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Synergistic interactions between peloruside A and other microtubule-stabilizing and destabilizing agents in cultured human ovarian carcinoma cells and murine T cells.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2011 Jul; Vol. 68 (1), pp. 117-26. Date of Electronic Publication: 2010 Sep 17. - Publication Year :
- 2011
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Abstract
- Purpose: Microtubule-stabilizing agents are an important class of anticancer compounds. Peloruside A and laulimalide bind to a different site on the microtubule to taxoid site drugs such as paclitaxel (Taxol(®)), docetaxel (Taxotere(®)), ixabepilone (Ixempra(®)), the epothilones, and discodermolide. The purpose of this study was to examine the synergistic interactions of these drugs when given in combination in relation to the differences in their binding sites on the microtubule.<br />Methods: Human ovarian carcinoma cells (1A9 cells) and murine T cells were treated with different combinations of microtubule-stabilizing or destabilizing agents. The compounds were given individually and in combination, and the antiproliferative activity was assessed to calculate a combination index (CI) from the equation: CI = D(1)/Dx(1) + D(2)/Dx(2) in which D(1) and D(2) are the concentrations of drug 1 and drug 2 that when given together give the same response as drug 1 and 2 alone (Dx(1) and Dx(2)). Thus, a CI value of less than 1.0 indicates a synergistic effect between the two drugs in which the response to the two drugs given together is greater than the additive response of the two drugs if given on their own.<br />Results: As anticipated from previous in vitro studies, peloruside A and laulimalide did not synergize with each other. They also failed to synergize with the microtubule-destabilizing agents vinblastine and 2-methoxyestradiol. Peloruside A and laulimalide did, however, synergize with the epothilones, as had been previously shown, but not with docetaxel or discodermolide.<br />Conclusions: Combining two microtubule-targeting agents with different binding sites does not guarantee a synergistic interaction in cells, and additional factors are likely to be involved. This study highlights the importance of preclinical testing of actual combinations of drugs before proceeding into clinical trials.
- Subjects :
- Animals
Bridged Bicyclo Compounds, Heterocyclic chemistry
Cell Line, Tumor
Cells, Cultured
Drug Synergism
Female
Humans
Inhibitory Concentration 50
Lactones chemistry
Macrolides chemistry
Mice
Mice, Inbred C57BL
Ovarian Neoplasms pathology
Spleen
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Cell Proliferation drug effects
Lactones pharmacology
Macrolides pharmacology
Microtubules drug effects
Ovarian Neoplasms drug therapy
T-Lymphocytes drug effects
Tubulin Modulators pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 68
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 20848285
- Full Text :
- https://doi.org/10.1007/s00280-010-1461-3