The Fluoroquinolone Toxicity Research Foundation

 
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Fluoroquinolone's Effect on Growth of Human Chondrocytes and Chondrosarcomas: In Vitro and In Vivo Correlation
Tumors/Metabolic Disease

Richard D Lackman, MD Philadelphia PA
Hinke A Multhaupt, PhD Philadelphia PA
Juan C Alvarez, MD Philadelphia PA
Patricia Rafferty, MT Philadelphia PA
Micheal J. Warhol, MD Philadelphia PA

It is known that fluoroquinolones are toxic for chondrocytes, however, the exact mechanism of fluoroquinolone arthropathy is unknown. We investigated the toxicity of ciprofloxacin on normal cartilage and cartilagenous tumors. We also characterized morphological effects of ciprofloxacin in vivo using chondrosarcoma specimens from treated patients. Normal human cartilage, enchondroma, and chondrosarcoma explants were cultured with ciprofloxacin doses between 0 and 20 mg/liter medium. Samples were collected up to 21 days of treatment and processed for electron and light microscopy. Cell proliferation, apoptosis, matrix organization and cellular morphology was compared using immunohistochemical and ultrastructural techniques. Ultrastructural analysis revealed large amount of glycogen in the cells, rough endoplasmic reticulum and prominent Golgi apparatus, and a proteoglycan layer surrounding the cells. With prolonged and increased doses of ciprofloxacin treatment, there was an increase in dilated rough endoplasmic reticulum, the appearance of phagosomes, and disintegrated bundles of vimentin filaments. Treated chondrocytes showed a decrease in cell proliferation, but there was no induction of apoptosis, or effect on the expression of extracellular matrix proteins. In contrast ciprofloxacin treated chondrosarcoma showed changes in cartilage matrix composition. Ultrastructural analysis demonstrated clumped glycogen, dilation of endoplasmic reticulum, numerous abnormal lysosomes and a decreased proteoglycan deposit surrounding the tumor cells. Treated chondrosarcoma ceased proliferating, and apoptosis was induced. In contrast, the in vitro growth of other non-cartilagenous malignant tumors like osteosarcoma and liposarcoma was unaffected by ciprofloxacin. Our results indicate that ciprofloxacin is toxic to chondrocytes. In vitro and in vivo treated chondrosarcomas are most severely affected.