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

• Published in: British journal of cancer Vol. 81; no. 8; pp. 1304 - 1310
• Main Authors: VANHOEFER, U, MÜLLER, M. R, HILGER, R. A, LINDTNER, B, KLAASSEN, U, SCHLEUCHER, N, RUSTUM, Y. M, SEEBER, S, HARSTRICK, A
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.12.1999
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Blotting, Western; Chemotherapy; dihydropyridines; Dihydropyridines - pharmacology; DNA Topoisomerases, Type I - metabolism; DNA Topoisomerases, Type II - metabolism; Drug Resistance, Neoplasm - genetics; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Medical sciences; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; PAK-200S; Pharmacology. Drug treatments; Phenotype; Regular; topotecan; Topotecan - pharmacokinetics; Topotecan - pharmacology; Tumor Cells, Cultured; Antineoplastic agent; Cell culture; Carcinoma; P Glycoprotein; Cytotoxicity; Inversion; Ovary; Isomerases; Multiple resistance; Established cell line; Mammary gland; Negative therapeutic reaction; Human; Enzyme; Treatment efficiency; DNA topoisomerase; Topotecan; Malignant tumor; In vitro; Female genital diseases; Mammary gland diseases; Ovarian diseases; Chemotherapy; Pyridine; Analog; Molecular biology
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6694384

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.