Inhibition of tumor implantation by intravesical gemcitabine in a murine model of superficial bladder cancer

Purpose: We determined if a single intravesical instillation of gemcitabine (2',2'-difluorodeoxycytidine) could prevent the implantation of urothelial cancer cells in the bladder wall of mice, and if 4 weekly treatments could eliminate early implanted bladder cancer in this model. Materials and Methods: Tumor implantation and orthotopic bladder tumors were induced in mice by electrocautery of the bladder wall and subsequent instillation of MB49 bladder cancer cells. In the first experiment the tumor cell suspension was left in place for 30 minutes, immediately followed by-bladder irrigation and a single intravesical. instillation of 250 or 500 mu g gemcitabine for 10, 30, 60 or 120 minutes. In the second experiment dwell time was 2 hours, bladders were not irrigated after tumor cell instillation and mice were treated with 4 weekly instillations starting 24 hours after tumor cell implantation. The animals were monitored for side effects and bladder cancer signs, and autopsied at the end of followup. Results: A single intravesical instillation of 500 jig gemcitabine (10 mg/ml) for 30 minutes decreased tumor outgrowth significantly from 90% (control) to 30% (chi-square test p = 0.022). Gemcitabine at 250 jig and prolonged instillations of 500 jig during 60 or 120 minutes were less effective. In the second experiment a short dwell time (30 minutes) was effective at 500 mu g doses, resulting in an outgrowth decrease in 89% (control) to 30% of mice, whereas longer instillations (greater than 120 minutes) resulted in significantly reduced tumor outgrowth (11% at 250 mu g). The apparent loss of efficacy as a factor of time could not be fully explained. Prolonged bladder distention caused by increased bladder volume due to diuresis may have resulted in trauma and caused enhanced susceptibility to tumor implantation. In the second experiment prolonged instillations (greater than 120 minutes) at 250 jig or higher doses (500 jig) were effective with 11% and 30% outgrowth, respectively. Conclusions: If given early (within 30 minutes.) after tumor cell seeding, gemcitabine is effective for preventing tumor cell implantation and the resulting tumor outgrowth.