Synergistic interactions between peloruside A and other microtubule-stabilizing and destabilizing agents in cultured human ovarian carcinoma cells and murine T cells.
OBJECTIVE
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.
Wilmes
Anja
A
Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand.
O'Sullivan
David
D
Chan
Ariane
A
Chandrahasen
Clarissa
C
Paterson
Ian
I
Northcote
Peter T
PT
La Flamme
Anne Camille
AC
Miller
John H
JH
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013154:Spleen; D013601:T-Lymphocytes / Q000187:drug effects*; D050257:Tubulin Modulators / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D007783:Lactones; D018942:Macrolides; D050257:Tubulin Modulators; C117305:laulimalide; C414085:peloruside A