title: Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neurology, Johns Hopkins University Baltimore, Maryland.
authors.forename: Gigi J
authors.initials: GJ
authors.lastname: Ebenezer
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Karen
authors.initials: K
authors.lastname: Carlson
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Diana
authors.initials: D
authors.lastname: Donovan
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Marta
authors.initials: M
authors.lastname: Cobham
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Ellen
authors.initials: E
authors.lastname: Chuang
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Anne
authors.initials: A
authors.lastname: Moore
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Tessa
authors.initials: T
authors.lastname: Cigler
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Maureen
authors.initials: M
authors.lastname: Ward
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Lane
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Anita
authors.initials: A
authors.lastname: Ramnarain
authors.affiliation: Breast Cancer Research Program, Weill Cornell Medical College New York City, New York.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vahdat
authors.affiliation: Neurology, Johns Hopkins University Baltimore, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Polydefkis