Effects of DL-alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, on the rat mammary tumour induced by 7,12-dimethylbenz[a]anthracene.

1. The effects of DL-alpha-difluoromethylornithine (RMI 71782; DFMO) on the tumours induced in female rats by a single oral administration of 20 mg 7,12-dimethyl-benz[a]anthracene (DMBA) have been investigated. 2. Treatment with DFMO (2% aqueous solution as sole drinking fluid) starting 30 days after administration of DMBA resulted in markedly fewer animals with tumours and greater than 90% reduction in the total number of tumours. 3. In rats bearing at least one palpable tumour, treatment with DFMO (2% in the drinking water) slowed significantly the rate of appearance of new tumours but affected to only a minimal extent the growth of existing tumours. Tumour ornithine decarboxylase activities and putrescine concentrations were reduced by treatment with DFMO; the activity of S-adenosyl-L-methionine decarboxylase was increased and the concentration of spermine either remained unchanged or increased depending on the length of treatment. 4. Cyclophosphamide, 100 mg/kg, injected once then repeated after 10 days, altered neither the rate of appearance of new tumours nor the growth of the existing tumours. Combined treatment with DFMO plus cyclophosphamide resulted in regression of the majority of tumours existing at the start of treatment and a marked reduction in the rate of appearance of new tumours. 5. In conclusion, DFMO has clear antitumoral activity against the rat mammary tumour induced by DMBA. The effects are manifested principally as a decreased rate of tumour appearance but meaningful effects on tumour growth are observed if the drug is administered during early tumour development or in combination with cyclophosphamide.