Neuropathy-inducing effects of eribulin mesylate versus paclitaxel in mice with preexisting neuropathy

Abstract

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.

Fig. 1

Effect of two chemotherapy regimens on mouse caudal nerve conduction velocity (a) and amplitude (b). Paclitaxel (0.75 MTD) administered to mice on a Q2Dx3 for 2 weeks regimen produced a significant decrease in caudal velocity and amplitude (Week 2). This effect persisted throughout an additional 2 week period, despite no additional dosing (Week 4). Thereafter, mice were treated with additional paclitaxel or eribulin mesylate, each administered at 0.5 MTD. Paclitaxel induced additional deficits in nerve conduction velocity and amplitude, with a significantly greater velocity deficit in the paclitaxel/paclitaxel group than in the paclitaxel/eribulin group at 6 weeks (p < 0.05), while additional eribulin mesylate had no significant additional effect (A and B; week 6 vs. week 4)

Fig. 2

Long-term effects of a single paclitaxel regimen on caudal nerve velocity (a) and amplitude (b). The deficit in conduction velocity induced by a single regimen of paclitaxel (0.75 MTD) is shown in (a) and appeared recovered by week 6, while the amplitude deficit was maintained through week 10 (b)

Fig. 3

Morphological analysis of mice with preexisting neuropathy (a–e). After perfusion, sciatic nerves at mid-thigh were harvested, processed for toluidine blue staining, and analyzed for axonal degeneration. (a–d) show cross-sectioned semi-thin (1 μm) plastic sections from nerve. (a) shows a representative nerve section from mouse receiving veh/veh treatment showing no axonal degeneration whereas nerve from paclitaxel/vehicle treated mouse show degeneration of myelinated axons (b). In (c), nerves from mice treated with paclitaxel plus paclitaxel show more degeneration of myelinated axons, of similar magnitude to that seen in nerves from mice treated with paclitaxel followed by eribulin (d). (e) shows the actual quantification numbers of degenerated myelinated axons in the whole cross-sectional area of the nerves. Values are ± SEM. N = 5 for each treatment, except vehicle/vehicle group, where n = 3