Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients

BACKGROUND: We sought to define the clinical and ultrastructure effects of ixabepilone (Ix), a microtubule-stabilizing chemotherapy agent on cutaneous sensory nerves and to investigate a potential mitochondrial toxicity mechanism. METHODS: Ten breast cancer patients receiving Ix underwent total neuropathy score clinical (TNSc) assessment, distal leg skin biopsies at cycle (Cy) 3 (80–90 mg/m(2)), Cy5 (160–190 mg/m(2)), and Cy7 (>200 mg/m(2)) and were compared to 5 controls. Skin blocks were processed for EM and ultrastructural morphometry of Remak axons done. RESULTS: At baseline, Ix-treated subjects had higher TNSc values (4.5 ± 0.8 vs. 0.0 ± 0.0), greater percentage of empty (denervated) Schwann cells (29% vs. 12%), altered axonal diameter (422.9 ± 17 vs. 354.9 ± 14.8 nm, P = 0.01), and axon profiles without mitochondria tended to increase compared to control subjects (71% vs. 70%). With increasing cumulative Ix exposure, an increase in TNSc values (Cy3: 5.4 ± 1.2, Cy7: 10 ± 4, P < 0.001), empty Schwann cells (39% by Cy7), and dilated axons (in nm, Cy3: 506.3 ± 22.1, Cy5: 534.8 ± 33, Cy7: 527.8 ± 24.4; P < 0.001) was observed. In addition, axon profiles without mitochondria (Cy3:74%, Cy7:78%) and mitochondria with abnormal morphology (grade 3 or 4) increased from 24% to 79%. Schwann cells with atypical mitochondria and perineuronal macrophage infiltration in dermis were noted. INTERPRETATION: This study provides functional and structural evidence that Ix exposure induces a dose-dependent toxicity on small sensory fibers with an increase in TNSc scores and progressive axonal loss. Mitochondria appear to bear the cumulative toxic effect and chemotherapy-induced toxicity can be monitored through serial skin biopsy-based analysis.