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Sequence-dependent synergism and antagonism between paclitaxel and gemcitabine in breast cancer cells: the importance of scheduling

The marked clinical anticancer activity of the paclitaxel (PTX) and gemcitabine (GEM) combination has suggested that the two drugs may interact more than additively. We have analyzed the in vitro growth and molecular interactions of the two chemotherapy drugs in a panel of human breast cancer cells. We evaluated cell viability in four breast cancer cell lines (i.e., MCF-7, MDA-MB-231, MDA-MB-468, and SKBR3) that were treated with PTX and GEM combined either simultaneously (PTX + GEM) or sequentially (PTX --> GEM; GEM --> PTX). PTX-GEM interactions at the cellular level were assessed mathematically employing both the isobologram analysis (Berenbaum) and the combination index (Chou-Talalay) method. PTX-GEM molecular interactions on the apoptotic markers PARP, Bcl-2 and Bax were analyzed by immunoblotting procedures. Apoptosis was detected using a DNA ladder assay. We observed significant synergistic growth inhibitory interactions when PTX was administered before GEM. Additive interactions were observed when both the simultaneous regimen and the GEM followed by PTX regimen were used. DNA ladder and Western blotting results in the PTX followed by GEM sequence revealed a significant increase in the apoptotic cell death of breast cancer cells related to the Bax/Bcl-2 apoptotic pathway. In summary, the occurrence of clinically relevant synergism between PTX and GEM suggests a sequence-dependent nature in human breast cancer cells. This synergistic interaction on the PTXright curved arrow GEM schedule appears to be related to an increase in the Bcl-2-related mitochondrial apoptotic pathway. The synergism that we have observed may explain the favorable clinical responses that have been achieved in clinical studies, in which patients are administered PTX first, and then GEM

© International Journal of Oncology, 2008, vol. 32, núm. 1, p. 113-120

Spandidos Publications

Autor: Oliveras Ferrarós, Cristina
Vázquez Martín, Alejandro
Colomer, Ramon
Llorens Duran, Rafael de
Brunet i Vidal, Joan
Menéndez Menéndez, Javier Abel
Data: 2008
Resum: The marked clinical anticancer activity of the paclitaxel (PTX) and gemcitabine (GEM) combination has suggested that the two drugs may interact more than additively. We have analyzed the in vitro growth and molecular interactions of the two chemotherapy drugs in a panel of human breast cancer cells. We evaluated cell viability in four breast cancer cell lines (i.e., MCF-7, MDA-MB-231, MDA-MB-468, and SKBR3) that were treated with PTX and GEM combined either simultaneously (PTX + GEM) or sequentially (PTX --> GEM; GEM --> PTX). PTX-GEM interactions at the cellular level were assessed mathematically employing both the isobologram analysis (Berenbaum) and the combination index (Chou-Talalay) method. PTX-GEM molecular interactions on the apoptotic markers PARP, Bcl-2 and Bax were analyzed by immunoblotting procedures. Apoptosis was detected using a DNA ladder assay. We observed significant synergistic growth inhibitory interactions when PTX was administered before GEM. Additive interactions were observed when both the simultaneous regimen and the GEM followed by PTX regimen were used. DNA ladder and Western blotting results in the PTX followed by GEM sequence revealed a significant increase in the apoptotic cell death of breast cancer cells related to the Bax/Bcl-2 apoptotic pathway. In summary, the occurrence of clinically relevant synergism between PTX and GEM suggests a sequence-dependent nature in human breast cancer cells. This synergistic interaction on the PTXright curved arrow GEM schedule appears to be related to an increase in the Bcl-2-related mitochondrial apoptotic pathway. The synergism that we have observed may explain the favorable clinical responses that have been achieved in clinical studies, in which patients are administered PTX first, and then GEM
Format: application/pdf
ISSN: 1019-6439 (versió paper)
1791-2423 (versió electrònica)
Accés al document: http://hdl.handle.net/10256/8261
Llenguatge: eng
Editor: Spandidos Publications
Col·lecció: Reproducció digital del document publicat a: http://www.spandidos-publications.com/ijo/32/1/113
Articles publicats (D-B)
És part de: © International Journal of Oncology, 2008, vol. 32, núm. 1, p. 113-120
Drets: Tots els drets reservats
Matèria: Mama -- Càncer
Breast -- Cancer
Medicaments antineoplàstics
Antineoplastic agents
Títol: Sequence-dependent synergism and antagonism between paclitaxel and gemcitabine in breast cancer cells: the importance of scheduling
Tipus: info:eu-repo/semantics/article
Repositori: DUGiDocs

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