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 (ODC) has been shown to be characteristic of tumor development and progression in humans and experimental animals. Therefore, we have examined the effects of 1, 3-diaminopropane dihydrochloride (DAP), a potent inhibitor of ODC, on rat two-stage urinary bladder 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 2 received basal diet and drinking water supplemented 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, and drinking water with or without DAP. Administration of DAP to group 1 significantly reduced tumor size, multiplicity and incidence, particularly of papillomas, when compared with group 2 values. DAP together with NaAsA (group 3) also decreased tumor size relative to the group 4 case. To determine the effects of DAP on the early stages of bladder carcinogenesis and its mechanisms, a similar protocol was conducted (experiment 2) with death after 20 weeks. DAP treatment caused complete inhibition (0% incidence) of papillary and/or nodular hyperplasia in group 1 but was without influence in group 3, as compared with the respective controls. Moreover, the ODC activity, bromodeoxyuridine labeling indices and mRNA expression levels of cyclin D1 in the urinary bladder mucosa, determined by northern blotting, were markedly lower in group 1 than in group 2, but values were comparable for both groups administered NaAsA. Assessment of mRNA expression levels of the angiogenic vascular endothelial growth factor suggested no involvement in the inhibitory effects of DAP on urinary bladder carcinogenesis. The results indicate that inhibition of ODC could reduce urinary bladder carcinogenesis in rats, particularly in the early stages, through antiproliferative mechanisms.
Salim
E I
EI
First Department of Pathology, Department of Pharmacology and Second Department of Biochemistry, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-Ku, Osaka 545-8585, Japan.
Wanibuchi
H
H
Morimura
K
K
Kim
S
S
Yano
Y
Y
Yamamoto
S
S
Fukushima
S
S
D000123:Acetyltransferases / Q000032:analysis; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D001205:Ascorbic Acid / Q000633:toxicity; D002085:Butylhydroxybutylnitrosamine / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002277:Carcinoma / Q000139:chemically induced / Q000517:prevention & control*; D003043:Cocarcinogenesis; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis / Q000235:genetics; D003959:Diamines / Q000494:pharmacology / Q000627:therapeutic use*; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D006965:Hyperplasia; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D009955:Ornithine Decarboxylase / Q000502:physiology; D065108:Ornithine Decarboxylase Inhibitors; D010212:Papilloma / Q000139:chemically induced / Q000517:prevention & control*; D011073:Polyamines / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D016588:Anticarcinogenic Agents; D001205:Ascorbic Acid; D002085:Butylhydroxybutylnitrosamine; D002273:Carcinogens; D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D003959:Diamines; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009955:Ornithine Decarboxylase; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099228:Diamine N-Acetyltransferase; C009475:trimethylenediamine; C495903:Cdk4 protein, rat