Objectives: Despite complete transurethral resection of superficial bladder tumors, the recurrence rate averages 88% at 15 years. Intravesical chemotherapy decreases the recurrence rate, particularly if given immediately after tumor resection. Anticancer drugs such as doxorubicin target topoisomerase II as do the quinolone antibiotics. We evaluated two fluoroquinolones independently and in combination with doxorubicin for cytotoxic effects against bladder cancer cells in vitro.
Methods: Three human transitional carcinoma cell lines, T24 (grade I), HTB9 (grade II), and TccSup (grade IV), were exposed to either ciprofloxacin or ofloxacin in concentrations ranging from 0 (control) to 1000 microg/mL for 24, 48, and 96 hours. In a separate experiment, a 30% cytotoxic dose (IC30) of doxorubicin was applied to the cell cultures for 1 hour and washed off, followed by exposure to ciprofloxacin or ofloxacin for 48 and 96 hours. Cytotoxicity was evaluated using the MTT colorimetric assay.
Results: At 96 hours, significant cytotoxicity (P <0.05) for ciprofloxacin was seen starting at 12.5 microg/mL (HTB9, TccSup) and 50 microg/mL (T24) and for ofloxacin at 12.5 microg/mL (HTB9) and 50 microg/mL (TccSup, T24). Maximum cytotoxicity with ciprofloxacin was 95.4+/-0.4% (HTB9, 400 microg/mL) and with ofloxacin was 95.2+/-0.3% (HTB9, 800 microg/mL). Exposure to doxorubicin (IC30, 1 hour) resulted in cell kill rates of 30.9+/-5.2% (T24), 50.7+/-2.7% (HTB9), and 25.4+/-10.6% (TccSup). The addition of as little as 25 microg/mL of ciprofloxacin increased kill rates to 78.5+/-1.2% (T24), 61.2+/-1.6% (HTB9), and 74.2+/-2.4% (TccSup); P < 0.05 relative to doxorubicin alone. Similarly, 50 microg/mL of ofloxacin significantly increased kill rates to 81.8+/-1.6% (T24), 63.3+/-2.5% (HTB9), and 67.8+/-2.0% (TccSup). Both drugs showed even greater synergism at higher concentrations.
Conclusions: Ciprofloxacin and ofloxacin exhibit significant time- and dose-dependent cytotoxicity against transitional carcinoma cells and significantly enhance the cytotoxicity of doxorubicin. These effects occur at concentrations achievable in the urine of patients after oral administration. This suggests that quinolone antibiotics might be useful as an adjunct to intravesical chemotherapy and might reduce seeding of cancer cells after transurethral resection of bladder tumors.