Cyclophosphamide and ifosfamide enhancement of bladder sensory nerve activity

Abstract

Background: A major limiting factor in the use of the cytotoxic agents cyclophosphamide and ifosfamide is the resulting uro-toxicity which can result in ongoing bladder pain, urgency, feelings of residual volume and dysuria. Both drugs have been shown to cause increased micturition frequency and bladder hyperactivity in experimental models suggesting changes in sensory activity may be involved in the bladder dysfunction after treatment. Aim: To determine the effect of cyclophosphamide and ifosfamide on bladder sensory nerve activity. Methods: Twelve week old male mice were administered either 100 mg/kg CPO or 200 mg/kg IFO by intra peritoneal injection and sacrificed 24 hours after treatment. Intravesicle pressure and bladder afferent nerve activity were measured during bladder filling and emptying in vitro. Results: As volume in the bladder increased both intravesicle pressure and bladder sensory nerve activity increased. Nerve activity after treatment with cyclophosphamide or ifosfamide was enhanced throughout bladder filling. At maximum distension the total nerve activity was increased significantly from 182 ±13 pulses per second (pps) in control animals, to 230 ±14 pps in cyclophosphamide treated mice (p < 0.05) and 226 ± 17 pps in ifosfamide treated mice (p < 0.05) (n >/- 6). Bladder compliance was not affected by systemic cyclophosphamide or ifosfamide pre-treatment. Conclusions: Both cyclophosphamide and ifosfamide enhance bladder sensory nerve activity without affecting bladder compliance. An increase in afferent sensitivity and firing may explain the pain, urgency and dysuria experienced by patients after treatment with cyclophosphamide and ifosfamide and provides a target for treating these adverse effects.