/22/medline PY - 1999/12/22/entrez SP - 1304 EP - 10 JF - British journal of cancer JO - Br J Cancer VL - 81 IS - 8 N2 - Recent data suggest that expression of the membrane P170-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 microM 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. SN - 0007-0920 UR - https://www.unboundmedicine.com/medline/citation/10604726/Reversal_of_MDR1_associated_resistance_to_topotecan_by_PAK_200S_a_new_dihydropyridine_analogue_in_human_cancer_cell_lines_ L2 - https://doi.org/10.1038/sj.bjc.6694384 DB - PRIME DP - Unbound Medicine ER -