NeuroTranslational Drug Discovery Program, Brain Science Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Neurotox Res. 2013 Oct;24(3):338-44. doi: 10.1007/s12640-013-9394-3. Epub 2013 Apr 30.
Eribulin mesylate (E7389, INN:eribulin mesilate Halaven(®)) is a non-taxane microtubule dynamics inhibitor currently in clinical use for advanced breast cancer. Other microtubule-targeting agents for breast cancer, including paclitaxel and ixabepilone, display a common treatment dose-limiting toxicity of peripheral neuropathy (PN). In an earlier study, we found eribulin mesylate had a lower propensity to induce PN in mice than either paclitaxel or ixabepilone. In the current study, we compared additional PN induced by paclitaxel versus eribulin mesylate when administered to mice with preexisting paclitaxel-induced PN. Initially, paclitaxel at 0.75 × its maximum tolerated dose (MTD; 22.5 mg/kg) was given on a Q2Dx3 regimen for 2 weeks. The second chemotherapy was 0.5 MTD eribulin mesylate (0.875 mg/kg) or paclitaxel (15 mg/kg) on a similar regimen, starting 2 weeks after the first. Initial paclitaxel treatment produced significant decreases in caudal nerve conduction velocity (NCV; averaging 19.5 ± 1 and 22.2 ± 1.3 %, p < 0.001) and amplitude (averaging 53.2 ± 2.6 and 72.4 ± 2.1 %, p < 0.001) versus vehicle when measured 24 h or 2 weeks after dosing cessation, respectively. Additional 0.5 MTD paclitaxel further reduced caudal NCV and amplitude relative to immediately before initiation of the second regimen (by 11 ± 2.1 and 59.2 ± 5 %, p < 0.01, respectively). In contrast, 0.5 MTD eribulin mesylate caused no further decrease in caudal NCV. In conclusion, unlike additional paclitaxel treatment, eribulin mesylate administered to mice with preexisting paclitaxel-induced PN had limited additional deleterious effects at 6 weeks. These preclinical data suggest that eribulin mesylate may have reduced tendency to exacerbate preexisting paclitaxel-induced PN in clinical settings.
甲磺酸艾瑞布林（E7389，通用名：eribulin mesilate 海乐卫(®)）是一种非紫杉烷类微管动力学抑制剂，目前用于治疗晚期乳腺癌。其他用于乳腺癌的微管靶向药物，包括紫杉醇和伊沙匹隆，均显示出外周神经病变（PN）这一共同的治疗剂量限制毒性。在早期研究中，我们发现甲磺酸艾瑞布林引起的 PN 倾向低于紫杉醇或伊沙匹隆。在当前研究中，我们比较了预先存在紫杉醇诱导的 PN 的小鼠接受紫杉醇与甲磺酸艾瑞布林时引起的额外的 PN。最初，以 2 周 Q2Dx3 方案给予紫杉醇，剂量为其最大耐受剂量（MTD）的 0.75 倍（22.5mg/kg）。第二个化疗方案为在类似方案下给予 0.5 MTD 甲磺酸艾瑞布林（0.875mg/kg）或紫杉醇（15mg/kg），起始时间为第一个化疗方案结束后 2 周。初次紫杉醇治疗后，在停止给药 24 小时或 2 周时，尾神经传导速度（NCV；分别平均降低 19.5 ± 1%和 22.2 ± 1.3%，p <0.001）和幅度（分别平均降低 53.2 ± 2.6%和 72.4 ± 2.1%，p <0.001）与载体相比均显著降低。此外，给予 0.5 MTD 紫杉醇与开始第二个方案前相比，进一步降低了尾神经 NCV 和幅度（分别降低 11 ± 2.1%和 59.2 ± 5%，p <0.01）。相比之下，0.5 MTD 甲磺酸艾瑞布林对尾神经 NCV 没有进一步降低。总之，与额外的紫杉醇治疗不同，预先存在紫杉醇诱导的 PN 的小鼠接受甲磺酸艾瑞布林治疗，在 6 周时，具有有限的额外有害作用。这些临床前数据表明，在临床环境中，甲磺酸艾瑞布林可能具有减轻先前存在的紫杉醇诱导的 PN 的趋势。
