The effect of penicillamine and related thiols on cyclophosphamide-induced cystitis and bone marrow suppression

When adult male Wistar-Kyoto rats had been injected intra-peritoneally with a dose of 100 mg/kg of cyclophosphamide (CP), their urinary bladders showed changes of thickening and haemorrhage visible macroscopically, and oedema, necrosis and haemorrhage of the mucosa visible microscopically. There was an increase in bladder weight from an average of 60 mg in untreated control rats to an average of 125 mg in the CP-treated rats. When in addition they had been given 400 mg/kg of a thiol drug, namely either penicillamine or its disulphide, or N-acetylcysteine (NAC) or its S-carboxymethyl derivative carbocysteine, the increase in bladder weight and the histologic changes of haemorrhagic cystitis were found to be prevented by the co-administration of penicillamine or NAC but not by penicillamine disulphide or carbocysteine. The leucopenia caused by CP was not prevented by co-administration of these thiol drugs. It is concluded that penicillamine, like NAC, is effective in preventing CP-induced cystitis but not at the expense of reducing the cytotoxicity of CP. The inefficacy of penicillamine disulphide and carbocysteine suggests that significant dissociation of the disulphide does not occur in vivo and that the thiol moiety is important in preventing the cystitis. Penicillamine, a thiol compound with anti-rheumatic and possible anti-tumour effects, may thus prove to be a very useful adjunct to CP therapy.