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Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 1, pp 117–126 | Cite as

Synergistic interactions between peloruside A and other microtubule-stabilizing and destabilizing agents in cultured human ovarian carcinoma cells and murine T cells

  • Anja Wilmes
  • David O’Sullivan
  • Ariane Chan
  • Clarissa Chandrahasen
  • Ian Paterson
  • Peter T. Northcote
  • Anne Camille La Flamme
  • John H. Miller
Original Article

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.

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.

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.

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.

Keywords

Anticancer drug Combination therapy Laulimalide Microtubule-targeting agent Peloruside A Synergy 

Abbreviations:

CFSE

Carboxyfluorescein succinimidyl ester

MDA

Microtubule-destabilizing agent

MDR

Multiple drug resistance

MSA

Microtubule-stabilizing agent

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenoyltetrazolium bromide

Notes

Acknowledgments

We would like to thank Kelly Bargh and Dora Leahy for expert technical assistance and Guy Naylor and Jonathan Singh for preparation of the chemical structures in Fig. 1. This work was supported in part by the Cancer Society of New Zealand, the Genesis Oncology Trust, the Wellington Medical Research Foundation, the New Zealand Foundation of Research, Science, and Technology, and Victoria University of Wellington.

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Anja Wilmes
    • 1
    • 2
  • David O’Sullivan
    • 1
    • 2
  • Ariane Chan
    • 1
    • 2
  • Clarissa Chandrahasen
    • 1
    • 2
  • Ian Paterson
    • 4
  • Peter T. Northcote
    • 1
    • 3
  • Anne Camille La Flamme
    • 1
    • 2
  • John H. Miller
    • 1
    • 2
  1. 1.Centre for BiodiscoveryVictoria University of WellingtonWellingtonNew Zealand
  2. 2.School of Biological SciencesVictoria University of WellingtonWellingtonNew Zealand
  3. 3.Chemical and Physical Sciences (PTN)Victoria University of WellingtonWellingtonNew Zealand
  4. 4.Department of ChemistryCambridge UniversityCambridgeUK

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