Inhibitory effects of 1,3-diaminopropane, an ornithine decarboxylase inhibitor, on rat two-stage urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine

Overexpression of ornithine decarboxylase (ODIC) has been shown to be chara cteristic of tumor development and progression in humans and experimental a nimals, Therefore, we have examined the effects of 1,3-diaminopropane dihyd rochloride (DAP), a potent inhibitor of ODC, on rat two-stage urinary bladd er carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN ). In experiment 1 (36 weeks), 6-week-old F344 male rats were administered 0.05% BBN in drinking water for 4 weeks and then divided into four groups. Animals of groups 1 and :1 received basal diet and drinking water supplemen ted with or without DAP (2 g/l), Groups 3 and 4 were given diet containing 5% sodium L-ascorbate (NaAsA), a typical urinary bladder tumor promoter, an d drinking water with or without DAP, Administration of DAP to group 1 sign ificantly reduced tumor size, multiplicity and incidence, particularly of p apillomas, when compared with group 2 values, DAP together with NaAsA (grou p 3) also decreased tumor size relative to the group 4 case. To determine t he effects of DAP on the early stages of bladder carcinogenesis and its mec hanisms, a similar protocol was conducted (experiment 2) with death after 2 0 weeks. DAP treatment caused complete inhibition (0% incidence) of papilla ry and/or nodular hyperplasia in group 1 but was without influence in group 3, as compared with the respective controls. Moreover, the ODC activity, b romodeoxyuridine labeling indices and mRNA expression levels of cyclin D1 i n the urinary bladder mucosa, determined by northern blotting, were markedl y lower in group 1 than in group 2, but values were comparable for both gro ups administered NaAsA, Assessment of mRNA expression levels of; the angiog enic vascular endothelial growth factor suggested no involvement in the inh ibitory effects of DAP on urinary bladder carcinogenesis. The results indic ate that inhibition of ODC could reduce urinary bladder carcinogenesis in r ats, particularly in the early stages, through antiproliferative mechanisms .