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

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.

Geographical differences in the proportion of human group A rotavirus strains within New Zealand during one epidemic season.

The prospect of future rotavirus vaccine programs means it is important to understand rotavirus strain diversity within New Zealand, especially if this was to influence vaccine effectiveness. The G-genotype of 359 group A rotavirus strains isolated from 416 stool samples collected from June 2005 to May 2006 (inclusive) from children less than 5 years of age in multiple centers throughout New Zealand was determined. G1 was the dominant circulating strain (55.8%) followed by G4 (21.4%), G3 (3.4%), G9 (3.4%) G2 (1.0%), and mixed infection (1.0%). Two less common strains, G6 and G8, were identified for the first time in New Zealand. P genotypes were determined for a random 10% of samples containing the common G-type strains, and all samples with an unusual G-type. All samples able to be tested contained P[8] bearing strains, except for G1P[4], G2P[4], and G8P[14] strains. Importantly, significant differences in strain frequency were found between samples collected from the North and South Islands of New Zealand. G1 was the most commonly identified strain in the North Island (81.9%); whereas G4 predominated in the South Island (39.6%). Of note, no significant differences in the relative frequency of rotavirus strains were observed between samples collected from children treated in hospital compared to samples collected from children seen by their primary healthcare provider in the community. Regional strain variation highlights the importance of ensuring multi-center surveillance to help monitor program effectiveness when rotavirus vaccines are introduced into New Zealand's national childhood immunization schedule.