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In order to clarify the mechanism of the pollakisuria caused in subjects by 1-hexylcarbamoyl-5-fluorouracil (HCFU), a new .antitumor agent, in a Phase 1 study, the effects of HCFU and its metabolites on a cat bladder movement were studied.HCFU and 1-ω-carboxypropylcarbamoy1-5-fluorouracil (CPRFU), one of its main metabolites, slightly accelerated bladder movement whereas 1-ω-carboxypentylcarbamoyl-5-fluorouracil (CPEFU), another main metabolite of HCFU, caused marked acceleration. However the other metabolites, such as 5-fluorouracil (5-FU), α-fluoro-β-alanine and e-aminocaproic acid, had no such effect. Furthermore CPEFU also accelerated rabbit and rat bladder movements.These data suggested that the pollakisuria caused in subjects by HCFU might be the result of stimulation of the bladder by CPEFU.The effect of CPEFU was inhibited by atropine and hexamethonium but not by diphenhydramine. CPEFU significantly potentiated the bladder contractions induced by stimulation of the central end of the pelvic nerve but not with a peripheral end. The acceleration of the bladder movement caused by CPEFU remained present in the intercollicular-prepontine decerebrate cat but disappeared in the spinal cat and postcollicular-midpontine decerebrate cat.Anticholinergic drugs, chlorpromazine and sulpiride, inhibited not only the acceleration of cat bladder movement due to CPEFU but also the pollakisuria caused in subjects by HCFU.These findings lead to the postulation that the pollakisuria caused by HCFU is due to stimulation by CPEFU of the micturition reflex center in the brain stem.

Effects of 1-Hexylcarbamoyl-5-fluorouracil (HCFU) and Its Metabolites on Bladder Movement