PFPC Daily - May 24, 2005

Sendzik J, Shakibaei M, Schafer-Korting M, Stahlmann R -
"Fluoroquinolones cause changes in extracellular matrix, signalling
proteins, metalloproteinases and caspase-3 in cultured human tendon
cells" Toxicology. 2005 May 9; [Epub ahead of print]

Antimicrobial therapy with fluoroquinolones can be associated with
tendinitis and other tendon disorders as an adverse reaction
associated with this class of antimicrobials. Here we investigated
aspects of the mechanism of quinolone-induced tendotoxicity in human
tenocytes focussing mainly on the question whether fluoroquinolones
may induce apoptosis. Monolayers of human tenocytes were incubated
with ciprofloxacin or levofloxacin at different concentrations (0, 3,
10, 30 and 100mg/L medium) for up to 4 days. Ultrastructural changes
were studied by electron microscopy, and alterations in synthesis of
specific proteins were determined using immunoblotting. At
concentrations, which are achievable during quinolone therapy, 3mg
ciprofloxacin/L medium significantly decreased type I collagen;
similar changes were observed with 3mg ciprofloxacin or 10mg
levofloxacin/L medium for the beta(1)- integrin receptors. Effects
were intensified at higher concentrations and longer incubation
periods. Cytoskeletal and signalling proteins, such as activated shc
or erk 1/2, were significantly reduced by both fluoroquinolones
already at 3mg/L. Furthermore, time- and concentration-dependent
increases of matrix metalloproteinases as well as of the apoptosis
marker activated caspase-3 were found. Apoptotic changes were
confirmed by electron microscopy: both fluoroquinolones caused
typical alterations like condensed material in the nucleus, swollen
cell organelles, apoptotic bodies and bleb formation at the cell
membrane. Our results provide evidence that besides changes in
receptor and signalling proteins apoptosis has to be considered as a
final event in the pathogenesis of fluoroquinolone-induced
tendopathies.

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