Background:

Intravesical chemotherapy promotes direct exposure of the cytotoxic agent to bladder cancers while limiting systemic absorption. However, significant local side effects (dysuria, frequency and urgency) are common. The urothelium releases mediators (ATP, acetylcholine, PGE₂) when stretched during bladder filling which activate sensory nerves to give sensation of fullness/pain. This normal function of the urothelium may be disrupted after intravesical treatment with chemotherapeutic agents such as gemcitabine.

Aim:

To investigate the effect of gemcitabine treatment on basal and stretch-induced release of these mediators from human urothelial cells.

Methods:

Human urothelial cells UROtsas were treated with increasing doses of gemcitabine for 1 hour. Following treatment, the basal and stretch-induced release (using hypotonic solution) of mediators was measured.

Results:

Following treatment with gemcitabine, stimulated release of ATP was unchanged but basal release of ATP from urothelial cells increased in a concentration-dependent manner. In the cells treated with 4mg/mL of gemcitabine, basal ATP release was significantly increased compared to control (16.4±2.5 to 6.0±0.7, p<0.05). Levels of basal and stimulated acetylcholine and prostanglandin E₂ release from urothelial cells were unchanged after incubation with gemcitabine.

Conclusions:

ATP has been shown to act on sensory nerves to initiate the micturition reflex and give rise to perceptions of pain (Burnstock 2009). The enhanced ATP release with gemcitabine treatment found in this study may explain the urological side effects of dysuria and increased frequency of urination observed in the clinical setting.