Some of the most significant therapeutic leads and agents used for the treatment of cancer target microtubule dynamics. Paclitaxel is an exceptional example that is currently used for treating a wide range of tumors. New, non-taxane microtubule stabilizers, including several epothilones, are advancing through clinical trials. Laulimalide is a potent microtubule stabilizer that binds to tubulin at a site that does not overlap the taxane-binding site. It is active against paclitaxel-resistant cancer cells. Notwithstanding its therapeutic potential, laulimalide is relatively unstable, rearranging to a more stable but less active isomer. The goal of this study was to evaluate the ability of laulimalide and two designed laulimalide analogues, C16-C17-des-epoxy laulimalide (LA1) and C20-methoxy laulimalide (LA2), to inhibit cell proliferation in combination with other tubulin-binding and non-tubulin-binding antiproliferative antimitotic agents. The synthetic laulimalide analogues retain the mechanism of action of the natural compound but do not share its instability. We studied the ability of the laulimalides to act synergistically with paclitaxel, 2-methoxyestradiol, and monastrol, an Eg5 kinesin inhibitor. The results show that all three of the laulimalides acted synergistically with paclitaxel and 2-methoxyestradiol to inhibit proliferation with the analogues exhibiting significantly larger synergistic effects. The combination of laulimalide and monastrol was not synergistic and provided only additive effects. The laulimalide analogues LA1 and LA2 had a greater degree of synergy with both paclitaxel and 2-methoxyestradiol than was observed with laulimalide. Our results show that the laulimalides together with other tubulin-binding antimitotic agents provide synergistic antiproliferative actions. The data are consistent with the previously reported ability of laulimalide and paclitaxel to act synergistically to polymerize tubulin in vitro. These important findings suggest that specific combinations of microtubule-targeting agents should be considered for clinical utilities as they have excellent potential to improve clinical response.

This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy. A prospective, multicenter PK study was conducted among 59 pregnant women (93.2% white) who were studied once during a trimester. One beverage with 30–95 mg caffeine was consumed, and a blood/urine sample was collected within 1 hour postingestion. Concentrations of caffeine and its primary metabolites were quantified from serum and urine by LC-MS/MS. There was a significant increase in dose-normalized caffeine serum and urine concentrations between the first and third trimesters (P< .05 and P< .01, respectively). Normalized theophylline concentrations also increased significantly in the third trimester in serum (P < .001) and in urine (P <.05). The caffeine urine/serum concentration ratio also increased in the last trimester (P < .05). No significant difference was found in normalized paraxanthine or theobromine concentrations. This study identified decreased caffeine metabolism and an increase in the active metabolite theophylline concentrations during pregnancy, especially in the third trimester, revealing evidence of the large role that pregnancy plays in influencing caffeine metabolism.

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