Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand.
Cancer Chemother Pharmacol. 2011 Jul;68(1):117-26. doi: 10.1007/s00280-010-1461-3. Epub 2010 Sep 17.
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.
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.
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.
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.
微管稳定剂是一类重要的抗癌化合物。Peloruside A 和 laulimalide 与紫杉烷类药物（如紫杉醇（Taxol(®)）、多西他赛（Taxotere(®)）、伊沙匹隆（Ixempra(®)）、埃坡霉素和 discodermolide）在微管上的结合位点不同。本研究旨在探讨这些药物在结合时的协同相互作用，以及它们在微管上结合位点的差异。
用人卵巢癌细胞（1A9 细胞）和鼠 T 细胞用不同组合的微管稳定剂或去稳定剂药物处理。将这些化合物单独或联合使用，并评估其抗增殖活性，以从方程中计算出组合指数（CI）：CI = D(1)/Dx(1) + D(2)/Dx(2)，其中 D(1)和 D(2)是当联合使用时，药物 1 和药物 2 的浓度，其产生的反应与药物 1 和 2 单独使用时相同（Dx(1)和 Dx(2)）。因此，CI 值小于 1.0 表明两种药物之间存在协同作用，即两种药物联合使用的反应大于两种药物单独使用时的相加反应。
正如之前的体外研究预期的那样，peloruside A 和 laulimalide 之间没有协同作用。它们也没有与微管去稳定剂长春碱和 2-甲氧基雌二醇协同作用。然而，peloruside A 和 laulimalide 与埃坡霉素协同作用，这与之前的研究结果一致，但与多西他赛或 discodermolide 没有协同作用。
将两种具有不同结合位点的微管靶向剂结合在一起并不能保证在细胞中产生协同相互作用，可能还有其他因素起作用。本研究强调了在进行临床试验之前，对实际药物组合进行临床前测试的重要性。
