New quinolones: in vitro effects as a potential source of clinical toxicity.
4-Quinolones affect mammalian cellular functions in vitro in several ways. High concentrations inhibit DNA replication, but individual genes are perhaps sensitive to lower concentrations of drug. Inhibition of cell proliferation differs widely among 4-quinolones. Ciprofloxacin and norfloxacin are the most antiproliferative, inhibiting cell growth by approximately 30% at 20 mg/L. Genotoxicity tests with 4-quinolones are probably "false-positive" as a result of increased [3H]thymidine uptake that is not related to DNA damage. Ciprofloxacin at greater than or equal to 10 mg/L causes significant strand breaks in DNA, which seemingly are quickly repaired and do not cause mutations or cancer. Production of immunoglobulin is inhibited by ciprofloxacin at a concentration of 5 mg/L, but production of the growth factor interleukin 2 (IL-2) is increased by 4-quinolones at the same concentration and is hyperinduced at higher concentrations. Thus the effects are very contradictory. Increased production of IL-2 may contribute to central nervous system adverse effects. 4-Quinolones in combination with theophylline or antiinflammatory drugs may inhibit gamma-aminobutyric acid receptor binding and thereby have adverse effects on the central nervous system. Some 4-quinolones induce crystalluria, which may be nephropathic.